Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Into a 500 mL round bottomed flask were added 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (11.80 g, 20.96 mmol), 2-methoxyphenyl boronic acid (3.76 g, 24.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.756 g, 1.08 mmol), acetonitrile (100 mL) and 100 mL of 2M Na2CO3 (aq). The flask was fitted with a reflux condenser and heated at 60° C. with rapid stirring under N2 for 8 h. The reaction mixture was filtered to obtain a grey-tan precipitate, which was dissolved in EtOAc and washed with water followed by brine. Concentration of this solution afforded 7.70 g (80%) of the title compound as a tan powder. 1H-NMR (500 MHz, d6-DMSO) δ 8.50 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.54 (dd, J=1.5, 7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39 (m, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.0 Hz, 1H), 3.80 (s, 3H), 2.34 (s, 3H); MS: m/z 456.9/458.9 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:25]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[CH:26][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C.[CH2:19]([NH:21][CH2:22]C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:19][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:22]
Reactant: BrCCCCCCCCc1ccccc1
Reactant: CCNCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To 538 mg of (8-bromooctyl)benzene were added 1 ml of ethanol and 1.05 ml of 50% aqueous diethylamine solution, and the mixture was stirred at a room temperature for 7.5 hours. To the mixture were added 30 ml of ethyl acetate and 5 ml of 5% sodium bicarbonate aqueous solution, and the resulting layers were separated. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol (9:1) to eliminate impurities appeared on the start point on thin layer chromatography. In this way, compound as colorless liquid, 378 mg of the title compound was obtained as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH2:25]>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH:25][C:9](=[O:11])[CH2:8][N:3]1[C:2]([CH3:1])([CH3:14])[CH2:6][CH2:5][C:4]1=[O:7]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CCOC(=O)CN1C(=O)CCC1(C)C
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1C(=O)CCC1(C)C

Procedure:
From 10 g. of ethyl 2,2-dimethyl-5-oxo-1-pyrrolidineacetate and 11 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine, following the procedure of Example 9, there is obtained cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-5,5-dimethyl-2-oxo-1-pyrrolidineacetamide as the hemihydrate; m.p. 94°-94.5° C. after recrystallization from isooctane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[C:33]([O:40][CH3:41])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>C(Cl)Cl.CO>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:32][C:33]=1[O:40][CH3:41])(=[O:36])[NH2:44]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.1 %

Procedure:
To a stirred solution of 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-methoxybenzoic acid (250 mg, 0.41 mmol) in methylene chloride (8 ml), HATU (154 mg, 0.41 mmol) and DIPEA (0.1 ml, 0.57 mmol) were added. The mixture was stirred for 5 min. at rt and ammonia in methanol (2N, 2 ml) was added and the mixture was stirred overnight. The solvent was reduced to 3 ml and loaded onto a silica gel column, eluted with 3% methanol and methylene chloride to give 230 mg desired product. (ES+) m/z Calcd: [(M+H)+]: 615. found: 615.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:15]1([NH2:26])[C:20](F)=[C:19](F)C(F)=C(N)C=1F.Cl.Cl.CO[C:31]1[C:35](OC)=[N:34][S:33](=[O:39])(=[O:38])[N:32]=1.C(N)C#C>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:31]2[C:35]([NH:26][CH2:15][C:20]#[CH:19])=[N:34][S:33](=[O:39])(=[O:38])[N:32]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: C#CCN
Agent: Cl
Solvent: CO
Product: C#CCNC1=NS(=O)(=O)N=C1NCCSCc1csc(NC(=N)N)n1
Reaction time: 0.25 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 3.42 g; 11.2 mmoles) in 25 ml of methanol was added to a well stirred cold (8°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol. After 15 minutes at 8°-10°, the solution was cooled to 1° in an ice-bath and a solution of 6.0 ml 2-propynylamine in 15 ml of methanol was added. The ice-bath was removed and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 50 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. Two of the fractions yielded crystalline product (1.74 g) from methanol. The product was dissolved in hot methanol, filtered through Celite, cooled and filtered to yield the title compound, mp 176°-178°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:2].[CH:23](O)=[O:24]>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH:23]=[O:24])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OCc2ccccc2)cc1
Reactant: O=CO
Solvent: Cc1ccccc1C
Product: CCOC(=O)CN(C=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 5.83 g of N-(4-benzyloxybenzyl)-glycine ethyl ester, 0.86 mL of formic acid, and 20 mL of xylene was refluxed for 2 hours using a Dean-Stark trap to remove the water produced in the reaction. After cooling, the reaction mixture was washed with 20% aqueous formic acid, water, saturated sodium bicarbonate solution, water, and brine. Finally the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to furnish 6.23 g of crude N-(4-benzyloxybenzyl)-N-formyl glycine ethyl ester, used in the following reaction without further purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:18])[CH2:16][OH:17])=[CH:14][C:9]=2[CH:8]=[CH:7][C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]1=2.[H][H].[CH2:25](I)[CH3:26]>CCOCC.O.CN(C)C=O>[CH2:25]([O:17][CH2:16][CH:15]([C:13]1[CH:12]=[CH:11][C:10]2[C:4](=[O:3])[C:5]3[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=3[CH:7]=[CH:8][C:9]=2[CH:14]=1)[CH3:18])[CH3:26]
