Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccncc1Cl
Reactant: CSc1ccc(S)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2cnccc2C=O)cc1
Temperature: 65 °C
Yield: 110.3 %

Procedure:
3-Chloroisonicotinaldehyde [prepared according to R. B. Moffett et al., J. Heterocycl. Chem. 1979, 16, 1459] (550 mg, 3.9 mmol), 4-methylsulfanyl-benzenethiol (732 mg, 4.7 mmol) potassium carbonate (700 mg, 5.1 mmol) and DMF (10 mL) were combined and the mixture was heated together at 65° C. for 2 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give the title compound (1.124 g) as a yellow oil. The 1H NMR spectrum showed the material to be of sufficient purity (90-95%) to be used without further purification; δH (CDCl3, 300 MHz) 2.52 (3H, s), 7.28 (2H, d), 7.40 (2H, d), 7.64 (1H, d), 8.39 (1H, s), 8.61 (1H, d), 10.42 (1H, s); MS m/z (ES−) 260 (M−H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[N:16]1([CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:6]=2[C:4]([OH:3])=[O:5])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CN1CCOCC1
Product: O=C(O)c1c(CN2CCOCC2)c2ccccc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 3-morpholin-4-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (Lit. 5) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 399.3 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][CH:16]([CH:20]4[CH2:22][CH2:21]4)[CH:17]4[CH2:19][CH2:18]4)=[N:13][CH:12]=[C:11]([C:23]#[N:24])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][CH:16]([CH:20]4[CH2:22][CH2:21]4)[CH:17]4[CH2:18][CH2:19]4)=[N:13][CH:12]=[C:11]([C:23]([NH2:24])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: N#Cc1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Temperature: 85 °C

Procedure:
To a stirred solution of 7-chloro-1-[(dicyclopropylmethyl)amino]-5H-pyrido[4,3-b]indole-4-carbonitrile (10.1 g, 30 mmol) in DMSO (300 mL) were added potassium carbonate (24.9 g, 180 mmol) and 30% H2O2 (36.8 mL, 360 mmol). The reaction mixture was heated to 85° C. for 5 h, treated with additional reagents (30.7 mL of 30% H2O2 and 20.8 g of potassium carbonate), heated to 85° C. for 3 h, cooled to room temperature, and diluted with EtOAc and water. The mixture was extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to provide the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.67 (s, 1H); 8.47 (s, 1H); 8.41 (d, 1H); 7.83 (br s, 1H); 7.78 (d, 1H); 7.26 (dd, 1H); 7.18 (br s, 1H); 6.57 (d, 1H); 3.61 (q, 1H); 1.35 (m, 2H); 0.51 (m, 2H); 0.32-0.40 (m, 6H). LRMS (APCI) calc'd for (C19H19ClN4O) [M+H]+, 355.1. found 355.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]([N:19]([CH3:20])[CH3:21])=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(N(C)C)c1OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(CO)c1OCc1ccccc1
Temperature: 57 °C
Reaction time: 8 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 2-(benzyloxy)-3-(dimethylamino)benzoate (9.1 g, 31.89 mmol, 1.00 equiv) and oxolane (180 mL). This was followed by the addition of LiBH4 (3.31 g, 152.10 mmol, 4.77 equiv) in several batches. The resulting solution was stirred for 8 h at 57° C. in an oil bath. The reaction was poured into 400 mL of water/ice. The resulting solution was extracted with 2×500 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 4.5 g (55%) of [2-(benzyloxy)-3-(dimethylamino)phenyl]methanol as yellow oil. MS (ESI) m/z 258 ([M+H]+).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=4)=[CH:14][N:13]([CH2:24][O:25]CC[Si](C)(C)C)[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[OH:25][CH2:24][N:13]1[C:9]2[N:10]=[CH:11][N:12]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:8]=2[C:15]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][CH:17]=2)=[CH:14]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)n2)c2c(N3CCOCC3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cn(CO)c3ncnc(N4CCOCC4)c23)n1

Procedure:
A solution of 6-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]pyridine-2-carbonitrile (C10) (110 mg, 0.252 mmol) in trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to provide the product as a yellow oil, which was used for the next step without additional purification.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11](OCC)=[O:12])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=O)C.[BH4-].[Na+]>C1COCC1.CO>[C:19]([O:18][C:16]([N:8]1[CH2:7][C@@H:6]([CH2:4][OH:3])[C@H:10]([CH2:11][OH:12])[CH2:9]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO)C1

