Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:23][C:24]([NH2:26])=[O:25].O>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:23][C:24]([NH2:26])=[O:25])=[CH:16][CH:17]=2)[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(O)cc2C1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.16 g of 60% NaH (0.004 mole) and 3.5 ml of anhydrous DMF were stirred at ambient temperature in a stream of nitrogen and 1 g (0.0038 mole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxy-tetralin in 9 ml of anhydrous DMF and 0.52 g (0.0038 mole) of 2-bromoacetamide in 2.5 ml of anhydrous DMF were added. It was stirred at ambient temperature for 6 hours then the mixture was poured into water. The precipitated product was filtered and the product of the heading was then obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][C:17](O)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Cl-].[NH4+].C1C[N:33]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][CH:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:16][C:17]([NH2:33])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(CC(=O)O)c2ccncc2)CCN(C)C1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(CC(N)=O)c2ccncc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyric acid (175 mg, 0.482 mmol) was dissolved in DCM (5 mL), ammonium chloride (51 mg, 0.964 mmol), PYBOP (300 mg, 0.578 mmol) and triethylamine (0.69 mL, 4.82 mmol) were added and the reaction mixture was stirred at RT for 4 h. The reaction progress was monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated and the crude product was purified by reverse phase chromatography to obtain 45 mg of 4-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyramide as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (d, 2H), 7.8 (d, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.9 (d, 1H), 4.63 (t, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 4.3 (dd, 1H), 4.0 (m, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 3.0 (m, 1H), 2.9 (m, 2H), 2.4 (d, 3H). Separation by chiral HPLC provides enantiomers II-229a-b.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:39])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C@@H:17]([C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH3:29])[CH:24]=[C:23]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:22]=2[F:38])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O)(C)(C)C>O.C(O)=O>[C:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C@@H:17]([C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH3:29])[CH:24]=[C:23]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:22]=2[F:38])[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)(=[NH:8])[NH2:39]
Reactant: CCOc1cc(OC2CCN(C)CC2)c(F)c([C@H](Nc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)C(=O)O)c1
Solvent: O=CO
Solvent: O
Product: CCOc1cc(OC2CCN(C)CC2)c(F)c([C@H](Nc2ccc(C(=N)N)cc2)C(=O)O)c1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
A solution of 5.1 g (S)-[4-(tert-butoxycarbonylamino-imino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid in 102 ml water/formic acid 1:1 was heated to 40° C. for 2.5 hrs. The solvents were evaporated in vacuo, the residue dissolved in water and the solution evaporated again (repeated twice). The residue was dissolved in methanol and 7N methanolic ammonia was added until pH=9, wereby a precipitate was formed. The mixture was cooled to 0° C., the solid isolated by suction filtration and dried. Afterwards it was suspended in water and the pH adjusted to 9 wiTh conc. ammonia. Suction filtration and drying gave 3 g (S)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenyl]-acetic acid. White solid. Mp.: 269° C. MS: 445 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH3:15]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-nitrobenzenesulfonyl chloride (6.7 g) was added ammonia water (10 ml) while ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (100 ml), and the extract was washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation of the solvent under a reduced pressure, to obtain 4-nitrobenzenesulfonamide (5.9 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][NH:20]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][N:20]2[C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: Clc1ccc2c(c1)NCC2
Product: Cc1[nH]c2ncnc(N3CCc4ccc(Cl)cc43)c2c1C

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine and 6-chloro-2,3-dihydroindole (1.1 equi-valents, see J. Org. Chem. 55(2), 580-584 (1990); CAS Reg. No. 52 537-00-5).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([C:13]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=3)=[N:17][N:16]=[N:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:45][C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[C:47]=1[NH:54][C:55](=O)[O:56]C1C=CC=CC=1>C(N(CC)CC)C>[CH2:1]([N:6]([CH2:31][C:28]1[CH:29]=[CH:30][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]2[N:14]([C:13]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:15]=[N:16][N:17]=2)=[CH:26][CH:27]=1)[C:55](=[O:56])[NH:54][C:47]1[C:48]([CH3:53])=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[CH3:45])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1cc(C)c(NC(=O)Oc2ccccc2)c(C)c1
Reactant: CCCCCN
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)Nc1c(C)cc(C)cc1C
Yield: 21.7 %

