Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:39])[N:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]([CH2:30][CH2:31]O)[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[O:45]=[C:43]1[C:42]2[C:41](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:40](=[O:50])[N:44]1[CH2:31][CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22]([NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)=[O:23])[C:25](=[O:39])[N:26]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCO)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN5C(=O)c6ccccc6C5=O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.38 mmol) and phthalimide (0.11 g, 0.76 mmol) in 10 mL of CH2Cl2 was added triphenyl phosphine (0.13 ml, 0.57 mmol), followed by diethyl azodicarboxylate (0.089 ml, 0.57 mmol) via a syringe. The reaction mixture was stirred at RT for 16 hours. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) to give the title compound as a light yellow solid (0.22 g, 88% yield). MS (ESI pos. ion) m/z: 658 (MH+). Calc'd exact mass for C37H28FN5O6: 657. 1H NMR (300 MHz, MeOH) 8.53 (1H, d, J=5.5 Hz), 8.28 (1H, d, J=9.0 Hz), 7.80-7.91 (5H, m), 7.50 (1H, s), 7.48 (2H, d, J=3.0 Hz), 7.26-7.36 (6H, m), 6.49 (1H, dd, J=5.4, 1.0 Hz), 4.27 (2H, t, J=5.5 Hz), 3.97 (3H, s), 3.74 (2H, t, J=5.5 Hz), 2.68 (3H, s).
Reaction SMILES: [C:1]1([NH:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=C(Cl)[N:12]=1>>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: O=CNc1ccccc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccccc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-phenyl-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[OH:19][CH2:11][CH:12]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: O
Product: CCOC(=O)c1cnn(C(CO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 1H-pyrazole-4-carboxylate (1.5 g, 10.7 mmol), yttrium (III) nitrate hexahydrate (82.0 mg, 0.214 mmol) and styrene oxide (1.21 ml, 10.7 mmol) was stirred at rt for 17 h, before it was adsorbed on celite. Purification by column chromatography (CombiFlash Companion, 12 g SiO2, heptane to EA) afforded the title compound. LCMS RtM=1.72 min, [M+H]+=261.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21]O)=[CH:16][N:15]=1.[ClH:23]>C(O)(=O)C>[ClH:1].[ClH:23].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH2:21][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([NH2:12])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:16][N:15]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: Nc1c(Cl)ccc2cccnc12
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Cc2cc(Cl)c(N)c3ncccc23)c(N)n1
Yield: 79 %

Procedure:
A solution of 7-chloro-8-aminoquinoline (C. C. Price and D. B. Guthrie, J. Amer. Chem. Soc. 1946, 68, 1592) (3.17 g, 17.7 mmol), 2,4-diamino-5-hydroxymethylpyrimidine (2.50 g, 17.7 mmol), and concentrated hydrochloric acid (2.50 mL) in glacial acetic acid (32 mL) was refluxed for 5 hr. The resulting precipitate was filtered from the cooled reaction mixture and washed with cold acetic acid and ether to give the title compound as tan solid (5.19 g, 79%); mp >290° dec. Anal. Calcd for C14H13ClN6.2HCl: C, 45.00; H, 4.05; N, 22.49; Cl, 28.46. Found: C, 44.89; H, 4.08; N, 22.44; Cl, 28.38.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH3:22])[C:14]([CH2:17][CH2:18]CC#N)=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:23].[Na+].[CH2:25]([OH:27])[CH3:26]>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH3:22])[C:14]([CH2:17][CH2:18][CH2:26][C:25]([OH:23])=[O:27])=[N:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1cc(NS(=O)(=O)c2ccccc2)cnc1CCCC#N
Agent: [Na+]
Product: Cc1cc(NS(=O)(=O)c2ccccc2)cnc1CCCC(=O)O

Procedure:
