Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]=[N+:18]=[N-:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:25]=[C:24]([Si:21]([CH3:23])([CH3:22])[CH3:20])[N:19]=[N:18]4)=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: [N-]=[N+]=Nc1ccc(-c2cn3cc(I)ccc3n2)cc1
Product: C[Si](C)(C)c1cn(-c2ccc(-c3cn4cc(I)ccc4n3)cc2)nn1

Procedure:
Then, 6-iodo-2-(4-azidophenyl)imidazo[1,2-a]pyridine as prepared above is allowed to react with trimethylsilyl acetylene to obtain 6-iodo-2-[4-(4-trimethylsilyl-1H-1,2,3,-triazole-1-yl)phenyl]imidazo[1,2-a]pyridine (FIG. 1, step 2) in accordance with known methods (for example, the method described in a literature, James T. Fletcher et al., Tetrahedron Lett, 2008, 49, p. 7030-7032), and then trimethylsilyl group is removed (FIG. 1, step 3), to obtain 6-iodo-2-[4-(1H-1,2,3,-triazole-1-yl)phenyl]imidazo[1,2-a]pyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 48.7 %

Procedure:
A mixture of 0.0449 g (0.000146 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0222 g (0.00016 mole) of 4-amino-benzoic acid, 0.8 mL of ethanol, 3.2 mL of water and 3 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-benzoic acid (I-62a) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]#[C:11][CH2:12][OH:13]>C(OCC)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCC#Cc1cc(F)c(F)cc1F
Agent: [Pd]
Solvent: CCOCC
Product: OCCCc1cc(F)c(F)cc1F

Procedure:
A solution of 3-(2,4,5-trifluorophenyl)prop-2-yn-1-ol (90 mg, 0.48 mmol) in diethyl ether (10 ml) was hydrogenated over 10% palladium on carbon at room temperature for 15 hours. The mixture was filtered through celite and the filtrate on evaporation gave an oil, which was flash chromatographed on silica using 10% ethyl ether/hexane. Fractions with Rf of about 0.16 on evaporation gave the title alcohol as a colorless oil.
Reaction SMILES: C([N:4](CC=C)[CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][CH:6]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:4][CH:5]1[CH2:9][CH:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:7][CH:6]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26]
Reactant: C=CCN(CC=C)C1CC(OCc2ccc(OC)cc2)CC1NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(COC2CC(N)C(NC(=O)OC(C)(C)C)C2)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl N-{2-[bis(prop-2-en-1-yl)amino]-4-[(4-methoxyphenyl)methoxy]cyclopentyl}carbamate (1.77 g, 4.25 mmol) in dry DCM (21 ml) was added 1,3-dimethyl-1,3-diazinane-2,4,6-trione (CAS number 769-42-6; 1.161 g, 7.44 mmol) and tetrakis(triphenylphosphane) palladium (0.113 g, 0.098 mmol). The reaction was stirred at 45° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture was concentrated in vacuo and purified by SCX chromatography (2M ammonia in methanol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.Cl.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:18][C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([O:15][CH3:14])=[O:23])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COC(=O)[C@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(OC)c(Cl)c1

Procedure:
Prepared in a similar manner to example 4 using 3-chloro-4-methoxy benzoic acid and D-leucine methyl ester hydrochloride. MS (M+H, 314.10).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:9]1[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)[C@H](Cc1cccnc1OC)NC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ncccc1CC1NC(=O)CNC1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 86 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(2-methoxy-3-pyridinyl)alaninate (1.018 g, 3.62 mmol) and N,N-diisopropylethylamine (0.63 mL, 3.62 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for 36 h. The solvent was partially removed under a vacuum and the solid formed was filtered, washed with MeOH and dried to give 3-((2-methoxy-3-pyridinyl)methyl)-2,5-piperazinedione (0.732 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH:10]=[CH:11]N(C)C)=[C:8]([N+:15]([O-])=O)[C:6](=[O:7])[N:5]([CH3:18])[C:3]1=[O:4]>CO.[Pd]>[CH3:1][N:2]1[C:9]2[CH:10]=[CH:11][NH:15][C:8]=2[C:6](=[O:7])[N:5]([CH3:18])[C:3]1=[O:4]
Reactant: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)c2[nH]ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Step 2 intermediate (0.40 g, 1.573 mmol) in MeOH (80 mL) was added 10% Pd—C (0.2 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 h. The mixture was filtered through a celite bed and was thoroughly washed with MeOH (50 mL). The filtrate was collected and evaporated and the residue thus obtained was purified by column chromatography to afford 0.120 g of the desired compound as an off-white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.23 (s, 3H), 3.38 (s, 3H), 6.17 (s, 1H), 7.25 (s, 1H), 12.09 (s, 1H); APCI-MS (m/z) 180.28 (M+H)+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2F)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
To 200 mg of N,N-dimethylformamide were added 65 mg 1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 45 mg of 3-methylaminoazetidine dihydrochloride, and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.2 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 52 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[CH:29][CH:28]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C3CCCCO3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl>CO>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[O:36])=[CH:29][CH:28]=2)[S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(OC3CCCCO3)cc2)c2ccc(C=CC(=O)N3CCOCC3)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(O)cc2)c2ccc(C=CC(=O)N3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-methoxy-N-[4-(3-morpholin-4-yl-3-oxo-propenyl)-phenyl]-N-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-benzenesulfonamide (0.028 g, 0.05 mmol) in 15 mL methanol was added 5 mL of 1N HCl. The reaction mixture was stirred at room temperature for 20 hr. The reaction mixture was washed twice with methylene chloride. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (magnesium sulfate), and concentrated. Radial chromatography (methylene chloride to 5% methanol/methylene chloride) provided N-(4-hydroxy-benzyl)-4-methoxy-N-[4-(3-morpholin-4-yl-3-oxo-propenyl)-phenyl]-benzenesulfonamide. 1H NMR (CDCl3) δ 7.54 (d, 2H, J=9.2 Hz), 7.52 (d, 1H, J=15.2 Hz), 7.27 (d, 2H, J=8.4 Hz), 6.99 (d, 2H, J=8.4 Hz), 6.92 (d, 2H, J=8.8 Hz), 6.91 (d, 2H, J=9.2 Hz), 6.71 (d, 1H, J=15.2 Hz), 6.63 (d, 2H, J=8.4 Hz), 4.59 (s, 2H), 3.85 (s, 3H), 3.75–3.55 (m, 8H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Yield: 68.8 %

