Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20])[C:8]([CH:23]=[O:24])=[CH:7]2.O1CCCC1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:20])([F:21])[F:22])[C:8]([CH2:23][OH:24])=[CH:7]2
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of 8-chloro-2-(2-(trifluoromethoxy)phenyl)quinoline-3-carbaldehyde (0.5427 g, 1.543 mmol) in tetrahydrofuran (7.715 mL, 1.543 mmol) at 0° C. was added SODIUM BOROHYDRIDE (0.08757 g, 2.315 mmol) and the mixture was stirred at 0° C. and allowed to warm to room temperature over 1 hour. After 1 h of stirring at 0° C., the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), and the organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methanol as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.58 (1H, s), 8.10 (1H, dd, J=8.3, 1.3 Hz), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.51-7.72 (5H, m), 5.54 (1H, s), 4.44 (2H, s); LC-MS (ESI) m/z 354.0 [M+H]+. The product was carried on crude without purification for the next step.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[Br:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2Br)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro -2H-indol-2-one (2 g, 9.48 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)) in concentrated sulfuric acid (20 mL) at −5° C., with stirring. The mixture was stirred for an additional 1 h at −5° C., then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([CH3:15])[CH2:10][CH2:9][CH:8]([CH3:16])[C:7]=2[CH:6]=1)=O.C(OC([N:24]1[CH2:29][CH2:28][CH:27]([C:30](=[S:32])[NH2:31])[CH2:26][CH2:25]1)=O)(C)(C)C.Br>>[CH3:15][CH:11]1[CH2:10][CH2:9][CH:8]([CH3:16])[C:7]2[CH:6]=[C:5]([C:3]3[N:31]=[C:30]([CH:27]4[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]4)[S:32][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CC1CCC(C)c2cc(C(=O)CBr)ccc21
Agent: Br
Product: CC1CCC(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 1.09 g (2.05 mmol) of 2-bromo-1-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 500 mg (2.05 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester. The product is in the form of the hydrobromide.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH:19]=[N:20][N:21]([CH3:22])[C:13]=3[C:12](=[O:23])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH:19]=[N:20][N:21]([CH3:22])[C:13]=3[C:12](=[O:23])[C:11]=2[CH:10]=1
Reactant: Cn1ncc2[nH]c3ccc(C(=O)c4ccccc4)cc3c(=O)c21
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc2[nH]c3ccc(C(O)c4ccccc4)cc3c(=O)c21
Yield: 71.5 %

Procedure:
A solution of 7-benzoyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 36, step 1, 33 mg, 0.11 mmol) in phosphorus oxychloride (3 ml) was refluxed for 3 h. After evaporation, the residue was dissolved in ethyl acetate (20 ml) and washed with saturated aqueous sodium bicarbonate (20 ml). The water layer was extracted with ethyl acetate (20 ml×2) and the combined organic layer was dried over sodium sulfate. Removal of solvent gave an oily residue, which was purified by preparative thin layer chromatography developing with ethyl acetate/hexane (2:1) to afford 24 mg (69%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[NH:8][C:9](=[O:12])[O:10][CH3:11])#[N:2].[Br:13]Br>C(O)(=O)C>[Br:13][C:6]1[S:5][C:4]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[C:3]([C:1]#[N:2])[CH:7]=1
Reactant: BrBr
Reactant: COC(=O)Nc1sccc1C#N
Solvent: CC(=O)O
Product: COC(=O)Nc1sc(Br)cc1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of compound methyl 3-cyanothiophen-2-ylcarbamate (11.5 g, 63 mmol) in acetic acid (500 mL) was added bromine (12 g, 75 mmol) at room temperature. The solution was heated at 60° C. with stifling for 1 hour and then concentrated and treated with water (500 mL). It was extracted with ethyl acetate (3×300 mL) and the combined extracts were dried over sodium sulfate and concentrated to give 14 g (89%) of methyl 5-bromo-3-cyanothiophen-2-ylcarbamate as a solid. 1H NMR 400 MHz CDCl3 δ 3.89 (s, 3H), 6.90 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[NH:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([O:25][C:23]([N:15]([CH2:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: BrCc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2ccccc2)nn1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 3-bromomethyl-6-phenylpyridazine (120 mg, 0.482 mmol) obtained in Reference Example 2-(a) in N,N-dimethylformamide (1.57 ml) were added di-tert-butyl iminodicarboxylate (127 mg, 0.585 mmol) and potassium carbonate (134 mg, 0.970 mmol), followed by stirring at 50° C. for 2 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1→1:1 (UV)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (180 mg) as a slightly yellow solid. (Yield: 97%)
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=2)(=[O:4])[CH:2]=[CH2:3].C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C.Cl>>[N:37]1([CH2:3][CH2:2][C:1]([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]2[C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][C:23]([C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=3)=[O:4])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(=O)N1CCC(Cc2ccccc2)CC1c1cc2cc(C(N)=O)ccc2[nH]1
Agent: Cl
Product: NC(=O)c1ccc2[nH]c(C3CC(Cc4ccccc4)CCN3C(=O)CCN3CCNCC3)cc2c1