Procedure:
Using n-pentylamine (304.2 mg), triethylamine (442.2 mg), [[2′-(N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl] bromide (400 mg) and phenyl 2,4,6-trimethylphenylcarbamate (233.8 mg), N′-pentyl-N-(2,4,6-trimethylphenyl)-N′-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]urea (113 mg) was obtained by a similar procedure as in Example 1. Yield: 22%.
Reaction SMILES: Cl[N:2]1[C:6](=O)CC[C:3]1=O.[CH3:9][O:10][C:11]1[C:19]2[O:18][C:17]([S:20]([OH:22])=[O:21])=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.[Li].Cl.CNC>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH3:3][N:2]([CH3:6])[S:20]([C:17]1[O:18][C:19]2[C:11]([O:10][CH3:9])=[CH:12][CH:13]=[CH:14][C:15]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc2cc(S(=O)O)oc12
Agent: CNC
Agent: Cl
Agent: [Li]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc2cc(S(=O)(=O)N(C)C)oc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Chlorosuccinimide (1 g) was added portionwise to 7-methoxybenzofuran-2-sulfinic acid, lithium salt (1.47 g) in dichloromethane (15 ml) at 0-5° C. under an inert atmosphere. The reaction was stirred at this temperature for 15 minutes and then warmed to ambient temperature and stirred for a further 15 minutes. The mixture was then flushed through a pad of celite, washing well with dichloromethane. The solvent was removed in vacuo to give a tan solid as the crude intermediate. This intermediate was added to a stirred solution of dimethylamine hydrochloride (0.67 g) and triethylamine (2.2 ml) in tetrahydrofuran (20 ml) at 0-5° C. under an inert atmosphere. The reaction was stirred at this temperature for 1 h and then warmed to room temperature and stirred for a further 48 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (2×40 ml) and water (50 ml). The combined organic phases were washed with 1M hydrochloric acid (2×20 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was washed with hexane (40 ml) to give the title compound as a tan solid (0.88 g).
Reaction SMILES: [NH3:1].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH2:2]([NH2:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:2](=[N:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: C(=NCc1ccccc1)c1ccccc1
Product: NCc1ccccc1
Yield: 64.6 %
Yield: 19.3 %

Procedure:
To test whether increasing the concentration of ammonia relative to the alcohol might reduce the formation of imines (for example by capturing the contemplated intermediate aldehyde and preventing its reaction with the primary amine), complex 1 (0.01 mmol), benzyl alcohol (2.5 mmol) and ammonia (8 atm) in toluene were heated under reflux in a Fischer-Porter tube for 130 min, to get benzylamine (64.6%) and N-benzylidenebenzylamine (19.3%) whereas the conversion of benzyl alcohol was 84.7% (compare to entry 6, Table 1). Thus, increasing the concentration of ammonia did not affect the extent of formation of imine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: C[C@@H](N)c1ccccn1
Solvent: C1COCCO1
Product: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (for a preparation, see Intermediate 8) (1 g, 3.00 mmol) in 1,4-dioxane (6.5 mL) was added (R)-1-(pyridin-2-yl)ethanamine (0.549 g, 4.49 mmol) and the mixture stirred at room temperature for 5 h. A further portion of (R)-1-(pyridin-2-yl)ethanamine (0.255 g, 2.25 mmol) was added and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified by chromatography (50 g column, cyclohexane/EtOAc gradient) to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N—((R)-1-(pyridin-2-yl)ethyl)quinolin-4-amine (1.15 g, 2.74 mmol, 92% yield) as an orange solid. LCMS: (Formate, 2 min), Rt 0.98 mins, MH+ 420.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.[CH:28]1([CH2:33]I)[CH2:32][CH2:31][CH2:30][CH2:29]1>COC1SC(=O)N(CSP(OC)(OC)=S)N=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH2:33][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:2]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)CC(C)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: COc1nn(CSP(=S)(OC)OC)c(=O)s1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC(C)=O)cc1
Temperature: -78 °C

