Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:29]1[CH:33]=[C:32]([CH:34]=O)[C:31]2[CH:36]=[CH:37][CH:38]=[CH:39][C:30]1=2>>[S:29]1[C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([CH2:34][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:17]3[C:16]4[C:11](=[C:12]([C:25]([F:28])([F:26])[F:27])[CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[CH:33]1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1csc2ccccc12
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4csc5ccccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and benzo[b]thiophene-3-carbaldehyde. MS (ESI) m/z 525.
Reaction SMILES: Br[CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1c(CBr)cn(-c2ccccc2)c2cc(Cl)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
In a 25 mL round-bottomed flask, crude 3-bromomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (0.184 g, 0.528 mmol) and sodium azide (34.3 mg, 0.528 mmol) were combined with DMF (3.5 mL) to give a yellow solution. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured over ice and the resulting white suspension was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, then concentrated to afford the crude product as slightly yellow oil. The crude was purified by flash chromatography using 15%-45% ethyl acetate/hexanes to afford 3-azidomethyl-7-chloro-1-phenyl-1H-quinolin-4-one (75 mg, 46% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CC#N>[CH2:23]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1)[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a mixture of ethyl 1H-pyrazole-4-carboxylate (35.0 g, 250 mmol) and K2CO3 (69.0 g, 500 mmol) in CH3CN (250 mL) was added BnBr (42.7 g, 250 mmol). The mixture was stirred at RT for 18 h and concentrated. The residue was suspended in EA (500 mL), washed with water (200 mL×2), dried over Na2SO4 and concentrated to give the desired compound as a white solid (53.0 g, 91.2%). 1H NMR (DMSO-d6) δ 8.46 (s, 1H), 7.88 (s, 1H), 7.41-7.19 (m, 5H), 5.37 (s, 2H), 4.21 (q, 2H, J=5.4 Hz), 1.25 (t, 3H, J=5.4 Hz). MS (ESI) m/e [M+1]+ 231.0.
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]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:21][CH:20]=1.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.[H-].[Na+]>CN(C)C=O>[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]([N:25]([S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:46])=[CH:37][CH:38]=2)(=[O:44])=[O:43])[S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])=[CH:21][CH:20]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-p-toluenesulfonamidophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 5 ml of dimethylformamide and then 1.0 g of p-toluenesulfonyl chloride in 5 ml of dimethylformamide are added dropwise to a suspension of 200 mg of 80% strength sodium hydride in 20 ml of dimethylformamide. After stirring at RT for 2 h, the mixture is added to ice-water and extracted with ethyl acetate/diethyl ether in the ratio 1:1. After drying and concentration of the organic phase, the residue is chromatographed on silica gel using a mixture of ethyl acetate/petroleum ether in the ratio 4:1. After concentration of the corresponding eluate fractions, the title compound of m.p. 120-130° C. is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[C:19]([CH:26]=O)=[CH:18]1.[ClH:28]>C(O)C>[ClH:28].[NH:17]1[C:25]2=[N:24][CH:23]=[CH:22][CH:21]=[C:20]2[C:19]([CH:26]=[C:6]2[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:18]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N(CC)CC)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(N(CC)CC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of ethyl 2-(diethylamino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.034 g, 0.15 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.022 g, 0.15 mmol) in ethanol (1.0 mL), 2M hydrochloric acid in ethanol (0.16 mL, 0.32 mmol) was added at ambient temperature. The mixture was refluxed for 3 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.023 g, y. 