Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH:23]([CH3:25])[CH3:24])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:16]=[CH:15]3)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(S(=O)(=O)n2ccc3cc(C4CN(C(=O)OC(C)(C)C)C4)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
3-(1H-Indol-5-yl)-azetidine-1-carboxylic acid tert-butyl ester (135 mg, 0.5 mmol) was dissolved in DMF (10 ml) and cooled to 0° C. Sodium hydride (35.7 mg, 0.74 mmol) was added, and the reaction mixture was stirred for 1 hour at 0° C. 4-Isopropyl-benzenesulfonyl chloride (98 μl, 0.55 mmol) was added slowly to the reaction mixture. Stirring was continued for 10 minutes. Cold water (100 ml) was added to the reaction mixture, and it was extracted twice with diethyl ether (80 ml). The organic layer was dried over magnesium sulphate, filtered, and the solvent was evaporated under reduced pressure to give a crystalline solid (75 mg, 33%). ESI-MS [m/z]: 355.15 [M-(Boc)+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C1COCC1>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CSc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
2-mercaptopyridine (2.6 g) was dissolved in THF (52 ml), triethylamine (3.9 ml) was added to the mixture, and then, a solution of 4-nitrobenzyl bromide (4.8 g) in. THF (24 ml) was added dropwise to the mixture. The reaction solution was stirred for 30 minutes at room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography, to give 2-[(4-nitrobenzyl)sulfanyl]pyridine (4.2 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([F:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([F:13])[CH2:11][O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H](F)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
After dissolving (S)-3-benzyloxy-2-fluoropropan-1-ol (CAS 197389-28-9) (6.00 g) and imidazole (2.44 g) in N,N-dimethylformamide (60 ml), the mixture was cooled on ice. Next, tert-butyldimethylchlorosilane (5.57 g) was added and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of ammonium chloride, water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The title compound (9.48 g) was thus obtained.
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]([C:36]1[CH:51]=[CH:50][C:39]([O:40][C:41]2[N:49]=[CH:48][CH:47]=[CH:46][C:42]=2[C:43](O)=[O:44])=[CH:38][CH:37]=1)=[O:35].[CH:52]([N:55](C(C)C)CC)(C)[CH3:53].C1C=CC(CCN)=CC=1>CN(C=O)C>[NH:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]=[C:26]1[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:40][C:41]2[N:49]=[CH:48][CH:47]=[CH:46][C:42]=2[C:43]([NH:55][CH2:52][CH2:53][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:15]=2)=[O:44])=[CH:50][CH:51]=1)=[O:35]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(c1ccc(Oc2ncccc2C(=O)O)cc1)c1nc2ccccc2[nH]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2ncccc2C(=O)NCCc2ccccn2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (122 mg, 0.321 mmol) was added to a mixture of 2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)nicotinic acid (105 mg, 0.292 mmol) and diisopropylethylamine (102 μL, 0.584 mmol) in DMF (1 mL) and the mixture was stirred at RT for 10 min. 2-Phenethylamine (55.4 μL, 0.438 mmol) was added, and the mixture was stirred at RT for 1 h. The mixture was purified by chromatography on silica gel to deliver 2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylnicotinamide as an off-white solid. MS (ESI, pos. ion) m/z: 463.1 (M+1). IC50 (uM) +.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:38][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:31][CH:32]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
17 mg (0.42 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 91 mg (0.42 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 127 mg (0.42 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 12 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 102 mg (50%) of the title compound as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl>CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][N:7]1[C:8]2[C:13](=[C:12]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 56 %

Procedure:
Ethyl-4-(2-tetrahydropyranyloxy)methylindole-2-carboxylate (5.1 g) (Chung-gi Shen et al., Heterocycles, 43, 1996, 891-898) and sodium hydride (741 mg, 60% in mineral oil) were stirred in DMF (100 ml) under argon at ambient temperature for 0 minutes. 3,4-Dichlorobenzyl chloride (2.79 ml) was added and the mixture stirred overnight, then partitioned between ethyl acetate (150 ml) and water (150 ml). The organic phase was washed with water (2×150 ml), dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using iso-hexane, then ethyl acetate:iso-hexane (5/95) as eluent to give the product as a yellow oil (4.39 g, 56%); NMR δ(CDCl3) 1.40 (t, 3H), 1.50-2.00 (m, 6H), 3.60 (m, 1H), 4.00 (m, 1H), 4.35 (q, 2H), 4.75 (m, 1H), 4.85 (d, 1H), 5.10 (d, 1H), 5.80 (s, 2H), 6.85 (m, 1H), 7.15-7.40 (m, 5H), 7.50 (s, 1H); M/z (+) 462.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=C(OC)[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=[N:22]C=CC=1B(O)O>>[F:1][C:2]1[CH:7]=[N:22][CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: OB(O)c1ccncc1F
Product: O=C(O)c1csc(-c2ccncc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (3-fluoropyridin-4-yl)boronic acid gave the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18].Cl[Ti:21]([Cl:33])(Cl)[C:22]1([CH3:31])[C:26]([CH3:27])=[C:25]([CH3:28])[C:24]([CH3:29])=[C:23]1[CH3:30]>C(OCC)C>[CH3:15][C:16]1[C:6]([Ti:21]([Cl:33])([C:22]2([CH3:31])[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([CH3:28])=[C:26]2[CH3:27])[O:14][C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH3:5])[C:1]([CH3:7])=[C:2]([CH3:3])[C:17]=1[CH3:18]
Reactant: Oc1ccc(F)cc1-c1ccccc1
Reactant: CC1=C(C)C(C)([Ti](Cl)(Cl)Cl)C(C)=C1C
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CC1=C(C)C(C)([Ti](Cl)(Oc2ccc(F)cc2-c2ccccc2)C2(C)C(C)=C(C)C(C)=C2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
1.90 g (10.09 mmol) of 2-phenyl-4-fluorophenol was dissolved in 80 ml of diethylether, and 4.8 ml of butyl lithium (2.5 M hexane solution) was slowly added dropwise thereto at 0° C. The mixture was allowed to react at room temperature for 5 hours, and then a solution of trichloro(pentamethylcyclopentadienyl)titanium (IV) (1.64 g, 5.5 mmol) in 10 ml of diethyl ether was slowly added dropwise thereto at −78° C. The reaction product was stirred at room temperature for 12 hours and filtered, and then volatile materials were removed therefrom. The residue was recrystallized from a mixed solvent of toluene/hexane at −35° C., thus obtaining 2.54 g of a orange-colored solid.
Reaction SMILES: O[C:2]1[N:7]=[C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]2=[N:4][C:3]=1[C:16]#[N:17].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:2]1[N:7]=[C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:5]2=[N:4][C:3]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nc2c(nc1O)-c1ccccc1C2=O
Product: N#Cc1nc2c(nc1Cl)-c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 17 h
Yield: 44 %

Procedure:
A suspension of 6 (671 mg, 3.0 mmol) in POCl3 (8.4 ml) was heated under stirring to 100° C. for 17 h. Excess of POCl3 was evaporated under reduced pressure and the crude was purified by flash chromatography on silica (CH2Cl2), affording 9 (320 mg, 44%) as yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13](O)=[O:14])[CH:12]=[C:6]2[C:5]=1[NH:16][C@@H:17]([C:19]1([CH3:22])[CH2:21][CH2:20]1)[CH3:18])(=[O:3])[NH2:2].C1C=CC2N(O)[N:30]=[N:29]C=2C=1.C(Cl)CCl.NN>CN(C=O)C.O>[NH:29]([C:13]([C:11]1[CH:12]=[C:6]2[C:5]([NH:16][C@@H:17]([C:19]3([CH3:22])[CH2:20][CH2:21]3)[CH3:18])=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]2[CH:10]=1)=[O:14])[NH2:30]
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(C(=O)O)cc12)C1(C)CC1
Reactant: On1nnc2ccccc21
Agent: NN
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(C(=O)NN)cc12)C1(C)CC1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-carbamoyl-4-((1-(1-methylcyclopropyl)ethyl)amino)pyrrolo[1,2-b]pyridazine-6-carboxylic acid (1.11 g, 3.67 mmol) in DMF (Volume: 10 mL) was added HOBT (0.675 g, 4.41 mmol) and EDC (0.915 g, 4.77 mmol) which was stirred at 23° C. for 1 hr. To the reaction mixture was added hydrazine (0.576 mL, 18.36 mmol) dropwise and stirred for 30 minutes, followed by the addition of 50 mL of water and stirred for 20 minutes. The solid was collected as the desired product (1.54 g). MS (ES+) m/z: 317.08 (M+H); HPLC: 91%, retention time: 1.935 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2>C(#N)C.O>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]=[C:14]4[C@:15]3([CH3:21])[CH2:16][CH2:17][C@H:18]([OH:20])[CH2:19]4)[C@@H:7]1[CH2:8][CH2:9][C@@H:10]2[OH:11]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: CC#N
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