Procedure:
A solution of the title B compound, [4-(2-oxo-propylsulfonyl)-phenyl]-acetic acid ethyl ester (8 g, 0.028 mol) in 5 mL of DMTP and 80 mL of THF is cooled to −78 g and then treated with 15 mL of LDA (2 M solution in THF/hexane, 0.030 mol). The reaction is maintained at −78° C. for 20 min and then treated with a solution of 5.91 g (0.028 mL) of cyclopentylmethyl iodide in a mixture of THF (10 mL) and DMTP (3 mL), and the reaction is maintained at −78° C. for 6 h and subsequently at RT for another 6 h. The reaction is quenched with saturated ammonium chloride solution (20 mL). The organic layer is separated and aqueous layer then extracted with ethyl acetate (2×50 mL). Both the organic layers are combined and then washed with water. The organic layer is dried over sodium sulfate, filtered and evaporated under vacuum to give a brown oil as a crude product which is purified by column chromatography over Silica gel (60-120 mesh) using 80/20—hexane/ethyl acetate as an eluent to give 3-cyclopentyl-2-[4-(2-oxo-propylsulfonyl)-phenyl]-propionic acid ethyl ester as a white solid.
Reaction SMILES: [OH-:1].[K+].[CH:3]([C:6]1[S:7][CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)([CH3:5])[CH3:4]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH:3]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:1])=[O:12])[CH:10]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1cc(C=O)cs1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)c1cc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of AgNO3 (1.01 g, 5.92 mmol)in 10 mL of H20 and 15 mL of a solution of KOH (1.63 g, 40.8 mmol) were sequentially added to a solution of 760 mg (4.9 mmol) of 2-isopropyl-4-thiophene carboxaldehyde, from step 34a above, in 25 mL of ethanol. The resulting black mixture was stirred at room temperature for 2 hours and filtered. The filtrate was washed with ether, then acidified with 6N HCl and extracted with ether. The extract was washed with H2O and brine, dried over MgSO4 and concentrated to give 680 mg (81%) of the title compound as a yellow solid. mp. 64°-67° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:22])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:22][CH3:23])[NH:19][C:20]=2[CH3:21])[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Yield: 29.9 %

Procedure:
By following the same procedure as in Example 10 using 0.32 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-thioxo-4-imidazoline, 10 ml of dry acetone, 0.15 g of potassium carbonate, and 0.15 g of methyl iodide and recrystallizing the product from cyclohexane, 0.1 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2-methylthioimidazole was obtained.
Reaction SMILES: [C:1]([C:3]([CH3:15])([CH3:14])[C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:2].[BH4-].[Na+]>C1COCC1>[C:1]([C:3]([CH3:15])([CH3:14])[CH:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C(C)(C)C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 300 mL four-necked flask were charged dry THF (105 mL) and tert-butyl 4-cyano-4-methyl-3-oxopentanoate (30.07 g, 0.142 mol), and sodium borohydride (3.24 g, 0.0854 mol) was added. The reaction mass was stirred at room temperature for 2 hr and disappearance of the starting material was confirmed by thin-layer chromatography (TLC). After the confirmation, the reaction mixture was used as it was in Example 3.
Reaction SMILES: [Mg].BrCCBr.[CH3:6][N:7]([CH3:12])[CH2:8][CH2:9][CH2:10]Cl.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:19](=[O:28])[C:18]=2[CH:29]=1.[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:19]([CH2:10][CH2:9][CH2:8][N:7]([CH3:12])[CH3:6])([OH:28])[C:18]=2[CH:29]=1
Reactant: O=C1c2cc(Br)ccc2OC12CCCCCC2
Reactant: CN(C)CCCCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN(C)CCCC1(O)c2cc(Br)ccc2OC12CCCCCC2
Temperature: 0 °C