Procedure:
2.4 g of 2-{4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butyl}-isoindole-1,3-dione (5.05 mmol) and 1.0 g of hydrazine hydrate (20.2 mmol) were dissolved in 20 ml of ethanol and heated to reflux for 1 h. The precipitate was filtered and the filtrate extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness to yield 1.2 g of the title compound.
Reaction SMILES: CC1(C)COB([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)OC1.Cl[C:34]1[N:39]=[C:38]([C:40]([O:42]C)=[O:41])[CH:37]=[N:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O1CCOCC1>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[C:19]1[N:13]2[CH2:12][C:11]3[C:15]([C:14]2=[N:17][N:18]=1)=[CH:16][C:8]([C:34]1[N:39]=[C:38]([C:40]([OH:42])=[O:41])[CH:37]=[N:36][CH:35]=1)=[CH:9][CH:10]=3
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(B3OCC(C)(C)CO3)cc1-2
Reactant: COC(=O)c1cncc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3cncc(C(=O)O)n3)cc1-2
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
A mixture of 8-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole (248 mg, 0.58 mmol) (as prepared in Example 26 Step (a)), methyl 6-chloropyrazine-2-carboxylate (100 mg, 0.58 mmol), dioxane (4.8 ml) and 2M aqueous Cs2CO3 solution (0.58 ml) was degassed with a stream of N2 for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.22 μmol) was added and the stirred mixture was heated at reflux for 1.5 h. The reaction was then cooled, allowed to stand for 15 min and the supernatent decanted off. The remaining salts were washed with further dioxane (5 ml) and then partitioned between water (20 ml) and CH2Cl2 (20 ml). The pH was adjusted to 6 by dropwise addition of 2N aqueous HCl and the aqueous phase was extracted with further CH2Cl2 (2×20 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white amorphous solid (89.8 mg, 34%); 1H NMR (400 MHz, CDCl3) δ 9.63 (1H, s), 9.19 (1H, s), 8.81 (1H, s), 8.38 (1H, dd, J=8.2, 1.7 Hz), 7.75 (1H, d, J=8.2 Hz), 7.56–7.48 (5H, m), 4.67 (2H, s), 2.64 (3H, s); m/z (ES+) 437 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>[C].[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2cccc(NS(C)(=O)=O)c2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cccc(CCc2ccc(C(=O)O)c(Nc3ccc(F)cc3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic acid 2.0 mL,dioxane 2.0 mL and 10% palladium-carbon 37 mg were added to the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(3-(methanesulfonamido)phenyl)vinyl)benzoate sequentially, and it was stirred under hydrogen atmosphere at room temperature for 5 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated. Trifluoroacetic acid 10 mL was added to the obtained residue, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(3-(methanesulfonamido)phenyl)ethyl)benzoic acid 75 mg of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]([OH:15])=[O:14].[N+:16]([O-])([O-:18])=[O:17].[K+]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COc1c(C(=O)O)ccc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: COc1c(C(=O)O)cc([N+](=O)[O-])c2ccccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 1-methoxy-naphthalene-2-carboxylic acid (20.2 g; 0.1 m) in glacial acetic acid (200 ml) was added a solution of potassium nitrate (10.1 g; 0.1 m) in concentrated sulphuric acid (10 ml). The temperature was maintained below 25° C. by means of a water bath. The reaction was stirred for four hours and poured into ice-water (500 ml). The product was collected by filtration, washed well with water and dried in vacuo at room temperature to give 1-methoxy-4-nitro naphthalene-2-carboxylic acid, m.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:14][C:15]1[N:16]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:6]=2[Cl:9])[N:17]=[CH:18][N:19]=1
Reactant: Nc1nc[nH]n1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.0 g) in dimethylformamide (5 ml) was added 3-amino-1,2,4-triazole (360 mg) and potassium carbonate (296 mg), the mixture was heated at 100° C. for 2hrs. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with ether (100 ml). The organic extracts were evaporated to dryness to give the title compounds as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:6][CH:7]=[CH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([CH2:6]/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(C=CCn2ccnc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(/C=C/Cn2ccnc2)cc1-c1ccc(F)cc1
Yield: 89 %

