Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: Clc1ccc(CSc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-chlorobenzyl-thio)-4-morpholino-pyrimido[5,4-d]-pyrimidine (m.p.: 135°-145° C.) and piperazine.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:18]([O:30][CH3:31])=[CH:19][C:20](C#N)=[C:21]([N:23]=[CH:24][N:25]([CH3:27])C)[CH:22]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[NH:35][N:34]=1>C(O)(=O)C>[C:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]3[C:20]([C:27]([NH:32][C:33]4[CH:37]=[C:36]([CH2:38][C:39]([OH:41])=[O:40])[NH:35][N:34]=4)=[N:25][CH:24]=[N:23]3)=[CH:19][C:18]=2[O:30][CH3:31])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(CC(=O)O)[nH]n1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCC1CCN(CCOC(C)(C)C)CC1
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCC1CCN(CCOC(C)(C)C)CC1
Yield: 67.1 %

Procedure:
N′-(5-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (654 mg, 1.5 mmol) in acetic acid (1.35 ml) was heated with (3-amino-1H-pyrazol-5-yl)acetic acid (214 mg, 1.52 mmol) at reflux for 45 minutes. Acetic acid was evaporated and the residue taken up in a mixture of dichloromethane:methanol. Excess diisopropylethylamine was added, and the solvent evaporated in vacuo. Dichloromethane was added to the solid, which was filtered and dried to yield {3-[(7-{2-[1-(2-tert-butoxyethyl)piperidin-4-yl]ethoxy}-6-methoxyquinazolin-4-yl)amino]-1H-pyrazol-5-yl}acetic acid as a white powder (530 mg, 66% yield):
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([O:13]C2CCCCO2)[CH:10]=[C:9]([CH3:20])[C:6]=1[CH:7]=[O:8].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:13][C:11]1[CH:10]=[C:9]([CH3:20])[C:6]([CH:7]=[O:8])=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:12]=1
Reactant: COCOc1cc(OC2CCCCO2)cc(C)c1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COCOc1cc(O)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
To a solution of 2-methoxymethoxy-6-methyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (9.8 g, 34.9 mmol) in MeOH (100 mL) was added PPTS (2.19 g, 8.7 mmol). The reaction mixture was stirred at room temperature for 12 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 80:20) to give 4-hydroxy-2-methoxymethoxy-6-methyl-benzaldehyde (5.4 g, 79%). 1H NMR (400 MHz, CDCl3): δ 10.47 (s, 1H), 6.65 (s, 1H), 6.57 (d, J=2.0 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 3.50 (s, 3H), 2.56 (s, 3H). MS (ESI) m/z=195 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][N:6](C(=O)C(F)(F)F)[CH2:5][C:4]1=[O:25])[CH3:2]>N.CO>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][C:4]1=[O:25])[CH3:2]
Reactant: CCN1C(=O)CN(C(=O)C(F)(F)F)Cc2cc(OC)c([N+](=O)[O-])cc21
Agent: N
Solvent: CO
Product: CCN1C(=O)CNCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A mixture of 1-Ethyl-7-methoxy-8-nitro-4-(2,2,2-trifluoro-acetyl)-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.59 g, 0.0016 mol) and 10% ammonia/methanol (30 mL) was stirred at room temperature for 2 hrs. The reaction was evaporated to give 1-Ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.43 g, 97%). Mp 132-134° C.; LCMS (m/e) 266 (M+1); 1H-NMR (DMSO, 400 Mz) δ 8.76 (br, 0.5H), 8.48 (br, 0.5H), 7.93 (s, 1H), 7.42 (s, 1H), 3.94 (s, 3H), 3.94-80 (q, 2H, J=6.82 Hz), 3.78 (s, 2H), 3.05 (s, 2H), 1.04-00 (t, 3H, J=7.07 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([O:19]C)=O)=[C:15]([OH:16])[C:4]1=2)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:19])=[C:15]([OH:16])[C:4]1=2)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)OC)=C2O
Solvent: Cc1ccccc1C
Product: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)Nc1ccccc1)=C2O
Yield: 56 %

