Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:10]2[C:11](=[O:12])[N:6]([C@@H:4]3[CH2:5][C@H:2]([O:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3]3)[C:7]3[N:8]([N:31]=[CH:32][N:33]=3)[C:9]=2[CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)#[N:27]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h
Yield: 57 %

Procedure:
To a mixture of 4′-{[4-(cis-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g), rhodium(I) acetate (0.003 g) and toluene (20 mL) was added dropwise ethyl diazoacetate (0.66 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([C@:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])([CH3:17])[CH2:9][S:10][CH2:11][C:12]([OH:14])=[O:13])[CH:7]=1
Reactant: CCOC(=O)CSC[C@](C)(NCc1ccc(OC)cc1OC)c1cc(Br)ccc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CN[C@@](C)(CSCC(=O)O)c2cc(Br)ccc2F)c(OC)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of (R)-ethyl 2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetate (3 g, 5.99 mmol, Eq: 1.00) in tetrahydrofuran (20 ml), methanol (10 ml), water (5 ml) was added at 23° C. lithium hydroxide (287 mg, 12.0 mmol, Eq: 2.0). The colourless reaction solution was stirred at 23° C. for 2 hours. The reaction mixture was neutralized with 1 N HCl (12.0 ml, 12.0 mmol, Eq: 2.0) (pH=5-6) and evaporated. The residue was triturated with dichloromethane/methanol 9:1 and solid Na2SO4 was added. The solid was filtered off and the filtrate was evaporated to dryness to give the crude (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetic acid (3.2 g, 6.1 mmol, 102% yield) as a white foam which was used without further purification. MS (ISN): m/z=470.6 [M−H]− and 472.5 [M+2−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: O=C(CBr)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(Cl)c1
Yield: 81.4 %

Procedure:
The title compound (2.65 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-bromo-3′-chloroacetophenone (1.92 g) according to the method of description 36.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26].O>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:27])([NH2:28])[CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (75 mL, 0.54 mol) was slowly added to a solution of 2,4-dichloro-3-nitroquinoline (André et al, U.S. Pat. No. 4,988,815, Example 2, 114 g, 0.470 mol) in anhydrous 1-methyl-2-pyrrolidinone (NMP) (450 mL), and the resulting black solution was cooled to 0° C. A solution of 1,2-diamino-2-methylpropane (42 g, 0.54 mol) in anhydrous NMP (42 mL) was added dropwise over a period of three hours. After the addition was complete, the reaction was allowed to warm to ambient temperature, stirred for five hours, and poured slowly into warm water (4 L) with vigorous stirring. A yellow precipitate formed, and the suspension was stirred for one hour at ambient temperature. The precipitate was isolated by filtration and washed with cold water until the filtrate was colorless. The solid was dissolved in dichloromethane (4 L), and the resulting solution was washed sequentially with saturated aqueous sodium carbonate and brine, dried over magnesium sulfate and sodium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure to provide 130 g of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine as a bright yellow powder.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:20]=[CH:21][N:22]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH:23]1([CH:26]=[CH:27][C:28]#[N:29])[CH2:25][CH2:24]1.C(#N)C.C1CCN2C(=NCCC2)CC1>ClCCl>[CH:23]1([CH:26]([N:17]2[CH:16]=[C:15]([C:13]3[N:12]4[CH:20]=[CH:21][N:22]=[C:11]4[CH:10]=[C:9]([C:7]4[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)[N:14]=3)[CH:19]=[N:18]2)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24]1
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=CC1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 50 °C
Yield: 58.8 %

Procedure:
To a flask charged with 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0600 g, 0.2046 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.1048 g, 1.125 mmol) was added 1 mL of acetonitrile and DBU (0.04588 mL, 0.3068 mmol) at ambient temperature with stirring. The flask was then sealed and heated to 50° C. overnight. The reaction mixture was diluted with dichloromethane and loaded directly onto a silica gel column and eluted with ethyl acetate with 0.5% ammonium hydroxide to afford the title compound (0.047 g, 0.1204 mmol, 58.86% yield). MS (apci) m/z=387.2 (M+H).
Reaction SMILES: [OH-].[Na+].O[N:4]=[C:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([C:15]([NH2:17])=[O:16])[CH:11]=2)[CH2:6]1.C1(C)C=CC(S(Cl)(=O)=[O:27])=CC=1>O>[C:5]([CH2:6][C:7]1[C:12]([C:13]([OH:14])=[O:27])=[CH:11][C:10]([C:15]([NH2:17])=[O:16])=[C:9]([O:18][CH3:19])[CH:8]=1)#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1C(N)=O)C(=O)C(=NO)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)cc1C(N)=O
Temperature: 50 °C
Yield: 88.7 %

