Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:15]#[N:16].Cl.[CH3:18][C:19]1[CH:23]=[C:22]([NH2:24])[S:21][N:20]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:24][C:22]1[S:21][N:20]=[C:19]([CH3:18])[CH:23]=1)#[N:16]
Reactant: Cc1cc(N)sn1
Reactant: CC[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H](Nc1cnc(C#N)c(Nc2cc(C)ns2)n1)C(N)=O
Reaction time: 20 h
Yield: 89.1 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)butanamide (90 mg, 0.375 mmol), 3-methylisothiazol-5-amine hydrochloride (70 mg, 0.464 mmol), K2CO3 (130 mg, 0.942 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. EtOAc and H2O were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)butanamide (106 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:24]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[CH3:37][S:38]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:24]([NH:25][C:26]([CH3:29])([CH3:30])[CH2:27][CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2)(=[O:40])=[O:39]
Reactant: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(N)ccc3[nH]2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCC(C)(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NS(C)(=O)=O)ccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
To a solution of 1-[5-aminoindole-2-carbonyl]-4-[3-(1,1-dimethylpropylamino)-2-pyridinyl]piperazine (EXAMPLE 41, 300 mg) in dry methylene chloride (6 ml) under nitrogen is added pyridine (119 μl) and methanesulfonyl chloride (57 μl). The mixture is stirred at 20°-25° for 24 hr and then diluted with methylene chloride (20 ml) and water (8 ml). The layers are separated and the organic phase is washed with saline (8 ml), dried over sodium sulfate, and concentrated to give a solid which is then chromatographed on silica gel (230-400 mesh, 34 g, 5-6 psi), eluting with methanol/chloroform (2.5/97.5). Pooling of the appropriate fractions, concentration to a solid, and recrystallization from chloroform gives the title compound, mp 232°-233° (decomp).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:9]([F:21])=[CH:8][C:7]=1[N:22]1[CH2:34][CH2:33][N:25]2[C:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=3[CH:32]=[C:24]2[C:23]1=[O:35])(=[O:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[C@@H:54]([CH3:59])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:22]2[CH2:34][CH2:33][N:25]3[C:26]4[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=4[CH:32]=[C:24]3[C:23]2=[O:35])=[CH:8][C:9]([F:21])=[CH:10][C:11]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[C@@H:54]([CH3:59])[CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: C[C@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 58.7 %

Procedure:
Following the procedures as described for compound 108f, reaction of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (74 mg) and 107e (60 mg) gave 107f as a yellow solid (60 mg, 59%). LCMS: [M+H]+ 668
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([O:24]C)=[O:23])[CH:8]=2)[NH:3]1.[OH-].[K+].O>CO>[O:1]=[C:2]1[C:11]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([OH:24])=[O:23])[CH:8]=2)[NH:3]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (50 mg, 0.15 mmol) in methanol (30 mL) was added potassium hydroxide (33.33 mg, 0.60 mmol) and water (1 mL) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with HCl (3 N) to give the precipitate, which was collected by filtration to afford 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylic acid as a light yellow solid (40.0 mg, 79%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
1.24 mL (1.24 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.4 g (0.83 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 5 hours. After cooling, the reaction is worked up by addition of 3 mL (3 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.3 g (76%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a cream-colored solid with a melting point of 61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[OH:26])[CH3:14])[CH:7]=[CH:6]2.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[O:26][C:27](=[O:29])[CH3:28])[CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3OC(C)=O)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of Example 5 with acetic anhydride and pyridine.
Reaction SMILES: [C:1]([C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:16](OC)(OC)OC.Cl>CO>[CH3:16][O:10][C:7]12[CH2:8][CH2:9][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:5][CH2:6]1)[C:1](=[O:3])[CH2:2]2
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Agent: Cl
Solvent: CO
Product: CCOC(=O)C12CCC(OC)(CC1)CC2=O
Temperature: 5 °C

Procedure:
To a stirred solution of Step 3 product (1 eq) and trimethyl orthoformate (4.00 eq) in MeOH (9.4 v/w) at 5° C. was bubbled HCl gas (approximately 5 eq) over 2 hours, maintaining a pot temperature of 5° C. Upon complete addition, the reaction mixture, under nitrogen, was heated to, and stirred at, reflux for 30 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: COC(=O)c1ccccc1C
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Yield: 87.3 %

