Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C[Al](C)C.[C:21]1(=[O:27])[O:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][OH:27])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C1CCCCO1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 9-ethyl-9H-carbazol-3-amine (300 mg, 1.43 mmol) in toluene (4 mL) was added trimethylaluminium (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of δ-valerolactone (0.129 mL, 1.43 mmol) in toluene (4 mL) at room temperature, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was cooled to 0° C., neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure to give N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxypentanamide (420 mg, 1.352 mmol, 95%) as a pale-yellow powder.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>O1CCCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH3:30])[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 93 %

Procedure:
This compound is obtained by reacting 1-trityl-4-hydroxymethylpyrazole (555 mg; 1.63 mmol) in dry tetrahydrofuran with sodium hydride (98 mg; 2.44 mmol) and iodomethane (0.5 mL; 8.15 mmol). Yield: 93% (536 mg, 1.51 mmol).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH:10](=O)[CH3:11].[Cl:13]CCl>[Cl-].[Zn+2].[Cl-]>[C:4]([O:6][CH2:11][CH2:10][Cl:13])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC=O
Reactant: ClCCl
Agent: [Cl-]
Agent: [Zn+2]
Product: COC(=O)/C=C/C(=O)OCCCl

Procedure:
Adopting methods and procedures according to Iyer, et al., Synth. Commun. 1995, 25(18), 2739, chloroethyl methyl (2E)but-2-ene-1,4-dioate was prepared from methyl hydrogen fumarate (MHF), acetaldehyde, and anhydrous zinc(II) chloride in anhydrous dichloromethane (DCM). 1H NMR (CDCl3, 400 MHz): δ 6.95 (d, J=16.0 Hz, 1H), 6.85 (d, J=16.0 Hz, 1H), 6.60 (q, J=5.2 Hz, 1H), 3.81 (s, 3H), 1.83 (d, J=5.2 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]1[C:12]([S:13]([NH:16][C:17]([NH:19][C:20]2[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=2)=[S:18])(=[O:15])=[O:14])=[C:11]([C:30]([O:32][CH3:33])=[O:31])[C:10]([CH3:34])=[N:9]1.BrBr>O>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([O:28][CH3:29])[N:21]2[S:18][C:17](=[N:16][S:13]([C:12]3[N:8]([CH3:7])[N:9]=[C:10]([CH3:34])[C:11]=3[C:30]([O:32][CH3:33])=[O:31])(=[O:15])=[O:14])[N:19]=[C:20]2[N:25]=1
Reactant: COC(=O)c1c(C)nn(C)c1S(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Agent: BrBr
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1c(C)nn(C)c1S(=O)(=O)N=c1nc2nc(OC)cc(OC)n2s1
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
To 50 ml of pyridine is added 4.3 g of N-(1,3-dimethyl-4-methoxycarbonyl-5-pyrazolesulfonyl)-N'(4,6-dimethoxy-2-pyrimidinyl)thiourea, and to the mixture is added 1.6 g of bromine while cooling at -6° C. to -8° C. After stirring at the same temperature for 1.5 hours, the reaction mixture is poured into 300 ml of water. The resulting crystals are filtered, washed with water, and dried. Recrystallization from acetonitrile gives 2.8 g of the title compound as colorless crystals
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:14])[NH:15][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
6(5H)-Phenanthridinone was prepared by the method described by Gauthier in U.S. Pat. No. 3,932,643. Briefly, to a well stirred solution of 9-fluorenone (15 g, 0.083 mol) in concentrated sulfuric acid (500 mL), sodium azide (8.1 g, 0.12 mol) was slowly added over a period of 3 hr at 0° C. The reaction mixture was stirred at room temperature for 2 hr, until nitrogen no longer evolved. The reaction mixture was then poured slowly over crushed ice, to produce a solid precipitate which was filtered and washed thoroughly with cold water to remove sulfuric acid. The solid was then dried under vacuum, to give pure 6(5H)-phenanthridinone (15 g, 93%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[CH:5]=C.[BH4-].[Na+]>C(Cl)Cl>[F:16][C:15]1[C:7]([CH2:4][CH2:5][OH:1])=[C:8]([CH:12]=[CH:13][C:14]=1[F:17])[C:9]([OH:11])=[O:10]
Reactant: O=[O+][O-]
Reactant: C=CCc1c(C(=O)O)ccc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(F)c1CCO