Procedure:
To a solution of NaOH (0.97 g, 19.2 mmol) in H2O (20 ml) was added 2-Hydroxyimino-6-methoxy-3-oxo-indan-5-carboxylic acid amide (1.5 g, 6.4 mmol). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (1.6 g, 8.32 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product as a solid (1.33 g, 89%). LC-MS: m/e 233 (M−1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]=1[O:15][CH3:16])[CH:4]=[C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)[CH2:21][CH2:20]1)[CH:12]=[CH:11]2
Reactant: COc1cc2ccc(CCl)cc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2ccc(CN3CCCN(Cc4ccc5cc(OC)c(OC)c(OC)c5c4)CC3)cc2c(OC)c1OC

Procedure:
2-Chloromethyl-6,7,8-trimethoxynaphthalene (222 mg) and homopiperazine (42 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.3, 0.219 mole and benzenesulfonyl chloride (44 g, 0.25 mole) in 500 ml of pyridine was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was extracted with dilute sulfuric acid and then was dried over magnesium sulfate. The volume was reduced to 400 ml, hexane was added and 39.2 g (50.6%) of the title compound was collected as a white, crystalline solid, mp 156.5°-158° C.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCO
Product: CCCCCOC1CCC(=O)N1
Temperature: 25 °C

Procedure:
A mixture of 2.5 g of 5-hydroxy-pyrrolidin-2-one and 1.25 g of Amberlite IR 120 H is agitated at 65° C. for 3 hours in 55 cm3 of n-pentanol. After cooling to ambient temperature, filtering, and distilling under reduced pressure, the residue is chromatographed on silica (eluent: ethyl acetate), and 2.68 g of the expected product is obtained. m.p. 42°-43° C.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][C:14]=1[CH2:15]O.C(N(CC)CC)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:43]([N:50]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:10]=2)[CH2:15]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Nc1ccc(CO)c(CCO)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCN(Cc1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
Methanesulfonyl chloride (0.041 mL) was added to a 0° C. solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (100 mg, 0.24 mmol) and triethylamine (0.084 mL) in THF (2 mL). TLC showed complete reaction after 30 min. Benzylamine (0.132 mL) was added and the contents stirred for 18 hrs at 25° C. and 60 hrs at 50° C. The solvent was removed under vacuum, the residue dissolved in methylene chloride (15 mL), washed with pH9 buffer, phases separated, and the organic phase dried with magnesium sulfate. Removal of the solvent under vacuum gave the crude product as a white solid (204 mg), which was repulsed in CDCl3 filtered off and dried to give the product as a white solid (46 mg, 39%). mp=230-32° C.
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]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[CH3:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:32]4[CH2:33][CH2:34][N:30]([CH3:29])[C:31]4=[O:35])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 84.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (412 mg) was obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc(Cl)c[n+]([O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1cc(Cl)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5-chloropyridine 1-oxide (90 mg, crude) in DCM (3 mL) was added TFA (1.5 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to afford the crude title product, which was used directly in the next step without further purification (80 mg, crude). MS (ESI) m/z 173.1 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=[O:2].[N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:6]=1[CH2:7]C(O)=O.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl.CC(C)=O>[ClH:3].[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:7]([C:6]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:5]=2)=[O:2])[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc2ccccc2n1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Cl
Product: O=C(c1ccc2ccccc2n1)N1CCN(Cc2ccccc2)CC1
Reaction time: 6 h

Procedure:
Thionyl chloride (6 ml) was added to a suspension of quinaldinic acid (3.463 g, 20 mmol) in chloroform (40 ml). After the resulting mixture was heated under reflux and stirring for 6 hours, the solvent was distilled off. The residue was dissolved in acetone (50 ml), followed by the addition of a solution of N-benzylpiperazine (10.576 g, 60 mmol) in acetone (50 ml). The thus-obtained mixture was stirred for 1 hour. A deposited precipitate was removed, and the solvent was distilled off. The residue was dissolved in ethyl ether. The resulting solution was washed with an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was dissolved in methanol, followed by the addition of concentrated hydrochloric acid (5 ml) for acidification. The solvent was distilled off and the thus-obtained residue was crystallized from a mixed solvent of ethanol and methanol, whereby 7.166 g of the title compound were obtained as white powder (yield: 97.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH2:16])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:24](=O)[CH3:25].C([BH3-])#N.[Na+].[C:31](#N)[CH3:32]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16]([CH2:24][CH3:25])[CH2:31][CH3:32])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC#N
Reactant: CC=O
Reactant: NCc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 8-chloro-1-(aminomethyl)-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine (1.42 g, 4.3 mmole) in 20 ml. of acetonitrile under nitrogen is treated successively with acetaldehyde (1.5 ml) and sodium cyanoborohydride (NaBH3CN) (550 mg). This mixture is treated dropwise, with a solution of 0.2 ml of acetic acid in 2 ml. of acetonitrile over a period of 1 hour and 30 minutes. [The addition is continued until the pH of the reaction mixture is between 6.4 - 6.8]. The mixture is stirred for 15 minutes at ambient temperature and concentrated in vacuo. The residue is treated with cold water saturated with sodium chloride and extracted with chloroform (5- ml., 3X). The chloroform solution is washed with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow oil. This oil is chromatographed over silica gel by eluting with 2% methanol-98% chloroformmixtures to afford 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1[OH:16])(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]=[C:50]=[O:51].[C:52]([O:56][CH2:57][CH2:58][CH2:59]O)(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH:58]([O:51][C:50](=[O:16])[NH:49][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[S:42][CH3:41])[CH3:59])(=[O:55])[CH:53]=[CH2:54]
Reactant: C=CC(=O)OCCCO
Reactant: CSc1ccccc1N=C=O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCC(C)OC(=O)Nc1ccccc1SC
Temperature: 60 °C