Procedure:
To a stirred solution of (±)-trans-pyrrolidine-1,3,4-tricarboxylic acid 1-tert-butyl ester 3,4-diethyl ester (15.85 mmol, 5 g) in a mixture of THF (50 mL) and methanol (50 mL) was added NaBH4 (4 g) portions wise over a period of 1 h. The volatiles were removed under reduced pressure. To the residue was added water and extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with ethyl acetate to provide (±)-trans-3,4-bis-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[S:29])[CH:24]=[CH:25][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=1)=[S:29]
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(C(F)(F)F)c1
Yield: 62.9 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.82 g, 4.04 mmol). Trituration in hexanes/ethyl acetate gave the product (1.12 g) in two crops; m.p. 177-178° C.
Reaction SMILES: C(C1C=C(NC(=O)C[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(C[CH2:35][N:36](C)[C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=CC=1>>[CH2:39]([O:38][C:37]([N:36]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CN(CCc1ccc(Br)cc1)C(=O)OCc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CN(CCc1ccc(B(O)O)cc1)C(=O)OCc1ccccc1
Yield: 74 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 28C (1.14 g, 3.3 mmol) was 5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 28D (760 mg, 74%) as a white solid. MS (ESI) m/z 313.97 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:27])=[S:26])=[CH:21][C:20]=3[CH2:28][CH2:29][CH3:30])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.Br[CH2:33][C:34](=O)[CH2:35][CH3:36].N1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][CH:33]=[C:34]([CH2:35][CH3:36])[N:27]=4)=[CH:21][C:20]=3[CH2:28][CH2:29][CH3:30])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Reactant: CCC(=O)CBr
Solvent: c1ccncc1
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
To a solution of methyl(5-{3-[4-(aminocarbonothioyl)-2-propyl-phenoxy]-propoxy}-1H-indol-1-yl)acetate (Example 52, 500 mg, 1.14 mmol) in ethanol (35 mL), was added 1-bromo-2-butanone (739 mg, 2.27 mmol) and pyridine (0.14 mL, 135 mg, 1.70 mmol). The reaction mixture was stirred for 3 h at 70° C. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (0-15% EtOAc in hexane) to give 89 mg (16%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.18-7.12 (m, 2H), 7.05 (d, 1H) 6.95-6.85 (m, 2H), 6.80 (s, 1H), 6.48 (d, 1H), 4.85 (s, 2H), 4.25-4.20 (m, 4H), 3.75 (s, 3H), 2.85 (q, 2H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.75-1.60 (m, 2H), 1.35 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].CC(C)([O-:19])C.[K+].[OH-].[K+].Cl>O.CN1C(=O)CCC1>[Cl:1][C:2]1[C:7]([OH:19])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(Cl)c1O
Temperature: 85 °C
Yield: 20.9 %

Procedure:
A solution of 2,3-dichloro-4,6-dinitrophenol (2.2 g, 0,008 mol, from previous example), 4.5 g of potassium t-butoxide, 0.4 g of potassium hydroxide, 30 mL of N-methyl pyrrolidinone, and 15 mL of water in a 100 mL round-bottomed flask with stir bar is heated to 85° C. for 6 hours. Upon completion, the reaction mixture is poured into 50 mL of aqueous hydrochloric acid. The resulting product is isolated by filtration, washed with cold water, and air dried. The product is recrystallized from a minimal amount of methanol to yield 1.97 g of 2-chloro-4,6-dinitroresorcinol (95% yield) (85% overall from 1,2-dichloro-3,5-dinitrobenzene).
Reaction SMILES: [F:1][C:2]([F:46])([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([O:28]CC4C=CC(OC)=CC=4)=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:43])([F:42])[F:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][C:2]([F:1])([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH3:27])[C:22](=[O:28])[NH:21][CH:20]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:41])([F:42])[F:43]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.077 mmol) in DCM (5 mL) was added TFA (0.012 mL, 0.154 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The mixture was concentrated to give crude product, which was purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mLl/min; Gradient Profile Description: 26-56 (B %)) to give N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (16.72 mg, 0.032 mmol, 41.0% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.01 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.36-7.26 (m, 3H), 7.23 (s, 1H), 4.12 (d, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.68 (t, J=12.8 Hz, 2H), 3.41 (t, J=17.1 Hz, 2H), 1.45 (t, J=6.9 Hz, 3H). ES-LCMS m/z 529 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Reactant: Cc1ccc(Br)nc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C)cn1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 2-bromo-5-methylpyridine [purchased from TCI] (0.827 g, 4.81 mmol), (5-(tert-butyl)-2-methoxyphenyl)boronic acid [Intermediate 5] (1.2 g, 5.77 mmol) and potassium carbonate (0.997 g, 7.21 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (277.8 mg, 0.24 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 35% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-methoxyphenyl)-5-methylpyridine (1.216 g, 99% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH:37]([CH:40]1[CH2:49][N:43]2S(=O)(=O)O[CH2:46][C@H:42]2[CH2:41]1)([CH3:39])[CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:46][C@H:42]1[CH2:41][CH:40]([CH:37]([CH3:39])[CH3:38])[CH2:49][NH:43]1
Reactant: Clc1cncc(Cl)c1
Reactant: CC(C)C1C[C@@H]2COS(=O)(=O)N2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)C1CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.3 %

