Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1(=O)[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20](=[NH:23])OC)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:26])[C:4]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:3]12.[CH3:32][OH:33].[CH3:34][NH2:35].CCOCC>C(Cl)(Cl)Cl>[ClH:1].[CH3:34][NH:35][C:20](=[NH:23])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:6]3[C:32](=[O:33])[C:27]4=[CH:28][CH:29]=[CH:30][CH:3]=[C:4]4[C:5]3=[O:26])=[CH:9][CH:10]=2)=[CH:25][CH:24]=1
Reactant: CO
Reactant: COC(=N)c1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: CN
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CNC(=N)c1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.5 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethyl]benzimidate hydrochloride in 150 ml of chloroform, was added 0.3 ml of a methanol solution containing 40% of methylamine. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.3 g of N-methyl-4-[2-(4-phthalimidomethylphenyl)ethyl]benzamidine hydrochloride; m.p. 270° C. or above.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.IC.[C:56](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][C:50]([O:52][CH3:53])=[O:51])[CH3:56])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1cc(CO)cc(CO)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN(C)c1cc(CO)cc(CO)c1
Temperature: 82 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a stirred solution of methyl 1-(3,5-bis(hydroxymethyl)phenylamino)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-oate (265c) (67 mg, 0.087 mmol) in anhydrous DMF (1.0 ml) was added iodomethane (7.06 μl, 0.113 mmol) and potassium carbonate (14.47 mg, 0.105 mmol). The reaction was stirred at 82° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by preparative TLC (10% MeOH/CH2Cl2) gave methyl 2-(3,5-bis(hydroxymethyl)phenyl)-5,8,11,14,17,20,23,26,29,32,35,38-dodecaoxa-2-azahentetracontan-41-oate (265d) (62 mg, 92%). 1H NMR (400 Hz, CDCl3): δ 6.65 (s, 3H), 4.59 (d, J=5.6 Hz, 4H), 3.74 (t, J=6.4 Hz, 2H), 3.67 (s, 3H), 3.61 (m, 46H), 3.54 (t, J=6.0 Hz, 2H) 2.98 (s, 3H), 2.59 (t, J=6.4 Hz, 2H), 2.55 (m, 2H); MS (m/z). found 820.5 (M+K)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[S:30][CH:31]=[N:32][N:33]=1>ClCCl>[S:30]1[CH:31]=[N:32][N:33]=[C:29]1[NH:28][C:17](=[O:19])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of (2S)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylaminohexanoic acid (1.09 g, 2.87 mmol) in dichloromethane (5 mL) is added 1,1-carbonyldiimidazole (0.47 g, 2.87 mmol). The resulting solution is stirred at 25° C. for 1 h and 2-amino-1,3,4-thiadiazole (0.29 g, 2.87 mmol) is added and the reaction is stirred for an additional 18 h. The mixture is diluted with dichloromethane (60 mL) and washed with 1 M aqueous sodium carbonate solution. The organic layer is dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 1:1 EtOAc-hexanes) to provide (2S)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylaminohexanoic acid 1,3,4-thiadiazol-2-ylamide as a foam (0.81 g, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)ccc1Cl

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid (10 g, CAS Reg. No. 91367-10−1) was dissolved in MeOH (210 mL) and H2SO4 (0.7 mL) was added. The mixture was then refluxed over night. Methanol was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and evaporated. The title compound was obtained as a light brown oil (10.16 g) and was used without further purification. 1H-NMR, (CDCl3): 7.27 (d, 1H), 6.83 (d, 1H), 6.77 (dd, 1H), 3.79 (s, 3H), 3.74 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].[V]>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [V]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 85 °C

Procedure:
Vanadium pentoxide (V2O5) (229 g) was added to water (500 mL), to thereby yield a mixture, and an aliquot of oxalic acid (477 g) was added to the mixture with stirring at 80-90° C. so as to dissolve the vanadium compound, to thereby yield a solution of vanadium oxalate. Another aliquot of oxalic acid (963 g) was added to water (400 mL), and the resultant mixture was heated to 50-60° C. To the mixture, a solution of chromic anhydride (CrO3) (252 g) in water (200 mL) was added under sufficient stirring so as to dissolve the components, to thereby yield a solution of chromium oxalate. The thus-yielded solutions were mixed at 50-60° C., to thereby prepare a V—Cr—containing solution. To the V—Cr—containing solution, a solution of phosphomolybdic acid (H3(PMo12O40)·20H2O) (41.1 g) dissolved in water (100 mL) and a solution of potassium acetate (CH3COOK) (4.0 g) dissolved in water (100 mL) were added. Subsequently, a 20 wt. % aqueous silica sol (containing 0.02 wt. % of Na2O) (2,500 g) was added, to thereby yield a slurry.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:21]=2)=[CH:16][C:15]=1[O:43][CH3:44]>N1C=CC=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:15]([O:43][CH3:44])[CH:16]=3)[C:28]=12
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 5 h
Yield: 60.2 %

