Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3](=[O:24])[CH2:4][O:5][C:6]([C:8]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12]CN[CH2:9]1)=[O:7].[F:27][C:28]1[CH:33]=[C:32]([C:34]2[O:38][N:37]=[C:36]([C:39]3[CH:52]=[CH:51][C:42]([CH2:43][N:44]([CH2:48]CO)CCO)=[CH:41][CH:40]=3)[N:35]=2)[CH:31]=[CH:30][C:29]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.N(CCO)CCO>>[CH3:25][C:2]([CH3:1])([CH3:26])[C:3](=[O:24])[CH2:4][O:5][C:6]([C:8]1([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:13][CH2:12][N:44]([CH2:43][C:42]2[CH:51]=[CH:52][C:39]([C:36]3[N:35]=[C:34]([C:32]4[CH:31]=[CH:30][C:29]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)=[C:28]([F:27])[CH:33]=4)[O:38][N:37]=3)=[CH:40][CH:41]=2)[CH2:48][CH2:9]1)=[O:7]
Reactant: OCCN(CCO)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Reactant: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCNC1
Solvent: OCCNCCO
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1

Procedure:
Condensation of piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester onto 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazole is performed as described in step II for the preparation of 2-[{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]benzyl}(2-hydroxyethyl)amino]-ethanol, with piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester replaced by diethanolamine. This procedures affords 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)=[O:4].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>CC#N>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:3]([NH:5][C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]3[C:7]=2[CH:8]=[N:9][NH:10]3)=[O:4])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: Cc1ccc(NC(=O)C(Cl)(Cl)Cl)c2cn[nH]c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(NC(=O)NCc2ccc(C(C)(C)C)cc2)c2cn[nH]c12
Temperature: 25 °C

Procedure:
2,2,2-Trichloro-N-(7-methyl-1H-indazol-4-yl)acetamide (72 mg, 0.25 mmol), 4-tert-butylbenzylamine (55 mg, 0.34 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.09 mL, 0.60 mmol) were combined in CH3CN (6 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with saturated aqueous NH4Cl solution. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 12.90 (br s, 1H), 7.94 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 7.47 (m, 2H), 7.37 (m, 2H), 7.25 (m, 2H), 6.84 (t, J=5.8 Hz, 1H), 4.26 (d, J=5.7 Hz, 2H), 2.35 (s, 3H), 1.27 (s, 9H); MS (ESI+) m/z 337 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(Cl)Cl>[CH3:1][C@H:2]1[N:7]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:37])[F:38])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
To a solution of 1,1-dimethylethyl(3R)-3-methyl-1-piperazinecarboxylate (605 mg, 2.56 mmol) in DCM (20 ml) was added DIPEA (1.12 ml, 6.39 mmol) and then portionwise 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (0.455 ml, 2.68 mmol) at room temp and the resultant mixture stirred under Ar for 16 h. DCM (75 ml) and a 1M HCl solution (75 ml) were added, the layers were separated and the organic layer was then washed with 2M NaOH solution (75 ml), the organic layers were separated, dried (MgSO4) and concentrated to dryness. 1,1-Dimethylethyl(3R)-3-methyl-4-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-1-piperazinecarboxylate was isolated as a slowly crystallizing white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)Cl>CO>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:11])=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1cnc(F)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1cnc(F)c(Br)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 3-bromo-2-fluoro-5-nitropyridine from Step 126a above (5.0 g, 23 mmol) in MeOH (100 mL) was added tin(II) chloride dihydrate. The mixture was heated at reflux for 3 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO3 and EtOAc resulting in formation of an emulsion which was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purification by chromatography (silica gel; hexane/EtOAc, 70:30) afforded 3.61 g (83%) of the title compound as a yellow solid: mp 91-92° C.; 1H NMR (CDCl3, 300 MHz) δ7.15 (dd, J=2.5, 7.5 Hz, 1H), (dd, J=2.0, 2.5 Hz, 1H); MS (DCI/NH3) m/z 191, 193 (M+H)+ 208, 210 (M+NH4)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([NH:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: NCCSc1cccc2nccn12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCSc1cccc2nccn12
Yield: 66.7 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine dihydrochloride (2.66 g, 10 mmoles) and triethylamine (4.32 ml, 31 mmoles) in N,N-dimethylformamide (24 ml) was added acetyl chloride (0.71 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethanol/ethyl acetate =1:3) to obtain 1.57 g of the desired product (66.8%, colorless crystals).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:38][CH3:39])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:24](OC2C=CC=CC=2)=[O:25])=[CH:16][C:15]=1[N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.[NH2:40][C:41]1[CH:48]=[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])[C:44]([C:45]#[N:46])=[CH:43][N:42]=1>C1COCC1>[C:45]([C:44]1[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:48][C:41]([NH:40][C:24]([N:21]2[C:22]3[C:17](=[CH:16][C:15]([N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)=[C:14]([CH:13]([O:12][CH3:11])[O:38][CH3:39])[N:23]=3)[CH2:18][CH2:19][CH2:20]2)=[O:25])=[N:42][CH:43]=1)#[N:46]
Reactant: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2C(=O)Oc1ccccc1
Reactant: COCCNc1cc(N)ncc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-n4ccnc4)c(C(OC)OC)nc32)ncc1C#N
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
A solution of LHMDS (1M in THF, 260 μL, 0.260 mmol) was added to suspension of phenyl 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 320, 49.7 mg, 0.126 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 25 mg, 0.130 mmol) in THF (1 ml) at −70° C. and the reaction mixture was stirred at −65° C. for 90 min. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate and water. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (2-3%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.79 min; ESI-MS 493.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH:8](O)[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15](=[O:25])[CH:16]([CH:22]([CH3:24])[CH3:23])C(OCC)=O)C>CCO.CCO.CCO.CCO.[Ti]>[CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH:16]([CH:22]([CH3:24])[CH3:23])[C:15]([OH:25])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(O)CC1CCCCC1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: [Ti]
Solvent: CCO
Product: CC(C)C(CC=CCC1CCCCC1)C(=O)O
Reaction time: 1 h

