Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:18]([O:22][C:23](=[O:40])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:40])[NH:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[C:14]1[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:13]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester gives “A81”; method 1: HPLC/MS: 1.38 min, [M+H]=406;
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7](O)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[CH3:23].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH:7]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:6]=2[C:5]([CH3:14])=[C:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:3]=1[CH3:23]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(O)C(C)(C)O2
Reactant: C1CCNC1
Product: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)C(N1CCCC1)C(C)(C)O2
Yield: 43 %

Procedure:
Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 236 and pyrrolidine, the title compound was synthesized in the same manner as in Example 297.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:35])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[CH2:23][C:22](=[O:35])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc([N+](=O)[O-])c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl }-carbamic acid tert.-butyl ester (Example K62) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (62 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:34]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1)#[N:2].[NH:36]([C:40](=[CH2:45])[C:41]([O:43][CH3:44])=[O:42])[C:37]([CH3:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([NH:36][C:40](=[CH:45][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:34][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[C:41]([O:43][CH3:44])=[O:42])(=[O:38])[CH3:39]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3I)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)NC(C)=O

Procedure:
2.72 g (4.60 mmol) of N-[2-(5-cyano-2-iodophenoxy)ethyl]-4-(1-t-butoxycarbonyl-4-piperidyloxy)benzamide and 1.32 g (9.22 mmol) of methyl 2-acetaminoacrylate were dissolved in 80 ml of acetonitrile. 272 mg (1.21 mmol) of palladium (II) acetate, 630 mg (2.07 mmol) of tri-o-tolylphosphine and 1.71 g (9.23 mmol) of tributylamine were added to the solution, and they were heated under reflux for 3 days. The solvent was evaporated, and the residue was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6])(O)=[O:2].Cl.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(N(C(C)C)C(C)C)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:1]([C@@H:4]([N:8]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[CH:5]([CH3:7])[CH3:6])=[O:2])=[CH:38][CH:39]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: NCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)NCCc1ccc(O)cc1)C(C)C
Reaction time: 1 h

Procedure:
0.5 g of the compound from Example 16, 0.21 g of tyramine hydrochloride, 0.225 ml of N-ethyldiisopropylamine, 0.164 g of 1-hydroxybenzotriazole and 0.296 g of dicyclohexylcarbodiimide are stirred at room temperature in 4 ml of DMF for 48 h. After evaporating the solvent in vacuo, the residue is stirred in a mixture of 4 ml of CH2Cl2 -MeOH-AcOH 94:3:3 for 1 h. After evaporating, the mixture is separated by means of flash chromatography (100 g, system N6). After lyophilizing from t-BuOH, the product is obtained as an amorphous powder. FAB-MS: m/e=555 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCCCCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCCO)O2
Yield: 23 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 356 mg CDI (2.2 mmol) and 468 mg 6-amino-1-hexanol (4.0 mmol) yielded 161 mg of 6-hydroxy-N-(6-hydroxyhexyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2(O)[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[Na+].[Na+].S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9](=[O:19])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)=CC1=O
Reaction time: 0.67 h
Yield: 189.6 %

Procedure:
A solution of the 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol (368 g, 1.47 mol) obtained in (a) in 40/60 petroleum (40 ml) was added in a steady stream to a solution of sodium dichromate (217 g, 0.74 mol) in dilute sulphuric acid (250 g, 2.6 mol 98% sulphuric acid in 1.5 liters of water). The reaction mixture was then held at a temperature between 10° and 30° C. and stirred for 40 minutes. Water (500 ml) and diethyl ether (700 ml) were added and the aqueous layer extracted twice with diethyl ether (2×700 ml). The organic phases were then combined and backwashed with saturated sodium bicarbonate solution (1×500 ml) and water (1×500 ml). The solvent was then flashed off to give 349 g crude 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-1-en-3-one as a beige coloured granular solid. Trituration in petrol gave a pure sample of the desired product, m.pt. 87°-90° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:14][CH:15]=1
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Then, 2.61 g of (4-(trifluoromethoxy)benzylidene)malononitrile was dissolved in 20 ml of tetrahydrofuran, and while stirring at room temperature, a suspension of 0.11 g of sodium borohydride in 5 ml of ethanol was added dropwise, followed by stirring at room temperature for 30 minutes. Then, 10% hydrochloric acid was added, and the mixture was extracted with diethyl ether. The organic layer was successively washed with 10% hydrochloric acid, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.20 g of (4-(trifluoromethoxy)benzyl)malononitrile (the intermediate (7)).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21]>>[CH2:19]([N:22]([CH2:23][CH2:24][CH3:25])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])[CH:3]=1)[CH2:20][CH3:21]
Reactant: CCCNCCC
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc(O)cc2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 7) and dipropylamine (Aldrich), the title compound was obtained as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:23])([F:24])[F:22])[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidine (example E.102) (0.40 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.49 g), which was subsequently deprotected.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH:19]1([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:21][CH2:20]1.C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:26]([C:25]3[CH:29]=[C:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]=3[O:23][CH2:22][CH:19]3[CH2:21][CH2:20]3)=[O:27])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example 2.6) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid. MS (m/e): 500.3 (M+H+; 100%)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)(O)[O-].[Na+].C(=O)=O.[CH3:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CO.CN(C)C=O>[C:1]([O:5][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]1[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=1[CH3:14])(=[O:4])[C:2]#[CH:3]
Reactant: Cc1ccccc1OCCCCBr
Reactant: C#CC(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CC(=O)OCCCCOc1ccccc1C
Temperature: 40 °C
Yield: 37.2 %