Procedure:
0.008 g of 2,6-di-tert-butyl-4-methylphenol, 0.004 g of Desmorapid Z, 4.8 g of 2-(methylthio)phenyl isocyanate in 8.5 g of ethyl acetate were initially introduced into a 50 ml round-bottomed flask and heated to 60° C. Thereafter, 3.7 g of 3-hydroxypropyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a light yellow liquid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:11]([C:23]#[N:24])=[C:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1.Cl.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>C(O)C>[NH2:7][C:8]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[CH:20][CH:21]=2)[C:11]([C:23]#[N:24])=[C:10]([S:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1
Reactant: CN(C)CCCl
Reactant: N#Cc1c(N)nc(SCc2ccccc2)c(C#N)c1-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccc3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.31 g (56.2 mmol) of potassium tert-butoxide are added to a solution of 8.39 g (23.4 mmol) of 2-amino-6-(benzylthio)-4-(4-hydroxyphenyl)pyridine-3,5-dicarbonitrile [preparation according to WO 01/25210, Example A 383, from 2-amino-4-(4-hydroxyphenyl)-6-mercaptopyridine-3,5-dicarbonitrile and benzyl bromide] in 105.5 ml of ethanol. The mixture is stirred at RT for 1 h, and 4.05 g (28.1 mmol) of 2-dimethylaminoethyl chloride hydrochloride are then added. The mixture is then stirred at +78° C. for 3 h. After cooling, the reaction mixture is filtered and the filtrate is concentrated using a rotary evaporator. The residue is purified directly by preparative HPLC (column: Merck 210 g RP silica gel Gromsil 1200DS-4 HR 10 μm, 50 mm×200 mm; mobile phase A=water+0.1% formic acid, mobile phase B=acetonitrile; gradient: 0 min 10% B→5 min 10% B→6 min 90% B→22 min 90% B→22 min 10% B→28 min 10% B; flow rate: 110 ml/min; wavelength: 220 nm).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:23]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:23])[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A 66 mg (1.65 mmol) portion of sodium hydride was added to 10 ml of DMF solution containing 300 mg (1.10 mmol) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and stirred at room temperature for 30 minutes, and then 103 μl (1.65 mmol) of methyl iodide were added thereto and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the resulting oil was purified by a silica gel column chromatography (60 cc; elution by ethyl acetate-hexane=1:5) to obtain 200 mg of the title compound (63% in yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccccc1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
Methyl ester (16) (500 mg, 1.48 mmol) was coupled to phenylboronic acid (150 mg, 1.23 mmol) using Method E. The crude compound was purified by column chromatography, eluting with a stepped gradient of 20-25% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=[C:4]([N:14]2[CH2:18][CH2:17][C:16]([C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[CH2:15]2)[N:3]=1.ClCCl.C(O)(=[O:37])C>[O-2].[O-2].[Mn+4]>[OH:37][CH:15]1[C:16]([C:23]2[CH:24]=[C:25]([Cl:31])[C:26]([Cl:30])=[C:27]([Cl:29])[CH:28]=2)([C:19]([F:22])([F:20])[F:21])[CH2:17][CH2:18][N:14]1[C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH2:8][NH:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: CCC(=O)NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2O)nc1C
Temperature: 25 °C
Reaction time: 100 h

Procedure:
N-({2-Methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-pyridin-3-yl}-methyl)propanamide (0.15 g) and manganese dioxide (1.2 g) were added to dichloromethane (20 ml), and acetic acid (2 ml) was added thereto in small portions at room temperature. The reaction mixture was stirred for 100 hours at room temperature, and filtered by suction on Celite. The filtrate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N-({6-[2-hydroxy-3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylpyridin-3-yl}methyl)propanamide (0.06 g).