Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH:11]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[NH3:31]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:31])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH:11]=2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3ncccc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3ncccc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 130 °C
Reaction time: 12 h

Procedure:
A mixture of 2.50 g of methyl 5-(1H-imidazo[4,5-b]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B5a) and 250 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 130° C. for 12 h. The reaction mixture was allowed to cool down to room temperature, concentrated, and the resulting residue was purified by flash chromatography (neutral alumina oxide, eluents: ethyl acetate/methanol). After crystallization from acetonitrile the title compound was obtained.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18]1([CH3:29])[CH:23]=[CH:22][C:21]([S:24](C#N)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:29][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:12]2[N:11]3[C:7](=[N:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=43)[S:6][N:5]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2nsc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.7 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (10.0 g, 40.4 mmole) and p-toluenesulfonyl cyanide (14.7 g, 81.0 mmole) in 120 mL of dichloromethane was stirred at room temperature for 20 h. The precipitate was filtered and washed with dichloromethane to yield 12.2 g (91%) of 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as white powder: mp 231-234° C.; 1H NMR (CDCl3)δ 8.53 (d, 1H), 8.04 (d, 2H), 7.82 (d, 1H), 7.56-7.44 (m, 4H), 2.53 (s, 3H) ppm; 13C NMR (CDCl3)δ 163.72, 150.38, 147.97, 147.54, 132.48, 130.30(2C), 129.97(2C), 128.49, 126.14, 123.06, 119.70, 114.67, 21.93 ppm; IR (KBr)ν 1592, 1525, 1444, 1337, 1151, 1081, 735 cm-1 ; HRMS calcd for C15H11N3O2S2 : 329.0293, found: 329.0300. Anal. Calcd for C15H11N3O2S2 : C, 54.70;Hf 3.37; N, 12.76. Found: C, 54.29;H, 3.14; N, 14.59.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2Cc3ccccc3C2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)C2Cc3ccccc3C2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-(indan-2-ylaminomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH3:18])[C:10]([NH:15][CH3:16])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH:22]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH3:18])[C:10]2[N:15]([CH3:16])[CH:22]3[O:24][CH:19]([C:11]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:21]3)=[CH:4][CH:3]=1
Reactant: O=CCCC=O
Reactant: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])NC
Agent: Cl
Solvent: CC#N
Product: CCN(Cc1ccc(Cl)nc1)C1=C([N+](=O)[O-])C2CCC(O2)N1C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a 50 ml round bottom flask was added 1.35 g (0.005 mol) N-((6-chloropyridin-3-yl)methyl)-N-ethyl-N′-methyl-2-nitroethene-1,1-diamine, 30 ml dry acetonitrile, 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 40% yield.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[NH2:25][NH2:26]>O1CCOCC1.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH:25][NH:26][C:14]([C:13]3[C:9]([C:7]4[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[N:10][N:11]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:12]=3)=[O:15])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(NNC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 72 %

Procedure:
Add a solution of 476 mg of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride in 25 ml of dioxane dropwise to 210 mg of hydrazine dihydrochloride in 2 ml of water, whereupon N,N'-bis-[3-(5-nitro-2-furyl)-1-phenyl-4-pyrazolylcarbonyl]hydrazine [m.p. 313° to 314° C (with decomposition) from dimethylformamide] precipitates with a yield of 72%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][C:28]([NH:30][CH3:31])=[O:29]>CN(C)C=O>[N:11]1([CH2:10][C:2]2[N:1]([CH2:27][C:28]([NH:30][CH3:31])=[O:29])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1c(Cn2nnc3ccccc32)nc2ccccc21
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1-(1H-Benzimidazol-2-ylmethyl)-1H-benzotriazole (500 mg, 2.00 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). Potassium carbonate (1.11 g, 8.00 mmol) and 2–Chloro-N-methylacetamide (237 mg, 2.20 mmol) were added. The reaction mixture was allowed to stir overnight at reflux. The solvent was evaporated under vacuum, and the white waxy residue taken up in methylene chloride (300 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×100 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (CH2Cl2/MeOH=15:1) to give 304 mg (47%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:24]1[N:28]2[CH:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]2=[N:26][CH:25]=1)CCC>CO.ClCCl>[N:14]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]([F:34])([F:35])[F:36])=[N:32][C:27]4=[N:26][CH:25]=3)[CH:3]=2)[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(-c2ccccc2-n2cncn2)c1
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccc4-n4cncn4)c3)cnc2n1

Procedure:
1-(3′-Bromobiphenyl-2-yl)-1H-[1,2,4]triazole (91 mg, 0.30 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-a]pyrimidine (0.25 mmol) by the method of Example 32. The product was obtained by preparative thin-layer chromatography on silica gel with 3% methanol in dichloromethane as eluent followed by high performance liquid chromatography to give 3-[2′-([1,2,4]triazol-1-yl)biphenyl-3-yl]-7-trifluoromethylimidazo[1,2-a]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 8.57 (1H, d, J 7), 7.95-8.11 (3H, m), 7.48-7.66 (7H, m), 7.35 (1H, J 8), 7.27 (1H, m); m/z (ES+) 407 (M++H).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:19]([N:22]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH2:3]([N:26]([C@H:24]([CH3:25])[CH2:23][N:22]([CH2:19][CH:20]=[CH2:21])[C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])[CH:2]=[CH2:1]
Reactant: C=CCN(C[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reactant: C=CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(C[C@@H](C)N(CC=C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C