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:12]=[C:13]([CH2:15][C:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCC(C)(C)Cc1c[nH]c(CCc2ccc(Br)cc2)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCc2ccc(Br)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole (33.4 g, 100 mmol) in methlyene chloride (500 mL) was added trityl chloride (41.8 g, 150 mmol) and triethylamine (42 mL, 300 mmol). The reaction was stirred for 2 h, then washed with water, dried over sodium sulfate and concentrated to give a residue. The residue was purified by silica gel column chromatography eluting with ethyl acetate/hexanes (2:8). The chromatography was repeated eluting with methylene chloride/2-propanol 99.8:0.02) and then methlyene chloride/methanol (95:5) to provide 2-[2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1-trityl-1H-imidazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N1CCCC1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J39) (291 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (330 mg, 64%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].CC([O-])=O.[K+].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Pd]>[C:1]([O:4][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
A one-liter flask is charged with 450 grams of acetic acid, 92 grams of toluene and a catalyst mixture containing 34.1 grams of 5 wt. % palladium on charcoal, 100 grams of KOAc and 14 grams of stannous acetate. While the flask containing the reaction mixture is constantly stirred at about 100° C., air is continuously blown through the reaction mixture at a rate of about 0.5 liter/min. measured at 25° C. and 760 mm Hg for about 9 hours. Gas chromatographic (G.C.) analysis of the reaction mixture shows that about 80 mol % of toluene is converted to form approximately 91.5 mol % of benzyl acetate, 7.5 mol % of benzyl aldehyde and 1 mol % of benzyl diacetate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.F[B-](F)(F)F.[CH3:16][O+](C)C>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:16])[CH:4]=2
Reactant: C[O+](C)C
Reactant: Brc1cccc2[nH]ncc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: Cn1cc2c(Br)cccc2n1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of 4-bromo-1H-indazole (2.24 g, 11.4 mmol) in ethyl acetate (110 mL) was added trimethyloxonium tetrafluoroborate (2.19 g, 14.8 mmol) at room temperature, and the mixture was stirred for 3 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (2.29 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)=[O:6].OP([O-])(O)=O.[K+].O.[C-:24]#[N:25].[K+]>CN(C)C=O>[OH:14][CH:13]([C:11]1[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:15])[Cl:16])=[O:6])[S:9][CH:10]=1)[C:24]#[N:25]
Reactant: [C-]#N
Reactant: O=Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1

Procedure:
To a mixture of 1.0 g. of 2-(β,β,β-trichloroethoxycarbonyl)amino-4-formylthiazole, 0.87 g. of KH2PO4, 6 ml. of water and 4 ml. of dimethylformamide is added 0.33 g. of KCN at room temperature and the mixture is stirred for 30 minutes. The reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is washed with water and dried. Evaporation of ethyl acetate gives α-hydroxy[2-(β,β,β-trichloroethoxycarbonyl)aminothiazol-4-yl]acetonitrile 1.127 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>C1COCC1>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC[C@@H](O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of the central building block, e.g. (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid (Intermediate 7) (24.2 mmol, 6.24 g) in dry THF (125 ml) at −25° C. was added NMM (2.5 eq, 60.4 mmol, 6.64 ml) followed by isobutylchloroformate (1.05 eq, 25.4 mmol, 3.3 ml). The resulting mixture was stirred at −25° C. for 30 min and an amine or an amine salt, e.g. (S)-2-amino-1-phenylethanol (1.51 eq, 36.5 mmol, 5 g) was then added. The mixture was allowed to gradually warm to rt. After 16 h, the solvents were removed. The residue was dissolved in AcOEt, washed twice with NH4Cl saturated solution, then twice with 10% NaHCO3 solution. The organic layer was dried over Na2SO4, filtrated and concentrated to afford the desired product, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidine-carboxylate (8.76 g, 96%) as a pale yellow oil in 88.5% purity by HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[CH:18]=2)[N:3]=1.C1CCCCC=1>C1COCC1.[Pd]>[NH2:1][C:2]1[N:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[N:3]=1
