Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([O:25]CC)=[O:24])=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:28].O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:28]
Reactant: CCOC(=O)c1ncc2ccc(-c3cccnc3-c3ccc(F)c(C)c3)cn12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ncccc2-c2ccc3cnc(C(=O)O)n3c2)ccc1F
Yield: 77.2 %

Procedure:
Ethyl 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate (2.1 g) and LiOH.H2O (400 mg) were stirred in THF/H2O (1:1, 60 mL) at 70° C. for 2 h. The reaction mixture was concentrated to dryness and diluted the pale yellow solid with water. The resulting semi-heterogeneous suspension was cooled in ice-bath, stirred and neutralized with aq. 3N HCl to pH 6. The solid aggregate was collected by filtration on Buchner funnel, washed with water and suction dried. Further processing the sample by drying over P2O5 in a vacuum desiccator provided the desired 6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylic acid (1.5 g, purity: 97%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:11]=2[Cl:25])[CH:5]=[N:4]1)[CH3:2].[CH2:27]=O>ClCCl.C(OCC)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([N:20]3[CH2:21][CH2:22][CH2:23][O:24][CH2:27]3)[C:11]=2[Cl:25])[CH:5]=[N:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(NCCCO)c2Cl)c1O
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCCOC3)c2Cl)c1O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 350 mg (0.87 mmol) of 1-ethyl-4-(2-chloro-3-(3-hydroxypropylamino)-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 1 mL of dichloromethane was diluted with 10 mL of diethyl ether and treated with 0.10 mL (1.3 mmol) of formalin. After stirring for 40 hours at ambient temperature, the reaction mixture contained a white precipitate and approximately one third of the starting material remained according to HPLC analysis. The solution was decanted and the solids remaining were dissolved in dichloromethane. The resulting solution was washed with water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 160 mg (43 percent of theory) of the title compound as tan crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:18][OH:19])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1.Cl.[F:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].[I-].[Na+]>C(#N)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[C:11](=[N:18][OH:19])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=4[CH:8]=[CH:7]3)[CH2:30][CH2:29]2)=[O:27])=[CH:34][CH:35]=1
Reactant: CN1CC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CN1CC(=NO)c2c(ccn2CCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 78.7 %

Procedure:
A suspension of 61 mg (0.2 mmol) of Compound 20, 54 mg (0.22 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 74 mg (0.88 mmol) of sodium hydrogencarbonate and 66 mg (0.44 mmol) of sodium iodide in 10 ml of acetonitrile was refluxed for 29 hours. Post-treatment and purification were conducted in a similar manner as in Example 20, whereby 75 mg of the title compound were obtained (yield: 79%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][OH:26])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(Cl)Cl>[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH:25]=[O:26])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a stirred suspension of pyridinium chlorochromate (98%, 34.0 g, 0.155 mol) and Celite (24 g) in 200 mL of dry CH2Cl2 was added N-Boc-3-piperidinemethanol (2) (22.15 g, 0.103 mol) in 30 mL of CH2Cl2 in one portion, and the mixture was stirred at room temperature overnight. The mixture was filtered by passing through a funnel filled with 20 g of Celite. After the solvent was removed, the remaining oily residue was purified by a flash column (silica gel; hexane:ethyl acetate, 4:1) to afford 3 as a colorless oil 17.5 g (80%).
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:6]=2[N:5]=[C:4]([CH3:24])[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C)C=CC=CC=1.C(O)C>C1C=CC=CC=1>[NH2:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:6]=2[N:5]=[C:4]([CH3:24])[C:3]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1c(C)nc2c(c1N)c1c(n2Cc2ccc(OC)cc2)CCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(c1N)c1ccccc1n2Cc1ccc(OC)cc1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 4-amino-9-(4-methoxyphenyl)methyl-2-methyl-5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indole-3-carboxylic acid, ethyl ester (D8) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a procedure similar to Description 7, using benzene as solvent instead of toluene. Product was obtained as white crystals from ethanol.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: CNC
Product: CN(C)c1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In an analogous manner as described in example 2, reaction of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile with dimethylamine (33% solution in absolute ethanol) in a sealed tube at 110° C. yielded 3-dimethylamino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a light brown amorphous solid; MS: 295 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[CH3:28][O:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([CH:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][C:2]3=[O:10])=[N:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: COCCOc1ccc2c(Cl)ncnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(C3C(=O)Nc4ccccc43)ncnc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
A solution of oxindole (319 mg, 2.4 mmol) in THF (3 ml) was added dropwise under nitrogen to sodium hydride (58 mg, 2.4 mmol, pre-washed with hexane) and the mixture stirred for 20 minutes at ambient temperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (191 mg, 0.8 mmol) in DMF (3 ml) was added and the mixture then heated at 70° C. for 1 hour. The mixture was allowed to cool and the solvent removed by evaporation. The mixture was partitioned between water and ether. The aqueous phase was separated and adjusted to pH7 with 2M hydrochloric acid. The resulting solid was collected by filtration and washed with water and ethanol. This solid was then suspended in ether, recollected by filtration, washed with ether and dried under vacuum to give 7(2-methoxyethoxy)-4-(oxindol-3-yl)quinazoline (200 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
1: Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0° C. and treat with Cs2 CO3 (100 g, 307 mmol, 0.66 eq). Stir the resulting off-white slurry for 15 min, then add CH3I (33 mL, 530 mmol, 1.15 eq) via syringe. After 1 h, add additional DMF (250 mL), stir the slurry for 14 h and partition between EtOAc (1.5 L) and half saturated aqueous NaHCO3 (500 mL). Separate the organic layer and extract the aqueous layer twice with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHCO3 (500 mL) and water (5×500 mL), then dry (Na2SO4) and concentrate to obtain 105.4 g (456 mmol, 99%) of methyl 3-(3,4-dichlorophenyl)-2-propenoate as light brown needles.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](=O)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.INC(=O)CCC(N)=O.[NH2:25][C:26]([NH2:28])=[S:27]>C(OCC)(=O)C.CO>[NH2:28][C:26]1[S:27][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)[N:25]=1
Reactant: CCOC(=O)CC(=O)c1cnc(Cl)cn1
Reactant: NC(N)=S
Agent: NC(=O)CCC(=O)NI
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1sc(N)nc1-c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
Ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate (Intermediate 45, 2.0 g, 8.77 mM) was dissolved in ethyl acetate (30 mL), to this amberlyst resin (2.0 g) and N-iodosuccinamide (2.1 g, 9.64 mM) were added and stirred for 1 h at room temperature. The resin was filtered and the filtrate was concentrated under reduced pressure to afford crude compound, which was dissolved in methanol (25 mL). Thiourea (0.99 g, 13.15 mM) was added to the reaction mixture and the reaction mixture was heated to reflux for 2 h. The methanol was concentrated under reduced pressure and the resulting residue was partitioned between sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulphate, filtered, concentrated under reduced pressure to obtain crude compound which was purified by flash column chromatography (gradient up to 50% of ethyl acetate/pet ether) to afford 500 mg (20.06%) of ethyl 2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:24]([O:41][CH3:42])[CH:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:24]([O:41][CH3:42])[CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 98.2 %