Procedure:
A mixture of 2-methyl-benzoic acid methyl ester (1.53 g, 10 mmol), N-bromosuccinamide (1.95 g, 11 mmol), and benzoyl peroxide (0.056 g, 0.21 mmol) in carbon tetrachloride (20 mL) was heated at reflux until the starting materials were mostly consumed. Workup and silica gel column chromatography using 5% ethyl acetate in hexane afforded 2-bromomethyl-benzoic acid methyl ester (2.0 g, 87%). GC-MS: m/z 230 (M1)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[CH:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH3:20])[CH2:10][C:9]=12)[CH2:3][CH3:4]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:20][N:11]1[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]2[CH:7]=[N:6][C:5]([C:2](=[O:1])[CH2:3][CH3:4])=[C:9]2[CH2:10]1
Reactant: CCC(O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.84 g (6.8 mmol) of 4,5-dihydro-3-(1-hydroxypropyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 16 g of manganese dioxide and 150 ml of methylene chloride is stirred at room temperature under an argon atmosphere for 2 hours. The manganese dioxide is filtered off under suction over a glass filter and the filtrate is evaporated in vacuo. After recrystallization of the residue from 100 ml of ethyl acetate, there is obtained 4,5-dihydro-5-methyl-3-propionyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 215°-216° C.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][N:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4][C:3]1=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)(C)C>[NH2:18][C:16]1[S:17][C:3]2[CH2:4][CH2:5][N:6]([C:9]([CH:11]3[CH2:13][CH2:12]3)=[O:10])[CH2:7][CH2:8][C:2]=2[N:15]=1
Reactant: NC(N)=S
Reactant: O=C1CCN(C(=O)C2CC2)CCC1Br
Solvent: CC(C)O
Product: Nc1nc2c(s1)CCN(C(=O)C1CC1)CC2
Yield: 11.4 %

Procedure:
A suspension of 5-Bromo-1-cyclopropanecarbonyl-azepan-4-one (3.87 grams, 14.8 mmol, obtained in above step) and thiourea (1.13 grams, 14.8 mmol) in isopropanol (40 mL) was refluxed for 6 hours. After completion of reaction, reaction mass was concentrated and the residue obtained was purified by flash chromatography (methanol/chloroform, 3/97) to obtain the title compound (0.4 grams).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:24])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 4-chloroaniline (16.2 g), toluene (120 ml), and pyridine (11 ml) at 0° C., cinnamoyl chloride (20.0 g) in 120 ml of toluene was added dropwise. After stirring 15 minutes at 0° C. the reaction mixture was poured into a mixture of ethyl acetate: water (250 ml:250 ml). The organic layer was separated and extracted with 5% aqueous HCl (3×250 ml), water (1×250 ml), 5% aqueous sodium bicarbonate (3×250 ml), dried over anhydrous sodium sulfate and evaporated yielding the amide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]([CH3:26])([CH3:25])[C:23]#[N:24])[C:16](=O)[C:15]12[O:32][CH2:31][CH2:30][CH2:29][O:28]1)(=[O:11])=[O:10].N>[Ni].CCO>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][N:24]=[C:16]3[C:15]3([O:28][CH2:29][CH2:30][CH2:31][O:32]3)[C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2CC(C)(C)C#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Temperature: 135 °C

Procedure:
3-[5′-{[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl]-2,2-dimethylpropanenitrile (1.00 g, 2.16 mmol), wet Raney Nickel (1.16 g) and 2M EtOH.NH3 (100 mL) was hydrogenated in a Parr Bottle (500 mL) at 56 lb/in2 H2 for 18 hours. The Raney nickel was removed by filtration through Sulka Floc. The filtrate was poured into a steel pressure vessel and was heated at 135° C. for 20 hours. The mixture was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH (97.75/1.5/0.75) to give the title compound as a white solid. Anal: Calc'd for C22H31N3O5S+0.2M H2O: C, 58.31% ; H, 6.98% ; N, 9.27% . Found: C, 58.10; H, 6.96; N, 9.06. NMR (400 MHz, DMSO-d6): consistent. MS: (ES+) m/z 450 [M+H]. Opt. Rotation: +75.02(calculated) at 25° C. in CH2Cl2 (1% concentration) at 589 wavelength; Analytical HPLC: major component=99.3% at 254 nm; m.p.: 169-171° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[N:9]=[C:10]([C:15]#[C:16][Si](C)(C)C)[C:11]([NH2:14])=[N:12][CH:13]=1>C1COCC1.C(OCC)(=O)C>[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:16][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cnc2[nH]ccc2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a 250 ml three necked round bottom flask, potassium tert-butoxide (4.2 g, 0.037 mole) was taken in THF (50 ml). To this, 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine (10.0 g, 0.037 mole) in THF (50 ml) was added dropwise at RT over 20 min under nitrogen atmosphere and the reaction mixture was stirred for 30 min at same temperature and 60 min at 65° C. The completion of the reaction was monitored by TLC using hexanes:ethyl acetate (8:2) as a mobile phase. After completion of the reaction, the reaction mixture was cooled to RT and diluted with ethyl acetate, filtered through high flow. Filtrate was collected and washed with water. The layers were separated and the aq. layer was re-extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 15-20% ethyl acetate in hexanes to yield 4.3 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CN(S(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 0.087 g (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 1 ml of dichloromethane, 0.064 g of benzene sulfonyl chloride and 0.052 g of pyridine were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched by addition of 1 M HCl (1 ml) and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, dried (MgSO4) and evaporated on the rotary evaporator to yield 0.113 g (95%) of the product as a light yellow foam.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]1[CH3:25])(=[O:11])[CH3:10].Cl[Si](C)(C)C.C(=O)(O)[O-].[Na+].C1C(=O)N([Br:43])C(=O)C1>C1COCC1>[Br:43][CH2:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]1[CH3:25])=[O:11]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1C(=O)CBr
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 110.4 %

