Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.[CH2:26]([O:28]CC)[CH3:27]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine is suspended in 10 ml of acetic anhydride and the suspension is stirred at RT for 1 h. The solution is treated with diethyl ether, and the precipitate is filtered off with suction and extracted with sodium hydrogencarbonate solution/ethyl acetate. After drying and concentration of the organic phase, the residue is recrystallized from ethyl acetate/methanol. 0.63 g (56.0% of theory) of the title compound of m.p. 218° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Clc1ccncc1
Agent: Cl
Product: O=C(O)c1cc(Cl)ccc1Nc1ccncc1
Yield: 40.8 %

Procedure:
5-Chloro-2-(4-pyridinylamino)benzoic acid was prepared from 25 g of 5-chloroanthranilic acid and 21 g of 4-chloropyridine hydrochloride according to the procedure of Example 1, part (a). There was obtained 14.2 g of 5-chloro-2-(4-pyridinylamino)benzoic acid, m.p. 306°-308° C. (decompn.).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39]([O:46][C:47](=[O:50])[CH2:48]Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:48][C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:50])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3cc(C)c(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3cc(C)c(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 250 mg 4-{2-[(4-Hydroxy-6,7-dimethyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 1.5 ml of DMF, 202 mg of cesium carbonate and 142 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 290 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][N:3]=1.NN>C(Cl)Cl.CCO>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[N:3][N:4]=1
Reactant: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2-[(3-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]-1H-isoindole-1,3(2 h)-dione (2.00 g, 7.40 mmol) in DCM (10.0 mL) and EtOH (10.0 mL) was charged with hydrazine (0.58 mL, 18.5 mmol) and stirred at rt for 8 h, then heated to 45° C. for an additional 16 h. The reaction was charged with an additional 0.5 equiv of hydrazine (0.116 mL, 3.70 mmol) and heated to 45° C. for 4 h. The reaction mixture was allowed to cool to rt then filtered through a fritted funnel and the cake was washed with 2 portions of cold 1:1 EtOH/DCM (75 mL) and the filtrate was concentrated resulting in 622 mg of a pale yellow solid which was taken on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 3.72 (s, 2H); MS (ES+): m/z 141.06 [MH+].
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.[Br:28]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:28][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: BrBr
Reactant: COc1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.51 g (0.043 mol) of sodium acetate are added to 9.8 g (0.033 mol) of (imidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 1 in 170 ml of chloroform, followed, dropwise, by a solution of 1.85 ml (0.036 mol) of bromine in 15 ml of chloroform, the medium being maintained at ambient temperature. On completion of the introduction, the mixture is stirred for a further 1 hour at the same temperature. The reaction medium is poured onto a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is separated by settling, washed with an aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in a toluene/dichloromethane mixture and then purified by filtration through a bed of silica gel, elution being carried out with toluene. After evaporation, 7.71 g of a yellow solid are collected. Melting point: 189° C.; 1H NMR (CDCl3): 4.10 (3H, s), 7.23-7.29 (1H, m), 7.41-7.46 (1H, m), 7.78 (1H, d), 7.96 (1H, d), 8.14-8.20 (2H, m), 9.90 (1H, d)
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.Cl.[N:16]1([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=3)[CH2:20][CH2:21]2)=[N:23]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Agent: Cl
Product: CC(=O)Nc1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 11 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.194 g, 0.915 mmol) and 3-piperazin-1-yl-1H-indazole hydrochloride (0.328 g, 1.372 mmol), and following the procedure outlined in Example 501, N-(4-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-acetamide was obtained as its hydrochloride salt (0.038 g, 0.101 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([N:10]([CH:37]2[CH2:39][CH2:38]2)[C:11]([C:13]2[N:34]([CH2:35][CH3:36])[C:16]3=[N:17][C:18]([NH:25][C:26]4[S:27][C:28]([C:31](O)=[O:32])=[CH:29][N:30]=4)=[C:19]4[N:23]=[CH:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[O:12])[CH2:9][CH2:8]1>>[CH:37]1([N:10]([CH:7]2[CH2:8][CH2:9]2)[C:11]([C:13]2[N:34]([CH2:35][CH3:36])[C:16]3=[N:17][C:18]([NH:25][C:26]4[S:27][C:28]([C:31]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:32])=[CH:29][N:30]=4)=[C:19]4[N:23]=[CH:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[O:12])[CH2:38][CH2:39]1
Reactant: C1COCCN1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N4CCOCC4)s3)nc21

