Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:42][CH2:43][C@H:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[OH:45]>O1CCCC1.ClCCl>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18]([NH:42][CH2:43][C@@H:44]([OH:45])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:19])=[O:8])=[CH:3][CH:2]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON=C1C[C@@H](CC(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106 %

Procedure:
To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 25 mg, 0.07 mmol) in tetrahydrofuran (1 ml) at −25° C. were added NMM (18 mg, 0.18 mmol) followed by isobutyl chloroformate (10 mg, 0.07 mmol). The reaction mixture was stirred 10 min then a solution of (S)-2-amino-1-phenylethanol (10 mg, 0.07 mmol) in tetrahydrofuran (1 ml). The reaction was allowed to warm up to room temperature and was stirred overnight. Dichloromethane was added and the organic phase was washed with NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4) and concentrated to afford 2-[(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino) pyrrolidin-2-yl]-N-[(2S)-2-hydroxy-2-phenylethyl]acetamide (35 mg). Yield: 94%. HPLC purity: 90%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8](=[O:22])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CCO.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:23][CH:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:9][C:8]2=[O:22]
Reactant: O=C(/C=C/c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(4-(trifluoromethoxy)phenyl)prop-2-en-1-one (8 g, 20 mmol) in EtOH (144 mL) and H2O (432 mL) was added NaOH (800 mg, 20 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na2SO4 and then concentrated in vacuo to give 6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-one (6 g, 80%). 1H-NMR (CDCl3): 2.91 (d, 1H), 3.04 (m, 1H), 5.49 (dd, 1H), 6.94 (m, 1H), 7.31 (d, 2H), 7.50 (d, 2H), 7.59 (m, 1H), 8.03 (s, 1H).
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[NH:15][C:14]=1[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1)[C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([CH2:2][C:3]3[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=3)=[C:14]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)[NH:15]2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(C(O)c2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a suspension of methyl 6-[hydroxyl(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-yl)methyl]pyridine-2-carboxylate (828 mg) in dichloromethane (21.2 mL) was added triethylsilane (1.35 mL) under ice-cooling. Then trifluoroacetic acid (0.649 mL) was added dropwise thereto, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 1 hour. Triethylsilane (1.35 mL) and trifluoroacetic acid (0.649 mL) were added thereto, and the mixture was stirred at room temperature for additional 5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (468 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.03 (3H, s), 4.48 (2H, s), 6.80 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.23-7.28 (1H, m), 7.37 (1H, d, J=8.8 Hz), 7.64-7.71 (1H, m), 7.94-8.00 (1H, m), 8.16 (1H, br s), 9.04 (2H, s), 9.17 (1H, s). ESI-MS (m/z): 375 (M+H)+
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[C:10]([NH:14][C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29]C(=O)[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11].CO>C(Cl)Cl>[C:10]([NH:14][C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23](=[C:22]([C:25]3[NH:33][C:32]4[CH2:31][CH2:30][N:29]=[C:6]([O:7][CH3:9])[C:27]=4[CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:24]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC1=NCCc2[nH]c(-c3cccc4nc(C)c(NC(C)(C)C)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Trimethyloxonium tetrafluoroborate (239 mg, 1.617 mmol, Sigma-Aldrich) was added to a red slurry of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193, 113 mg, 0.32 mmol) in DCM (10 mL) and the resulting mixture was stirred at RT for 1 h when the solid had begun to stick to the side of the flask; MeOH (2 mL) was added to bring all the solid into solution and stir at RT for 16 h when a mixture of product and starting material was observed via lcms. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give N-(tert-butyl)-8-(4-methoxy-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-methylquinoxalin-2-amine (351, 16 mg, 14% yield) as a rust colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.66 (s, 9H) 2.55 (s, 3H) 2.82 (t, J=7.73 Hz, 2H) 3.84 (t, J=7.73 Hz, 2H) 3.88 (s, 3H) 4.84 (s, 1H) 6.80 (d, J=1.96 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.63 (dd, J=8.12, 1.27 Hz, 1H) 7.91 (dd, J=7.63, 1.37 Hz, 1H) 12.54 (br. s., 1H). 13C NMR (101 MHz, CDCl3) δ ppm 21.30, 21.51, 28.68, 46.23, 51.32, 52.37, 100.94, 110.83, 124.51, 124.72, 125.43, 126.11, 131.26, 135.55, 136.41, 136.91, 145.19, 148.40, 161.58. MS (ESI, pos. ion) m/z: 364.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:31][CH3:32])=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:34])([CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:31][CH3:32])=[C:15]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[S:11][C:10]([CH3:34])([CH3:33])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)C=C3c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1C#Cc1ccc(C(=O)O)cc1)C(c1ccc(C)cc1)=CC(C)(C)S2
Temperature: 45 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 4-[[4-(4-methylphenyl)-2,2-dimethyl-7-methoxy-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 215, 64.0 mg, 0.113 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 50 mg (83%) of the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.2 Hz), 7.56 (2H, d, J=8.2 Hz), 7.28-7.14 (5H, m), 7.06 (1H, s), 5.76 (1H, s), 3.96 (3H, s), 2.36 (3H, s), 1.47 (6H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][S:11]([C:14]3[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.FC1C=C(OC)C=C(F)C=1CN.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:45][C:46]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([F:78])[C:47]=1[CH2:48][N:49]1C2N=CC=CC=2S(=O)(=O)N(C2C=CC(OC)=C(OC)C=2)[C:50]1=[O:71].FC1C=CC2N(C(C3C=CC=CC=3F)C)C(=O)N(C3C=CC=C(SC)C=3)S(=O)(=O)C=2C=1>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:50](=[O:71])[N:49]([CH2:48][C:47]4[C:72]([F:78])=[CH:73][C:74]([O:76][CH3:77])=[CH:75][C:46]=4[F:45])[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:14]=4[S:11]3(=[O:13])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S(=O)(Nc1ccc2ncsc2c1)c1cccnc1Cl
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: COc1cc(F)c(CN)c(F)c1
Agent: CSc1cccc(N2C(=O)N(C(C)c3ccccc3F)c3ccc(F)cc3S2(=O)=O)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(F)c(CN2C(=O)N(c3ccc4ncsc4c3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (60 mg, 0.12 mmol) was prepared in two steps from N-(1,3-benzothiazol-6-yl)-2-chloropyridine-3-sulfonamide (IntC9) (300 mg, 0.92 mmol) and 2,6-difluoro-4-methoxybenzylamine (176 mg, 1.01 mmol) at 140° C. in a sealed tube; followed by triphosgene (288 mg, 0.97 mmol) in 1,4-dioxane (5 mL) at 110° C. for 16 h using the methods of (95) then (63).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12])[O:8][C:26]1[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(C#N)n1C)C(F)(F)F
Product: CC(c1ccc(Oc2ccc(C(=O)O)cn2)cc1Cl)C(O)(c1ccc(C#N)n1C)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 227, step 3, from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyrrole-2-carbonitrile (Example 232 step 2) and methyl 6-chloronicotinate (CAS Reg. No. 73781-91-6). White foam. MS (m/e, ISP neg. ion)=477.9 [M−H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(-c2cccc(O)c2)c2c1C(=O)NC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccc(N)c3c2CNC3=O)c1
Yield: 59.5 %