Procedure:
23.15 g (0.15 mol) of 1-cyclohexyl-3-buten-2-ol, 6.85 g (0.03 mol) of tetraethyl orthotitanate and 61.5 ml (0.30 mol) of isopropylmalonic acid diethyl ester are placed in a flask and stirred for 1 hour at 170° and then for 24 hours at 200°. Excess malonic acid ester is distilled off at 20 mbar, and the residue is dissolved in 120 ml of ethanol and, after the addition of 120 ml of 6N KOH, stirred under reflux for 7 hours. After cooling, the reaction mixture is filtered and the filtrate is extensively concentrated by evaporation in a rotary evaporator. The aqueous phase is extracted once with ether, acidified to pH 1 with 6N HCl while cooling with ice and then extracted three times with ether. The combined organic phases are washed with brine, dried with MgSO4 and concentrated by evaporation in a rotary evaporator. The residue is distilled at 137°-140°/0.025 mbar.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([F:30])[CH:6]=1.Cl[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33]>>[F:30][C:7]1[CH:6]=[C:5]([CH:4]=[N:3][NH:2][C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33])[CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[O:20][CH:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17][C:16]=2[CH:27]=1)=[O:10]
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3F)ccc2O1
Reactant: CCCOC(=O)Cl
Agent: Cl
Product: CCCOC(=O)NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)c(F)c1

Procedure:
The title compound was prepared as described in Example 85 from 436 mg (1.0 mmol) of the amidine from Example 69 and 135 mg (1.1 mmol) propyl chloroformate. Yield: 0.29 g (60%) of a white crystalline solid, m.p. 157-159° C.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([CH2:14][N:5]2[CH:6]=[C:2]([I:1])[N:3]=[CH:4]2)[CH2:17][CH2:16]1
Reactant: Ic1c[nH]cn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cn(CC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.7 %

