Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Yield: 83.4 %

Procedure:
Using 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (1.55 mg, 5.00 mmol), 1-fluoro-4-nitrobenzene (0.78 g, 5.50 mmol) and potassium carbonate (0.69 g, 5.00 mmol), and in the same manner as in Example A18(ii), the title compound (1.80 g, 83%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[CH3:24])[NH2:20])([O-:16])=[O:15]>N1C=CC=CC=1>[CH3:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:18][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 3-trifluoromethylbenzoyl chloride (9.9 ml), 3-nitro-4-methylaniline (10 g) and pyridine (100 ml) was stirred and heated to 80° C. for 2 hours. The reaction mixture was evaporated and the residue was triturated under 2N aqueous hydrochloric acid solution. The solid so obtained was isolated, washed in turn with a saturated aqueous sodium bicarbonate solution, water and isohexane and dried under vacuum at 55° C. to give N-(4-methyl-3-nitrophenyl)-3-trifluoromethylbenzamide as a solid (21.9 g); NMR Spectrum: (DMSOd6) 7.49 (d, 1H), 7.78 (m, 1H), 7.99 (m, 2H), 8.27 (m, 2H), 8.51 (s, 1H), 10.77 (s, 1H); Mass Spectrum: M−H− 23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:10])=[O:11])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:23])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(c1ccc(Cl)cc1C(O)c1ccccc1Cl)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 1 h

Procedure:
To 6 g of N-{4-chloro-2-[(2-chlorophenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 50 ml of DMF at 0° C. is added portionwise 0.674 g of sodium hydride. After 1 hour at 0° C., 1.4 ml of ethyl 2-bromoacetate are introduced and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 1.3 g of the expected product.
Reaction SMILES: [BH4-].[Li+].[CH3:3][S:4]([C:7]1[CH:30]=[CH:29][C:10](/[CH:11]=[C:12]2/[C:13]([CH3:28])=[C:14]([CH2:24][C:25](Cl)=[O:26])[C:15]3[C:20]/2=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=3)=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C1COCC1>[CH3:3][S:4]([C:7]1[CH:8]=[CH:9][C:10](/[CH:11]=[C:12]2/[C:13]([CH3:28])=[C:14]([CH2:24][CH2:25][OH:26])[C:15]3[C:20]/2=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=3)=[CH:29][CH:30]=1)(=[O:5])=[O:6]
Reactant: CC1=C(CC(=O)Cl)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(CCO)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1

Procedure:
Lithium borohydride (1.38 mmol) in THF (2 ml) is added to the solution of (Z)-1-(4-methylsulfonylbenzylidene)-5-dimethylamino-2-methyl-3-indenylacetyl chloride (2.78 mmol) in THF (20 ml) at 0° C. The reaction is quenched with HCl after 5 minutes (10%, aqueous, 30 ml). Ethyl acetate (50 ml) is added to extract the product.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:10]([C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)[S:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=1)#[N:11]
Reactant: N#Cc1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(C#N)c3)cs2)CC1
Yield: 50.7 %

Procedure:
A solution of 3-(2-bromo-1,3-thiazol-4-yl)benzonitrile (990 mg, 4.90 mmol), tert-butyl piperazine-1-carboxylate (1.37 g, 7.34 mmol) and potassium carbonate (677 mg, 4.90 mmol) in dimethylformamide (16 ml) was stirred at 120° C. for 6 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 920 mg (50.7%) of the desired product as a solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:33][CH2:32][N:31]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:30][C@H:29]4[OH:34])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f43) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]([NH:29][C:6]([O:5][CH3:1])=[O:7])=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc([N+](=O)[O-])cc2C(=O)OC)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2C(=O)OC)ccn1
Temperature: 55 °C
Reaction time: 5 h
Yield: 180.3 %

