Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:51][CH:50]=1)[NH2:47])C.CCN(C(C)C)C(C)C.CO.O>>[Cl:61][C:59]1[CH:58]=[CH:57][C:56]([F:62])=[C:55]([C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:46]([CH2:45][C@@H:44]([OH:63])[C:43]([OH:64])=[O:42])[NH:47][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])=[CH:50][CH:51]=2)[CH:60]=1
Reactant: CCOC(=O)[C@H](O)CN(N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: COc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a mixture of 3-methoxy-isoxazole-5-carboxylic acid (140 mg, 1.0 mmol) and HATU (373 mg, 1.0 mmol) in DMF (5.0 mL, 64 mmol) was added (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (300.0 mg, 1.0 mmol) and DIPEA (0.3 mL, 1.6 mmol). The resulting mixture was stirred at room temperature overnight until the reaction was complete. The mixture was partitioned between EtOAc (10.0 mL) and water (3.0 mL). The organic layer was washed with water (2×3.0 mL), saturated aqueous NaCl (3.0 mL), dried over Na2SO4, filtered and concentrated to yield a yellowish oil. The oil was purified by flash chromatography (2×4 g stacker column, 0-100% EtOAc/hexanes). The desired fractions were combined and concentrated to yield a light yellowish oil. The oily residue was then treated with a mixture of MeOH (5.0 mL, 120 mmol) and water (1.0 mL, 56 mmol). LiOH monohydrate (68.6 mg, 1.6 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was treated with EtOAc (10.0 mL) and acidified with 1N HCl until pH˜3. The organic layer was washed with saturated aqueous NaCl (2×3.0 mL), dried over Na2SO4, filtered and concentrated to yield the title compound as a white foam (289.7 mg). MS m/z [M+H]+ calc'd for C21H19ClFN3O6, 464.09. found 464.0.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:7][C:8]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:11])[CH3:6])=[N+]=[N-]>C(O)C.ClCCl.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:7][C:8]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[O:11])[CH3:6]
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN=[N+]=[N-])cc1OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CN)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of (S)-2-(2-azido-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (505 mg) in a mixture of ethanol (5 mL) and dichloromethane (3 mL) was added 10% palladium on activated carbon (60 mg), and the mixture was stirred under hydrogen atmosphere (1 atm) for 3 hours at ambient temperature. The resulting mixture was filtered through celite and washed with ethanol. The filtrate and the washings were combined and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with 10% methanol in chloroform to give (S)-2-(2-amino-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (393 mg) as a solid substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([C:39](Cl)=[O:40])=[N:33]1>CC1CCCO1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([C:39]([NH:2][C@H:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:40])=[N:33]1
Reactant: COc1cc(C(=O)Cl)nn1-c1ccccc1F
Reactant: CCOC(=O)C[C@H](N)c1ccccc1C
Agent: Cl
Solvent: CC1CCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)c1cc(OC)n(-c2ccccc2F)n1)c1ccccc1C

Procedure:
A solution of ethyl (S)-3-amino-3-(2-methyl-phenyl)-propionate hydrochloride (42.4 g, 174 mmol) in 2-methyltetrahydrofuran (200 ml) was added to the suspension of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl chloride in ca. 200 ml of 2-methyltetrahydrofuran obtained in step 1. Triethylamine (33.5 g, 331 mmol) was added dropwise under ice cooling. After the complete addition of the triethylamine the conversion was complete and water was added. The phases were separated and the organic phase was washed with water and evaporated. The residue was dissolved in 2-methyltetrahydrofuran (500 ml) and washed with 1 M hydrochloric acid. The organic phase was dried and the solvent was removed under reduced pressure to give 70.4 g (99% over two step) of the title compound as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Solvent: O
Solvent: NC1CCCCC1
Product: O=C(O)CCCc1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
Prepared analogous to Example 9 from 4-(2',4'-dichloro-4-biphenylyl)-4-hydroxy-butyric acid. Melting point of the cyclohexylamine salt: 154°-155° C. (from water).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C@H:15]2[C@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C@:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]2)=[O:14])=[N:7][CH:6]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@:18]2([C:28]#[N:29])[C@H:17]([CH2:38][C:39]([CH3:41])([CH3:40])[CH3:42])[NH:16][C@@H:15]([C:13]([NH:12][CH2:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:43])=[O:3])=[CH:6][N:7]=3)=[O:14])[C@@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[C:31]([F:37])[CH:32]=1
Reactant: CCOC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 101.3 %

Procedure:
In a manner similar to the method described in Example 380, chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-nicotinic acid ethyl ester (73.8 mg, 0.117 mmol) in THF (8 ml) was combined with lithium hydroxide hydrate (35.9 mg, 0.855 mmol) in water (4 mL). It was stirred at room temperature to give chiral 6-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-nicotinic acid as a white lyophilized solid (71.3 mg, 100%). HRMS (ES+) m/z Calcd C30H28Cl2F2N4O3+H [(M+H): 601.1580. Found: 601.1581.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:23][OH:24])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1c(-c2ccc(Cl)cc2)nn2ccccc12
Yield: 50.7 %