Procedure:
To a mixture of ethyl (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoate (1.20 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 3 hrs. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give (2E)-3-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-2-propenoic acid as colorless crystals (1.12 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(#N)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([Cl:21])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Temperature: 70 °C
Yield: 57.8 %

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100%) to yield the title compound as a yellow oil (3 g, 57.8%). LC-MS: 260 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:3]1
Reactant: CN1CCN(c2ncccc2C(=O)O)C(c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ncccc2CO)C(c2ccccc2)C1
Yield: 88.5 %

Procedure:
In 150 mL of THF was dissolved 10.2 g of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carboxylic acid under nitrogen atmosphere. To 300 mL of THF was added 10.2 g of lithium aluminum hydride, and the above THF solution was added in a thin stream to the mixture over 50 minutes under reflux. After refluxing the mixture for 4 hours, the mixture was cooled to 0° to 5° C., and 40.5 mL of water was gradually added in a thin stream thereto. Aluminum hydroxide was separated therefrom by filtration, and the filtrate was concentrated with an evaporator. The residue was allowed to recrystallize from an ether, to give 8.6 g of 2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-methanol. Its yield was 98%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([O:21]CC4C=CC=CC=4)=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].CO.Cl>CN1CCCC1=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=[O:20])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OCc4ccccc4)cc3c2n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2n1
Yield: 100.4 %

