Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[Cl:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[Cl:25]
Reactant: O=C(O)c1cccnc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1Cl

Procedure:
A solution of O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride, (1.11 g, 2.84 mmol), 2-chloronicotinic acid (0.45 g, 2.84 mmol), EDC (0.60 g, 3.13 mmol), HOBT (0.46 g, 3.41 mmol) and NMM (0.467 ml, 0.43 g, 4.26 mmol) in DCM (25 ml) was stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM (50 ml) and 10% NaHCO3 solution (30 ml). The organic layer was separated, dried over MgSO4 and the solvent removed under vacuum to give a pale yellow solid that was recrystallized from EtOAc/hexane to give the title compound as an off white solid (1.14 g, 81%), δH (CDCl3) 8.46 (1H, dd, J 2.0, 4.7Hz), 8.05 (1H, dd, J 2.0, 7.6Hz), 7.34 (2H, m), 7.25 (2H, m), 7.11 (2H, m), 6.96 (3H, m), 5.24 (2H, s), 5.06 (1H, m), 3.80 (3H, s) and 3.24 (2H, m).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[CH2:5]([O:7][C:8]([C:10]1[S:27][C:13]2[N:14]=[C:15]([NH2:26])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[CH3:25])[C:12]=2[CH:11]=1)=[O:9])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:5]([O:7][C:8]([C:10]1[S:27][C:13]2[N:14]=[C:15]([NH2:26])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:2][CH2:3][CH3:4])=[CH:20][C:19]=3[CH3:25])[C:12]=2[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cc2c(-c3ccc(O)cc3C)nc(N)nc2s1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(N)nc3sc(C(=O)OCC)cc23)c(C)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
1-Bromopropane (15 uL; 0.17 mmol) was added to a solution of 2-Amino-4-(4-hydroxy-2-methyl-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (50 mg: 0.152 mmol) and potassium carbonate (25 mg; 0.18 mmol) in DMF (15 mL). Reaction mixture was heated to 50 degrees C. for 18 hours. Reaction mixture was allowed to cool and solvent removed in vacuo. Residue was partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (20 mL). Organic phase was dried over Na2SO4 and filtered, filtrate solvents removed in vacuo to afford a yellow solid purified by flash chromatography on silica gel (eluting ethyl acetate in hexane) to afford product as yellow solid (45 mg; 80%)
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-phenyl-propylamine (0.071 mL, 0.5 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-phenyl-propyl)-2,3-dihydro-isoindol-1-one (0.054 g, 48%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.72 (t, 2H), 3.66 (t, 2H), 4.25 (s, 2H), 7.14-7.42 (m, 7H), 7.90 (d, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:22])[C@:19]([OH:21])([CH3:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.I(C1C=CC=CC=1C(O)=O)(=O)=O>C1(C)C=CC=CC=1.CS(C)=O>[CH3:20][C@:19]1([OH:21])[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:22])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH:4]=[CH:3]1)[CH2:9][CH2:10]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Temperature: 67.5 °C

Procedure:
A mixture of mestanolone (55.3 g, 0.182 mol) and IBX (76.5 g, 0.273 mol, 1.5 eq.) in 1800 ml toluene:DMSO (2:1) was heated at 65-70° C. for 48 h after which time the beginning clear solution turned into a suspension. TLC (thin layer chromatography) indicated the disappearance of starting mestanolone and the appearance of the desired product and two by-products. After cooling to RT (room temperature), the reaction mixture was filtered on a frit and solid washed with ethyl acetate (2×200 ml). The filtrate was diluted with 1000 ml of ethyl acetate and the resulting organic phase was washed with 1000 ml each of 5% NaHCO3, water, and brine. After drying over sodium sulfate, removal of the solvents on a rotavapor gave ˜56.0 g of a crude products mixture containing the required product (i.e., 17α-methyl-17β-hydroxy-5α-androst-1-en-3-one) along with two minor by-products.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([S:23][CH3:24])[CH:12]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:26]=1.ClCCl.[Mg].[OH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([S:23]([CH3:24])=[O:32])[CH:12]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:26]=1
Reactant: CSc1cc(-c2nc3c(C)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: O
Agent: [Mg]
Solvent: ClCCl
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(S(C)=O)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 0.20 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-methylthio-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 5 ml of dichloromethane and 0.5 ml of water was added 0.18 g of magnesium bis(monoperoxophthalate) hexahydrate (MMPP), and the resulting mixture was stirred at room temperature for 22 hours. Water was added to the reaction mixture, and the mixture was extracted with methyl t-butyl ether. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.20 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-methylsulfinyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:19]=[CH:20][NH:21][C:14]=23)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:23][CH2:24][O:25][CH3:26].BrOBr>O.CS(C)=O>[CH3:26][O:25][CH2:24][CH2:23][N:21]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[S:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[CH:19]=[CH:20]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc3cc[nH]c23)cc1
Agent: BrOBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCCn1ccc2nccc(Sc3ccc([N+](=O)[O-])cc3)c21
Reaction time: 0.75 h