Procedure:
This compound was prepared according to Example 20 using morpholine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-(morpholine-4-carbonyl)thiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[C:14]([CH3:23])=[C:15]([S:19]([NH:11][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[C:9]([CH3:10])[N:8]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: COCc1ccc(N)nc1C
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COCc1ccc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-methoxymethyl-6-methyl-pyridin-2-ylamine (0.058 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.094 g) as an off-white foam (0.093 g). MS (ESI−): 339.0 ([M−H]−)
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:23](O)(C)C>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH:6]([CH3:23])[CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC[O-]
Product: CC(C)OC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C

Procedure:
To a chilled (0° C.), stirred solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (0.68 g) in anhydrous isopropyl alcohol (10.2 ml) was added titanium (IV) ethoxide (0.17 ml) via syringe under a nitrogen atmosphere. The solution was warmed to room temperature and refluxed for 6.5 hours. The isopropyl alcohol was removed under reduced pressure and the residue dissolved in ethyl acetate (100 ml). The solution was washed twice with 50 ml portions of saturated aqueous NH4Cl solution, twice with 50 ml portions of saturated aqueous NaHCO3 solution and once with 50 ml of brine. The organic and aqueous phases were separated and the organic phase dried (Na2SO4), filtered, and concentrated to an oil. The crude mixture was purified using preparative HPLC (silica gel, 35% ethyl acetate in dichloromethane as the loading solvent and eluent). The appropriate fractions were combined and the solvents were removed under reduced pressure yielding 0.54 g of 1,2,3,3 a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, isopropyl ester, as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:13][CH:14]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CS(C)=O.O>[CH2:46]([N:19]1[C:15]([CH:14]([NH:20][C:21]([N:23]2[CH2:24][CH2:25][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:27][CH2:28]2)=[O:22])[CH2:13][C:5]2[CH:6]=[C:7]3[C:11](=[C:3]([CH2:1][CH3:2])[CH:4]=2)[NH:10][N:9]=[C:8]3[CH3:12])=[N:16][N:17]=[N:18]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnn[nH]2)cc2c(C)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nnnn2Cc2ccccc2)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid [2-(7-ethyl-3-methyl-1H-indazol-5-yl)-1-(1H-tetrazol-5-yl)-ethyl]-amide (30 mg, 0.05 mmol, 1.0 equiv), sodium carbonate (18.0 mg, 3.0 equiv), and benzyl bromide (8 μL, 1.1 equiv) were combined in dimethylsulfoxide and the mixture stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine (3×), dried over sodium sulfate, and concentrated. Purification by preparative HPLC afforded a mixture of the two alkylated regioisomers which were not separated. LC/MS: tR=1.68 min, 619.44 (MH)+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[CH:8][N:7]=1.O>C(O)C>[Cl:5][C:6]1[CH:11]=[C:10]([O:1][CH2:2][CH3:3])[CH:9]=[CH:8][N:7]=1
Reactant: CC[O-]
Reactant: Clc1cc(I)ccn1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccnc(Cl)c1

Procedure:
33 ml sodium ethoxide was added to 19.2 g 2-chloro-4-iodopyridine in 150 mL ethanol. The reaction was refluxed overnight. Then water was added and extracted with tert-butyl-methylether. The organic layer was evaporated and the residue cleanded by chromatography on silica gel (petrolether/EtOAC:9/1) to yield 5 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[NH:11][C:10]=2[CH3:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[N:11]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2cccc([N+](=O)[O-])c2c1Sc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indole (3.76 kg, 11.8 mol) and potassium carbonate (1.80 kg, 13.0 mol) were suspended in acetonitrile (32.7 kg). Water (0.53 kg) and a solution of ethyl bromoacetate (2.17 kg, 13.0 mol) in acetonitrile (5.75 kg) were added followed by an acetonitrile line rinse (2.97 kg). The mixture was heated at 50° C. for 6 hours then allowed to cool to 20° C. and held at this temperature overnight. Water (35.4 kg) was added to the reaction mixture and stirring continued for 30 minutes at 15° C. The solid product was collected by filtration, washed with acetonitrile (2.95 kg) then dried in a vacuum oven at 40° C. to afford [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indol-1-yl]acetic acid, ethyl ester as a bright yellow solid, 4.33 kg (91%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7](O)[C:6]=2[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH:8]=[CH:7][C:6]=2[CH:14]=1
Reactant: Cc1cc2c(cc1Br)C(O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c(cc1Br)C=CC(C)(C)O2