Reactant: CCI
Reactant: [H][H]
Reactant: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC(C)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 40 °C

Procedure:
0.48 G. of a 50% mineral oil dispersion of sodium hydride is added to a solution of 2.64 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol in 30 ml. of dimethylformamide. The mixture is warmed to 40°C and stirred until hydrogen evolution ceases. 3.0 G of ethyl iodide is added and the mixture heated to 60°C for 3 hrs. Water and ether are added and the ethereal solution is washed with water, dried and evaporated to yield 1-ethoxy-2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propane.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:33][C:10]([CH:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(Cl)s2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(Cl)s3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 1-(5-chloro-1,3-thiazol-2-yl)-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (83.9 mg) in acetic acid (1.8 mL) was added ammonium acetate (278 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (83.9 mg, yield 89%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[NH:14][C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[Na].[CH3:30]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.CO>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH3:30])[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(CCCNC(=O)c2[nH]c(-c3ccccc3)c3cc(Cl)ccc23)OCCO1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(C(=O)NCCCC2(C)OCCO2)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide in 160 ml. of dimethylformamide is treated under an atmosphere of argon at 0°-5° C. with a solution of 2.1 g. of sodium in 40 ml. of methanol. The mixture is then stirred at room temperature for 30 minutes and subsequently added dropwise to a solution of 18.6 g. of p-toluenesulfonic acid methyl ester in 20 ml. of dimethylformamide. The mixture is subsequently stirred at room temperature for 30 minutes and then at 80° C. for 1 hour. After cooling, the mixture is poured on to 400 ml. of ice-water and, after the addition of 20 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue obtained is chromatographed on 500 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The uniform fractions are combined and evaporated, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide having a melting point of 137°-139° C. Recrystallization from ethanol yields colorless crystals of the same melting point.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22]CC2C=CC=CC=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(OCc4ccccc4)nc3N21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 3.90 g (9.86 mmol) (4R,9aR)-6-benzyloxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 21, intermediate) in 30 ml methanol:ethyl acetate (1:1 v/v) 0.20 g 10% palladium on charcoal was added and the reaction was hydrogenated at atmospheric pressure for 2 h. After filtration over dicalite speed plus the filtrate was evaporated and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to afford the desired compound as a colorless foam (82.0%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][O:25][C:26]1([C:30]2[S:31][C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:34]=2)[CH2:29][CH2:28][CH2:27]1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:32]2[S:31][C:30]([C:26]3([O:25][CH2:24][O:23][CH3:22])[CH2:27][CH2:28][CH2:29]3)=[N:34][CH:33]=2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Cl)cnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(OCOC)CCC2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3ccn4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-chloro-4-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 1D) (7.12 g, 16.46 mmol), bis(triphenylphosphine)palladium dichloride (0.809 g, 1.15 mmol), and 2-(1-(methoxymethoxy)cyclobutyl)-5-(tributylstannyl)thiazole (Example 1C) (10.45 g, 21.39 mmol) in N,N-dimethylformamide (54.9 ml) was heated to 70° C. for 1 hour. The reaction was cooled to room temperature and quenched by the addition of an aqueous potassium fluoride solution (19 g in 100 mL water) and ethyl acetate (200 mL). The mixture was stirred vigorously overnight and was then filtered through diatomaceous earth, eluting with ethyl acetate. The layers were separated, and the organic layer was washed with aqueous saturated bicarbonate solution and water. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 35% ethyl acetate in hexane, to afford the title compound. MS ESI(+) m/z 504 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C1COCC1.CC(O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 0.97 g (4 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 0.91 g (4.8 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After acidification with acetic acid, the solvents were removed under vacuum, and the residue is dissolved in water. After being washed with EtOAc, the aqueous solution is basified with aqueous ammonia, and the product is extracted into EtOAc and dried, to give 1.15 g (77%) of the title compound: mp (MeOH) 204–206° C.