Procedure:
A stirred mixture of 2.72 g of magnesium turnings in 32 ml of diethyl ether containing about 0.5 ml of 1,2-dibromoethane was treated with a solution of 13.62 g of freshly distilled 3-dimethylaminopropyl chloride in 32 ml of ether at a rate sufficient to produce and maintain reflux. After the addition, a solution of 16.53 g of 5-bromo-spiro[benzofuran-2(3H),1'-cycloheptan]-3-one in 65 ml of benzene was added, followed by an additional 32 ml of ether and the mixture was refluxed overnight under nitrogen. After 14.5 hours of reflux, the mixture was cooled in ice water and treated cautiously with 140 ml of saturated aqueous ammonium chloride solution. The mixture was then poured into a separatory funnel, the flask was rinsed with a few hundred ml's of distilled water, and the combined mixture was extracted with ether (2×400 ml). The combined organic extracts were washed with water (250 ml) and saturated sodium chloride solution (250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil which crystallized to a solid. This material was triturated with petroleum ether and filtered to afford 8.74 g of crude product. Preparative HPLC purification of this material was performed using two columns and 5% methanol/dichloromethane as a solvent. The purest fractions containing the desired material were combined and concentrated in vacuo to a solid. This material was triturated with hexane, filtered and dried to afford 4.16 g of a solid, m.p. 126°-128° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=3[S:10][C:11]=2[CH:12]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CCO>[C:1]1([C:7]2[C:8]3[CH:28]=[CH:27][CH:26]=[CH:25][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1sc2ccccc2c1-c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1sc2ccccc2c1-c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(1-(3-phenylbenzo[b]thiophen-2-yl)ethyl)isoindoline-1,3-dione (170 mg, 0.443 mmol) and hydrazine, monohydrate (0.215 mL, 4.43 mmol) in EtOH (5 mL) was heated to 50° C. overnight. After 18 h, a precipitate had developed. The precipitate was removed by filtration, rinsed with EtOH, and concentrated under reduced pressure. The concentrate was dissolved in DCM, adsorbed onto silica gel and purified by column chromatography using 10% of MeOH in DCM as eluent to give 1-(3-phenylbenzo[b]thiophen-2-yl)ethanamine as a colorless, crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.51 (d, J=6.5 Hz, 3H), 1.74 (br. s., 2H), 4.55 (q, J=6.5 Hz, 1H), 7.30-7.38 (m, 2H), 7.41-7.57 (m, 6H), 7.87-7.91 (m, 1H); LC-MS (ESI)] m/z 237.1 [M-16]−.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:11]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccc(Br)cc2)c2ccccc2c1=O

Procedure:
The product from Example 195B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.34 (d, J=7.1, 1H), 8.08-8.03 (m, 1H), 8.03-7.98 (m, 1H), 7.97-7.92 (m, 1H), 7.56 (d, J=8.6, 2H), 7.44-7.36 (m, 4H), 7.35-7.31 (m, 2H), 3.67 (s, 2H); MS (DCI+) M/Z 519 (M+NH4)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][C:41](OCC)=[O:42]>C1COCC1.CCCC(C)C.CCOCC>[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][C:41](=[O:42])[CH2:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazine (13.3 g, 39.2 mmol) in THF (200 mL) at −70° C. was added LHMDS (75 mL, 75 mmol) drop wise and the reaction stirred for 20 minutes. A solution of ethyl 3-pyrimidin-2-ylpropanoate (9.2 g, 51 mmol) in THF (55 mL) was then added at −70° C., warmed to −20° C. and stirred for 2 hours. The reaction was then quenched by addition of a saturated solution of NH4Cl (250 mL), extracted twice with EtOAc (3×250 mL), combined organics were washed with brine (250 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid. The solid was stirred for 20 minutes in 20% isoHexane/ether (100 mL), filtered and washed with isoHexane and dried to give 4-pyrimidin-2-yl-1-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butan-2-one as an off white solid (15.2 g, 32.2 mmol, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH:7]=[N:13][NH:14][C:15]([NH2:17])=[S:16]
Reactant: NNC(N)=S
Reactant: COc1ccccc1C=CC=O
Product: COc1ccccc1C=CC=NNC(N)=S
Yield: 45 %

Procedure:
The compound is prepared according to the method described in Example 1A from 2-methoxycinnamaldehyde (6 mmol) and from thiosemicarbazide (6 mmol). Yield 45%.