Procedure:
A stirred solution of the product of step d (27.1 g) in dry toluene (300 ml) is treated with p-toluenesulphonic acid (1.15 g) and heated under reflux for 2 h with water formed being removed via a Dean-Stark apparatus. The cooled solution is washed with aqueous sodium carbonate (100 ml, 2M), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product. This is purified by chromatography (silica gel, hexane) to give the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:19]=1[Cl:27]>CN(C=O)C>[Cl:27][C:19]1[N:20]=[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]2[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Clc1nc2ccccn2c1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (600 mg, 4.2 mmol) was dissolved in anhydrous DMF (20 mL), and then potassium carbonate (1.75 g, 12.7 mmol) and 3-(bromomethyl)-2-chloroimidazo[1,2-a]pyridine (5.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 0-12% DCM/MeOH to afford the title compound (165 mg, 15% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.85 (s, 2H), 6.03 (bs, 1H), 7.10 (t, J=6.7 Hz, 1H), 7.39 (t, J=7.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.59 (d, J=6.8 Hz, 1H); LRMS (ES+) m/z 307 (85%, M+1).
Reaction SMILES: [C:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:1]2[CH2:5][CH2:4][CH2:3][CH:2]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cc(C2=CCCC2)ccn1
Temperature: 90 °C
Yield: 85.8 %

Procedure:
To a solution of 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (681 mg, 3.51 mmol) and 2-chloro-4-iodopyridine (700 mg, 2.92 mmol) in 1,4-dioxane (12 mL) was added 2.0 M aqueous Na2CO3 (4.39 mL, 8.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (67.6 mg, 0.059 mmol). The reaction mixture was heated at 90° C. for 3.5 h then cooled to room temperature, diluted with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0% to 10% EtOAc/hexanes) to afford 450 mg (86%) of 2-chloro-4-cyclopent-1-enyl-pyridine as a white solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[NH:3][C:2]1=[O:12].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[O:12]=[C:2]1[NH:3][C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=2)[NH:1]1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2cc(S(=O)(=O)O)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
2,4(1H, 3H)-Quinazolinedione (10 g) was added portionwise to a stirred mixture of 65% fuming sulphuric acid (10 ml) and concentrated sulphuric acid (40 ml) at room temperature. After the addition was complete, the mixture was stirred at 55°-60° for 30 minutes, cooled, poured onto ice (100 g) and stood in a refrigerator for 1 hour. The colourless crystals were filtered, washed with a little ice-cold 6 N hydrochloric acid and finally dried in a vacuum oven to give the hydrated title compound, (14.7 g, m.p. >300°).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH3:28])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1
Yield: 79.5 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 1.5 g (11.6 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.09 g (79%) of 7-chloro-3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 105°-108°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 557.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].Br[CH2:23][CH2:24]Cl.O>CS(C)=O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]([O:16][CH3:17])=[O:15])[CH2:24][CH2:23]2)[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: ClCCBr
Reactant: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
The compound (1.76 g) obtained in step 1 was dissolved in DMSO (30 mL), sodium hydride (0.59 g) was added at 0° C., and the mixture was stirred for 5 min. To the reaction mixture was added 2-bromo-1-chloroethane (0.77 mL), and the mixture was stirred at room temperature for 45 min. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (10% ethyl acetate/hexane) to give methyl 1-[3,5-bis(trifluoromethyl)phenyl]cyclopropanecarboxylate (1.80 g, 94%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:24]4=[C:25]([C:27](=[O:37])[C:28]([CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:29][N:23]4[C:22]4[CH:21]=[CH:20][C:19]([Br:38])=[CH:18][C:17]3=4)[CH:26]=2)[CH:9]=[N:10][CH:11]=1)(=O)C.[OH-].[Na+]>CO.O>[Br:38][C:19]1[CH:20]=[CH:21][C:22]2[N:23]3[CH:29]=[C:28]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:27](=[O:37])[C:25]4[CH:26]=[C:14]([O:13][CH2:12][C:8]5[CH:9]=[N:10][CH:11]=[C:6]([CH2:5][OH:4])[CH:7]=5)[CH:15]=[C:16]([C:17]=2[CH:18]=1)[C:24]3=4
Reactant: CC(=O)OCc1cncc(COc2cc3c(=O)c(Cc4cccnc4)cn4c5ccc(Br)cc5c(c2)c34)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cncc(CO)c4)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2-(5-acetoxymethyl-3-pyridylmethyloxy)-10-bromo-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 24 was suspended in methanol (10 ml), and to the suspension was added an aqueous solution of sodium hydroxide (a solution prepared by dissolving 85 mg of sodium hydroxide in 0.8 ml of water), and the mixture was stirred at room temperature for 1 hour. The crystals precipitated were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (180 mg, 97%).