Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10](C(C)=C)[C:9]1=[O:20].[C:21]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:34]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:20])[CH2:32][CH2:33]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C=C(C)n1c(=O)n(CCCCCCCl)c2ccccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 7.3 parts of 1-(6-chlorohexyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 5.15 parts of 1-(diphenylmethyl)piperazine, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and refluxed for one hour with 12 parts of a concentrated hydrochloric acid solution and 40 parts of ethanol. The solvent is evaporated and the residue is taken up in water. The free base is liberated in the conventional manner with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from methanol. The product is filtered off and recrystallized from N,N-dimethylformamide, yielding 1-{6-[4-(diphenylmethyl)-1-piperazinyl]hexyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 189.7° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: ClCCCCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCn1cnc2ccccc21
Temperature: 60 °C
Yield: 59.9 %

Procedure:
1H-benzimidazole (11.8 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 12.5 g of 1-(4-chlorobutyl)-1H-benzimidazole, with a yield of 60.0%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][N:21]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][N:21]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]2=3)=[CH:8][CH:7]=1)[CH3:2]
Reactant: O=c1c2ccccc2c2ccccc2n1CCCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCn2c(=O)c3ccccc3c3ccccc32)cc1
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.376 g) in dimethylformamide (5 mL) was treated with 55% sodium hydride (0.085 g), stirred for 15 minutes and then 5-(3-bromopropyl)-5,6-dihydro-6-oxophenanthridine (0.613 g) in dimethylformamide (5 mL) was added. The mixture was stirred at room temperature for 22 hours and worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-hexane; 7:13), and crystallization of the resulting solid from ethyl acetate-tetrahydrofuran gave 0.4 g of 4-[3-(5,6-dihydro-6-oxo-5-phenanthridinyl)propoxy]-alpha-oxobenzeneacetic acid ethyl ester, mp 95°-97° C. A second crop of the title compound (0.16 g, mp 95°-97° C.) was recovered from the mother liquor.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:17])[C:9](N1CCOCC1)=[O:10].[Mg].[Cl-].[NH4+].O.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]>O1CCCC1.C(Br)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:9](=[O:10])[C@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:17]
Reactant: Fc1ccccc1Br
Reactant: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCBr
Product: C[C@@H](OC1CCCCO1)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In tetrahydrofuran (100 ml) were dissolved 1-bromo-2-fluorobenzene (5.6 ml), ethyl bromide (0.37 ml) and 4-[(2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy) propionyl]morpholine (11.3 g). To the mixture was added magnesium (turnings, 1.33 g). The mixture was stirred for 2 hours at room temperature. To the reaction mixture were added a saturated aqueous ammonium chloride solution (40 ml) and water (40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10:1→8:1) to give (2R)-2'-fluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (8.7 g) as a pale yellow oily substance.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8]>C1(C)C=CC=CC=1.C1COCC1>[CH:7]([C@H:6]1[C:10](=[O:11])[O:12][C:1](=[O:2])[NH:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1NC(=O)OC1=O
Temperature: 55 °C
Yield: 47.32 %

Procedure:
30.4 ml (57.47 mmol, 1.08 eq.) of a 20% solution of phosgene in toluene were added slowly at r.t. to a stirred solution of 6.26 g (53.44 mmol) L-valine (81a) in 63 ml dry THF. After the complete addition the mixture was heated at 55° C. for 4 h. Then a stream of nitrogen was bubbled through the solution and passed after that through a 1M aq. NaOH-solution for 20 min. before the solvent was evaporated. Recrystallization of the obtained residue from PE/Ether (2:1) yielded 3.62 g (25.29 mmol, 47.32%) (S)-4-Isopropyl-oxazolidine-2,5-dione (86) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CC(C)S(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(=O)(=O)C(C)C)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and propane-2-sulfonic acid [5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide (which was obtained in Example 27) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.25 (d, J=6.8 Hz, 6 H), 1.55–1.75 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.75 (m, 5 H), 2.92 (t, J=7.7 Hz, 2 H), 3.05–3.15 (m, 1 H), 3.45–3.60 (m, 2 H), 4.46 (dd, J=7.8, 4.5 Hz, 1 H), 6.78 (d, J=8.2 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2 H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 7.04 (d, J=9.0 Hz, 2 H), 7.23 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 569.0 (MH+); HRMS Calcd. for C26H41N4O6S2 (MH+): 569.2462. Found: 569.2458.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4cccc5c4OCC5)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:16])[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]=2[CH3:13])[CH:4]=1)#N.[H-].C([Al+]CC(C)C)C(C)C.[O:27]1CCCC1>CCCCCC>[CH3:13][C:9]1[C:8]([CH3:14])=[C:7]([CH3:15])[C:6]([CH3:16])=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH:1]=[O:27])=[CH:4]2