Procedure:
trans-2-Phenyl-1-cyclopropanecarbonyl chloride (42 mg, 0.231 mmol) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol) in pyridine (1.0 mL). After 5 hours, the solvent was evaporated and the residue was purified by flash column chromatography to give N1-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-trans-2-phenylcyclopropane-1-carboxamide (80 mg, 60%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.77 (m, 2H), 1.85 (m, 2H), 2.06 (m, 3H), 2.36-2.45 (m, 8H), 2.62 (m, 1H), 3.00 (m, 2H), 3.10 (m, 2H), 3.96 (s, 3H), 4.75 (m, 1H), 5.54 (bs, 2H), 7.14-7.33 (m, 7H), 8.10 (s, 1H), 8.36 (s, 1H), 8.54 (d, J=8.50, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ =581.4, Rt=1.77 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:38]([N:40]([CH2:47][CH3:48])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:39]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:45][CH2:46][CH:41]([N:40]([CH2:47][CH3:48])[CH2:38][CH3:39])[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CCN(CC)C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(CC)CC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with diethyl-4-piperidinylamine (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C38H50Cl2N5O2 [(M+H)+] 678.3336, observed 678.3335.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>CN(C)C=O>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: Ic1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To 4-iodo-1H-imidazole (Preparation 71, 3.0 g, 15.3 mmol) in N,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72 g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirring at room temperature for 2.5 h, water (200 ml) was added and the reaction mixture was filtered and washed with water. The crude solid was chromatographed on silica gel eluting with hexane:ethyl acetate (5:1 and then 2:1). The material was then recrystallised from hexane and dichloromethane to give the title compound as a white solid (4.0 g, 59%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=1.[CH2:15]([NH:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Cl)[CH3:16].O>C1COCC1.CCOCC>[CH2:15]([NH:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:14][C:12]1[CH:13]=[C:8]([Cl:7])[CH:9]=[N:10][CH:11]=1)[CH3:16]
Reactant: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Oc1cncc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
To a suspension of potassium t-butoxide (1.5 g) in THF (15 mL) was added 3-chloro-5-hydroxypyridine (1.79 g, mmol). To this solution was added a solution of N-ethyl-2-chloro-5-nitrobenzamide (2.76 g, mmol) in THF (15 mL). The resulting mixture was heated at 50° C. for 84 hr. After cooling, the reaction mixture was diluted into a mixture of water and ether. Solids were collected by filtration, washed with water then with ether, and dried under vacuum to afford N-ethyl 5-nitro-2-(3-chloro-5-pyridyloxy)benzamide (2.0 g, 52%). mp 165-167° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=1.[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>CO>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: CCC(=O)Nc1cc(N)ccc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)ccc1O

Procedure:
Following the procedures of Example 3, 2.0 g. (0.0096 mol) of 4-nitro-2-propionamidophenyl (prepared from propionic acid and 2-amino-4-nitrophenyl) is hydrogenated in a mixture of 100 ml. of ethanol, 0.3 g. of 10% palladium-on-carbon and 1.34 ml. of concentrated hydrochloric acid in a Parr apparatus. Filtration and evaporation of the solvent gives 4-amino-2-propionamidophenol hydrochloride. The latter (2.0 g., 0.0096 mol) in a methanol solution is treated with 1 equivalent of triethylamine under nitrogen atmosphere. The solution of the free amine is added to a refluxing mixture of one equivalent of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 30 ml. of methanol under nitrogen. The reaction mixture is refluxed for 18 hours, filtered and the solid is recrystallized from ethanol to yield 5-acetyl-4-hydroxy-3-[1-(4-hydroxy-3-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 228°-229° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:18][CH3:17])=[O:10])[CH2:6]1
Reactant: CN
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2c(C)cccc2Cl)C1
Reaction time: 72 h
Yield: 146.6 %

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 3.5 mL (0.045 mole) of 40% aqueous monomethylamine. After stirring for 72 h the reaction mixture was diluted with 200 mL of water and the precipitated solid collected by filtration to give 5.6 g of wet white product. The crude product was recrystallized (after drying) from benzene/ligroin, yielding 2.9 g (75.9%) of white crystalline product, mp 119°-121° C.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.[CH2:37]([C@H:42]1[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH2:40][CH3:41].O1CCCC1>O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[CH:48][C@H:45]2[CH2:46][CH2:47][C@H:42]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44]2)=[CH:13][CH:14]=1
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Reactant: c1ccc([P+](CCCc2ccc(OC3CCCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H]1CC[C@H](C=CCCc2ccc(OC3CCCCO3)cc2)CC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of 4.0 g of [3-(4-[tetrahydro-2-pyranyloxy]phenyl)-1-propyl]triphenylphosphonium bromide, 1.3 g of trans-4-pentylcyclohexanecarboxaldehyde and 50 ml of absolute tetrahydrofuran was treated portionwise with 0.8 g of solid potassium t-butylate. After completion of the addition the reaction mixture was stirred for a further two hours and then poured into 500 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene gave 1.0 g of 1-[tetrahydro-2-pyranyloxy]-4-[4-(trans-4-pentylcyclohexyl)-3-butenyl]benzene (cis/trans mixture).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[CH2:73][C:74]([N:76]=[C:77]=[S:78])=[O:75]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:77]([NH:76][C:74](=[O:75])[CH2:73][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=2[O:66][CH3:65])=[S:78])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1
Yield: 52 %