Procedure:
To the solution of 24B (0.33 g, 0.772 mmol) in MeOH (7.72 ml) was added ammonium chloride (0.413 g, 7.72 mmol) and zinc (0.505 g, 7.72 mmol). The reaction was stirred at 55° C. for 5 h. The reaction was cooled to rt, filtered, and the filtrate was concentrated. The residue was partitioned between EtOAc and sat. NaHCO3 and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated to afford the aniline (0.317 g, 103%) as a yellow solid. MS (ESI) m/z: 398.2 (M+H)+. To a cooled (−78° C.) clear solution of the aniline (0.317 g, 0.798 mmol) and pyridine (0.097 ml, 1.196 mmol) in DCM (7.98 ml) was added dropwise methyl chlorocarbonate (0.074 ml, 0.957 mmol). The reaction was stirred at −78° C. for 1 h, the reaction was quenched with sat. NH4Cl and the reaction was allowed to warm to RT. The reaction was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM (1×). The combined organic layers were washed with sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a brown foam. Purification by normal phase chromatography provided 24C (0.304 g, 84%) as a white solid. MS (ESI) m/z: 456.2 (M+H)+.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][NH:65][C:64](=[O:67])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][NH:65][C:64](=[O:67])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CNC(=O)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83.7 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen- 2-em-3-carboxylate (10.61 g, 17 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (5.92 g, 16.2 mmol, compound of Reference Example 19-4) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (9.9 g, yield: 83.7%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C.O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:13][NH2:14]
Reactant: NN
Reactant: Clc1ccc2ccccc2n1
Solvent: CCO
Solvent: O
Product: NNc1ccc2ccccc2n1

Procedure:
To a solution of 2-chloroquinoline (15 g) in ethanol (150 ml) was added hydrazine hydrate (40 ml), the resulting solution was heated at reflux for 6 hours then diluted with water (400 ml) and extracted with diethyl ether (3×200 ml). The collected organic phase was washed with brine (300 ml), dried and concentrated under vacuum to afforg the title compound as a solid (13 g), 1H--NRM (DMSO); 4.29(s,2H), 6.83 (d,1H), 7.15(m,1H), 7.47(m,1H), 7.52(d, 1H), 7.62(dd, 1H), 7.86(d,1H), 8.05(s,1H)
Reaction SMILES: [CH2:1]1[S:27][CH:5]([C@H:6]([C@H:15]([CH2:24][CH2:25][OH:26])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH2:3]1[S:4][CH:5]([C@H:6]([C@H:15]([CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:27][CH2:1][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: OCC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)C1SCCCS1
Product: CC(=O)OCC[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)C1SCCCS1

Procedure:
Step (4'): The primary hydroxyl group of Compound 68 is acetylated with acetic anhydride to produce 5-O-acetyl-2,3-di-O-benzyl-4-deoxy-L-erythro-pentose trimethylene dithioacetal [Compound 69] of the formula ##STR109##
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:13]=[C:12]([Cl:11])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: Clc1cc(Cl)cc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,5-dichloroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 317-318° C.). MS(ES+) m/z 278 (M+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6](COCC[Si](C)(C)C)[C:7]([C:9]3[CH:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:26][C:25]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[CH:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=3)=[N:6][C:5]=2[CH:24]=1
Reactant: CSc1cc(-c2nc3cc(C)c(C)cc3n2COCC[Si](C)(C)C)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1cc(-c2nc3cc(C)c(C)cc3[nH]2)n[nH]1
Yield: 63.5 %

Procedure:
A mixture of 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole [90 mg, Reference Example 1 (a)], hydrochloric acid (2 ml, 4N) and ethanol (4 mL) mixture was adjusted to 7 by addition of saturated sodium bicarbonate solution. The resulting solid was filtered, then washed with water and then dried in a vacuum oven to give 5,6-dimethyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole (38 mg). LC-MS (METHOD A): RT =2.22 minutes; 259 (M+H)+. (b) 6-Chloro-5-methyl-2-(5-methylsulfanyl-1H-pyrazol-3-yl)-1H-benzoimidazole
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)C(C)C)C.[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:19]([C:22]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:42])=[CH:36][C:35]=3[Cl:44])=[CH:30][CH:29]=2)[C:25]([CH3:45])=[N:24][C:23]=1[CH3:46])(=[O:21])[NH2:20]
Reactant: CCOC(=O)CCN
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 150.4 %