Reactant: Cc1ccc(C(=O)n2nc(Nc3cccc(OCc4ccccc4)c3)nc2N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: C1=CCCCC1
Product: Cc1ccc(C(=O)n2nc(Nc3cccc(O)c3)nc2N)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 12.4 %

Procedure:
To a solution of 5-amino-3-[3-(benzyloxy)phenylamino]-1-(4-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-14) (0.50 g, 1.3 mmol) in THF (20 mL) was added cyclohexene (10 mL) and 10% Pd/C (0.10 g). The reaction was stirred at 90° C. under N2 for 48 h, then filtered through diatomaceous earth, washing with THF, and concentrated to give a yellow-orange solid. Purification by flash chromatography (95:5 CH2Cl2/CH3OH) followed by triturated in CH2Cl2 afforded 5-amino-3-[3-(hydroxy)phenylamino]-1-(4-(methyl)phenyl)carbonyl-1H-1,2,4-triazole (Ia-15) (0.05 g, 14%) as a yellow solid: Rf 0.22 (95:5 CH2Cl2/CH3OH); mp (DSC) 2 endothermic events, 214.7-217.5° C., 322.1-329.8° C., 1 exothermic event, 226.8-228.8° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J=8.1 Hz, 2H), 8.13 (d, J=8.2 Hz, 2H), 7.77 (s, 2H), 7.36 (d, J=8.1 Hz, 2H), 6.99-6.94 (m, 3H), 6.29-6.25 (m, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 158.2, 157.6, 157.3, 142.9, 142.0, 130.6,129.7, 129.1, 128.5, 107.8, 107.4, 104.0, 21.0; IR (ATR) 3363, 1668 cm−1; APCI MS m/z 310 [C16H15N5O2+H]+; HPLC (Method A) 96.9% (AUC), tR=11.5 min. Anal. Calcd for C16H15N5O2.0.50H2O: C, 60.47; H, 4.92; N, 22.03. Found: C, 60.87; H, 4.65; N, 21.75.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:13]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]=2[NH2:1])=[O:15])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Nc1c(C(=O)Nc2ccc(Cl)cc2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
A suspension of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (500 mg, 2.46 mmol) in thionyl chloride (2.0 mL) is stirred at room temperature for about 15 min before it becomes a clear solution. After removal of the solvent, the crude acid chloride is taken in anhydrous DCM (5.0 mL), and transferred dropwise to a solution of 4-chloroaniline (376.7 mg, 2.95 mmol) and TEA (1.03 mL, 7.38 mmol) in anhydrous DCM (5.0 mL) at 0° C. The reaction mixture is allowed to warm up to room temperature in an hour and lots of precipitate is generated. After filtration, the precipitate is washed with water, followed by small amount of DCM, and air-dried to provide crude 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (4-chloro-phenyl)-amide (506.2 mg, 66% yield) as a white solid product; HPLC-MS calculated for C16H13ClN4O (M+H+) 313.1. Found: 313.0.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].[NH2:6][C:7]1[N:12]=[C:11]([CH2:13][O:14][CH2:15][CH3:16])[NH:10][C:9](=[O:17])[CH:8]=1.[OH-].[Na+].S(=O)(=O)(O)O>O>[NH2:6][C:7]1[N:12]=[C:11]([CH2:13][O:14][CH2:15][CH3:16])[NH:10][C:9](=[O:17])[C:8]=1[N:1]=[O:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOCc1nc(N)cc(=O)[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(N)c(N=O)c(=O)[nH]1

Procedure:
17.7 g (0.256 moles) of sodium nitrate are added to a solution of 39.5 g (0.233 mole) of 6-amino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 336 ml (0.336 mole) of 1 N sodium hydroxide. A solution of 17.9 ml (0.320 mole) of 96% sulphuric acid diluted in 179 ml of water is then added dropwise at between 0° and 5° C. The precipitate formed is isolated by filtration immediately after completion of the addition. The solid obtained is washed with cold water and then with ethyl ether. After drying, it is used in the next step without further purification. Yld: 46.2 (quantitative), m.p. 163°-165° C. An analytical sample was obtained by recrystallization from methanol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=3)[C:10]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:11][CH:12]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[NH2:29][C:24]1[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([C:9]2[CH:8]=[C:7]([CH2:6][N:4]3[CH2:5][CH:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:3]3)[CH:12]=[N:11][C:10]=2[NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:23]=1