Procedure:
To a cooled (−78° C.) solution of LDA (5.69 mL, 11.4 mmol) in THF (100 mL) was added dropwise over 40 minutes a solution of tert-butyl 4-acetyl-3-methylpiperidine-1-carboxylate (2.29 g, 9.48 mmol) in THF (40 mL). After an additional 25 minutes, chlorotrimethylsilane (2.41 mL, 18.9 mmol) was added dropwise over 20 minutes. After stirring for 1 hour the reaction was poured into 600 mL saturated sodium bicarbonate and extracted with ether (2×400 mL). The combined ether layers were washed with brine, dried, filtered, and concentrated to afford crude TMS-enol ether, which was then redissolved in 500 mL THF and cooled to 0° C. and treated with sodium bicarbonate (1.20 g, 14.2 mmol), followed by NBS (1.69 g, 9.48 mmol). The reaction was allowed to warm to ambient temperature while stirring for 90 minutes at which point it was poured into 400 mL of saturated sodium bicarbonate solution and extracted with Et2O and the combined organic layers were washed with saturated NaHCO3, brine, dried, and concentrated to give the title compound (3.35 g, 110% yield) as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.2 %

Procedure:
To a mixture of 5.18 g of ethyl cis-2-benzyloxy-1-cyclopentane carboxylate and 120 mL of tetrahydrofuran was added 63.0 mL of a 1 M aqueous lithium hydroxide solution, followed by stirring at room temperature for 2 days. The reaction liquid was concentrated under reduced pressure, and then to the residue were added water and 1 M hydrochloric acid to adjust the pH to about 2, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 3.73 g of cis-2-benzyloxy-1-cyclopentanecarboxylic acid as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[OH-].[Na+].[C:17]1([CH2:23][C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:24]#[N:25])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#CCc1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 4 h

Procedure:
To a stirred mixture of 21 parts of 1-chloro-4-nitro-2-(trifluoromethyl)benzene, 180 parts of sodium hydroxide solution 60%, 2parts of N,N,N-triethylbenzenemethanaminium chloride and 90 parts of tetrahydrofuran is added dropwise a mixture of 11.7 parts of benzeneacetonitrile and 27 parts of tetrahydrofuran at 30° C. Upon completion, stirring is continued for 4 hours at 50° C. After cooling, the reaction mixture is poured onto crushed ice. The whole is acidified with a hydrochloric acid solution (pH 1) while the temperature is kept below 20° C. The product is extracted with benzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is crystallized from 70 parts of 2,2'-oxybispropane at 0° C, yielding 4-nitro-α-phenyl-2-(trifluoromethyl) benzeneacetonitrile; mp. 70.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH:12]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:26])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2
Reactant: CCOC(=O)CCN
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a mixture of 4-{[1-(5-chloro-1-methyl-1H-indol-2-yl)heptyl]amino}benzoic acid (300 mg) synthesized above, β-alanine ethyl ester hydrochloride (174 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (158 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (349 mg, 93%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[O:26]C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].[ClH:38]>C(Cl)Cl.O>[ClH:38].[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:28])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH2:25])=[CH:18][C:17]=2[OH:26])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-nitrobenzamide (3.8 g; 0.01 mol) [prepared as described in Example 1] in methylene chloride (70 ml) was added to another solution of boron tribromide (2.84 ml; 0.03 moles) in methylene chloride (20 ml). The mixture was stirred at room temperature for 24 hours and then poured into a mixture of a saturated solution of sodium bicarbonate in water (250 ml) and methylene chloride (100 ml). The decanted organic solution was dried and the solvent removed in vacuo to give a paste which was triturated with petroleum ether. The residue obtained was treated with a saturated solution of ethanolic hydrogen chloride to give 3 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-amino-5-nitrobenzamide hydrochloride, m.p. 248°-250° C. (dec).