Procedure:
At room temperature, 1.18 g of 8-benzyloxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 17) is hydrogenated under a hydrogen pressure of one bar for 2 hours in a mixture of 60 ml of N-methylpyrrolidone, 20 ml of methanol, and 10 ml of 1N hydrochloric acid with 498 mg of palladium on carbon (10%). After vacuum-filtering over kieselguhr, the mixture is concentrated. The residue is extracted in a mixture of ethyl acetate, ethanol, and petroleum ether, thus obtaining 900 mg of 8-hydroxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester in the form of a hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.C(O)C.[NH:15]([C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[NH2:16].OCC[N+](C)(C)C>CO>[NH2:9][C:8]1[CH2:7][CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[N:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[N:16]=1
Reactant: NNc1nc2ccccc2s1
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: C[N+](C)(C)CCO
Solvent: CCO
Solvent: CO
Product: NC1=NN(c2nc3ccccc3s2)C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of 3.28 g. of p-chlorocinnamonitrile, 50 ml. of absolute ethanol, 3.1 g. of 2-hydrazinobenzothiazole and 1.0 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours. The reaction mixture is cooled and the precipitate is collected by filtration. The solid is washed with ethanol to yield 3.2 g. of crude product. This material is recrystallized from acetone to give 1.65 g. of the product of the Example as yellow crystals, m.p. 273°-275° C.
Reaction SMILES: Cl.[NH:2]([CH2:9][C:10]([O:12]CC)=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-:15][C:16]#[N:17].[K+]>>[O:15]=[C:16]1[NH:17][C:10](=[O:12])[CH2:9][N:2]1[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N#C[O-]
Reactant: CCOC(=O)CNCC(=O)OCC
Agent: Cl
Agent: [K+]
Product: CCOC(=O)CN1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
Concentrated hydrochloric acid (24.0 mL) was gradually dropped into 350 mL of an aqueous solution containing 27.5 g of diethyl iminodiacetate and 23.3 g of potassium cyanate. After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate several times and the extracts were combined followed by drying over sodium sulfate. The dried extract was concentrated and the residue was recrystallized from ethanol to give 11.1 g of ethyl 2,4-dioxoimidazolidine-1-acetate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]([CH2:16][NH:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:11]([C:13](O)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]3[CH2:16][N:17]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)[C:13](=[O:14])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1c2nc(-c3ccc(Cl)cc3)n(-c3ccccc3F)c2CN1C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
A mixture of 2-(4-chloro-phenyl-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid I-5 k (1.2 g, 2.59 mmol), EDC (994 mg, 5.18 mmol), HOAt (704 mg, 5.18 mmol), and triethylamine (1.1 ml, 7.76 mmol) in CH2Cl2 (200 ml) was stirred for 17 hours at room temperature. The reaction mixture was washed with sat'd aq NaHCO3 and sat'd aq. NaCl, dried and concentrated in vacuo. The crude residue was purified on SiO2-gel using a solvent gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give 4A-1 as a white solid (752 mg, 73%): +APCI MS (M+1) 396.2; 1H NMR (CDCl3): δ 7.61-7.59 (m, 2H), 7.42-7.37 (m, 6H), 4.60 (m, 1H), 4.50 (s, 2H), 2.0 (m, 2H), 1.8-1.65 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](OCl)[CH2:9]CC.CSCC(OCC)=O.O>C(Cl)Cl.CN(P(N(C)C)(N(C)C)=O)C.[Ni].CO>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:8]1
Reactant: CCCCOCl
Reactant: Nc1ccccc1
Agent: [Ni]
Agent: CCOC(=O)CSC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
The synthesis was carried out with reference to the disclosure of Reference Article 11. There was dissolved aniline (34) (16.8 mmol) in methylene chloride, the resulting solution was cooled to −70° C., a solution (8 ml) of separately synthesized BuOCl (16.8 mmol) in methylene chloride was dropwise added to the cooled solution and then the mixture was stirred at −70° C. for 15 minutes. To the reaction solution, there was dropwise added a solution (8 ml) of separately synthesized MeSCH2CO2Et (16.8 mmol) in methylene chloride over not less than one hour and the mixture was further stirred for 2 hours. To the resulting reaction solution, there was dropwise added a solution (8 ml) of TEA (16.8 mmol) in methylene chloride over not less than 30 minutes, the mixture was stirred for 15 minutes at that temperature and then the temperature thereof was raised up to room temperature. To the mixture, there was added 10 ml of water, the mixture was then stirred for 15 minutes, followed by concentration, addition of ether (20 ml) and a 2M HCl (13 ml), extraction with ether, drying of the extract and the subsequent concentration thereof. The resulting compound (4.25 mmol) was dissolved in HMPA (5 ml) and an LR reagent (2.1 mmol) was added in an argon atmosphere. After the post-treatment, Ra—Ni (4-spoonful) and MeOH (60 ml) were added to the mixture and the latter was refluxed with heating for one hour. The Raney-Ni catalyst was removed from the reaction system through decantation, the solution was concentrated, followed by drying of the concentrate and purification by column chromatography (3 cm) to thus give indole (35) in a yield of 3.76 mmol (88%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].CC1C=[CH:19][C:20](S(O)(=O)=O)=[CH:21][CH:22]=1.C1(=O)CCC1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][CH2:22]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: O=C([O-])O
Agent: O=C1CCC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC2(CCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 221.1 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (110 mg, 0.502 mmol), PTSA (9.5 mg, 0.050 mmol), cyclobutanone (1.0 mL, 13.3 mmol) and acetic acid (1 mL) was stirred at 80° C. for 16 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL). Extraction with EtOAc (100 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave a yellow solid. This residue was purified by column chromatography (Purif, silica gel, EtOAc to 95:5 EtOAc/MeOH) to afford yellow solid (30 mg). This solid was triturated with EtOAc/hexane and collected by filtration to afford the title compound (25.6 mg, 19%) as a yellow solid:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13](=[O:20])[NH:12][C:11]2[CH:21]=[CH:22][CH:23]=[N:24][C:10]1=2)=[O:8].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]3[CH:21]=[CH:22][CH:23]=[N:24][C:10]2=3)=[O:8])[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21
Product: CN1CCN(CCCCCC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 36 %

Procedure:
Using the procedure of Example 9, the product of Step A was reacted with 1-methyl-piperazine to obtain a 36% yield of 5,11-dihydro-11-[6-(4-methyl-1-piperazinyl)-caproyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 179°-181° C. after crystallization from ethyl acetate.