Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:18]=1[C:19]#[N:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:18]=2[C:19]#[N:20])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Product: N#Cc1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCCCC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(1-piperidinyl)benzonitrile to give 1-benzyl-N-[2-cyano-3-(1-piperidinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH2:12][CH2:13][P:14](=[O:17])([OH:16])[OH:15])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=2.C(N(CC)[CH:22]([CH3:24])[CH3:23])(C)C.Cl[CH:28]([O:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:29]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:31]([O:30][CH:28]([O:17][P:14]([CH2:13][CH2:12][N:8]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]2[C:2](=[O:1])[C:10](=[O:11])[C:9]1=2)(=[O:15])[O:16][CH:28]([O:30][C:31](=[O:38])[C:23]1[CH:22]=[CH:24][CH:37]=[CH:32][CH:33]=1)[CH3:29])[CH3:29])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(Cl)OC(=O)c1ccccc1
Reactant: O=c1c2c(c1=O)N(CCP(=O)(O)O)CCCN2
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(OC(=O)c1ccccc1)OP(=O)(CCN1CCCNc2c1c(=O)c2=O)OC(C)OC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 36 h

Procedure:
A solution of the starting [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid (19.22 mmol, 5 g) in dry DMF (100 mL) was treated with N,N-diisopropylethylamine (76.88 mmol, 13.39 mL). The reaction mixture was stirred for 30 minutes at ambient temperature after which benzoic acid-1-chloroethyl ester (57.66 mmole, 10.65 g, synthesis described below) was added. The mixture was then stirred at 70° C. for 36 hours, cooled to ambient temperature and diluted with citric acid (2% aqueous solution, 70 mL). The product was extracted with ethyl acetate (3×50 mL), washed with sodium bicarbonate (3%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was flash chromatographed on silica gel. Elution with a gradient of 2 to 8% methanol in chloroform afforded 1.66 g (15.5%) of a stereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 8) [MS (ES+): m/e 557 (M+H)] and 0.73 g (6.8%) of a less polar diastereoisomer of [2-[8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl]ethyl]-phosphonic acid bis[1-(benzoyloxy)ethyl]ester (example 9) [MS (ES+): m/e 557 (M+H)].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][N:13]3C(OC(C)(C)C)=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][NH:13]3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccncc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(-c2ccc3c(c2)NCC3)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 100 ml flask was added tert-butyl 6-(pyridin-4-yl)indoline-1-carboxylate 50.B (202 mg, 0.68), 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 2 hours at which time the solvent was removed to give 6-(pyridin-4-yl)indoline TFA salt 50.0 as a light yellow solid (300 mg, 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)nc2c1
Yield: 81 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 81%). 1H NMR (300 MHz, CDCl3): δ 3.57 (s, 4H), 3.75-3.87 (m, 6H), 4.09-4.16 (m, 4H), 6.84 (d, J=9.3 Hz, 2H), 6.91-7.27 (m, 3H), 7.56-7.63 (m, 1H), 8.16 (d, J=9.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C([BH3-])#N.[Na+]>CCO.CC(O)=O>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH:16]2[CH2:17][CH2:18]2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(N)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.860 g, 3.16 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.703 g, 15.79 mmol) in EtOH (25 mL) and HOAc (2.5 mL) was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.073 g, 1.159 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 3) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.560 g, 41%). The racemic product was separated by chiral SFC (Table 2, Method 6) to give 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 22%) and 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:34][C:35](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:36].CCOC(C)=O>C(Cl)Cl>[ClH:24].[ClH:24].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]([CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[C:35](=[O:36])[CH3:34])=[CH:11][N:10]=[CH:9]2)=[CH:25][CH:26]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CNCCNc2cccc(Cl)c2)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCNc1cccc(Cl)c1)Cc1cncn1Cc1ccc(C#N)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of the diamine 8 (150 mg) in 2.5 mL of CH2Cl2 was added triethylamine (0.057 mL). The solution was cooled to 0° C., and acetic anyhydride (0.019 mL) was added. The reaction was stirred overnight, allowing it to gradually warm to room temperature. The mixture was poured into EtOAc and washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. This material was purified by silica gel chromatography (2.5-5% MeOH/CH2Cl2), taken up in CH2Cl2 and treated with 1 M HCl/ether solution, and concentrated in vacuo. The product hydrochloride 1 was isolated as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]1[C:38](=[O:39])[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)OC1CNN(C(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
4-(2,2-Dimethylpropionyloxy)-pyrazolidine-1-carboxylic acid 1-benzyl ester, 30,(1.45 g, 4.23 mmol) is dissolved in dichloromethane (21 mL). The solution is cooled to 0° C. and triethylamine (1.30 mL, 9.31 mmol) added dropwise via syringe. The cold bath is removed and the reaction allowed to warm to room temperature and continue stirring 20 minutes. 4-Fluorophenylacetic acid (848 mg, 5.50 mmol) is added. After stirring for 5 minutes, the reaction mixture is transferred via cannula into a solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrogen chloride in dichloromethane (21 mL) maintained at 0° C. The reaction is allowed to stir and gradually warm to room temperature over 12 hours. The reaction is washed with a 5% aqueous solution of Na2CO3 (2×50 mL). The combined aqueous layers are extracted several times with dichloromethane (50 mL) and the combined organic layers washed with brine, dried, filtered and concentrated in vacuo. The crude product is purified over silica (2:1 to 1:1 hexane/ethyl acetate) to afford 1.71 g (91% yield) of the desired product as a white solid.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Br:10][C:11]1[C:12]([CH3:22])=[N:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=1.[K].O>CN(C=O)C>[Br:10][C:11]1[C:12]([CH3:22])=[N:13][C:14]([N:17]([CH2:2][O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc(NS(C)(=O)=O)ncc1Br
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(COCC[Si](C)(C)C)S(C)(=O)=O)ncc1Br
Reaction time: 0.33 h