Procedure:
0.4 mL of allyl alcohol and 1.5 mL of diisopropyl azodicarboxylate were added dropwise at room temperature in an argon atmosphere to a solution containing 1 g of the compound obtained in Step 2 and 2 g of triphenylphosphine dissolved in 100 mL of tetrahydrofuran, and then reacted for 16 hours. The reaction solution was diluted with water, followed by extraction with ethyl acetate (100 mL×2). Then, the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (acetone:hexane=1:2) to obtain 550 mg of the compound of interest as a colorless oil (50%).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2ccc(C)cc2C(=O)N1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=COc2ccc(C)cc2C(=O)N1CCCCBr

Procedure:
950 mg of 4,5-dihydro-3,7-dimethyl-1,4-benzoxazepin-5-one was dissolved in 30 ml of acetone, 4.3 g (4 equivalents) of 1,4-dibromobutane and 2.1 g (3 equivalents) of potassium carbonate were added, then the resultant mixture was heated and refluxed for 10 hours.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1
Reactant: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2c1cnn2C1CCCCO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of 2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (100 mg, 0.266 mmol) in tetrahydrofuran (2.7 ml) were added 3,4-dihydro-2H-pyran (36 μl, 0.399 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.069 mmol), and the resulting mixture was stirred for 4 hours while being maintained at 70° C. The reaction solution was allowed to cool, and then was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (99.6 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=1.[Cl:34]N1C(=O)CCC1=O>CN(C=O)C>[Cl:34][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH3:25])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 37.4 %

Procedure:
Following General Procedure H, (R)-tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (0.67 g, 1.5 mmol) was reacted with N-chlorosuccinimide (0.29 g, 1.6 mmol) in DMF (10 mL) to afford the desired product (0.28 g, 35%) as a brown solid: ESI MS m/z 499 [C26H27ClN2O4S+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[CH:9]1([C:18]#[N:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][C:9]1([C:18]#[N:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: N#CC1CCc2ccccc21
Reactant: BrCCC1OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(CCC2OCCO2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2(2-bromoethyl)-1,3-dioxolane (14.09 ml, 120.1 mmole) was added to a solution of 1-indanecarbonitrile (15.63 g, 109.2 mmole) in 100 ml of THF and cooled to 0° C. After the dropwise addition of 1M LHMDS (120 ml) the solution was stirred at 0° C. for 20 min then at room temperature for 20 min. After the removal of solvent the residue was flashed of silica using 15% EtOAc and Hexanes to afford 1-[2-(1,3-dioxolan-2-yl)ethyl]-1-indanecarbonitrile as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:16][C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1.O>CN(C)C(=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:16][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: COc1cc(C=O)c(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 80 °C
Yield: 267.3 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 3.0 g, 5 mmol) in N,N-dimethylacetamide (120 mL) was added sodium hydride (60% dispersion in mineral oil, 0.8 g, 19 mmol) portion wise. After the addition was complete, the reaction was stirred for 30 minutes after which 2-chloromethyl-1-methyl-1H-benzoimidazole (212, 2.9 g, 16 mmol) was added and then heated at 80° C. overnight. The reaction mixture was then poured into water (1 L) with stirring and the precipitated solid was filtered, washed with water and dried to give the desired compound (213, 4.2 g, 84% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].[F:25][C:26]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[O:31][N:30]=1)([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([NH:21][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:26]([F:25])([CH3:27])[CH3:28])[CH:33]=2)=[O:36])[CH:22]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)F)no4)c(F)cc3F)c2cc1OC
Yield: 31 %

Procedure:
To a stirred solution of 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmoles) from the previous step and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate described in Example 42A (96 mg, 0.32 mmoles) in anhydrous DMF (10 mL), was added 4-(dimethylamino)pyridine (20 mg, 0.16 mmoles) and diisopropylethylamine (80 μL, 0.45 mmoles) and the reaction heated to 70 C overnight. The reaction was then concentrated to an oil and purified by silica gel chromatography eluting with a gradient of ethyl acetate/dichloromethane, 3-80%, to afford 1-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (46.33 mg, 31% yield) as a white solid. 1H (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.92 (s, 1H), 8.57 (s, 1H), 8.13 (m, 1H), 7.67 (m, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 6.12 (s, 1H), 3.98 (s, 6H), 1.65 (d, J=21 Hz, 6H); LCMS (ESI) m/z (M+H)+ 504.
Reaction SMILES: [C:1](=[NH:5])(OC)[CH3:2].[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:22])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][N:8]=1>C(#N)C.C(O)(=O)C>[Cl:22][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([NH:6][C:1](=[NH:5])[CH3:2])=[N:8][NH:9]2)=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Reactant: COC(C)=N
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(=N)Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Reaction time: 0.08 h