Procedure:
A sealed vial was charged with potassium hydroxide (0.124 g, 2.21 mmol) and DMSO (5 mL). 7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine (0.150 g, 0.553 mmol) was added and the reaction was stirred for 45 minutes. 1-Bromo-2-methoxyethane (0.104 ml, 1.11 mmol) was added, the system was flushed with argon, and the reaction was stirred at RT for 2 hours. LC-MS indicated starting material remaining, so 1 eq. bromoether was added and the reaction stirred for two more hours. The reaction was diluted with water and extracted four times with DCM and twice with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-5% MeOH:DCM) to afford 1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine as an orange oil that solidified under high vacuum. MS: M+H+=330.1
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:16])=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[O:17]1CCC[CH2:18]1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1.C(N(CC)CC)C>[O:1]1[C:2]2[CH:15]=[C:6]3[CH:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:5]3=[CH:4][C:3]=2[NH:16][C:18]1=[O:17]
Reactant: CCOC(=O)c1cc2cc(O)c(N)cc2o1
Reactant: C1CCOC1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc3oc(=O)[nH]c3cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 0.9 g (4.2 mmol) of ethyl 5-hydroxy-6-aminobenzofuran-2-carboxylate [Helv. Chim. Acta 77, 100. (1994)], 60 ml of tetrahydrofuran, 3.1 ml of 20% phosgene in toluene solution and 2.0 ml of triethylamine is stirred at room temperature for 1 h. The tetrahydrofuran is distilled off in vacuum, water is added to the residue and the product is extracted with ethyl acetate. The combined organic layers are washed with 5% aqueous sodium hydrogencarbonate solution, water, 1 N hydrochloric acid solution and again with water, dried over sodium sulfate and concentrated to yield 1.0 g (96%) of the title compound as oil.
Reaction SMILES: [C:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[CH:2]=1.[C:19]([C:23]1[C:24]([OH:34])=[C:25]([CH2:30][CH2:31]CO)[CH:26]=[C:27]([CH3:29])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20].[NH2-].[Na+]>CN(C)C=O>[C:19]([C:23]1[C:24]([OH:34])=[C:25]([CH2:30][CH2:31][CH2:18][O:17][C:15]([C:1]2[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=3[OH:34])=[O:8])[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH2:31][CH2:30][C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:24]=3[OH:34])=[O:12])[CH:2]=2)=[O:16])[CH:26]=[C:27]([CH3:29])[CH:28]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(CCCO)c(O)c(C(C)(C)C)c1
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CCCOC(=O)c2cc(C(=O)OCCCc3cc(C)cc(C(C)(C)C)c3O)cc(C(=O)OCCCc3cc(C)cc(C(C)(C)C)c3O)c2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
Into a 100 ml reactor equipped with a condenser, thermometer and nitrogen introducing thin tube were charged 1.54 g (6.00 mmol) of trimethyl 1,3,5-benzenetricarboxylate, 4.00 g (18.00 mmol) of 3-(3-tert-butyl-2-hydroxy-5-methylphenyl)-1-propanol and 20 ml of N,N-dimethylformamide. The pressure of the reaction system was reduced to 20 mmHg and 75 vol% (15 ml) of N,N-dimethylformamide was distilled away to dry the reactants, solvent and apparatus. The reaction system was cooled to room temperature, and the vacuum was broken by introducing dry nitrogen. 0.07 g (1.8 mmol) of sodium amide was immediately added to initiate the ester exchange reaction. The reaction system was heated at 50° to 60° C. under 20 mmHg for 2 to 3 hours, and then heated at 60° to 80° C. under 20 mmHg for 2 to 3 hours while distilling N,N-dimethylformamide. Thereafter, the reaction mixture was further heated at 100° to 120° C. under 5 mmHg for 2 to 3 hours. When the reaction was completed, the reaction product was neutralized with dilute hydrochloric acid and then chloroform was added. After liquid separation and dehydration with anhydrous sodium sulfate, the organic solvent was removed under reduced pressure. After separation by silica gel chromatography (solvent: chloroform), 2.60 g (3.16 mmol) of the desired product was obtained. The yield was 53%. The physical properties of the product are shown below.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(C(C#N)=C(C#N)C#N)#N.ClCCO[CH:21]([O:29][CH2:30][CH2:31][Cl:32])[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[N:26][CH:27]=1>C(#N)C>[Cl:32][CH2:31][CH2:30][O:29][CH:21]([C:22]1[CH:27]=[N:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:5]#[N:6]
Reactant: ClCCOC(OCCCl)c1ccc(Cl)nc1
Reactant: C[Si](C)(C)C#N
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC#N
Product: N#CC(OCCCl)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
Trimethylsilyl cyanide (1.88 mL) and tetracyanoethylene (240 mg) were added to a solution of 5-[bis-(2-chloroethoxy)methyl]-2-chloropyridine (2.67 g) in acetonitrile (50 mL), and the reaction solution was heated under reflux for five hours. The reaction solution was left to cool to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the resulting residue. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=8:1) to obtain 2.04 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:63][N:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][N:64]5[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 9) (0.27 g, 0.63 mmol, 1 eq), DIPEA (0.21 mL, 1.26 mmol, 2 eq) and TBTU (0.22 g, 0.69 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (91 μl, 0.75 mmol, 1.2 eq). The RM was then stirred at rt for 4 hours before washing with water, concentrating in vacuo and purifying the residue by preparative RP-HPLC-MS (Preparative 1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.14 g, 44%).
Reaction SMILES: [C:1]([CH:9](Br)[CH2:10][CH2:11][Cl:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16](=[S:20])[O:17]CC>O1CCOCC1>[CH3:14][N:15]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]([CH2:10][CH2:11][Cl:12])[S:20][C:16]1=[O:17]
Reactant: CCOC(=S)NC
Reactant: O=C(c1ccccc1)C(Br)CCCl
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2)c(CCCl)sc1=O

