Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:28][C@@H:29]([F:30])[C@@H:25]([CH2:24][NH:23][CH:20]5[CH2:21][CH2:22]5)[CH2:26]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 48.9 %

Procedure:
Using 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (199 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (131 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (148 mg).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[S:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1>CN(C=O)C>[O:27]=[C:19]1[N:20]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:18]1[CH:15]1[CH2:16][CH2:17][S:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1[nH]c2ccccc2n1C1CCSCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 1 h

Procedure:
Sodium hydride (68.3 mg of a 60% dispersion in mineral oil, 1.71 mmol) followed by tert-butyl bromoacetate (0.189 mL, 1.28 mmol) was added to a solution of 1-tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one from Step B (200 mg, 0.854 mmol) in DMF (5 mL). After 1 h, the reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (10 mL). The organic layer was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, gave the title compound. MS: m/z=349 (M+1).
Reaction SMILES: [ClH:1].Cl.FC1C=CC(C2C=NC(N3CCNCC3)=NC=2)=CC=1.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)=O)(C)(C)C>>[ClH:47].[ClH:1].[Cl:48][C:43]1[CH:42]=[C:41]([C:38]2[CH:37]=[N:36][C:35]([N:32]3[CH2:31][CH2:30][NH:29][CH2:34][CH2:33]3)=[N:40][CH:39]=2)[CH:46]=[CH:45][C:44]=1[Cl:47]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1
Agent: Cl
Agent: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Product: Clc1ccc(-c2cnc(N3CCNCC3)nc2)cc1Cl
Yield: 90 %

Procedure:
Prepared according to the method for the preparation of 5-(4-fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride, from 4-[5-(3,4-Dichlorophenyl)pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (0.93 g), to furnish the title compound as an off-white solid (0.78 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OC(C)(C)C)=O.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:1][N:2]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: CCCCN(C)C(=O)CCCCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCN(C)C(=O)CCCCCCCN
Reaction time: 1 h

Procedure:
Combine 8-(t-butoxycarbonyl)amino-octanoic acid methyl-butyl-amide and 4M hydrochloric acid in dioxane (10 mL). After 1 hour, the reaction mixture is evaporated in vacuo to give a residue. Triturate the residue with diethyl ether to give a solid. Collect the solid by filtration and dry in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][S:23][CH3:24])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CC1CCC(N(CCSC)C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCN(C(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1
Reaction time: 3.75 h

Procedure:
To a solution of ethyl 2-[4-[tert-butoxycarbonyl(2-methylsulfanylethyl)amino]cyclohexyl]acetate (2.11 g, 5.89 mmol) in methanol (10 mL) and THF (10 mL) was added NaOH (10 mL, 1M aqueous). The resulting solution was stirred for 3.75 hours then acidified with HCl (2M, aqueous to pH 2). This mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (25 g silica; eluted with 20-60% ethyl acetate in hexanes) to give the title compound as a 6.9:1 mixture of trans to cis isomers.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]2[C:21]([CH:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1>O1CCCC1.ClCCl.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[C:21]([CH:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:28][CH:29]=1)=[O:30]
Reactant: OC1CCC(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2ncccc2C2CCC(O)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyridin-3-yl)cyclopentanol (780 mg, 1.943 mmol) in tetrahydrofuran (20 mL) and dichloromethane (50 mL) was treated with manganese dioxide (1351 mg, 15.54 mmol). The reaction was stirred at 23° C. under nitrogen. After 3 h, the reaction was filtered through celite, the filter cake washed with tetrahydrofuran (200 mL), the filtrates combined, concentrated in vacuo and purified by silica gel chromatography (eluant: 1-5% methanol/dichloromethane), affording the product as a white solid. MS (ESI, pos. ion) m/z: 400.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+].Cl>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[Cl:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Temperature: 78 °C
Yield: 65.3 %