Procedure:
[2-(Chloromethoxy)ethyl]trimethylsilane (0.4 ml) was added to a solution of the product from step (i) in DMF (10 ml) and stirred for 20 min. The mixture was poured into water, extracted with ether, washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica eluting with 20% EtOAc/isohexane. Yield 0.53 g.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][O:7][N+:8]([O-:10])=[O:9])[C:3](Cl)=[O:4].[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:16]1)([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[C:12]([CH:15]1[CH2:19][S:18][CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]1[C:3](=[O:4])[C:2]([CH3:11])([CH3:1])[CH2:6][O:7][N+:8]([O-:10])=[O:9])([OH:14])=[O:13]
Reactant: CC(C)(CO[N+](=O)[O-])C(=O)Cl
Reactant: O=C(O)C1CSC(c2ccccc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO[N+](=O)[O-])C(=O)N1C(C(=O)O)CSC1c1ccccc1
Reaction time: 0.75 h
Yield: 38 %

Procedure:
A solution of 5.2 g of 2,2-dimethyl-3-nitroxypropanoyl chloride in 100 ml of tetrahydrofuran was added at 0° C. under nitrogen to a solution of 6.0 g of 4-carboxy-2-phenylthiazolidine and 4.0 g of potassium carbonate in a mixture of 50 ml of tetrahydrofuran and 150 ml of water. After stirring the resulting solution for 45 minutes the mixture was concentrated under reduced pressure to about 150 ml and then acidified to pH=2 with citric acid. The resulting mixture was extracted with diethyl ether and the organic phase was dried over sodium sulphate and evaporated. The residue was purified by chromatography (silica, petroleum ether 60-80: ethyl acetate: acetic acid/8:8:1). Yield 38%. Empirical formula C15H18N2O6S. Molecular weight 354. Melting point 35°-38° C. TLC system: petroleum ether 60-80: ethyl acetate: acetic acid/4:4:1. Rf 0.50.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[N:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1.CO.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[CH3:1][O:15][C:14]([C:11]1[N:12]=[N:13][C:8]([Cl:7])=[CH:9][CH:10]=1)=[O:16]
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Oxalyl chloride (1.14 mL, 13.09 mmol), was added dropwise to an ice-cold suspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9 g, 11.9 mmol), J. Het. Chem. 29(6), 1583-92; 1992] in a mixture of dichloromethane (50 mL) and N,N-dimethylformamide (1 drop) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30 mL) and cooled to 0° C. Methanol (485 μL, 11.9 mmol) was added and the mixture was stirred at 0° C. for 1 hour. Sodium hydrogen carbonate solution was then added to the reaction mixture and the aqueous layer was separated and extracted with dichloromethane (×2). The combined organic solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 65% yield, 1.33 g.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1>[CH2:17]([CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Reactant: c1ccc(CC2CCCN2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCCC2Cc2ccccc2)nc(-c2ccncc2F)cc1=O