Procedure:
To a solution of 4-iodo-1H-imidazole (800 mg, 4.12 mmol) in DMF (50 mL) was added cesium carbonate (5.37 g, 16.5 mmol) and (bromomethyl)cyclopropane (1.6 mL, 16.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with water, sat'd LiCl and sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/heptane) to isolate first 590 mg (58%) of 1-cyclopropylmethyl-4-iodo-1H-imidazole as a pale yellow oil followed by 227 mg (22%) of 1-cyclopropylmethyl-5-iodo-1H-imidazole as a pale yellow oil.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[CH2:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC=Nc2cc3c(cc21)OCO3
Product: Clc1ccnc2cc3c(cc12)OCO3

Procedure:
6,7-Methylenedioxy-4-quinolone (5.0 g, 26.5 mmol) was boiled in POCl3 (75 mL) for 45 min and then cooled. Excess phospohoryl chloride was removed under reduced pressure and ice water (100 mL) was added to hydrolyze any residual phosphoryl chloride. The mixture was basified (pH 9) with ammonium hydroxide, and the solid precipitate was filtered. This material was extracted into ethyl ether (8×100 mL), and the ether solution was dried (MgSO4) and evaporated to provide 4.55 g as a white solid, in 83%; mp 127.5-128° C. (lit. mp 129° C.); 1H NMR (CDCl3) δ 6.15 (s, 2H), 7.35 (d, 1H, J=4.7), 7.39 (s, 1H), 7.49 (s, 1H), 8.56 (d, 1H, J=4.7); 13C NMR (CDCl3) δ 99.8, 102.2, 106.1, 119.9, 123.7, 129.8, 141.2, 147.7, 149.1, 151.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23]O)=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[C:19]2[CH2:23][N:29]2[C:25](=[O:35])[C:26]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:27]3[C:28]2=[O:30])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=1[F:15])=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1cc(Cl)ccc1-n1ccnc1CO)c1c(F)cccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1cc(Cl)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 17, 5-chloro-2',6'-difluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-chloro-2',6'-difluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[N:2].[C:25](Cl)(=[O:29])[CH2:26][CH2:27]C>>[C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:25]([CH2:26][CH3:27])=[O:29])[C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1)#[N:2]
Reactant: COc1cc(OC)cc(C(=O)Nc2sc3c(c2C#N)CCNC3)c1
Reactant: CCCC(=O)Cl
Product: CCC(=O)C1NCCc2c1sc(NC(=O)c1cc(OC)cc(OC)c1)c2C#N

Procedure:
Prepared according to general procedure A starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3,5-dimethoxybenzamide (compound B1) and butyric acid chloride.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([SH:16])[CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: Cc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cccc(Sc2ccc(N)cc2)c1
Yield: 90.1 %

Procedure:
The general procedure in example 39 was followed. 4-Iodoaniline (219 mg, 1.0 mmol), m-thiocresol (119 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 4-(3-tolyl)sulfanylaniline (194 mg, 90% yield) as pale yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=4/1). Rf=0.4 (hexane/ethyl acetate=4/1). 1H NMR (CDCl3, 300 MHz) δ 7.28 (dt, 2 H, J=7.5 Hz, 0.9 Hz), 7.08 (t, 1 H, J=7.8 Hz), 6.91 (t, 3 H, J=7.5 Hz), 3.71 (brs, 2 H), 2.26 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 138.8, 138.1, 136.2, 128.9, 128.1, 126.4, 124.6, 117.5, 116.1, 100.0, 21.8. IR (neat, cm−1) 3460 (broad), 3377 (broad), 3211, 3051, 3027, 2919. MS (EI) m/z (relative intensity) 219 (100), 92 (80). HRMS (EI), Cald. for C13H13NS 215.0769. Found 215.0766.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][N:16]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][N:16]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2nc(S)[nH]c2c1
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3ccc(F)cc3[nH]2)c1C