Procedure:
To a solution of 3,5-dichloropyridine (228 mg, 1.542 mmol) in THF (2.6 mL) at −78° C. was added lithium diisopropylamide, 2.0 M heptane/THF/ethylbenzene (0.976 mL, 1.953 mmol) dropwise. After stirring for 45 min, a solution of (3aR)-5-isopropyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (211 mg, 1.028 mmol) in THF (3.0 mL) was added dropwise at −78° C. The resulting mixture was allowed to warm to room temperature and then stirred for 3 h. After evaporation of the solvent, the resulting brown solid was treated with 2 N HCl (3 mL) and EtOH (3 mL) and heated at 80° C. for 2 h. The reaction mixture was concentrated to remove the EtOH. The resulting mixture was treated with ice and basified with 2 N NaOH to pH-10 and extracted with EtOAc (2×10 mL). The extracts were dried, evaporated and purified by ISCO, chromatograph through a REDISEP™ pre-packed silica gel column (12 g), eluting with a gradient of 0% to 5% MeOH (with 2 M NH3) in DCM to give 3,5-dichloro-4-(((2R)-4-isopropylpyrrolidin-2-yl)methyl)pyridine (102 mg, 0.373 mmol, 36.3% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 2H), 3.35-3.51 (m, 1H), 2.84-3.08 (m, 3H), 2.35-2.44 (m, 1H), 1.80-1.93 (m, 1H), 1.55-1.69 (m, 1H), 1.31-1.49 (m, 2H), 1.02-1.17 (m, 1H), 0.85 (t, J=6.7 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][CH:9](C)[C:10]2[N:14]([CH2:15][CH2:16][CH3:17])[CH:13]=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[CH2:21](O)C>[Pd]>[CH3:21][N:8]([CH2:9][C:10]1[N:14]([CH2:15][CH2:16][CH3:17])[CH:13]=[N:12][N:11]=1)[C:7]1[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: CCCn1cnnc1C(C)Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: CCCn1cnnc1CN(C)c1ccc(N)cc1
Reaction time: 18 h

Procedure:
A mixture of 4-nitro[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)]aniline (1.0 g), and 10% Pd-C (0.3 g) in ethanol was stirred strongly for 18 hours under hydrogen atmosphere. Pd-C was removed by filtration, the reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with diethylether, to give 4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]aniline (0.50 g) as brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])[CH:3]=1
Reactant: Cc1ccnc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(-c2cccc(N)c2)c1
Yield: 98.8 %

Procedure:
A suspension of 3-(4-methylpyridin-2-yl)nitrobenzene (100 mg) in ethanol (2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 10 mg) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-methylpyridin-2-yl)aniline (85 mg).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>ClCCl>[C:18]([O:21][CH2:22][C:23]([N:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:1]([CH3:3])[CH3:2])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(C)NC1CCCCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N(C(C)C)C1CCCCC1
Yield: 99.5 %

Procedure:
To a solution of 5.0 g of N-isopropylcyclohexylamine and 4.3 g of triethylamine in 100 ml of dry dichloromethane was added dropwise 5.8 g of acetoxyacetyl chloride with stirring under ice-cooling, and the mixture was stirred for 16 hours at room temperature. The reaction mixture was successively washed with an aqueous sodium bicarbonate solution and water, dried under reduced pressure to obtain 8.5 g of 2-acetoxy-N-cyclohexyl-N-isopropylacetamide in an oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH3:23][NH2:24].C1COCC1>CO.C(OCC)(=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[N:6][C:5]=1[C:3]([NH:24][CH3:23])=[O:4]
Reactant: CN
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (108 mg, 0.26 mmol) in anhydrous methanol (0.5 mL) was added 2M methylamine in THF (1.3 mL, 2.6 mmol, 10 eq), and the reaction mixture was stirred at room temperature under N2 for 3 days. The reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to reverse-phase preparative HPLC [Gemini-NX (100×30 mm, 10 micron), 0.1% FA in water/acetonitrile, 5-85%, ramp time in 10 minutes, flow at 60 ml/min] to afford the title compound as a white solid (48.3 mg, 44.8%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 10.89 (s, 1H), 8.95 to 8.91 (m, 1H), 8.86 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 6.51 (t, J=6.8 Hz, 1H), 2.81 (d, 4.0 Hz, 3H); LCMS (method E2): RT=12.23 min, [M+H]+=412.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1c(N)sc2cc(Cl)ccc12
Product: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(Cl)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-chlorobenzo[b]thiophene-3-carbonitrile and 2-fluoronitrobenzene, 6-chloro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile is obtained.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[CH3:30])[N:24]=1>>[F:31][C:29]([C:25]1[N:26]=[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:28]=[CH:23][N:24]=1)([F:32])[CH3:30]
Reactant: CC(F)(F)c1nccc(Cl)n1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(C)(F)F)n3)cnc2n1

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (567 mg, 1.4 mmol) and 4-chloro-2-(1,1-difluoroethyl)pyrimidine (209 mg, 1.17 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 gave 3-[2-(1,1-difluoroethyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:13])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:14]([CH:9]1[CH2:8][C:7](=[O:13])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10]1)[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)OCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1CC(=O)c2ccc(OC)cc2O1
Yield: 41 %

Procedure:
A solution 11.9 g of 7-methoxy-4-chromanone, 13.8 ml of 3-buten-2-ol and 120 mg of p-toluenesulfonic acid in 14 ml of 2,2-dimethoxypropane and 120 ml of anhydrous toluene was boiled under reflux for 24 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 6.3 g (41%) of (RS)-2-(2-buten-1-yl)-7-methoxy-4-chromanone were obtained as a yellow oil.