Procedure:
To a solution of 3.5 g (11.7 mmol) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 65 ml of anhydrous EtOH was added 3.25 g of hydroxylamine hydrochloride, followed by a solution of 2.92 g (11.7 mmol) NaOH in 8 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was evaporated and poured into a solution of 6 ml 6N HCl and 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and dried over MgSO4. After evaporation of the solvent under vacuum, 5.11 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant furnished 1.86 g (50.7%) of 1-(2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1025.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][C:11](=[O:21])[N:12]([CH3:20])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:10]1[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]([CH3:20])[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: Cn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(C)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 20 g of 4.5-diphenyl-1-methyl-4-imidazolin-2-one, 160 cc. of DMF, 19 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C)C=O>[CH3:21][S:22]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:24])=[O:23]
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1F)C2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1F)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a suspension of 60% sodium hydride (0.16 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.80 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanesulfonylchloride (0.41 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane), and the resulting crystals were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-fluorophenyl)-4,5,6,7-tetrahydroindol-4-one (0.47 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=2)[NH:4][CH:3]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:24]1([S:30]([N:4]2[C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]=[C:10]3[C:2]([I:1])=[CH:3]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1c[nH]c2ncc(-c3ccccc3Oc3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(-c3ccccc3Oc3ccccc3)cnc21
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of the crude azaindole 26 (prepared in the previous step) in dichloromethane (373 mL) was sequentially added, benzenesulfonyl chloride (12.6 mL, 99.1 mmol), 50% aqueous sodium hydroxide (12.2 mL) and tetrabutylammonium hydrogen sulfate (2.82 g, 8.3 mmol). After 2 h stirring the mixture was partitioned between dichloromethane and saturated brine. The organic extract was dried (MgSO4), filtered and concentrated to afford the azaindole 27 (24.2 g, 68% from 25) as a tan coloured solid. 1H NMR (400 MHz; CDCl3) δ 6.89-6.92 (m, 2H), 7.01-7.05 (m, 2H), 7.22-7.28 (m, 3H), 7.33-7.37 (m, 1H), 7.45 (dd, J=7.6, 2.0 Hz, 1H), 7.47-7.52 (m, 2H), 7.60 (tt, J=7.6, 1.3 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 8.20-8.22 (m, 2H) and 8.64 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9]O)[S:7][CH:8]=1)([CH3:3])[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[Cl:13][CH2:9][C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: CC(C)c1csc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1csc(CCl)n1
Reaction time: 0.33 h

Procedure:
(4-Isopropyl-1,3-thiazol-2-yl)methanol (10 g, 63.6011 mmol) dissolved in dichloromethane (60 ml) was added with thionyl chloride (7 ml, 95.40 mmol) under ice cooling, and then the reaction solution was returned to room temperature and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was subjected to azeotropy with toluene and then diluted with diethyl ether, and further neutralized with saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, then dried over magnesium sulfate and concentrated under reduced pressure. The title compound was obtained as the residue without purification (11 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccc(Cl)cc2N)cc1
Yield: 87.8 %

Procedure:
Following General Procedure A, the title compound (2.2 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (1.3 g, 8.14 mmol), methyl 4-(bromomethyl)benzoate (1.86 g, 8.14 mmol) and K2CO3 (5.6 g, 40.73 mmol) in DMF (20 ml).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH:7]=1)([O-:10])=[O:9]
Reactant: c1cn[nH]c1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-n2cccn2)cc([N+](=O)[O-])c1
Temperature: 120 °C
Yield: 86 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (10 g, 38.6 mmol) in DMF (100 ml) were added pyrazole (5.26 g, 77.2 mmol, 2.0 eq.), copper(I) oxide (1.104 g, 7.72 mmol, 0.2 eq.) and cesium carbonate (25.15 g, 77.2 mmol, 2.0 eq.) and the mixture was heated at 120° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography over silica gel (30% ethyl acetate in hexane) to afford the compound in 86% yield (8.2 g). 1H NMR (300 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.7 (d, 1H), 8.5-8.48 (m, 2H), 8.32 (t, 1H), 7.84 (d, 1H), 6.62 (t, 1H), 2.08 (s, 3H); LC-MS (ESI): Calculated mass: 246.22; Observed mass: 247.1 [M+H]+ (rt: 0.6 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>ClCCCl>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1cc(N2CCC(NC3CC3)CC2)ccc1[N+](=O)[O-]
Yield: 93.2 %

Procedure:
1-(3-Methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18, 0.70 g, 2.80 mmol), cyclopropanamine (0.160 g, 2.80 mmol) and sodium triacetoxyborohydride (0.889 g, 4.20 mmol) in DCE (15 mL)/THF (5 mL) were stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The crude residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (10% MeOH/EtOAc) to give the title product (0.76 g, 93%). m/z 292.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]([CH:2]1[CH2:4][CH2:3][CH:1]([CH:2]2[CH2:4][CH2:3][CH:2]([CH:4]=[CH2:4])[CH2:1][CH2:3]2)[CH2:3]1)[CH2:1][CH3:2]
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(C2CCC(CCC)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 206.8 %