Procedure:
A steam of O3 was bubbled through a solution of 2-allyl-3,4-difluorobenzoic acid (13 g, 0.065 mol) in absolute CH2Cl2 (200 mL) at −78° C. until the mixture was turned blue. Then NaBH4 (7.25 g, 0.196 mol) in was added to the above mixture, and the final mixture was stirred at room temperature overnight. The solution was concentrated. Water was added at 0° C., and the mixture was acidified by adding 6 N HCl, and was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give 3,4-difluoro-2-(2-hydroxyethyl)benzoic acid (8.2 g, crude).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=2)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cnc(C)nc1Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-(2-methyl-4-chloro-5-pyrimidinyl)-acetate (3 g, 14 mmol), 3-trifluoromethyl phenol (3 g, 14 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stirred at +80° C. for 3 hours. The mixture is diluted with ether and washed with brine. Drying over MgSO4 and evaporation of the solvent gives pure ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-acetate as an oil. 1H(CDCl3); 8.36 (s, 1H); 7.50-7.25 (m, 4H); 3.90 (s, 2H); 3.85 (s, 3H); 2.5 (s, 3H).
Reaction SMILES: C(C(NC([C:12]1[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=1[C:14]([N:16]([S:25]SC1C=CC=CC=1)[CH:17]([CH:21]([CH3:24])[CH2:22][CH3:23])[C:18]([OH:20])=[O:19])=[O:15])=O)C(C)CC)(O)=O.BrBr>ClCCl>[CH3:24][CH:21]([CH2:22][CH3:23])[CH:17]([N:16]1[C:14](=[O:15])[C:13]2[CH:33]=[CH:34][CH:35]=[CH:36][C:12]=2[S:25]1)[C:18]([OH:20])=[O:19]
Reactant: CCC(C)C(NC(=O)c1ccccc1C(=O)N(SSc1ccccc1)C(C(=O)O)C(C)CC)C(=O)O
Agent: BrBr
Solvent: ClCCl
Product: CCC(C)C(C(=O)O)n1sc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5.3 g (10.0 mmol) of [S-(R*,R*)]-2-[2-[2-(1-carboxy-2-methylbutylcarbamoyl) phenyldisulfanylbenzoylamino]-3-methylpentanoic acid (from Preparation 19) in 200 mL of dichloromethane was added dropwise 2.4 g (15.0 mmol) of liquid bromine. The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness in vacuo. The residue was triturated with dichloromethane. The dichloromethane was removed by evaporation in vacuo to remove excess bromine. The residue was partitioned between dichloromethane/5% aqueous sodium bicarbonate (200 mL each). The aqueous layer was separated, washed with fresh dichloromethane, and acidified to pH 1.5 with 6.0 M hydrochloric acid. The acidic aqueous solution was extracted with dichloromethane (2×75 mL). The organic layers were combined, washed with water, dried (MgSO4), filtered and concentrated to dryness in vacuo to give 4.8 g of the title compound, mp 50-52° C.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CC(C)CN
Agent: [N-]=C=S
Solvent: CCCCC
Product: CC(C)CNC(=S)NC1(N=NC(C)(C)C)CCCCC1
Reaction time: 4 h