Procedure:
A solution of methyl 4-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate (E and Z isomers) (1.9 g; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5 ml; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. After evaporation and acidification with 12N HCl (1.5 ml), the resulting solid was washed with distilled water and ether, taken up in dichloromethane/methanol (99/1) to give 4-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoic acid (E isomer) after evaporation as a foam. Yield: 89%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:8]2[C:6]3[N:7]=[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccc(F)cc4)ncnc23)CC1
Reactant: C1CNCCN1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccc(F)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-(4-fluorobenzylamino)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 210°-212° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cl)ccc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.3 %

Procedure:
To a solution of 6-chloropyridazin-3-ol (0.5 g, 3.83 mmol, WO2011015629) in DMF (5 mL) was added potassium carbonate (1.059 g, 7.66 mmol, Rankem) followed by ethyl 2-bromoacetate (0.960 g, 5.75 mmol, Spectrochem). The reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with water (2 mL) and the product was extracted with EtOAc (3×20 mL). Combined organic layers were washed successively with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and evaporated under vacuum to afford ethyl 2-(3-chloro-6-oxopyridazin-1(6H)-yl)acetate 0.5 g (60.3%) as pale yellow solids. 1H NMR (400 MHz, CDCl3): δ 7.266-7.236 (d, J=12 Hz, 1H), 6.965-6.945 (d, J=7.6 Hz, 1H) 4.819 (s, 2H) 4.273-4.230 (m, 2H) 1.309-1.279 (m, 3H); MS m/z=217.2 (M+H)+.
Reaction SMILES: O[C:2](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:6][C:5]1=O)[CH3:3].O.[NH2:20][NH2:21]>C(O)C>[CH3:3][C:2]1[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:6][C:5]=2[NH:21][N:20]=1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2ccccc2C)CC1=O
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 90.4 %

Procedure:
A solution of 2-(1-hydroxyethylidene)-5-(2-methylphenyl)cyclohexane-1,3-dione (0.45 g) and hydrazine hydrate (0.1 g) in ethanol (10 ml) was refluxed for 15 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazol-4-one (0.40 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10](Cl)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[NH3:13].O>O1CCOCC1.CO>[Cl:1][C:2]1[C:3]([C:10]([NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: N
Reactant: CSc1ncc(Cl)c(C(=O)Cl)n1
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CSc1ncc(Cl)c(C(N)=O)n1
Temperature: 5 °C
Reaction time: 15 h
Yield: 53 %

Procedure:
15 g (67.2 mmol) of 5-chloro-2-(methylsulfanyl)pyrimidine-4-carbonyl chloride are dissolved in 35 ml of dioxane and cooled to 5° C. 57.3 g (0.4 mol) of 7N ammonia in methanol (about 12% strength solution) are slowly added dropwise to the cooled solution. During the addition, the reaction temperature was kept below 15° C. After the dropwise addition had ended, the reaction mixture was allowed to warm to room temperature and stirred for about 15 hours. The mixture was then added to water and the precipitated 5-chloro-2-(methylsulfanyl)pyrimidine-4-carboxamide was isolated (7.7 g, yield 53% at a purity of 95%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1([N+:21]([O-:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:13]=[CH2:14]>C(Cl)Cl>[N+:21]([C:15]1([CH2:12][CH:13]2[CH2:14][O:9]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:23])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC1([N+](=O)[O-])CCCCC1
Solvent: ClCCl
Product: O=[N+]([O-])C1(CC2CO2)CCCCC1
Reaction time: 0.3 h

Procedure:
A 1 neck 500 mL round bottom flask equipped with dropping funnel, temperature controller, nitrogen outlet, stir bar and condenser is charged with approximately 37 g of mCPBA (72% pure, 0.15 mols) and 100 mL of CH2Cl2. The reaction slurry is warmed to dissolve all the solids in CH2Cl2. Once a clear solution is obtained, 20 g (0.12 mols) of 1-allyl-1-nitrocyclohexane (11) is added slowly. After complete addition, the reaction is refluxed for 2 hrs and stirred for 48 h at room temperature. The progress of the reaction is monitored by GC. After the duration of almost 50 h, the composition of the epoxide in the reaction mixture is approximately 38.5%. Solid mCPBA that crashes out of solution is removed by gravity filtration. The organic layer is washed with 10% Na2CO3 (3×30 mL) followed by brine (3×30 mL). The organic layer is dried under MgSO4 and excess solvent stripped off under rotary evaporator. This affords 11.8 g of crude material. The retention time of the epoxide on the GC is 18.3 minutes. The presence of epoxide is confirmed by GC-MS CI. The parent ion is not detected due to the labile nature of NO2 groups. However, the fragment minus the NO2 is observed. CI GC/MS, [C9H15O]+=139.