Reaction SMILES: Cl.N1C=C(C[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:18][C:13]=3[CH2:12][N:11](C(C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:10][CH2:9]2)N=C1.C([O-])([O-])=O.[K+].[K+].Br[CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:45]([O:47][CH3:48])=[O:46]>CO>[C:49]1([CH:44]([N:11]2[CH2:12][C:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:15][C:14]=3[NH:8][CH2:9][CH2:10]2)[C:45]([O:47][CH3:48])=[O:46])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccc3)cc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C(c1ccccc1)N1CCNc2ccc(-c3ccccc3)cc2C1
Reaction time: 18 h
Yield: 59.1 %

Procedure:
To a stirred suspension of Compound B of Example 12 (220 mg, 1.0 mmol) in MeOH in the presence of solid K2CO3 at room temperature under argon was added methyl bromophenylacetate (0.18 mL, 1.1 mmol). The mixture was stirred for 18 h, the solvent was removed, and the residue was purified by flash column chromatography (3:2, hexanes and ethyl acetate) to give 1,2,3,5-tetrahydro-a,7-diphenyl-4H-1,4-benzodiazepine-4-acetic acid, methyl ester as an oil (220 mg, 63%). This material was reacted as described for Compound D of Example 1 to afford Example 222 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[O:13]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:19][C:20]2[N:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=2)[CH2:14]1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:27][CH2:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:19][O:18][C@H:15]3[CH2:16][CH2:17][O:13][CH2:14]3)[N:25]=2)[N:7]=1
Reactant: NCc1cccc(CO[C@H]2CCOC2)n1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Yield: 72.5 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (17.24 g, 82.46 mmol), 6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethylamine (18.89 g, 90.70 mmol) and triethylamine (12.64 mL, 90.70 mmol) in propan-2-ol (165 mL) was heated at reflux for 2 h, cooled and the resulting precipitate was filtered, washed with cold propan-2-ol and dried to give the title compound (22.66 g, 73%) as a pink solid; LC-MS retention time 1.46 min, (M+H)+ 379.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.Cl>O.C(Cl)Cl>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[N:7]3[O:8][C:9](=[O:11])[N:10]=[C:6]3[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccc(Cl)cc2)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
5.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 7 ml. of triethylamine and 150 ml. of methylene chloride. 3.4 ml. of 4-chlorobenzoyl chloride in 35 ml. of methylene chloride are added dropwise while stirring and cooling to about 0° C. The mixture is subsequently stirred at about 0° C. for 1 hour. Water is then added thereto and the pH is adjusted to 4 with dilute hydrochloric acid solution. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure p-chloro-N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 192°-194° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2c1
Temperature: 80 °C
Yield: 63 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (160 mg, 0.72 mmol), 5-methoxy-3-(piperidin-4-yl)-1H-indole (obtained as described in PCT Int. Appl. WO 2004006922, Intermediate 37) (166 mg, 0.72 mmol) and DIPEA (0.138 mL, 0.79 mmol) in DMF (2 mL) were stirred and heated at 80° C. for 1 hour. The resulting mixture was cooled to room temperature and quenched in water (10 mL) to give a precipitate. The solid was collected by filtration, washed sequentially with water, acetonitrile and ether, and air dried to give 6-[4-(5-methoxy-1H-indol-3-yl)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (189 mg, 63%) as a colourless solid.