Reactant: COc1ccc(Nc2ncc(CN3CC(N)C3)cc2-c2nc(C)nc(N)n2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ncc(CN3CC(NS(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
A solution of 4-(5-((3-aminoazetidin-1-yl)methyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (106 mg, 0.269 mmol) and triethylamine (56.2 μL, 0.404 mmol) in DCM (2.7 mL) was treated with MsCl (20.85 μL, 0.269 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 6% 2 M ammonia in MeOH/DCM to give N-(1-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)azetidin-3-yl)methanesulfonamide (10 mg, 7% yield) as yellow solid. m/z (ESI, +ve ion) 472.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH2:15]([Mg]Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>CCOCC>[NH2:1][C:2]1[NH:7][CH:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCc1nc(C)c2n1N=C(N)NC2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.) was added to benzyl magnesium chloride (prepared from benzyl chloride (6.3 g.) and magnesium (1.2 g.)) in ether (400 ml.), and the mixture was stirred for 4 hours at room temperature. Aqueous ammonium chloride (50 ml., 20%) was added and the aqueous layer was separated and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated and the residue was chromatographed on silica gel (100 g.). Fractions eluted with ethyl acetate were discarded. The fractions eluted with a mixture of ethyl acetate and methanol (4:1) were evaporated to give 2-amino-4-benzyl-3,4-dihydro-5-methyl-7-propylimidazo [5,1-f]-as-triazine as a gum (0.83 g.). This gum (0.7 g.) and acetyl chloride (0.3 ml.) in glacial acetic acid (10 ml.) were heated at 100° for 2.5 hours. Acetic acid was distilled off and the residue was crystallised from a mixture of ethanol and ethyl acetate to give a white solid, m.p. 240°-241°.
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([O:24]C)=[O:23])[CH:8]=2)[NH:3]1.[OH-].[K+].O>CO>[O:1]=[C:2]1[C:11]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:22]([OH:24])=[O:23])[CH:8]=2)[NH:3]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (50 mg, 0.15 mmol) in methanol (30 mL) was added potassium hydroxide (33.33 mg, 0.60 mmol) and water (1 mL) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with HCl (3 N) to give the precipitate, which was collected by filtration to afford 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylic acid as a light yellow solid (40.0 mg, 79%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N([O-])=[O:13].[Na+].C>S(=O)(=O)(O)O.O>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([OH:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)ccc1Cl
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
5-Amino-2-chlorobenzoic acid (85%, 10 g, 49.7 mmol) was suspended in diluted sulphuric acid (1.25%, 800 mL) and cooled to 5° C. on an ice bath. Sodium nitrite (59,72 mmol) dissolved in water (150 mL) was added slowly while keeping the temperature of the reaction below 5° C. After addition of the sodium nitrite the reaction was stirred for another 45 min at 5-10° C. until a clear solution was obtained. The reaction mixture was poured into hot (70-85° C.) water (1.5 L), charcoal added and the reaction mixture heated at reflux for 25 min. Filtration and extraction with ethyl acetate afforded 6.7 g of the desired product as light brown crystals
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].Cl.[CH2:8]([O:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O>[Cl:1][CH:2]([Cl:6])[C:3]([NH:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccccc1)C(Cl)Cl
Yield: 82 %

Procedure:
Prepared in 82% yield (2.6 g, 11.1 mmol) from the reaction of 2,2-dichloroacetyl chloride (2.0 g, 13.6 mmol) with O-benzylhydroxylamine, hydrochloride (2.15 g, 13.6 mmol) via general procedure A. Rf=0.52 (3:1, hexanes:EtOAc); 1H NMR (400 MHz, CD3CN) δ 9.89 (br s, 1H), 7.63-7.17 (m, 4H), 6.02 (s, 1H), and 4.89 (s, 2H); 13C NMR (101 MHz, CD3CN) δ 162.2, 136.1, 130.4, 129.7, 129.4, 78.8, and 65.6; IR (film) 3135 (br), 2996, 2880, 2860, 1700, 1677 (st), 1531, 1468, 1454, 1367, 1341, 1214, 1200, 1046, 1027 cm-1; HR-APPIMS calculated for C9H9Cl2NO2 (M*)+233.0005, observed 232.9976.