The protocol was performed as follows. (1) Prepared 0.5 mM compound in acetonitrile/water 35:65. For androst-5-ene-30,170-diol, prepared 0.145 mg/mL, or 29.0 μL of a 1 mg/mL stock plus 171 μL solvent. For the standard curve dilutions of the 0.5 mM stock was used to obtain final concentrations of androst-5-ene-3β,17β-diol at 10 μM, 5 μM and 1 μM. (2) Set up samples as follows. Each assay consisted of an androst-5-ene-3β,17β-diol control and 1-8 unknown compounds. Tubes for each compound was follows: 1-0′2-0′3-0′4-0′*5-0′*6-5 μM 7-1 μM 8-30′9-30′10-30′ where * designated denatured microsome negative control reaction tubes. For additional compounds numbering was started at 11, 21, 31, etc. (3) Added 315 μL PBS (pH 7.3-7.5) to each tube. Added 10 μL of the appropriate test article solution to each tube. (4) The internal standard/acetonitrile solution. (5) The NADPH regenerating system (NRS) was 125 μL per tube. To PBS added 1.7 mg/ml NADP, 7.8 mg/ml glucose-6-phosphate, 6 units/mL glucose-6-phosphate dehydrogenase. Fresh NRS for each experiment was kept on ice until use. (6) Each reaction used 125 μL of NRS in each tube. (7) Removed liver microsome preparation from −80° C. freezer and thawed in a room temperature water bath. The microsomal preparation was at a concentration of 20 mg/ml. Each reaction used 0.25 mg/tube and was diluted to a concentration of 5 mg/ml in PBS (i.e. 4-fold dilution) and kept on ice. (8) For the zero-time and denatured microsome control tubes 500 μL acetonitrile at −20° C. was added. Zero time tubes were transferred to ice and denatured microsome controls were preincubated at 37° C. for 5 minutes. (9) Assay tubes containing the microsomal preparation was also preincubated for 5 min at 37° C. (10) For each incubation tube, the reaction was started by addition of 50 μL of the microsome preparation and vortexing to mix. (11) Each reaction was terminated by adding 500 μL acetonitrile at −20° C. and vortexing. (12) After the reaction was terminated, 100 μL from each reaction tube was transferred to a fresh tube and 200 μL of water and 1400 μL of methyl-t-butyl ether was added to each tube. The tubes were Vortexed and centrifuged at 13,000 rpm for 10 min on a microfuge. The tubes were then put on a dry ice-methanol bath until aqueous layer was frozen solid. (13) The methyl-t-butyl ether was transferred from each tube to a fresh tube and the solvent was evaporated ether under nitrogen and the precipitate was then resuspended in 10 μL acetonitrile/water 35:65 and analyzed by LCMS. Results are shown in the table below for the incubation times shown below.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.Cl.[N:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[S:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=3)[CH2:20][CH2:21]2)=[N:23]1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C

Procedure:
Starting from N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-acetamide (11.96 g, 56.5 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (16.58 g, 73.5 mmol), (N-{4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-acetamide was prepared according to the general method as outlined in Example 501. The titled product was obtained as an off-white solid, (19.04 g, 48.3 mmol). Yield=85%. 98.8% purity by HPLC; mp 176.5–178.° C.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.C([Mg]Cl)(C)C.C(OCC)(=O)C.[C:17]([OH:22])(=[O:21])[CH:18]([CH3:20])[CH3:19]>O>[C:17]([OH:22])(=[O:21])[C:18]1[CH:20]=[CH:5][CH:1]=[CH:2][CH:19]=1
Reactant: CC(C)C(=O)O
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To compound (L-2) (14.16 g, 61.0 mmol) in a second dry round bottom flask under N2 is added 70 mL of dry THF. The mixture is cooled to about −10° C. To the cold mixture is slowly added isopropyl magnesium chloride (63.3 ml, 2 M, 127 mmol). The resulting mixture is then stirred at −10° C. for about 20 min. Then, this mixture is slowly cannulated drop wise into the flask containing the (L-1) reaction while maintaining the temperature at −20° C. After addition is complete, the reaction is slowly warmed to RT and stirred at RT for about 1.6 hours. The reaction mixture is then cooled to −10° C. and quickly cannulated to another flask containing 15 mL of ethyl acetate and 10 mL of isobutyric acid at −10° C. under N2. After stirring for about 5 minutes, 10 mL of water is rapidly added. The cooling bath is removed, and the reaction mixture is stirred for 10 minutes at RT. The mixture is transferred to a separation funnel, and water (200 mL) is added. The water layer is extracted with EtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2M) to pH 3, and is extracted with EtOAc (3×500 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material is purified by silica gel column chromatography using 0-10% MeOH in DCM to afford benzoic acid (L-3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C@H:10]([C:20](O)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:20](=[O:21])[NH:23][C:24]2[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=2)[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH2:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2cccc(Br)c2)C1