Procedure:
To 9.1 grams (.0394 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.88 grams (.0394 moles) of isobutylamine at room temperature. The reaction mixture became viscous so pentane was added and the reaction was stirred an additional 4 hours and the pentane stripped off to leave a yellow solid weighing 11.6 grams (97% crude yield). The product melted at 90°-93° C. and the infrared spectrum of the product had a strong broad band at 1520-1550 cm-1 and a NH band at 3270 cm-1. There was only a trace of the isothiocyanate band at 2040 cm-1 which was present in the starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:33])=[O:32]
Reactant: NCCO
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)NCCO)n2C)n(CCC)c1=O
Yield: 57.2 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.2 ml (20.3 mmol) of ethanolamine. The resulting crude crystals were recrystallized from toluene to give 600 mg (yield 55%) of Compound 14 as yellow plates.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28]/[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[N:30]\[O:31][CH3:32]>C(#N)C.O>[CH3:32][O:31]/[N:30]=[C:29](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO/N=C(\CBr)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 0.001 mmol) in acetonitrile was added potassium carbonate (0.27 g, 0.002 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 0.001 mmol) and refluxed at 80° C. for 3 h. RM was diluted with water and extracted with ethyl acetate, Organic layer was washed with water and brine solution, dried over anhydrous Na2SO4 and concentrated to get crude product which was purified by comb flash to get white gummy solid as product (0.25 g, Yield: 60%): MS (ESI, 120 eV): m/z=418 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.59-7.63 (m, 2H), 7.37-7.42 (m, 4H), 7.26-7.28 (m, 3H), 7.15 (d, 2H), 6.88-6.90 (d, 2H), 5.15 (s, 2H), 4.03-4.10 (m, 2H), 3.99 (s, 3H), 2.87-2.93 (t, 2H), 2.54-2.60 (t, 2H), 1.17-1.19 (t, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(C)(C)C=O)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C=O)c1cccc(O)c1
Temperature: 212.5 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3-methoxyphenyl)-2-methylpropanal (20.0 g, 112 mmoles) in 90 mL of N-methylpyrrolidinone was added thiophenol (11.5 mL, 112 mmoles) and anhydrous K2CO3 (1.55 g, 11.2 mmoles). The mixture was stirred at 210-215 ° C. for 3 h. After cooling, the mixture was partitioned between Et2O and 5% aqueous NaOH. The aqueous layer was acidified with dilute HCl and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. Chromatography of the residue using 25% EtOAc—hexane as eluent gave the title compound, 10.3 g, as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21](C)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].O[NH:44]S(O)(=O)=O>C1COCC1.CCCCCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:44])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)NO
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(N)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 43.9 %

Procedure:
Under nitrogen, a solution of 4.55 g (13.2 mmol) of 1-[2-(4-fluoro phenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene (from Step 10 of Example 1) in 50 mL of THF at -78° C. was treated with 6.3 mL (0.27 mmol) of n-butylllithium (2.5 M in hexane) over a period of 5 minutes. The reaction was stirred at ambient temperature for 25 minutes, cooled to -78° C., and treated with 19.8 mL (19.8 mmol) of tributylborane (1.0 M in THF). The resulting dark brown solution was stirred at ambient temperature for 30 minutes and then at reflux for 14 hours prior to the addition of 8.7 g (106 mmol) of sodium acetate, 37 mL of water, and 5.2 g (46 mmol) of hydroxyamine-O-sulfonic acid. The resulting light orange mixture was stirred at ambient temperature for 6 hours and the aqueous phase extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 2.0 g (40%) of 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1yl)benzenesulfonamide as a colorless solid: mp 117°-118° C.; NMR (CDCl3) §1.24 (s, 6H), 2.70 (s, 4H), 4.72 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.09 (dd, J=9 and 7 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.74 (d, J=9 Hz, 2H). HRMS. Calc'd for C19H20FNO2S: 345.1199. Found: 345.1194. Anal. Calc'd for [C19H20FNO2S+0.27 H2O]: C, 65.14; H, 5.91; N, 4.00; S, 9.11. Found: C, 65.07; H, 5.94; N, 3.86; S, 9.29.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]=[N:11]2)=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)OCn2ncc(=O)[nH]c2=O)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1ccc(C(=O)OCN2NCC(=O)NC2=O)cc1