Procedure:
The 3-methyl-4-phenyl-5-β-chloroethyl-4-thiazolin-2-one is prepared in the following manner. A solution of 21.9 g of 1-benzoyl-1-bromo-3-chloropropane and 5 g of ethyl N-methyl-thiocarbamate in 50 cc of dioxan is heated under reflux for 10 hours, and then evaporated to dryness under reduced pressure, M.P. = 88°-90° C (from hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:21])(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][Cl:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 3-benzyloxybenzyl alcohol (3.0 g, 14.0 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (1.39 mL, 16.8 mmol) and triethylamine (2.34 mL, 16.8 mmol) on an ice bath, and the solution was stirred overnight. The reaction solution was diluted with dichloromethane, washed with aqueous solution of 5% sodium bicarbonate, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 1-benzyloxy-3-chloromethyl-benzene (2.2 g, 67%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH2:17]C)([CH2:15]C)[CH2:14][C:4]=12)[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:23]([NH:25][NH2:26])=O>>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[O:10][C:8]([C:6]3[S:7][C:3]([CH2:1][CH3:2])=[C:4]4[CH2:14][C:13]([CH3:15])([CH3:17])[CH2:12][CH2:11][C:5]=34)=[N:26][N:25]=2)[CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: Cc1cc(C(=O)NN)cc(Cl)n1
Reactant: CCc1sc(C(=O)O)c2c1CC(CC)(CC)CC2
Product: CCc1sc(-c2nnc(-c3cc(C)nc(Cl)c3)o2)c2c1CC(C)(C)CC2