Procedure:
The 1-acryloyl-(4-benzyl)-piperidinyl-indole-5-carboxamide above was reacted with tert-butyl-1-piperazine carboxylate as described before. The product was deprotected using methanolic HCl. M+ 458.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CS([C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(N)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
A DMF suspension (50 ml) of 3.0 g (17.8 mmol) of methyl 6-amino-3-hydroxypicolinate, 3.9 g (17.8 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 1.23 g (8.9 mmol) of potassium carbonate in a 100 ml round bottomed flask, was stirred at 80° C. for 4 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, concentrated and purified by silica gel chromatography (n-hexane/AcOEt=1/1+0.1 MeOH) to obtain 4.43 g (yield: 81.3%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:30])[CH:11]([C:17]1[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:22]=1)[C:12](OCC)=[O:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH:11]([C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:10]([CH3:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C
Reactant: Nc1ccc(F)cc1
Product: CC(C)C(C(=O)Nc1ccc(F)cc1)c1nc(N2CCOCC2)cc(=O)[nH]1

Procedure:
The product is prepared according to the procedure described in example 70, using 0.023 ml of 4-fluoroaniline and 36 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate in place of the ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate. After purification by silica column chromatography, eluent: 94/03/03 CH2Cl2/CH3CN/MeOH, 15 mg of N-(4-fluorophenyl)-3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH2:21][C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:28][C:29]1[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[N:32]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:30]=1>>[CH3:38][C:33]1[C:34]([C:35]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([N:8]3[CH2:9][CH2:10][CH:11]([N:14]([CH2:21][C:22]4[N:23]=[C:24]([CH3:27])[S:25][CH:26]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:12][CH2:13]3)[CH2:3][CH2:4]2)=[O:36])=[C:29]([CH3:28])[N:30]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:32]=1
Reactant: Cc1nc(CN(c2ccccc2)C2CCN(C3(C)CCNCC3)CC2)cs1
Reactant: Cc1nc(-c2ccccc2)nc(C)c1C(=O)O
Product: Cc1nc(CN(c2ccccc2)C2CCN(C3(C)CCN(C(=O)c4c(C)nc(-c5ccccc5)nc4C)CC3)CC2)cs1

Procedure:
It is prepared from (4′-methyl-[1,4′]bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-amine and 4,6-dimethyl-2-phenyl-pyrimidine-5-carboxylic acid using a procedure as described for Example 1 of PCT/EP02/03871. MS/ESI 595 [M+H]+. (4′-Methyl-[1,4′]bipiperidinyl-4-yl)-(2-methyl-thiazol-4-ylmethyl)-phenyl-amine used as a starting material may be prepared using procedures described in example 83 of PCT/EP02/03871. MS/ESI 385 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH2:10][S:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=2[CH2:14][N:15]=1>C(O)C>[Cl:20][C:16]1[C:13]2[CH2:14][NH:15][C:9](=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][S:11][C:12]=2[CH:19]=[CH:18][CH:17]=1
Reactant: ClC1=NCc2c(Cl)cccc2SC1
Reactant: Nc1ccccc1
Solvent: CCO
Product: Clc1cccc2c1CNC(=Nc1ccccc1)CS2
Temperature: 25 °C