Procedure:
A mixture of 10 g of propiolic acid, 12 g of anhydrous sodium bicarbonate in 150 ml of anhydrous methanol was heated to 40° C. with stirring. When evolution of carbon dioxide ceased, the reaction mixture was cooled to a temperature 10° C. or less. The resultant precipitate was collected and dried under reduced pressure for two days. A mixture of 1 g of the sodium propiolate thus obtained and 2.64 g of 4-(2-methylphenoxy)butyl bromide in 30 ml of anhydrous N,N-dimethylformamide was heated at 110° C. under nitrogen atmosphere for four hours with stirring. After the reaction was completed, the reaction solution was poured into ice-water, and extracted twice with toluene. The combined toluene layer was washed successively with a saturated aqueous ammonium chloride solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.937 g of 4-(2-methylphenoxy)butyl propiolate (compound 10).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: NC1CCCCC1
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NC2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 867 mg (8.74 mmol) of cyclohexylamine was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 237 mg (yield: 76.6%) of the title compound.
Reaction SMILES: N1CCCCC1.C1C2C(COC([NH:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]3[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]4[CH:47]=[CH:46][CH:45]=[C:44]5[C:40]=4[CH:41]=[CH:42][NH:43]5)=[O:36])=[CH:31][C:30]=3[Cl:48])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C)C=O>[NH2:24][CH2:25][C@@H:26]([C:50]([O:52][CH3:53])=[O:51])[NH:27][C:28](=[O:49])[C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[CH:42][NH:43]3)=[O:36])=[CH:31][C:30]=1[Cl:48]
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Piperidine (88 μL, 0.89 mmol) was added to a solution of 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL). The solution was stirred at room temperature for 30 min and then the solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give 3-amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester as an off-white solid (59 mg, 81%). N,N-Dimethylformamide (5 mL) was added, followed by HOAT (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), and thiophene-2-carboxylic acid (18 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 18 h. Water was added, and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-[(thiophene-2-carbonyl)amino]-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (58 mg, 78%). A solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in tetrahydrofuran/methanol/water (3:1:1) was added, and the solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified by HPLC to give 3-(thiophene-2-carbonyl)amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (45 mg, 80% from ester, 48% for three steps) as a white powder.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9](=[CH:19]O)[C:8]2=O.C(O)(=O)C>CO>[Cl:4][C:5]1[CH:14]=[CH:13][C:12]2[N:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][C:9]3[CH:19]=[N:3][N:2]([CH3:1])[C:8]=3[C:7]=2[CH:6]=1
Reactant: CCC(=O)N1CC(=CO)C(=O)c2cc(Cl)ccc21
Reactant: CNN
Solvent: CO
Solvent: CC(=O)O
Product: CCC(=O)N1Cc2cnn(C)c2-c2cc(Cl)ccc21
Yield: 39.6 %

Procedure:
Methylhydrazine(30.56 g) was added dropwise to a mixture of 6-chloro-3-hydroxymethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline(160.3 g) and acetic acid (75.8 ml) in methanol(1.6 liters) with stirring and cooling over a period of 10 minutes. After being stirred for 1 hour at room temperature, the mixture was filtered by sunction and the filtrate was evaporated in vacuo after addition of acetic acid (160 ml) to it. The residue was neutralized with aqueous sodium hydroxide under ice cooling. The resulting precipitate was collected by filtration, washed with water and recrystallized from aqueous methanol and then ethanol to give 8-chloro-4,5-dihydro-1-methyl-5-propionyl-1H -pyrazolo[4,3-c]-quinoline (65.84 g). The physical data of the compound was identical to that of the object compound of Example 3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (107.9 mg, 0.30 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (60 mg, 1.50 mmol, 5.00 equiv) in water (3 mL) with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated under vacuum and diluted by 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with methanol. This resulted in 54 mg (50%) of 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16]C(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:22](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:22])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2F)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.69 g, 9.67 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (7.45 mL, 97 mmol) and stirred at RT for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (10 mL) was cooled to 0° C. and added acetic anhydride (4.5 mL, 48.3 mmol). The reaction was gradually allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a colorless oil. [M+1]=221.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:19]1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccsc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccsc4)cc3c2C1
Yield: 52.7 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.086 mMol) thiophene-3-carboxylic acid, 6.8 mg (53%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C:13]1[NH:14][C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([CH3:18])[N:17]=1.Cl.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH2:10])=[CH:5][C:4]=1[C:13]1[NH:14][C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([CH3:18])[N:17]=1
Reactant: [H][H]
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(Cl)c(N)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Yield: 35.9 %

Procedure:
A mixture of 2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (6.4 g), 1N-hydrochloric acid (37 ml) and 10% palladium on carbon (3 g) in methanol (100 ml) was subjected to catalytic reduction at ambient temperature under atmospheric pressure of hydrogen gas for 3 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in water and the solution was adjusted to pH 8.0 with 20% aqueous potassium carbonate. The resultant mixture was extracted with ethyl acetate and extract was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (96:4 V/V). The fractions containing object compound were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-(2-methoxy-4-chloro-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (2.1 g).