Yield: 79.6 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.24 g, 1.0 mmol), (2RS)-2-benzyl-pyrrolidine (0.20 g, 1.2 mmol) and triethylamine (0.3 g, 3.0 mmol) in tetrahydrofuran (4 ml) was stirred for 5 hours at 40° C. The solution was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform/ethyl acetate=3/2) to afford 2-((2RS)-2-benzyl-pyrrolidin-1-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.29 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:34])[C:9]([N:11]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[C:27]3[CH3:33])[CH2:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37]I>CN(C=O)C.O.CCOC(C)=O>[CH3:37][N:29]1[C:30]2[C:26](=[CH:25][C:24]([N:11]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=3)[C:9](=[O:10])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:34])=[CH:32][CH:31]=2)[C:27]([CH3:33])=[N:28]1
Reactant: Cc1n[nH]c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)C(=O)c3ccc(F)cc3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C)c2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)C(=O)c3ccc(F)cc3)cc12
Reaction time: 5 h

Procedure:
To a solution of 0.32 mmol 2-(4-Fluoro-phenyl)-N-(3-methyl-1H-indazol-5-yl)-2-oxo-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (step 1) in 5 ml dry DMF was added 1.1 eq. NaH and the RM stirred at RT for 30 min. 5 eq. MeI was added and stirring continued for 5 h. Addition of 5 ml H2O, concentration, repartioning between EtOAc and H2O, gave after separation of the layers and concentration the target compound (157 mg) MS(m/e): 485.1 [M+H]+ which was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH2:22][NH2:23])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([Cl:35])=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[ClH:35].[ClH:35].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:23][CH2:22][CH:11]2[CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][CH2:13][N:12]2[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(N2CCN(Cc3ccccc3)C(CN)C2)c1
Product: COc1cccc(N2CCN(Cc3ccccc3)C(CNC(=O)c3ccc(NS(C)(=O)=O)cc3)C2)c1
Product: Cl

Procedure:
In a manner similar to Preparation 3, react 4-(3-methoxyphenyl)-1-(phenylmethyl)-2-piperazinemethanamine (3.1 g, 10 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (3.3 g, 15 mmol) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][OH:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][OH:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(CO)(c2ccc(Br)cc2)CC1
Temperature: 75 °C

Procedure:
To a round bottom flask containing (8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.88 g, 14.91 mmol) was added acetone (34 ml) and water (17 ml) at room temperature. p-toluenesulfonic acid (57 mg, 0.30 mmol) was then added and the mixture heated to 75° C. for 1 hour. The content was cooled to room temperature and concentrated under reduced pressure to remove the excess acetone. The resulting aqueous mixture was extracted with EtOAc twice. The combined organic portion was dried over sodium sulfate and concentrated to afford the title compound as white solid. (4.22 g) LC/MS, ESI-MS: non-ionizable, RT: 1.05 (Condition E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][CH:7]=[C:6]2[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH2:19][CH2:18][N:17]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:16][CH2:15]2)=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ncc(N3CCNCC3)c2c1
Reactant: CS(=O)(=O)Cl
Product: COc1ccc2c(Cl)ncc(N3CCN(S(C)(=O)=O)CC3)c2c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 19.72 %