A solution of 5-benzenesulphonamido-2-(3-cyanopropyl)-3-methylpyridine (1.5 g) in ethanol (100 ml) and 15% w/v sodium hydroxide solution (20 ml) was refluxed for 8 hours. The ethanol was removed under reduced pressure and the pH of the remaining aqueous was adjusted to pH 4 when a white solid crystallised. The solid was collected and recrystallised from methanol to give the title compound (0.7 g) as white needles. m.p. 169°-179° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[S:12][C:11](=[O:13])[NH:10][C:9]3=[O:14])=[CH:6][CH:7]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Into 10 ml of pyridine were dissolved 0.50 g of 5-(4-amino-phenyl) thiazolidine-2,4-dione, and after added 0.46 g of p-toluenesulfonyl chloride, the mixture was stirred for 1 hour at room temperature. After the completion of reaction, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with 10% hydrochloric acid, washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from benzene to obtain 0.65 g of title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccccn2)cc1
Temperature: 77 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of 4-formyl-phenylboronic acid (5.0 g, 33.0 mmol) and 2-bromopyridine (5.53 g, 35.0 mmol, 1.05 equiv.) in 265 mL of 4:3 toluene/95% ethanol was degassed with nitrogen for 30 minutes and then heated under a nitrogen atmosphere, resulting in a clear solution. A slurry of Pd(PPh3)4 (0.77 g) in 50 mL of a 4:4 mixture of toluene and 95% ethanol was added, followed by 50 mL of 3M aqueous Na2CO3. The resulting mixture was gently refluxed at 77° C. After 16 hours, the reaction mixture was cooled to room temperature, and the solid removed by filtration. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was extracted with toluene (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and dried over sodium sulfate. The solution was filtered, and the filtrate concentrated under reduced pressure to give a yellow oil. Purification by Biotage chromatography (40+M cartridge; gradient, 0 to 5% methanol/dichloromethane) gave 4.13 g (68%) of (3) as a light-yellow solid. TLC Rf(hexane/ethyl acetate, 2:1)=0.25; 1H NMR (CDCl3) δ 10.1 (s, HCO), 8.77 (d, 1H), 8.20 (d, 2H), 8.00 (d, 2H), 7.81 (m, 2H), 7.31 (q, 1H); MS (M)+=184; HPLC tR 1.2 minutes.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]1.[F:34][C:35]([F:63])([F:62])[C:36]1[CH:37]=[C:38]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:39][O:40][CH2:41]C1(C2C=CC=CC=2)CCCNCC1>>[F:34][C:35]([F:62])([F:63])[C:36]1[CH:37]=[C:38]([CH:55]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:57]=1)[CH2:39][O:40][CH2:41][C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Reactant: CCN1CCCC(CCOCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Product: CCN1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Yield: 62 %

Procedure:
Isomer B of 4-((3,5-bis(trifluoromethyl)benzyloxy)ethyl)-1-ethyl-4-phenylazepane was made from Isomer B of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane in the same manner as described above to give the product as a clear sticky oil (2 mg, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:15]#[N:16])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[F:8].[Br:19]N1C(=O)CCC1=O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:15]#[N:16])[C:5]([Br:19])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C#N)cc(-c2ccccc2)c(F)c1N
Solvent: CC(=O)O
Product: COc1c(N)c(F)c(-c2ccccc2)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
5-Amino-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-234) (500 mg, 2.06 mmol) was dissolved in acetic acid (9.5 ml), and at room temperature, N-bromosuccinimide (441 mg, 2.48 mmol) was gradually added. After stirring under nitrogen atmosphere at room temperature for 1 hour, the solvent was evaporated away under reduced pressure. The residue was fractionated with ethyl acetate and aqueous 1M sodium hydroxide solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:1) to obtain the entitled compound (592 mg, 89%) as a pale brown solid.