Procedure:
Starting from the amine 177, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 179 was obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6 ppm: 12.58 (s, 1H), 11.75 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 8.72 (dd, 1H, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72 (d, 1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H), 7.00 (d, 1H, J=7.8 Hz), 6.92 (dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H, J=5.1 Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C)C1C=CC=CC=1.Cl[C:23]([N:25]=[C:26]=[O:27])=[O:24]>ClCCl>[C:7]1([CH:5]2[N:6]3[C:23](=[O:24])[NH:25][C:26](=[O:27])[CH:1]=[C:2]3[O:3][CH2:4]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1=NC(c2ccccc2)CO1
Reactant: O=C=NC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: O=c1cc2n(c(=O)[nH]1)C(c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To 2-methyl-4-phenyl-4,5-dihydrooxazole (5.70 g, 35.4 mmol) and N,N-dimethylaniline (4.68 g, 6.83 mmol) in dichloromethane (25 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (3.80 g, 35.4 mmol). The mixture was allowed to warm to room temperature and was stirred for 14 h, during which time a thick white precipitate formed. The suspension was filtered, and the solid was triturated with diethyl ether (3×10 mL) to give a white powder (8.07 g, 99%). 1H NMR (TMS/CDCl3, 300 MHz): 7.44-7.24 (m, 5H); 5.57 (dd, J=3.3, 8.1 Hz, 1H), 5.12 (s, 1H); 5.00 (dd, J=8.1, 8.7 Hz, 1H); 4.54 (dd, J=3.3, 8.7 Hz, 1H); 3.04 (s, 1H). MS=231.0 ((M+H)+).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[C:2]#[CH:3].Br[C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=1>C1COCC1.C(NC(C)C)(C)C.[Cu]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>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:3]#[C:2][CH2:1][N:4]2[C:12]3[C:7](=[CH:8][C:9]([CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)=[N:21][CH:22]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#CCn1ccc2cc(CN3CCCC3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Brc1ccc(C#CCn2ccc3cc(CN4CCCC4)ccc32)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Under an argon atmosphere 5 mg (0.03 mmol) CuI and 18 mg (0.03 mmol) Pd(PPh3)2Cl2 are added to a solution of 337 mg (1.41 mmol) 1-prop-2-ynyl-5-pyrrolidin-1-ylmethyl-1H-indole and 345 mg (1.41 mmol) 2,5-dibromo-pyridine in 50 mL THF and 0.4 mL diisopropylamine and the reaction mixture is stirred for 17 h at RT. The mixture is evaporated down i. vac., the residue is taken up in 30 mL EtOAc, the organic phase is washed with 30 mL water and 30 mL saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 95:5:0.5).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].Br[CH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.BrCC1CCCCO1>>[CH3:1][C:2]1[SH:3]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20]
Reactant: Cc1nc2cc3c(cc2s1)C1(CO3)C(=O)Nc2ccccc21
Reactant: BrCC1CCOCC1
Agent: BrCC1CCCCO1
Product: CC1=Nc2cc3c(cc2[SH]1CC1CCOCC1)C1(CO3)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1-(tetrahydro-2H-pyran-4-ylmethyl)spiro[furo[2,3-f][1,3]benzothiazole-7,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 186-187° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.66-7.60 (m, 1H), 7.34-7.27 (m, 1H), 7.13-7.07 (m, 1H), 7.06-6.91 (m, 3H), 5.04-4.97 (m, 1H), 4.78-4.72 (m, 1H), 4.07-3.93 (m, 3H), 3.52-3.35 (m, 3H), 2.52 (s, 3H), 2.32-2.15 (m, 1H), 2.07-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.57-1.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.4, 169.3, 160.6, 149.2, 143.1, 132.7, 129.1, 128.7, 123.7, 123.0, 122.3, 119.9, 108.7, 108.5, 81.5, 67.9, 62.4, 58.1, 46.6, 34.3, 30.9, 20.2, 14.6; MS (ES+) m/z 407.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=CC=1C.[H][H]>[Ni].CO>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1Cl
Solvent: CO
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-chlorotoluene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].