Reactant: C1CCOC1
Reactant: Cc1c(C)c(C)c2cc(C#N)ccc2c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: Cc1c(C)c(C)c2cc(C=O)ccc2c1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under nitrogen atmosphere, 0.8 g of 2-cyano-5,6,7,8-tetramethylnaphthalene was dissolved in 30 ml of tetrahydrofuran, and 5.7 ml of a 1.0M solution of diisobutylaluminum hydride in hexane was added to the resulting solution at 0° C. The resulting mixture was stirred at room temperature for 2.5 hours, quenched with methanol and a saturated aqueous solution of ammonium chloride successively, and extracted with ethyl acetate (50 ml×2) . The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and filtered. The resulting filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography to give 0.68 g of the title compound as an oil.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)=[O:12])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:23][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([S:13][C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(SC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 4 h

Procedure:
To a stirred solution of the title D compound, (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester (1.5 g, 3.22 mmol) in methanol (15 mL) is added sodium hydroxide (0.26 g, 6.44 mmol) in water (10 mL) at RT. The reaction mixture is stirred for 4 h. The reaction mixture is concentrated at reduced pressure, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is concentrated and triturated with 1:1 methyl-t-butyl ether and hexane to give (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26]Br)[CH2:20]1)=[O:18])[CH3:15].O>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1CCCN(CCBr)C1
Reactant: OCCCc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCN(CCOCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Sodium hydride (1.5 g, 37 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 3-phenyl-1-propanol (5.0 g, 37 mmol) in toluene (25 ml) placed under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at ambient temperature and then heated at reflux for 45 minutes. The reaction mixture was allowed to cool and another portion of sodium hydride (1.5 g, 37 mmol, 60% oil dispersion) was added followed by toluene (25 ml). The suspension was heated at reflux for 15 minutes and allowed to cool. Keeping the temperature below 40° C. 1-(2-bromoethyl)-3piperidinecarboxylic acid ethyl ester hydrobromide (12.6 g, 37 mmol, EP 374801) was added portionwise. The reaction mixture was stirred for 3 days and then left for 3 weeks. The mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was extracted with 5% citric acid solution (3×100 ml). The combined acidic phases were extracted with ethyl acetate (100 ml) which was discarded. 4N sodium hydroxide was added to the aqueous phase until pH 8 and then it was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution and dried (Na2SO4). The solvent was evaporated in vacuo to give 3.2 g of 1-(2-(3-phenyl-1-propyloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH:21]=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CO[C:25](C)(C)[CH3:26]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH:21]([C@H:18]1[CH2:19][CH2:20][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1)=[CH:25][CH3:26]
Reactant: O=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Reactant: COC(C)(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC=C[C@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
A suspension of 5.892 g of ethyltriphenylphosphonium bromide in 75 ml of tert.-butyl methyl ether was treated with 1.801 g of potassium tert.-butylate while stirring and gassing with nitrogen and stirred at room temperature for 1.5 hours. Subsequently, the suspension was treated dropwise at 2° C. within 45 minutes with a solution of 2.269 g of trans-4-(3',4'-difluoro-4-biphenylyl)cyclohexanecarboxaldehyde (prepared according to Example 3) in 17 ml of tert.-butyl methyl ether, stirred for a further 45 minutes and concentrated in a vacuum. The residue (9.7 g) was taken up in 50 ml of hexane, stirred and filtered. Concentration of the filtrate in a vacuum and chromatographical purification of the crude product obtained on silica gel with methylene chloride gave 2.464 g of 4-[trans-4-(propenyl)cyclohexyl]-3',4'-difluorobiphenyl (89.7% Z; 10.1% E).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH2:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:17]N1C(=O)CCC1=O>>[Cl:17][C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([C:10]=1[NH2:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Product: CCOC(=O)c1c(N)c(Cl)cc(OC)c1OC
Yield: 55 %

Procedure:
Following the procedure employed in Example 27, treatment of ethyl 2,3-dimethoxy-6-aminobenzoate with N-chlorosuccinimide gave a 55% yield of the title compound after EtOH crystallization; mp 60-62%.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@:2]([NH:1][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[O:15][CH3:14])([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C[C@](N)(CO)c1cc(Br)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CN[C@@](C)(CO)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (R)-2-amino-2-(5-bromo-2-fluorophenyl)propan-1-ol (9.2 g, 37.1 mmol, Eq: 1.00) in 1,2-dichloroethane (145 ml) was added at 23° C. 2,4-dimethoxybenzaldehyde (6.16 g, 37.1 mmol, Eq: 1) followed by sodium triacetoxyborohydride (15.7 g, 74.2 mmol, Eq: 2.0). The reaction mixture was stirred at 23° C. overnight. The reaction mixture was extracted with sat NaHCO3/CH2Cl2 twice. The combined organic layers were dried over Na2SO4, filtered off and evaporated totally. The residue was purified by silica gel chromatography with 0-50% EtOAc in heptane to give the (R)-2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propan-1-ol (14.1 g, 35.4 mmol, 95.5% yield) as a light brown oil. Mass (calculated) C18H21BrFNO3 [398.27]; (found) [M+H]+=398.0, 400.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(O)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:32])=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2c2ccc(F)cc2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of (±)-(3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 2 (45 mg, 0.10 mmol), methylsulfonamide (12 mg, 0.12 mmol), triethylamine (0.021 mL, 0.15 mmol), and tetrahydrofuran (1.0 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol) followed by 4-dimethylaminopyridine (15 mg, 0.12 mmol) at room temp. The reaction was stirred at room temp overnight. The reaction was concentrated and purified by reverse-phase HPLC (40 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 20.6 mg, 0.0394 mmol, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-0.92 (m, 1H), 1.72-1.89 (m, 1H), 2.84-3.04 (m, 2H), 3.35 (s, 3H), 3.98 (ddd, J=13.67, 10.94, 5.08 Hz, 1H), 5.95 (d, J=11.33 Hz, 1H), 6.65-7.58 (m, 6H), 7.67 (d, J=8.98 Hz, 1H), 7.75-7.89 (m, 2H), 8.16 (d, J=8.20 Hz, 1H), 12.17 (s, 1H). ES-MS m/z 523 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28]Br.O>CN(C)C=O>[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28][N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1
Reactant: C1=Cc2ccccc2N(CC2CNCCO2)c2ccccc21
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCN1CCOC(CN2c3ccccc3C=Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.05 g) in dimethylformamide was added a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.2 g) in dimethylformamide under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of 3,3-dimethylallyl bromide (0.12 g) in dimethylformamide, and the reaction mixture was stirred at room temperature for 3 hours, cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-{4-(3,3-dimethylallyl)-2-morpholinylmethyl}-5H-dibenz[b,f]azepine. M.P. 99°-100° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(#N)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1c2nc(C3=CC4CN(S(C)(=O)=O)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 40 mg, 0.11 mmol, 1.0 equiv) was added to anhydrous acetonitrile (1.0 mL) followed by the sequential addition of DIPEA (55 μL, 0.31 mmol, 3.0 equiv) and methanesulfonyl chloride (12 μL, 0.16 mmol, 1.5 equiv). After 10 min at RT, LCMS showed complete consumption of starting material. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 26-1 as a white solid. MS ink (M+H): calculated=461.1123; observed=461.1129.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].[N:16]1[CH:21]=[CH:20][CH:19]=C[C:17]=1[C:22]([OH:24])=[O:23].C(=O)CC>C1COCC1>[CH2:14]([CH:13]1[C:12]2[C:17](=[N:16][CH:21]=[CH:20][CH:19]=2)[C:22](=[O:23])[O:24]1)[CH3:15]
Reactant: O=C(O)c1ccccn1
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CCC=O
Solvent: C1CCOC1
Product: CCC1OC(=O)c2ncccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (20.3 ml, 120 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 60 ml of dry THF is added. The reaction mixture is cooled to −78° C. The cooled reaction mixture is treated dropwise with nBuLi solution (64 mL of a 2.5 M solution in hexanes, 160 mmol) and the reaction is let stir at −78° C. for 5 min. A solution of picolinic acid (4.92 g, 40 mmol) in THF (60 mL) is added dropwise to the reaction at −78° C. The reaction is stirred at −78° C. for 1 h and is then warmed to −20° C. for 30 min. The reaction mixture is treated with propionaldehyde (7.2 ml, 100 mmol, 2.5 eq) dropwise at −50° C. The reaction is stirred at −20° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water and ether. The aqueous layer is collected and extracted with dichloromethane and ether (6×50 ml). The aqueous phase is concentrated and the residue is dissolved in EtOH (30 mL) and acetic acid (2 mL) and heated at reflux overnight under argon. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel) to give the title compound (0.70 g, 11%).