Reaction SMILES: C(O)C.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C(N(CC)CC)C>[N+:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]=[CH:6]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1Nc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 150 ml of absolute ethanol were added 1H-indol-5-amine (8.06 g), 4-chloro-3-nitropyridine (10.0 g) and triethylamine (8.5 ml), and this mixture was heated to 60° C. and stirred for 2 hours. The mixture was cooled, the ethanol evaporated, and the residue taken up in a water/ethyl acetate mixture. This was treated with Na2CO3 (aq) to adjust the pH to 10. The organic layer was collected, the aqueous layer extracted again with ethyl acetate, and the organics were combined, washed with water and dried (sat. NaCl, anh. MgSO4).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:19][C@@H:18]([NH:20]C(=O)C(F)(F)F)[C:15]3([CH2:17][CH2:16]3)[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:30][CH2:29]1.[OH-].[K+].Cl>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:19][C@@H:18]([NH2:20])[C:15]3([CH2:16][CH2:17]3)[CH2:14]2)[C:9]([CH3:27])=[C:8]2[C:3]=1[C:4](=[O:34])[C:5]([C:31]([OH:33])=[O:32])=[CH:6][N:7]2[CH:28]1[CH2:30][CH2:29]1
Reactant: Cc1c(N2C[C@@H](NC(=O)C(F)(F)F)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N2C[C@@H](N)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A mixture of 0.26 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-((S)-7-trifluoroacetylamino-5-azaspiro[2.4]hept-5-yl)quinoline-3-carboxylic acid, 0.18 g of potassium hydroxide and 1.8 ml of water was stirred at room temperature for 0.5 hour. The reaction mixture was neutralized with 10% hydrochloric acid to pH 8, the deposited crystals were collected by filtration and washed with water to give 0.21 g of the desired compound, which was recrystallized from acetonitrile to afford 0.16 g of yellow prisms, m.p. 216.5°-218° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]([CH:22]([F:24])[F:23])([OH:21])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[F:25][CH:2]([F:1])[C:3]([CH:22]([F:23])[F:24])([OH:21])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(C#CC(O)(C(F)F)C(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(/C=C/C(O)(C(F)F)C(F)F)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of 4,4-difluoro-3-difluoromethyl-3-hydroxy-1-(4-phenylsulfonylphenyl)but-1-yne (555 mg, 1.49 mmol) in tetrahydrofuran (15 mL) was added LAH (65 mg, 1.71 mmol) in one portion and the mixture was allowed to stir for 18 hours. The reaction was quenched with Na2SO4.10H2O, filtered and evaporated. The resulting material was purified by chromatography, with diethyl ether:hexanes (60:40) as the eluent, followed by chromatography, with diethyl ether:hexanes (50:50) as the eluent. The resulting material was recrystalized from methyl tert-butylether:hexanes to give the title compound; mp 123.0°-123.5° C.; NMR (CDCl3): 7.93-7.88 (m,4, Ar), 7.59-7.47 (m,5, Ar), 7.03 (d,1, J=16.2, vinylic), 6.33 (d,1, J=16.2, vinylic), 5.89 (t,2, J=54.8, CF2H), 3.02 (s,1, OH); MS: m/z=375(M+1). Analysis for C17H14F4O3S: Calculated: C, 54.54; H, 3.77; Found: C, 54.30; H, 3.84.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:26][S:25][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:7][N:6]=2)[CH:9]=1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: OB(O)c1ccccc1
Product: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Obtained according to general procedure 1 from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (0.7 g, 1.616 mmol) and phenyl boronic acid (0.232 g, 1.939 mmol). Yield: 0.5 g (72% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:38])=O>C1(C)C=CC=CC=1>[Cl:38][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(Br)cc3C2=O)c(OC)c1
Solvent: Cc1ccccc1
Solvent: Cc1ccc(N(C)C)cc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(Br)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (3.0 g, 7.4 mmol) and N,N-dimethyl-p-toluidine (2.1 mL, 14.8 mmol) were mixed in toluene (30 mL) and heated to 100° C. Then phosphorus oxychloride (745 μL, 8.1 mmol) was added dropwise and heating at 100° C. was continued for 2.5 h. The resulting dark red solution was evaporated and the residue dissolved in THF (10 mL) and used directly in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[C:21]([CH:26]=1)[C:20]([NH:19][CH2:18][CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)=[O:31])#[N:28]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1ccc(C#N)cc1C(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine are dissolved in 120 ml of dioxan, and 28.3 g (0.1 mol) of N-(2-bromoethyl)-5-cyano-2-methoxybenzamide are added and the whole is then stirred at room temperature for 60 hours. A solution of potassium carbonate is then added to the reaction mixture and the whole is then extracted with methylene chloride. The methylene chloride solution is washed neutral with water and concentrated in a water-jet vacuum. A light yellow crystalline product remains behind which is suspended in 200 ml of ethanol and stirred for 2 hours. The solid product is then filtered with suction and subsequently washed with 20 ml of ice-cold ethanol. 