Procedure:
In a similar manner to Step 1 of Example 304, 7-amino-4-(3-hydroxyphenyl)isoindolinone (137 mg, 0.569 mmol) was dissolved in acetonitrile (7.0 mL), and the solution was treated with tert-butyldimethylsilyl chloride (155 mg, 1.02 mmol) and DBU (0.154 mL, 1.02 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-amino-4-(3-tert-butyldimethylsilyloxyphenyl)isoindolinone (120 mg, yield 59%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH2:23][CH3:24])[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]=2[CH:15]=[CH2:16])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C>[NH:8]([C:9]1[C:10](=[O:25])[N:11]([CH2:23][CH3:24])[N:12]=[C:13]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]=1[CH2:15][CH3:16])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: C=Cc1c(-c2ccccc2)nn(CC)c(=O)c1Nc1cccc(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1c(-c2ccccc2)nn(CC)c(=O)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of the title compound of example 3 (67 mg, 0.19 mmol) and 10% palladium on charcoal (50 mg) in ethanol (10 mL) was shaken under hydrogen at room temperature and 4 bar for 2 h. The catalyst was filtered off and the solvent was removed under reduced pressure to yield the title compound (71% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[N+:15]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=1)([O-:17])=[O:16]
Reactant: COc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccc(O)cc2)c1
Yield: 94.1 %