Reactant: N#Cc1cccc(N)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)Nc2cccc(C#N)c2)[C@H](c2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Cool a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.50 g, 1.35 mmol) in pyridine (5 mL), to 0° C., and add 3-aminobenzonitrile (0.18 g, 1.48 mmol) followed by phosphorous oxychloride (0.14 mL, 1.50 mmol). Stir the mixture at 0° C. for 1 h then dilute with water. Extract the mixture with EtOAc and wash the combined organic portion with a 2 N solution of hydrochloric acid until the pH of the aqueous washings is strongly acidic. Wash the organic phase with brine then dry over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography to provide 0.53 g of trans-3-(3-bromo-phenyl)-4-(3-cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[C:8]2([Cl:17])[Cl:16])(=[O:4])=[O:3].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[CH2:18]([NH:25][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[C:8]2([Cl:17])[Cl:16])(=[O:4])=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1C(=O)C(Cl)(Cl)c2cc(S(=O)(=O)Cl)ccc21
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)C(Cl)(Cl)c2cc(S(=O)(=O)NCc3ccccc3)ccc21
Reaction time: 8 h

Procedure:
To a solution of 5-chlorosulfonyl-N-methyl-3,3-dichloro-2-oxindole (120 mg, 382 umol) in methylene chloride (5 mL) was added benzyl amine (50 uL, 458 umol) dropwise. After stirring overnight, 3 N hydrochloric acid was added along with an additional volume of methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered, and silica gel flash chromatography (35 to 55% ethyl acetate/hexanes) yielded the title compound. ES (−) MS m/e=383 (M−H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][NH2:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.Cl[C:23]([O:25][CH:26]([CH2:28][CH3:29])[CH3:27])=[O:24]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([NH:14][NH:15][C:23]([O:25][CH:26]([CH3:27])[CH2:28][CH3:29])=[O:24])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Oc2ccccc2)c1
Reactant: CCC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)NNc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.0 g of 3-phenoxyphenyl hydrazine, 100 ml of ethyl acetate and 2.5 ml of pyridine were added and the resultant solution was then stirred at room temperature for 30 minutes. Then, 2.5 ml of sec-butyl chloro-formate was added dropwise to the solution and stirred for 1 hour at room temperature. The solution was then washed twice, each time with 100 ml of water. After each wash, the aqueous fraction was removed from the organic (ethyl acetate) fraction. The resulting ethyl acetate fraction was then dried over anhydrous sodium sulfate, evaporated under reduced pressure, and then purified by column chromatography on silica gel, to produce 1.5 g of 1-methylpropyl 2-(3-phenoxyphenyl)hydrazine carboxylate as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH2:21][CH2:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2c(c1)CCO2
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2,3-dihydro-benzofuran-5-carboxylic acid. MS: 406.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([CH3:13])([CH3:12])[CH:8]([CH3:11])[C:9](=O)[C:4]=2[CH:3]=1.[BH4-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:11])=[CH:9][C:4]=2[CH:3]=1
Reactant: CC1C(=O)c2cc(Br)ccc2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1=Cc2cc(Br)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
6-Bromo-3,4-dihydro-4-oxo-2,2,3-trimethyl-2H-benzo[b]pyran (407 g) (see Preparation 3) was dissolved in ethanol (1500 ml), cooled in an ice bath and sodium borohydride (61.4 g) was added portionwise over 20 minutes. The mixture was stirred at room temperature for 3 hours, the solvent removed under reduced pressure, the residue dissolved in diethyl ether and the mixture washed first with water and then with brine. The organic layer was dried (anhydrous magnesium sulphate) and the solvent removed to yield the crude alcohol. This was dissolved in toluene (1000 ml), paratoluenesulphonic acid (40 g) added and the mixture heated under reflux (with removal of water) for 2 hours. The solvent volume was reduced to approximately 500 ml and the solution was washed with aqueous sodium carbonate solution and then brine. The organic phase was dried (anhydrous magnesium sulphate) and the solvent removed under reduced pressure to yield 6-bromo-2,2,3-trimethyl-2H-benzo[b]pyran (350 g) as an orange oil.