Procedure:
A solution of aniline (4.8 ml) in dry ethanol (10 ml) was added dropwise at room temperature to a stirred solution of 3,6-dichloro-2,5-dihydro-1,4-benzothiazepine (2.5 g) in dry ethanol (65 ml). The reaction mixture was heated under reflux for 91/2 hours, cooled to room temperature, filtered and the solvent was removed from the filtrate by evaporation at reduced pressure. The oily residue was separated into fractions by chromatography on a silica gel support using chloroform/ethanol (50:1) as eluent. Purification of those fractions containing the product by flash chromatography using ethyl acetate/hexane (2:3) as eluent gave 6-chloro-3-phenylimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 0.27 g (m.p. 150°-152° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH3:16].[CH3:17]CCCCC>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][O:12][CH3:17])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[CH3:16]
Reactant: CCCCCC
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(CO)O2
Solvent: C1CCOC1
Product: COCC1Cc2c(Cl)c(C)cc([N+](=O)[O-])c2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the 7C in 200 ml of tetrahydrofuran (THF) was added slowly drop-by-drop to a stirred mixture of 5.7 g of freshly hexane-washed sodium hydride in 100 ml of THF, under nitrogen, at 25°-28° C. After gas ceased to envolve, 42.6 g of methyl iodide was added drop-by-drop over 5 minutes. The mixture was stirred for 18 hours at room temperature, mixed with ice water, and the resulting mixture was extracted with methylene chloride. The extract was washed with cold water, dried (MgSO4) and the solvent was evaporated. The residue was chromatographed over silica gel, using a 1:24 mixture of THF and hexane as eluent. The first fraction that was collected was recrystallized from ether to give 4-chloro-2,3-dihydro-2-(methoxymethyl)-5-methyl-7-nitrobenzofuran (7D), as a tan solid, m.p.: 117°-119° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([CH3:24])[N:19]=[C:20]([CH3:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1nc(C)c(C)c(NCCN)n1
Product: Cc1nc(C)c(C)c(NCCNCC(O)COc2ccccc2)n1

Procedure:
3.0 g. Phenyl glycidyl ether and 7.2 g. 4-(2-aminoethylamino)-2,5,6-trimethylpyrimidine are stirred for 20 hours at 60° to 70° C. in 5 ml. isopropyl alcohol, whereafter the mixture is separated with a column of silica gel, using methylene chloride-methanol-triethylamine (20:2:1 v/v/v) as elution agent. By recrystallizing from ethyl acetate, with the use of fullers' earth and active charcoal, there are obtained 2.9 g. (44% of theory) of the desired product in the form of colorless crystals; m.p. 119°-121° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: C1CNC1
Product: O=c1[nH]c2cc(CN3CCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and azetidine to give a yellow solid. MS m/z: 375.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:8]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:3][CH2:2]1.CC(O)=O.[OH-].[Na+].[CH3:34][C:35]([CH3:37])=O>>[CH3:34][CH:35]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=3)[C:8]=2[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:3][CH2:2]1)[CH3:37]
Reactant: FC(F)(F)c1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2[nH]nc(-c3ccc(C(F)(F)F)cc3)c2-c2ccncc2)CC1
Reaction time: 120 h

Procedure:
To a solution of 5-(4-piperidyl)-4-(4-pyridyl)-3-[4-(trifluoromethyl)phenyl]pyrazole (Example C-83) (300 mg, 0.7 mmol) in 50 mL of acetone was added 1 mL of AcOH and NaBH(OAc), (15 g, 70.8 mmol). The mixture was warmed to reflux and was stirred for 5 days. The reaction mixture was poured onto 100 mL of 2.5 N NaOH and was extracted with ethyl acetate (2×100 mL). The extracts were combined and washed with brine (1×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to afford the title compound: MS (M+H): 415 (base peak).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[C:9]([C:23](=O)[NH:24][CH2:25][CH:26]=[CH2:27])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.[CH:29]([NH:31][NH2:32])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:23]2[N:24]([CH2:25][CH:26]=[CH2:27])[CH:29]=[N:31][N:32]=2)=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: NNC=O
Reactant: C=CCNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCn1cnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Yield: 10.4 %