Procedure:
2-(4-Methylbenzoyloxymethyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (2.1 g) is dissolved in ethanol (100 ml), and the mixture is added with platinum oxide (400 mg) and stirred at room temperature for 3 hours in an atmosphere of hydrogen. After the completion of the reaction, the catalyst is filtered off, and the filtrate is concentrated in vacuo to give a pale yellow liquid. The liquid is purified by chromatography over silica gel using a mixture of chloroform/methanol as an eluent to give white crystals of 2-(4-methylbenzoyloxymethyl)-3,5-dioxo-hexahydro-1,2,4-triazine (Compound No. 73). The product is recrystallized from a mixture of ethanol/n-hexane. Yield, 1.35 g (62.2%). M.P., 163.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C(OC[C@@H](O)C)C1C=CC=CC=1>>[Br:1][C:2]1[C:3]([O:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CO)Oc1ncccc1Br
Agent: C[C@H](O)COCc1ccccc1
Product: C[C@@H](CO)Oc1ncccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol using (S)-1-(benzyloxy)propan-2-ol. 1H NMR (400 MHz, CDCl3) δ 8.07-7.97 (m, 1H), 7.79 (m, 1H), 6.76 (m, 1H), 5.26-5.12 (m, 1H), 3.77 (t, J=6.1, 2H), 3.35 (s, 1H), 1.36 (d, J=6.3, 3H).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1cccc(Cl)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3-chloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=231 (M+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:40]=[CH:39][C:18]([CH2:19][C:20]23[C:28](=[O:29])[N:27]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=4)[C:26](=[O:38])[N:25]2[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:17][CH:16]=1)=[O:6]>CO.O>[C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]23[C:28](=[O:29])[N:27]([C:30]4[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=4)[C:26](=[O:38])[N:25]2[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:39][CH:40]=1)([OH:6])=[O:4]
Reactant: COC(=O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
An aqueous solution of NaOH (2 mL; 0.5 N) was added to a solution of 6-[4-[2-(2-methoxycarbonylethyl)phenyl]benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in MeOH (7 mL) and the mixture was stirred for 18 hours. The reaction mixture was acidified, diluted with water and extracted with EtOAc. The extract was washed with water, brine, dried (MgSO4), filtered, and concentrated to give the titled compound (0.109 g). MS (m/z) 559 (M++Na).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][CH:39]([NH:44][C:45](=O)C(F)(F)F)[CH2:38]2.Cl.[CH:52](O)(C)C>>[CH3:52][N:44]([CH3:45])[CH:39]1[CH2:38][C:37]2[C:41](=[CH:42][CH:43]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:40]1
Reactant: CC(C)O
Reactant: Nc1ccc2c(c1)CC(NC(=O)C(F)(F)F)C2
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 180 °C

Procedure:
The title compound was synthesized by combining N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (200 mg, 0.43 mmol) (prepared according to a procedure similar to that described in Example 27, Step C), N-(5-amino-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (127 mg, 0.52 mmol), hydrochloric acid (0.043 mmol, 43 μL 1M HCl/diethylether) and 2 mL isopropanol in a sealed vessel. The vial and contents were heated in a microwave synthesizer at 180° C. for 30 min. The reaction was cooled and concentrated. The residue was partitioned between EtOAc and saturated NaHCO3. The organic was washed with brine, dried with MgSO4 and concentrated. The crude material was purified by silica gel column chromatography (0-100% gradient; (90% DCM:9% MeOH:1% NH4OH/DCM)). Purification provided 278 mg (95%) of the coupled adduct. ESIMS (M+H)+=684.20.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([NH:19][CH3:20])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22].N1C=CC=CC=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([N:19]([CH3:20])[S:29]([CH3:32])(=[O:31])=[O:30])[CH:16]=[CH:15][C:14]=3[Cl:21])[C:5]2=[N:4][C:3]=1[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2c(OCc3cc(N(C)S(C)(=O)=O)ccc3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 34.6 %

Procedure:
To a solution of 3-bromo-8- (2-chloro-5-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (60 mg), pyridine (16 mg) and 4-dimethylaminopyridine (10 mg) in methylene chloride (2 ml) was added mesyl chloride (22 mg) in one portion at 5° C., and the mixture was stirred for 9 hours at ambient temperature. The precipitate was filtered off and the residue was washed with methylene chloride and diethyl ether respectively. The filtrate was concentrated in vacuo and the residue was purified by preparative thin-layer chromatography on silica gel (methanol:methylene chloride=1:10, V/V) to give 3-bromo-8-[2-chloro-5-(N-methyl-N-methylsulfonylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (25 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1CCCN(C)C1=O>>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]#[N:18])[C:7]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][C:8]1=2
Reactant: Cn1c2c(c3cccc(Br)c31)C(=O)NCC2
Reactant: CN1CCCN(C)C1=O
Product: Cn1c2c(c3cccc(C#N)c31)C(=O)NCC2
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (1.1 g) and cuprous cyanide (1.0 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (30 ml) was heated at 180° for 24 h. The mixture was poured onto ice (ca. 500 ml) and ferric (III) chloride (20 g), and stirred for 1 h. It was then extracted with dichloromethane (3×300 ml), and the combined organic extracts were washed with water (2×300 ml) and concentrated in vacuo. The residue was triturated with hexane (250 ml) followed by a mixture of ether/hexane (50:50; 100 ml) and finally with ether (60 ml) to give the title compound (620 mg), m.p. 230°-231°.