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.150 g, 0.380 mmol) and ethyl formate (0.090 mL, 1.12 mmol) were dissolved in anhydrous ethanol (4 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.7 mL, 1.9 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were subsequently washed with 0° C. EtOH to afford the pure 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.105 g, 0.248 mmol, 65%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][S:8]([OH:11])(=O)=[O:9].[CH2:12]([C:14]1[C:15](=[O:26])[NH:16][C:17]([CH3:25])=[C:18]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([C:14]1[C:15](=[O:26])[NH:16][C:17]([CH3:25])=[C:18]([C:20]2[S:21][C:22]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:23][CH:24]=2)[CH:19]=1)[CH3:13]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc(-c2cccs2)c(C)[nH]c1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Phosphorus pentachloride (4.67 g, 22.4 mmol) is placed in a three neck round bottom flask and cooled to 0° C. Chlorosulfonic acid (6.53 g, 56.0 mmol) is added slowly. The reaction is stirred until the fuming action stops and the reaction mixture becomes clear. Then a solution of 3-ethyl-6-methyl-5-(thiophen-2-yl)-1H-pyridin-2-one (4.92 g, 22.4 mmol) of the above reaction in chloroform (35 mL) is added dropwise, and stirring at 0° C. is maintained for 5 min, then at room temperature. After 30 min, the reaction is poured into ice water (200 mL) and extracted with dichloromethane. The organic layer is washed with water, dried (sodium sulfate), filtered and concentrated and the residue is triturated with hepatane-30% ethyl acetate to afford the title compound (6.88 g, 97% yield) as a yellow solid. MS: m/e=318 (M+H). 1H-NMR (D6-DMSO, δ ppm) 13.2 (br s, 1H); 7.25 (s, 1H); 7.05 (d, 1H, J=3.2 Hz); 6.82 (d, 1H, J=3.2 Hz); 2.39 (q, 2H, J=7.4 Hz); 2.27 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:5]=[C:4]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:3]=3)[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2ccccn2)nc1NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCc2ccccn2)nc(NCc2ccccn2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in the presence of N-ethyl-diisopropylamine in dioxane at 90° C. during 18 hours to yield 4-(4-phenyl-piperazin-1-yl)-2,6-bis-[(pyridin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, yellowish solid; MS: [M+H]+=478.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][CH3:10])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CSc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
10.0 g (0.072 mol) of 3,5-dimethylbenzenethiol, 9.95 g (0.072 mol) of potassium carbonate and 0.46 g (1.4 mmol) of tetrabutylammonium bromide are suspended in 20 ml of dimethylsulfoxide under argon. Iodomethane (10.2 g, 0.072 mol) is added dropwise, and the mixture is stirred 16 h at ambient temperature. After pouring the mixture into water, the product is extracted with ether, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product 9.6 g (0.063 mol; 88%) is obtained as a slightly yellow oil, and is used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:19]([NH:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1)=[O:23])[CH3:22]
Reactant: COC(=O)c1cscc1N
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1cscc1C(=O)OC

Procedure:
A mixture of 50.0 g (0.258 mol) of methyl 4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g (0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethyl chlorocarbonate was refluxed for 5 hours. The insoluble matter was filtered off, the filtrate was evaporated down in vacuo and the residue was crystallised from petroleum ether. 59.0 g (99.8% of theory) of colourless crystals of melting point 52° C. were obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:29][O:30]C1C=C(C2C=C(C(O)=O)NN=2)C=CC=1>>[ClH:2].[CH3:29][O:30][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)[CH:7]=[CH:8][CH:3]=1
Reactant: COc1cccc(-c2cc(C(=O)O)[nH]n2)c1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cl
Product: COc1cccc(-c2cc(C(=O)Nc3ccc([C@@H]4CNCCO4)cc3)[nH]n2)c1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(3-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (CAS-890591-64-7) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. White solid. MS (ISP): 379.2 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH:38]([C:42](O)=[O:43])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:42]([CH:38]2[CH2:39][CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37]2)=[O:43])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (74) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-3-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 19 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (30%→50% ethyl acetate in hexanes) affording the desired product (81) as a solid. ESMS: MH+ 590.6
Reaction SMILES: C[O:2][C:3]1[N:4](CCCC2C=CC=CC=2)[CH:5]([CH3:24])[C:6]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.Cl>CO>[CH3:24][C:5]1[NH:4][C:3](=[O:2])[N:8]([CH2:5][CH2:6][CH2:7][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: COC1=NC(c2cccc([N+](=O)[O-])c2)=C(C(=O)OC(C)C)C(C)N1CCCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(CCCc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.6 %

Procedure:
A solution of 1,6-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-1-(3-phenylpropyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester (1.96 g. 4.34 mmoles) in methanol (20 ml) was treated with 2.5 N hydrochloric acid (5 ml) and the resulting mixture was allowed to stir at room temperature overnight. A colorless solid precipitated out. Methanol was evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate and evaporated. The residue was crystallized from dichloromethane/isopropyl ether to provide the title compound as a colorless solid (1.61 g), melting point 149.5-151.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:6]2[CH2:5]1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1(C)C=CC=CC=1.O>C(O)(=O)C>[CH2:5]1[C@H:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][C:9]3[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=3[N:7]2[CH2:21][CH2:22][N:4]1[CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: C1CNCCN1
Reactant: ClCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1N1CCN(CCN3CCNCC3)C[C@@H]21
Yield: 24.6 %