Procedure:
33 mg of methyl acetimidate are added to 50 mg of 3-amino-6-chloro-5-phenyl-1H-indazole in 3 ml of acetonitrile and 12 mg of acetic acid. The reaction is placed under microwave radiation at 180° C. for 5 min. After the usual treatments and purification through silica, 35 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamidine are obtained.
Reaction SMILES: [CH2:1]1[CH2:14][N:13]2[C:4]3[C:5]([CH2:10][CH2:11][CH2:12]2)=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=3[CH2:2]1.[CH3:15][C:16]([CH3:25])([CH3:24])[C:17](=O)[CH2:18][C:19](OC)=[O:20]>ClCCl>[CH3:15][C:16]([C:17]1[O:9][C:6]2[C:7](=[CH:8][C:3]3[CH2:2][CH2:1][CH2:14][N:13]4[C:4]=3[C:5]=2[CH2:10][CH2:11][CH2:12]4)[C:19](=[O:20])[CH:18]=1)([CH3:25])[CH3:24]
Reactant: Oc1ccc2c3c1CCCN3CCC2
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(=O)c2cc3c4c(c2o1)CCCN4CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
8-Hydroxyjulolidine (1.0 g, 5.29 mmol) and methyl 4,4-dimethyl-3-oxopentanoate (1.0 g, 6.32 mmol) were heated together under nitrogen at 200° C. for 4 hours, after which time more methyl 4,4-dimethyl-3-oxopentanoate (0.5 g, 3.16 mmol) was added and heating was continued for 2 hours. After cooling to room temperature, the reaction mixture was dissolved in dichloromethane and applied to a short column of silica gel (approx. 200 g). Elution with dichloromethane removed non-polar by-products, while subsequent elution with ether afforded 11-[1,1-dimethylethyl]-9-oxo-2,3,6,7-tetrahydro-1H,5H-[1]benzopyrano[6,7,8-ij]quinolizine (1.12 g, 71% yield) as a brown oil which solidified on standing. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:5][S:6]([CH2:9][C:10](O)=O)(=[O:8])=[O:7].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:21]=1C=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([O:30][CH3:31])[CH:21]=[C:20]([O:19][CH3:18])[C:27]=1/[CH:10]=[CH:9]/[S:6]([CH2:5][C:4]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:2]([OH:1])[CH:3]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1O
Reactant: COc1cc(OC)c(C=O)c(OC)c1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(O)c2)c(OC)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of the 2-((3-hydroxy-4-methoxybenzyl)sulfonyl)acetic acid (1.9 g, 7.3 mmol, 1 eq), 2,4,6-trimethoxybenzaldehyde (1.58 g, 8.0 mmol, 1.1 eq.), benzoic acid (134 mg, 0.15 eq.) and piperidine (81 mg, 0.13 eq.) in toluene (50 mL) was heated at reflux temperature for 2-3 h with continuous removal of water using a Dean-Stark trap. When the reaction was complete by TLC analysis, the reaction mixture was cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract was washed with saturated aqueous sodium bicarbonate solution (50 mL), dilute hydrochloric acid (50 mL), and water (50 mL) and dried (sodium sulfate). Volatile components were removed in vacuo to yield the crude product, which was purified by recrystallization from isopropanol to yield 1.8 g (62.5%) of the desired (E)-5-((2,4,6-trimethoxystyryl-sulfonyl)methyl)-2-methoxyphenol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].Cl.[CH:12](OCC)(OCC)OCC>>[Cl:10][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:9][N:8]2[CH3:12]
Reactant: CCOC(OCC)OCC
Reactant: CNc1ncnc(Cl)c1N
Agent: Cl
Product: Cn1cnc2c(Cl)ncnc21

Procedure:
To 5.0 g (31 mmol) of 5-amino-4-chloro-6-methylaminopyrimidine suspended in 200 ml of triethyl orthoformate was added 2.6 ml of concentrated HCl and the resultant mixture stirred overnight at room temperature (r.t.). The white precipitate was then collected, washed with ether which was then combined with the orthoformate which was concentrated to give pure 6-chloro-9-methylpurine by tlc (thin layer chromatography) (silica, 90:10 CHCl3 :CH3OH). The filtered solid was returned to 150 ml ethyl orthoformate, treated with 1.0 ml concentrated HCl and stirred at 60° C. for 18 hours. The solution was evaporated and the solids combined to give 5 g (94%) of 6-chloro-9-methylpurine, m.p. 205°-207° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][C:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]2[C:24]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:25][N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=23)=[N:17]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 3-[2-(2-t-butoxycarbonylmethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.15 g) in dry dichloromethane (0.5 ml) at room temperature was added trifluoroacetic acid (0.46 ml). After stirring for one day at room temperature, the solution was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified with 1N-hydrochloric acid to pH 3 and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ethanol--water to give 3-[2-(2-carboxymethyl-1-cycloheptenyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]- pyridine (0.083 g).