Procedure:
Phosphorus pentachloride (0.67 g, 3.22 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-(N-allylcarbamoyl)quinoxaline (Preparation 18, 1.0 g, 2.93 mmol) in toluene (40 mL) at room temperature and then heated under reflux for 1 hour. After being cooled, formylhydrazine (0.585 g, 8.79 mmol) and triethylamine (0.592 g, 8.79 mmol) were added and the mixture heated under reflux for 1 hour. After being cooled, the mixture was partitioned between ethyl acetate (60 mL) and 10% w/w aqueous potassium carbonate solution (60 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using toluene:ethyl acetate (1:0 changing to 1:1, by volume) to afford 6,7-dichloro-2,3-dimethoxy-5-(4-allyl-4H-1,2,4-triazol-3-yl)quinoxaline (0.112 g, 10%) as a white solid, mp 206-208° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Br:25][C:26]1[CH:31]=[CH:30][C:29](CO)=[C:28]([CH3:34])[CH:27]=1>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:20][Br:24])=[C:28]([CH3:34])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(Br)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
Triphenylphosphine (11.35 g, 43.27 mmol) followed by carbon tetrabromide (14.35 g, 43.27 mmol) were added to a solution of (4-bromo-2-methyl-phenyl)-methanol (7.25 g, 36 mmol) in CH2Cl2 (200 mL). The mixture was stirred at room temperature for 5 hours. The solution was concentrated to 15 mL. The residue was purified by flash column chromotography (1% to 10% EtOAc in Hexane) gave the product as brown oil (9.25 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ: 2.39 (3 H, s) 4.45 (2 H, s) 7.17 (1 H, d, J=8.08 Hz) 7.29 (2 H, m) 7.30 (1 H, dd, J=8.08, 2.02 Hz) 7.34 (1 H, s).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].Br[Mg][CH:25]=[CH2:26]>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:12]([N:8]2[CH2:7][C@H:6]([C:4](=[O:5])[CH:25]=[CH2:26])[CH2:10][C:9]2=[O:11])[CH3:13])=[CH:19][CH:18]=1
Reactant: C=C[Mg]Br
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: -66 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (3R)-N-methoxy-1-[(1R)-1-(4-methoxyphenyl)ethyl]-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (15 g, 48.96 mmol, 1.00 equiv) in tetrahydrofuran (150 mL), followed by the addition of bromo(ethenyl)magnesium in THF (1 M) (147 mL, 3.00 equiv) dropwise with stirring at −66° C. The resulting solution was stirred at −66° C. for 3 h, poured into 250 mL of water/ice and diluted with 250 mL of ethyl acetate. The resulting solution was extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford (4R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-4-(prop-2-enoyl)pyrrolidin-2-one 1.19.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17](O)=[O:18])[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6].Br.Br.[S:28]1[C:32]2[CH2:33][CH:34]([NH2:37])[CH2:35][CH2:36][C:31]=2[N:30]=[C:29]1[NH2:38]>>[NH2:38][C:29]1[S:28][C:32]2[CH2:33][CH:34]([NH:37][C:17](=[O:18])[CH2:16][N:11]3[C:12]([CH3:15])=[CH:13][CH:14]=[C:9]([NH:8][S:5]([CH2:4][C:3]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=4[Cl:1])(=[O:6])=[O:7])[C:10]3=[O:20])[CH2:35][CH2:36][C:31]=2[N:30]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[3-{[(2-chloro-4 -fluorobenzyl)sulfonyl]amino}-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O>C(O)(=O)C.[Pd]>[CH3:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[CH2:6][CH2:5][CH2:4]2
Reactant: COc1cc(C)c2c(c1C)C(O)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(C)c2c(c1C)CCC2
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 4,7-dimethyl-6-methoxy-1-indanol (4.0 g) in acetic acid (100 ml) was added palladium black (600 mg) and hydrogenation was carried out at room temperature for 3 hours. The catalyst was filtered off and the mother liquor was distilled under reduced pressure. To the residue was added ethyl acetate, washed with water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 4,7-dimethyl-5-methoxyindane (3.5 g) (Compound A-9). The physical properties and NMR spectrum data thereof are shown in Table 1.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH:7]=[CH:6][C:5]=12.Cl>O1CCOCC1>[N:12]1([CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3=[N:1][O:2][N:3]=[C:4]3[CH:9]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3nonc3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc2nonc2cc1CCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate (470 mg, 1.4 mmol) was then dissolved in dioxane (10 mL) and added 7 mL of 4M HCl in dioxane. The reaction was stirred at room temperature overnight. Evaporated off all solvent and the residue was taken up in ethyl acetate basified with 1N NaOH. The ethyl acetate was separated and washed with brine then dried over Na2SO4 and evaporated to dryness. The residue was purified by chromatography using 5% (NH4OH:MeOH 1:10) in 95% DCM to yield 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole. 1H-NMR (600 MHz, CDCl3): δ 7.72 (d, J=9.2 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H), 2.92 (t, J=4.9 Hz, 2H), 2.88 (t, J=7.6 Hz, 1H), 2.65 (t, J=7.6 Hz, 1H). LC-MS: M+1=233.