Procedure:
A mixture of 1.3 g (15.5 mmole) of (14bR)-2-(2-chloroethyl)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]-pyrazino [1,2-a]azepine [prepared as described in step (a) above], 3.6 g of piperazine and 30 ml of toluene was header under reflux for 16 hours. At the end of this time, the mixture was cooled and water was added. Sufficient of a 10% w/v aqueous solution of acetic acid was then added to make it acidic. The aqueous layer was separated, neutralized with a 10% w/v aqueous solution of sodium hydroxide, and extracted with diethyl ether. The solvent was then removed by evaporation under reduced pressure, to give 1.38 g (yield 92%) of the title compound.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:6][CH:5]=1.[CH3:17][C:18]1[C:19]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>>[CH3:17][C:18]1[C:19]([N:25]2[CH2:26][CH2:27][N:28]([C:3]([C:4]3[CH:9]=[CH:8][C:7]([N:10]4[CH2:14][CH2:13][O:12][C:11]4=[O:15])=[N:6][CH:5]=3)=[O:16])[CH2:29][CH2:30]2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(N2CCOC2=O)nc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 22.1 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using 6-(2-oxooxazolidin-3-yl)nicotinic acid methyl ester (250 mg) described in Preparation Example 138 and 1-(3,5-dimethylpyridin-2-yl)piperazine (233 mg) described in Preparation Example 47, the title compound (95 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.CCN(CC)CC.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:25]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(-c3ccccc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (30.4 mg, 0.090 mmol) (Starting Material 1), Et3N (38 μL, 0.271 mmol), tri-o-tolylphosphine (1.7 mg, 0.006 mmol) (Aldrich), Pd(OAc)2 (0.6 mg, 0.003 mmol)(Aldrich), and phenylboronic acid (16.5 mg, 0.136 mmol) (Aldrich) in 362 μL of dry N,N-dimethylformamide (Fisher Scientific) was heated at 100° C. for 24 h. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo to remove N,N-dimethylformamide, and then directly purified by flash chromatography (Merck Silica gel 60, 70-230 mesh, 10% ethyl acetate-hexanes then 25% ethyl acetate-hexanes elution) to provide pure (Z)-1,3-dihydro-4-phenyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Yield 21.9 mg, 85%) as an orange solid (mp 184-185° C.).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CCc1ccccc1-n1nc(C(C)(C)C)cc1N
Product: CCc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-ethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 479.10 [M+H]+; tR=3.3 min (System 3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[C:3]=1[C:4]([CH2:13][NH:14][CH:15]([CH:21](OCC)OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:6]2>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][C:5]=3[NH:6][C:7]=2[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(NCc1c[nH]c2c(C#N)ccc(Br)c12)C(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2[nH]c3c(C#N)ccc(Br)c3c2cn1
Temperature: 90 °C
Yield: 34.1 %

Procedure:
To a solution of ethyl 2-(((4-bromo-7-cyano-1H-indol-3-yl)methyl)amino)-3,3-diethoxypropanoate (1.12 g, 2.56 mmol) in toluene (51.1 mL) at 0° C. was added dropwise titanium tetrachloride (1 M in CH2Cl2, 8.94 mL, 8.94 mmol). The mixture was heated at 90° C. for 3 h. The mixture was cooled to room temperature and partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated. The resulting dark yellow solid was suspended in methanol, then collected by filtration and air-dried to afford the desired product as a yellow solid (300 mg, 29% yield), contaminated with partially aromatized material (ethyl 9-bromo-6-cyano-4,5-dihydro-3H-pyrido[4,3-b]indole-3-carboxylate and/or ethyl 9-bromo-6-cyano-2,5-dihydro-1H-pyrido[4,3-b]indole-3-carboxylate) and ethyl 9-bromo-6-cyano-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-3-carboxylate, which was used without further purification. LCMS (M+H)+ m/z 343.9, 345.9.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:4][CH:1]1[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)OCc1ccccc1
Reaction time: 2 h
Yield: 587.7 %

Procedure:
To a solution of cyclopropylamine (5.0 g, 87.5 mmol) and triethylamine (30 mL) in dichloromethane (100 mL) at 0° C. was added dropwise benzyl chloroformate (15.0 ml, 10.5 mmol) and the resulting mixture was stirred for 2 h. Additional benzyl chloroformate (1 mL) was added and the resulting reaction mixture was stirred overnight. The reaction was then quenched by addition of a saturated NaHCO3 and the separated aqueous phase was extracted several times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (15% EtOAc to 5% MeOH/EtOAc) to give cyclopropyl-carbamic acid benzyl ester (11.8 g, 71%).