Procedure:
6-methoxy-4-(piperazin-1-yl)isoquinolin-1-ol (0.15 g, 0.578 mmol) was taken in methane sulfonyl chloride (0.090 mL, 1.157 mmol) and added phosphorous oxychloride (5 mL) and stirred for 1 h at 110° C. The volatiles were evaporated and the crude was poured into ice. This solution PH was adjusted to 9.0 and extracted with ethyl acetate and washed with brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude sample was purified by silica gel chromatography using 45% ethyl acetate in pet ether to get 1-chloro-6-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)isoquinoline (0.041 g, 0.114 mmol, 19.72% yield) as solid. 1H NMR (300 MHz, DMSO-d6): ppm 8.18 (d, J=9.16 Hz, 1H) 7.98 (s, 1H) 7.42-7.50 (m, 1H) 7.38 (s, 1H), 3.99 (s, 3H), 3.41 (br. s., 4H) 3.19 (br. s., 4H) 3.00 (s, 3H). MS: MS m/z 346.20 (M++1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:18].S(OC)(OC)(=O)=O>CC(C)=O>[F:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:1])=[C:13]2[C:9]=1[CH2:10][CH2:11][C:12]2=[O:18]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2c(F)ccc(O)c21
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(F)c2c1C(=O)CC2

Procedure:
In a nitrogen atmosphere, to 300 g powdered potassium carbonate in 1.5 1 of acetone is added 121 g II under stirring, followed by 83 ml of dimethyl sulphate. After heating to reflux for 2 hrs, the solvent is distilled off, water is added and the mixture refluxed for a further hour. Extraction with methylene chloride and evaporation gives 125 g of crude III, which is purified by crystallization from EtOAc, m.p. 118°-120°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:29])[C:27]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:14][C:13]=3[CH:26]=2)[NH:9][C:8]1=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH3:6][C:7]1([CH3:29])[C:27]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:19][C:18]=4[O:24][CH3:25])=[N:14][C:13]=3[CH:26]=2)[NH:9][C:8]1=[O:28]
Reactant: COc1cc(O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reaction time: 2 h

Procedure:
0.53 g. (4.6 mmol) methanesulphonyl chloride was added dropwise at 25° C. to a solution of 1.5 g. (4.6 mmol) 7,7-dimethyl-2-(2-methoxy-4-hydroxyphenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one and 0.46 g. (4.6 mmol) triethylamine in 20 ml. dimethylformamide. After 2 hours, the dimethylformamide was distilled off in a vacuum. The residue was worked up with water and filtered off with suction. The residue was recrystallised from ethanol. There were obtained 1.3 g. (70.6% of theory) of the title compound; m.p. 233°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][C:32]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]2[C:33]=1[CH2:34][CH2:35][CH2:36][CH:37]2[NH2:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:43][CH:37]1[C:38]2[C:33](=[C:32]([CH3:31])[CH:41]=[C:40]([CH3:42])[CH:39]=2)[CH2:34][CH2:35][CH2:36]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(C)c2c(c1)C(N)CCC2
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3c(C)cc(C)cc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 5,7-dimethyl-1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[CH3:6])[CH3:2].[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N(CCCC(C)=O)C(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C(C)N(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C

Procedure:
To a solution of 4-6 (12 g, 40 mmol), 2-amino-3-formylpyridine (6.3 g, 52 mmol), proline (4.6 g, 40 mmol) and ethanol (300 mL) was heated at reflux for 15 h. After cooling and evaporation, the residue was chromatographed (silica gel, 1:1 chloroform/ethyl acetate) to give 4-7 as a yellow oil.