Procedure:
2-Chloro-4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridine is synthesized from 3,5,5-triethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2-chloro-6-methyl-isonicotinic acid hydrazide in analogy to Example 9; LC-MS: tR=1.22 min, [M+1]=388.25.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)C.O.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN>CN(C=O)C.O>[CH3:33][NH:35][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixture was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol) and methanamine hydrochloride (8.01 mg, 0.119 mmol). The reaction was stirred at room temperature overnight. To the stirred solution was added water (2 mL) and the precipitate was filtered, collected, and dried in vacuum to afford the title compound (23.8 mg, 46.2%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.14 (q, J=4.5 Hz, 1H), 7.58-7.80 (m, 3H), 6.82-7.04 (m, 3H), 4.51 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.2, 2.7 Hz, 1H), 3.30-3.51 (m, 3H), 3.23 (br. s., 4H), 2.74 (d, J=4.5 Hz, 3H), 2.61 (td, J=12.7, 2.7 Hz, 1H), 2.49 (br. s., 3H), 2.04 (d, J=12.6 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H), 1.33-1.59 (m, 3H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Cl:7][C:8]1[CH:9]=[C:10](I)[C:11]([NH2:14])=[N:12][CH:13]=1.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(=O)C(=O)O
Reactant: Nc1ncc(Cl)cc1I
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 110 °C

Procedure:
Pyruvic acid (0.43 ml, 6.24 mmol) was added to a solution of 5-chloro-3-iodopyridin-2-ylamine (Preparation 56, 500 mg, 2.08 mmol), palladium acetate (23 mg, 0.10 mmol) and DABCO (700 mg, 6.24 mmol) in anhydrous DMF (20 ml). The reaction mixture was degassed with argon for 20 min, then heated to 110° C. for 16 h. The solvent was removed in vacuo and the residue suspended in water (10 ml) and acetic acid (5 ml) and then filtered. The solid was dissolved in EtOAc (50 ml), extracted into 2N NaOH solution (50 ml) and the organic layer discarded. The aqueous solution was acidified with concentrated HCl and extracted into EtOAc (2×40 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as a beige solid. δH (CD3OD): 7.14 (1H, s), 8.14 (1H, d), 8.35 (1H, d).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[C-:29]#[N:30].[Na+]>CN1C(=O)CCC1.[Ni](Br)Br>[C:29]([C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:24])([CH3:25])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1)#[N:30]
Reactant: [C-]#N
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(C#N)cc(N2CCOCC2)c1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 39.9 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), sodium cyanide (24.5 mg, 0.5 mmol), nickel(II) bromide (54.6 mg, 0.25 mmol) in NMP (0.5 mL) was stirred for 10 minutes at 200° C. with microwave. After removal of the solid, the residue was purificated by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-cyano-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (39 mg, 40%) as a white solid: LC/MS m/e calcd for C23H25N3O3 (M+H)+: 392.5, observed: 392.2.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH2:7][CH:8](F)[C:9]3[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=3[C:14]([F:17])([F:16])[F:15])[C:4]=2[CH:3]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[OH:33][C@@:26]1([C:24]#[C:25][C:2]2[CH:23]=[CH:22][C:5]3[O:6][CH2:7][CH2:8][C:9]4[N:10]([N:11]=[C:12]([C:18]([NH2:20])=[O:19])[C:13]=4[C:14]([F:17])([F:16])[F:15])[C:4]=3[CH:3]=2)[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nn2c(c1C(F)(F)F)C(F)COc1ccc(Br)cc1-2
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)c(C(F)(F)F)c2CCO3)C1=O
Yield: 59 %

Procedure:
Similar to as described in General Procedure G, racemic 9-bromo-4-fluoro-3-(trifluoromethyl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a white solid 8.9 mg (59%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C-:11]#[N:12].[K+].[NH4+:14].[Cl-]>[NH4+].[OH-].CCO>[NH2:14][C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH2:2][CH3:3])[C:11]#[N:12]
Reactant: CCC(=O)c1ccccc1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(N)(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 81 %

Procedure:
A mixture of propiophenone (30 g), KCN (34.5 g) and NH4Cl (30 g) in 180 mL of conc. NH4OH and 120 mL of EtOH is stirred at ambient temperature for 4 days. The reaction mixture is concentrated under vacuum and ether was added to the solid residue. The ether suspension is filtered and solid is washed with ether. Excess 1M of HCl in ether is added to the filtrate to precipitate HCl salt. The white solid is collected by filtration, washed with hexane and ether, and dried to give 29 g of the title compound as HCl salts. The white solid is basified with excess aqueous NaHCO3 and extracted with CH2Cl2. The extract is washed with brine, dried and concentrated to give 19 g of the titled compound as clear oil.