Procedure:
THF (50 ml) was added to methyltriphenylphosphonium bromide (6.27 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −15° C. t-BuOK (1.97 g) in a THF (20 ml) solution was added, and the stirring was continued for another 1 hour. 4-(3-Propylcyclopentyl)-cyclohexanone4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (3.0 g) in a THF (20 ml) solution was added dropwise and the mixture was stirred for another 2 hours. The reaction mixture was warmed to room temperature and was extracted with toluene after the addition of water (50 ml). The resulting organic layer was washed with water and dried over anhydrous sulfate, and the solution was concentrated under reduced pressure to a volume of about 50 ml. The concentrate was poured into n-hexane (200 ml) and solids deposited were filtered off. The solvent of the resulting solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: n-heptane) and then purified by means of a preparative HPLC system, Model PLC-561 made by GL Sciences Inc. to give 1-(3-propylcyclopentyl)-4-vinylcyclohexane (2.0 g).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOCC>C1COCC1>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]#[N:16])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: N#CC1CCC(OCc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCC(OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
To a solution of 4-(benzyloxy)cyclohexanecarbonitrile (1.26 g, 5.85 mmol, 1.0 equiv) in THF (dry, 30 mL) was added a solution of LDA (3.95 mL, 2.0 M Heptane/THF/toluene, 1.35 equiv) dropwise at −78° C. under N2. The resulting yellow solution was stirred at −78° C. for 2 hrs. Ethyl chloroformate (2.79 mL, 29.26 mmol, 5.0 equiv) was then added by syringe dropwise. The solution was stirred at −78° C. and allowed to warm to room temperature slowly and stirred overnight. The reaction was quenched by addition of H2O (20 mL), HCl (1.0 N, 20 mL). It was then extracted with EtOAc (3×40 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4 and then concentrated to give pale yellow residue. Ether (40 mL) was added and stirred for 5 min, filtered to remove the white solid. The ethereal solution was concentrated to give the yellow oil which was purified by CombiFlash (25 g silica gel column, EtOAc/Hexane: 0-20%) to afford 565 mg (yield 33%) of ethyl 4-(benzyloxy)-1-cyanocyclohexanecarboxylate as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.50 (s, 3H), 3.18-3.28 (m, 4H), 3.73-3.78 (m, 4H), 4.14 (s, 3H), 6.86 (dd, J=12.2 Hz, 2H), 7.00-7.60 (m, 5H), 7.71 (d, J=8.2 Hz, 1H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCl.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: Cl
Reactant: CN(Cc1ccc(O)c(Br)c1)C1CCCCC1
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(Cc1cc(Cl)c(O)c(Br)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
3.6 gm of N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine hydrochloride were dissolved in 50 ml of 90% acetic acid and admixed with a solution of 0.75 gm of chlorine in 15 ml of glacial acetic acid while cooling with ice water. After stirring for a short time, the solution was poured into a mixture of ice and 10 N sodium hydroxide solution and extracted three times with methylene chloride. The organic phase was evaporated to dryness. The residue was purified by means of column chromatography over silicagel with ethyl acetate as the eluant, yielding N-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamine, m.p. 136°-138° C, of the formula ##STR29## after recrystallization from ethanol/ether.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.F[B-](F)(F)F.[N:16]1([O:25][C:26](N(C)C)=[N+](C)C)[C:20]2C=CC=CC=2N=N1.CNOC>C(N(CC)C(C)C)(C)C.CN(C)C=O>[Br:1][C:2]1[C:3]([C:8]([N:16]([O:25][CH3:26])[CH3:20])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1cc(Br)c(C(=O)O)n1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nn(C)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (2.04 g, 10 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.21 g, 10 mmol), N,O-dimethylhydroxylamine (1.22 g, 20 mmol) in N,N-Diisopropylethylamine (5 mL) and N,N-Dimethylformamide (20 mL) was stirred for 12 h at room temperature. The mixture was concentrated in vacuum, and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give the titled product as a colorless oil (2.4 g, 97%). LC/MS m/z 247 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][C:8]=1[Cl:10])[N:1]=[C:13]([OH:14])[N:12]=[CH:4]2
Reactant: Nc1cc(Cl)c(Br)cc1C=O
Reactant: NC(N)=O
Product: Oc1ncc2cc(Br)c(Cl)cc2n1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-5-bromo-4-chlorobenzaldehyde (5 g, 21.46 mmol) and urea (18 g, 300.0 mmol) was stirred at 180° C. for 5 hours. LCMS monitored the reaction was completed. The mixture was cooled to room temperature, washed with water (100 mL×3) and filtered. The filtration cake was dried to get the title compound as a yellow solid (6 g (crude, 100%). MS (ES+) C8H4BrClN2O requires: 258, 260, found: 259, 261 [M+H]+.