5-Cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxybenzamide is obtained in the filtration residue in the form of white powder of melting point 167°-169°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1.C(Cl)Cl.[OH2:18].CC#N>O>[C:10]([O:9][C:8]([NH:7][C:4]1([CH2:3][C:2]([OH:18])=[O:1])[CH2:5][CH2:6]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)NC1(CCO)CC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
RuCl3.H2O (124 mg, 0.6 mmol) was added to a solution of tert-butyl 1-(2-hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaIO4 (19.0 g, 90 mmol) in DCM/H2O/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H2O (100 mL), and extracted with DCM (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0˜30% gradient elution EtOAc/petroleum ether) to afford 2-(1-(tert-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([O:22]CC)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:14]1([N:10]2[C:8]3[N:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:20]([OH:22])=[O:21])[C:7]=3[C:12]([CH3:13])=[N:11]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn(C2CCCCC2)c2nc(C3CC3)cc(C(=O)O)c12

Procedure:
The title compound was prepared in the same manner as described for intermediate 52 using ethyl 6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (820 mg, 2.5 mmol) and sodium hydroxide (7.51 mL, 7.51 mmol). The final product was collected as a solid, 0.660 g (88%). LCMS E-S (M+H)=300.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.11 (m, 4H), 1.16-1.31 (m, 1H), 1.36-1.55 (m, 2H), 1.70 (d, J=12.38 Hz, 1H), 1.80-1.98 (m, 6H), 2.32 (m, J=7.80, 7.80, 5.05, 4.86 Hz, 1H), 2.55 (s, 3H), 4.60-4.73 (m, 1H), 7.40 (s, 1H), 13.71 (br. s., 1H).
Reaction SMILES: C([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C:16]#[C:17][C:18]([CH3:24])(C)[C:19](OC)=O)(=O)CCC.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH:18]([C:17]1[NH:6][C:7]2[C:8]([CH:16]=1)=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)([CH3:24])[CH3:19]
Reactant: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
A mixture of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (0.50 g, 1.5 mmol) and TBAF (790 mg, 3.0 mmol) in DMF (20 mL) was heated at 70° C. for 24 h. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was extracted with ether (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=20/1) to give 2-isopropyl-5-nitro-1H-indole (100 mg, 33%). 1 H NMR (400 MHz, CDCl3) δ 8.68(s, 1 H), 8.25(br s, 1 H), 8.21 (dd, J=2.4, 10.0 Hz, 1 H), 7.32(d, J=8.8 Hz, 1 H), 6.41(s, 1 H), 3.07-3.14(m, 1 H), 1.39(d, J=6.8 Hz, 6 H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:12][CH2:13][C:14]([C:2]1[S:1][C:5]2[C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:15]
Reactant: O=C1NCCCc2ccsc21
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)c1cc2c(s1)C(=O)NCCC2
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 2 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 2 g of chloroacetyl chloride in 25 ml of dichloromethane was added 4.8 g of aluminum chloride. The mixture was stirred for 30 minutes, refluxed under heating for an hour and then poured into water. The precipitated crystals were collected by filtration and washed with isopropyl alcohol to give 2 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, m.p. 221°-223° C. (decomposition).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][OH:22]>>[CH3:12][N:11]1[C:4]2[N:5]([C:6](=[O:8])[N:7]=[C:2]([O:22][CH2:21][CH2:20][C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)[CH:3]=2)[CH2:9][C:10]1([CH3:14])[CH3:13]
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCc1cccs1
Product: CN1c2cc(OCCc3cccs3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 2-(thiophen-2-yl)ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][N:22]1[CH:26]=[N:25][C:24]([NH2:27])=[N:23]1>>[CH3:15][C:13]1[N:12]=[CH:11][N:10]([C:5]2[CH:4]=[CH:3][C:2]([NH:27][C:24]3[N:25]=[CH:26][N:22]([CH2:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:32])([F:16])[F:31])[CH:19]=4)[N:23]=3)=[CH:9][C:6]=2[C:7]#[N:8])[CH:14]=1
Reactant: Nc1ncn(Cc2cccc(C(F)(F)F)c2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4cccc(C(F)(F)F)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=51%). MS ISP (m/e): 424.2 (100) [(M+H)+].