Procedure:
10.6 g of 5-fluoro-2-benzimidazolethiol were suspended in 570 ml of alcohol and treated with 13.1 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. A solution of 5 g of sodium hydroxide in 130 ml of water was added dropwise thereto while cooling with ice, the mixture was left to boil at reflux overnight and then concentrated to about 1/3 of the volume in a vacuum. After the addition of 500 ml of water the resulting crystals were filtered off and washed thoroughly firstly with water and then with ether. There was obtained 5-fluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 128°.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][C:26]#[CH:27]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:27]#[C:26][CH2:25][O:24][CH3:23])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: COCC#Cc1cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
To a suspension of N-(4-chlorobenzyl)4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g), and Pd(PPh3)2Cl2 (0.079 g) followed by addition of propargyl methyl ether (0.27 mL). The reaction is stirred at rt for 18 h. The reaction mixture is partitioned between H2O (100 mL) and CH2Cl2 (100 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×100 mL). Combined organic layers are washed with a saturated aqueous NH4Cl solution (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2). The resulting impure material is re-purified via column chromatography (heptane:2-propanol, 10:1; CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield to yield 0.260 g (30%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[CH2:21][CH2:20][C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([NH:46][C:22]([C:10]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH2:20][CH2:21][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:26][CH:25]=2)[CH:9]=1)=[O:24])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a suspension of 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid (176 mg, 0.5 mmol) in DCM (3 mL) was added carbonyldiimidazole (97 mg, 0.6 mol) and the mixture was stirred for 1 hour at 20° C. Benzylamine (109 μL, 1 mmol) was added and the mixture was stirred overnight. Solid was collected by filtration and washed by DCM and dried under high vacuum to give the title compound (90 mg); 93% MS (ES): 442 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1(C(OCC)=O)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:7]1)=[O:5])C.C(O)(=O)C.Cl>O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:8](=[O:9])[O:7][C:6]=2[C:4]([OH:5])=[O:3])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(C(=O)OCC)OC(=O)c2ccccc2C1(O)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1oc(=O)c2ccccc2c1-c1ccc(F)cc1
Yield: 97.4 %

Procedure:
A stirred mixture of 3,3-bis(ethoxycarbonyl)-4-(4-fluorophenyl)-4-hydroxy-3,4-dihydroisocoumarin (3.85 g), glacial acetic acid (40 ml) and concentrated hydrochloric acid (40 ml) was heated at reflux for 2 hours. The mixture was then cooled and poured onto a mixture of ice and water (200 ml), and the resulting solid was filtered off and washed with water, to give 4-(4-fluorophenyl)isocoumarin-3-carboxylic acid (2.65 g) in the form of a white powder, m.p.218°-220° C. [Elemental analysis: C,67.4; H,3.41; F,6.73%; calculated: C,67.6; H,3.19; F,6.68%].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34][CH2:35]2)=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCNCC2)cc1)c1ccccc1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)c1ccccc1C
Yield: 78.9 %

Procedure:
Methanesulfonyl chloride (35 mg, 0.31 mmol) was added at 0° C. to a solution of (R)-1-(3-methoxypyridazin-4-yl)-3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropan-1-one (64 mg, 154 μmol) and N,N-diisopropylethylamine (79.6 mg, 0.62 mmol) in dichlormethane (2.5 mL). The ice bath was removed, then after 1 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane/ethyl acetate gradient) produced the title compound (60 mg, 79%). Light yellow gum, MS: 494.3 [M+H]+.
Reaction SMILES: [CH3:1]C1C=CC(S(OCC2CC3C=C(F)C=C(C4C=CC=CC=4F)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[CH:43]=[C:44]([F:54])[CH:45]=[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3F)[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:54][C:44]1[CH:45]=[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:1])[C:40]2[O:39][CH:38]([CH2:37][NH2:34])[CH2:42][C:41]=2[CH:43]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4F)c3O2)cc1
Reactant: [N-]=[N+]=NCC1Cc2cc(F)cc(-c3ccccc3F)c2O1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CN)C2
Yield: 77 %

Procedure:
Treatment of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.84 g, 4.42 mmol) with sodium azide (1.15 g, 17.67 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.111 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.02 g (77%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 240-247° C. (dec); Anal. calcd. for C15H13F2NOHCl: C, 60.51; H, 4.74; N, 4.7. Found: C, 60.33; H, 4.69; N, 4.4.