Procedure:
Solid 4-methoxy-3'-nitrobiphenyl (1.63 g) was dissolved in acetic acid (25 ml) and then concentrated hydrobromic acid (48%, 25 ml) was added (CAUTION). The mixture was heated at reflux for 2 hours and was then cooled. The reaction mixture was partitioned between ether and water. The organic layer was dried over anhydrous magnesium sulfate, the solution filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:ether (9:1) to give the sub-title compound as a yellow oil (1.44 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 106.3 %

Procedure:
To a solution of ethyl (RS)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (40 mg, 0.10 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was stirred under an atmosphere of H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 100%). which was used without further purification.
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12](Cl)=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(Cl)[Cl:22]>ClCCl>[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Cl:22])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Reactant: ClSCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester and 4.1 g of sodium hydrogen carbonate are placed in 100 ml of dichloromethane and cooled in an ice bath. In the course of 3 minutes, a solution of 3.2 g of sulfur chloride in 10 ml of dichloromethane is added, and when the addition is complete the ice bath is removed. The mixture is stirred at room temperature for 2 hours and filtered off with suction, and the filtrate is concentrated by evaporation. The residue crystallises after the addition of diethyl ether. Filtration yields 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 129-131° C. in the form of the hydrochloride. Extraction of the mother liquor with semi-saturated aqueous sodium hydrogen carbonate solution and removal of the ether by distillation yield 2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)C1CCCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCCCC4)cc23)CC1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.10 mMol) cyclohexanecarboxylic acid, 20.6 mg (100+%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH2:21][NH:22][CH3:23].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:22]([CH3:23])[CH2:21][C:13]1[N:12]([CH3:11])[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CNCc1cc2ccccc2n1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
A solution of 2-bromobenzoyl chloride (1.85 g, 8.45 mmole) in CH2Cl2 (10 mL) was added dropwise to a solution of 1-methyl-2-(methylaminomethyl)indole (1.47 g, 8.45 mmole) and Et3N (3.6 mL, 25.8 mmole) in CH2Cl2 (50 mL) at 0° C. The reaction was stirred at 0° C. for 15 min, then was allowed to warm to RT. After 2 hr, the mixture was concentrated in vacuo, and the residue was diluted with H2O. The mixture was extracted with Et2O, and the combined Et2O layers were dried (MgSO4) and concentrated in vacuo. The oily residue was triturated with Et2O/petroleum ether to afford the title compound (2.6 g, 87%) as a white solid: MS (ES) m/e 357 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1=[O:22])=O)(C)(C)C.[ClH:23]>C(O)C>[ClH:23].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]1=[O:22]
Reactant: CCOC(=O)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN1CCCC[C@H](N)C1=O
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of 49 (3.143 g, 0.0100 mole) in 20 mL of ethanol at 0° C. was added 12N HCl in ethanol (27.0 mL, 0.32 mol) in one portion. The solution was stirred at 0° for 5 min and then allowed to stir at ambient temperature for one hr. The solvent was evaporated, anhydrous acetonitrile (100 mL) was added and the solvent was reevaporated. The residue was pumped at <1 mm Hg on a vacuum pump for 20 hrs to afford 2.410 g (96% yield) of product 50 as a pale yellow foam. TLC (silica gel; CH2Cl2, methanol, conc. NH4OH : 25, 5, 1): Rf=0.63.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.[CH2:14]([Cl:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl.C(#N)C>C(Cl)(Cl)Cl.C(O)C>[ClH:22].[CH2:14]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCl
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Agent: Cl
Solvent: CCO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC1CCc2c(C)cc(C)c(O)c21
Reaction time: 4 h
Yield: 15.1 %