Procedure:
A mixture of ethyl 3-aminopropanoate hydrochloride (88 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford ethyl 3-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)propanoate (387 mg, 151%) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(F)c2)C1=O
Yield: 52.1 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (236 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F-].[Cs+].[N+](C1C=C(S(O[CH2:26][C@H:27]2[O:29][CH2:28]2)(=O)=O)C=CC=1)([O-])=O.O>CN(C=O)C>[O:29]1[CH2:28][C@H:27]1[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1cccc2[nH]ccc12
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
4-Hydroxyindole (3.0 g) was dissolved in DMF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (10.12 g) was added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (5.84 g, 99.3% e.e.) was added thereto and the mixture was stirred for 30 hours at the same temperature. After the reaction, water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/isopropyl alcohol; 20:1) to give 4.01 g of (S)-4-(2,3-epoxypropoxy)indole (yield 94.1%, optical purity 99.2% e.e.) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[N:17]1([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN1C(=O)CCC1>[N+:14]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:24]=1)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])([O-:16])=[O:15]
Reactant: CC(C)OC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(N2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1ccc(Nc2cccc(N3CCCCC3)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a mixture of isopropyl 4-chloro-3-nitrobenzoate (3.0 g, 12.3 mmol) and 2a (2.16 g, 12.3 mmol) in anhydrous NMP (5 ml) was added triethylamine (1.71 ml, 12.3 mmol) and the mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was partitioned between ethyl acetate and water. The organic phase was extracted with diluted hydrochloric acid (4M). The aqueous extract was rendered alkaline by addition of aqueous sodium hydroxide (12M) and extracted with ethyl acetate. This organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographied on silica gel using a mixture of ethyl acetate and petroleum ether (1:1 v/v) as the eluent to yield isopropyl 3-nitro-4-(3-(1-piperidinyl)anilino)benzoate (2.55 g, 54%) as a red oil. This intermediate product was dissolved in ethanol (50 ml) hydrogenated at ambient pressure. The resulting diamine was treated with formic acid (25 ml) at 80° C. for 1 hour. The reaction mixture was poured into water (100 ml) and rendered alkaline by addition of aqueous sodium hydroxide (10M). The crude product was filtered off, washed with water and dried. Purification was achieved by treatment with activated carbon in refluxing 2-propanol followed by trituration with diethyl ether. Yield of 4e1: 1.27 g (53%). M.p. 160-161° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:17][C:18](=[O:41])[C@@H:19]([CH:24]([C:34]([O:36]C(C)(C)C)=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:17][C:18](=[O:41])[C@@H:19]([CH:24]([C:34]([OH:36])=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
A solution of 1.26 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(tert.-butoxycarbonyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml dichloromethane was treated with 5 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give 1.30 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(carboxy)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:21][CH2:20][NH:28][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[N:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Reactant: NCCc1ccccc1
Product: Fc1ccc(-n2nccc2-c2ccnc(NCCc3ccccc3)c2)cc1
Temperature: 190 °C
Yield: 70 %

Procedure:
A mixture of 2-chloro-4-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (Example 46; 0.6 g, 0.002 mol) and phenethylamine (20 mL) was heated at 190° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.55 g (70% yield) of product as a yellow oil: Anal. Calc'd. for C22H19FN4: C, 73.72; H, 5.34; N, 15.63. Found: C, 73.33; H, 5.46; N, 15.22.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.C1C(=O)N([Cl:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:26]
Reactant: CCOC(=O)Cc1ccc(N)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.