Procedure:
To a solution containing 1.77 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene and 2 ml of trethylamine in 100 ml of chloroform was added dropwise 2.23 g of octyl chloride at room temperature. Then the reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed with a diluted hydrochloric acid, water, an aqueous solution saturated with sodium bicarbonate, water and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue thus obtained was dissolved in ethanol, tna an ethanol saturated with hydrogen chloride gas was added thereto form a hydrochlodide. Recrysttallized form acetonitrile to obtain 0.49 g of 2,3-dihydro-1-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochloride. Colorless needle-like crystals. Melting point: 120°-121° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:24]=4[OH:31])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+].Cl.C(OCC)(=O)C>CO>[Cl:30][C:25]1[C:24]([OH:31])=[C:23]([CH:28]=[C:27]([Cl:29])[CH:26]=1)[CH2:22][N:19]1[CH2:18][CH2:17][CH:16]([CH2:15][NH:14][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After suspending 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid methyl ester (993 mg, 2.14 mmol) in methanol (10 ml), an aqueous lithium hydroxide solution (4M, 5.4 ml, 21.4 mmol) was added. The reaction mixture was stirred at 50° C. for 2 hours and then cooled to room temperature. 1N hydrochloric acid was added dropwise to adjust the pH to approximately 6.0. Ethyl acetate (1 ml) was then added and the mixture was stirred for 3 hours, after which the precipitate was filtered out to obtain 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid. The compound was identified by LC-MS.
Reaction SMILES: [Li+].[Cl-].C1C[O:6][CH2:5]C1.Br[C:9]1[CH:10]=[C:11]([C:16]2([C:19]#[N:20])[CH2:18][CH2:17]2)[CH:12]=[C:13]([Br:15])[CH:14]=1.CN(C=O)C.[NH4+].[Cl-]>O.C(OCC)(=O)C>[Br:15][C:13]1[CH:12]=[C:11]([C:16]2([C:19]#[N:20])[CH2:18][CH2:17]2)[CH:10]=[C:9]([CH:5]=[O:6])[CH:14]=1
Reactant: C1CCOC1
Reactant: N#CC1(c2cc(Br)cc(Br)c2)CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2cc(Br)cc(C=O)c2)CC1
Temperature: -20 °C
Yield: 83.2 %

Procedure:
LiCl in THF (5.429 mL of 14% w/v, 5.233 mmol) was placed in an oven-dried 3-necked flask under nitrogen. The flask was cooled to −20° C. and 1-(3,5-dibromophenyl)cyclopropane-1-carbonitrile (1.5 g, 4.984 mmol) was added in one portion. The temperature was maintained between −20 and −10° C. for 90 minutes. DMF (400.7 mg, 424.5 μL, 5.482 mmol) was then added and the reaction allowed to warm to room temperature overnight. NH4Cl (sat. aq. soln.) was added followed by ethyl acetate and water. The mixture was extracted three times with ethyl acetate, the combined organics dried over MgSO4 and the solvent removed under reduced pressure. The crude product was purified on silica (Companion, 24 g) eluting with 2-30% EtOAc:Petrol ether to give 1-(3-bromo-5-formyl-phenyl)cyclopropane-1-carbonitrile as a white solid (1.037 g, 83%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.FC(F)(F)C(O)=O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COc2ccc3ccccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2cc(OC[C@@H]3CCNC3)ccc2c1
Yield: 98.9 %

Procedure:
The procedure is the same as for Example 2 (Stage 2.2) starting from 1.75 g (5.34 mmol) of tert-butyl (R)-3-(naphth-2-yloxymethyl)pyrrolidine-1-carboxylate and 5.00 ml (67.31 mmol) of trifluoroacetic acid. 1.20 g of product are obtained in the form of an oil.