Procedure:
5-Ethyl-2,5-dihydro-4-hydroxy-2-methyl-N-phenyl-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 15 from methyl 5-ethyl-2,5-dihydro-4-hydroxy-2-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and aniline a yield of 56% of theory. M.p.: 268° C. (decomposition; from xylene).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1>CO.[Rh]>[OH:1][CH2:2][C@@H:3]1[C@:11]2([CH3:12])[C@@:6]([OH:19])([CH2:7][C@@H:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C[C@]12CC[C@H](c3ccccc3)C[C@@]1(O)CC[C@@H]2CO
Agent: [Rh]
Solvent: CO
Product: C[C@]12CC[C@H](C3CCCCC3)C[C@@]1(O)CC[C@@H]2CO
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A mixture of 2.00 g of (1S,3aS,5S,7aR)-1-hydroxymethyl-5-phenyl-7a-methylperhydroinden-3a-ol, intermediate in the synthesis of (II-ag) and 0.85 g of 5% Rhodium on alumina powder in 30 ml of methanol was hydrogenated at room temperature at 60 psi. in a Parr apparatus, for 4 hrs. The mixture was then filtered through celite and the solvent was evaporated under reduced pressure to give 1.94 g of (1S,3aS,5S,7aR)-1-hydroxymethyl-5-cyclohexyl-7a-methylperhydroinden-3a-ol as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19]Br)=[O:4].[CH3:21][O:22][C:23](=[O:36])[CH2:24][NH:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][N:25]([CH2:24][C:23]([O:22][CH3:21])=[O:36])[S:26]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)(=[O:28])=[O:27])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1-c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.4 %

Procedure:
A mixture of 5-bromo-2-bromomethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.82 g, 7.03 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.71 g, 7.03 mmol), sodium iodide (2 g, 14.1 mmol) and potassium carbonate (1.94 g, 14.1 mmol) in DMF (60 mL) was stirred at r.t. for 48 h. Brine (120 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes) to give 2.67 g of the title compound. MS: (+) m/z 585.21, 587.10 (M+Na, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
2-(3,4-Dichlorophenyl)acetic acid (25.0 g, 122 mmol) was dissolved in MeOH (122 mL) at ambient temperature. Sulfuryl dichloride (8.89 mL, 122 mmol) was then added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a light yellow oil which was used without further purification. MS (m/z)=219 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C@@H:6]([OH:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+].Cl>[OH-].[Na+]>[CH2:9]([NH:1][C@H:2]([C@@H:6]([OH:8])[CH3:7])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: C[C@H](O)[C@@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.2 %

Procedure:
To (2R,3S)-2-amino-3-hydroxybutanoic acid (14.7 g, 123 mol) in NaOH (50%, 70 mL) was added benzaldehyde (14 mL, 123 mmol). The white slurry was stirred at room temperature for 18 h and then cooled to 0° C. NaBH4 (675 mg, 17.9 mmol) was added in two portions over 10 minutes Cooling bath was removed and the thick slurry was stirred at room temperature for 40 minutes and addition NaBH4 (659 mg, 17.4 mmol) was added and stirred at 0° C. for 40 minutes Benzaldehyde (10 mL, 99 mmol) was added, cooled to 0° C. and additional NaBH4 (700 mg, 18.5 mmol) was added. After 5 minutes warmed up to room temperature and stirred for 2 hour. The reaction mixture was acidified with HCl (conc.) to pH of (about 3) and then filtered precipitate, washed with cold water and dried to give (2R,3S)-2-(benzylamino)-3-hydroxybutanoic acid (3.4 g, 13.2%) of white solid. MS [M+H] found 210.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[OH:25]>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[O:25][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(Oc2ccccc2C#N)c(Oc2ccccc2C#N)c(C(C)(C)C)c1
Yield: 90.1 %

Procedure:
The compound 1,2-bis-(2-cyanophenoxy)-3,5-di-tert-butylbenzene was prepared, according to the procedure of Example 1, by reacting 2-fluorobenzonitrile with 1,2-dihydroxy-3,5-di-tert-butyl benzene. The product was recrystallized from ethanol to give a 90.1% yield of the title compound with the formula: ##STR12##
Reaction SMILES: [C:1]([CH2:9][C:10]([CH3:12])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1>CO>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][C:10]([CH3:12])=[N:31]2)=[CH:26][CH:25]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1=NN(c2ccc(Br)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzoylacetone (3.63 g, 0.0224 mol) and N,N-diisopropylethylamine (2.88 g, 0.0224 mol) in anhydrous methanol (160 mL), 4-bromophenylhydrazine hydrochloride was added and the resulting mixture was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting mixture was partitioned between a 5% solution of citric acid solution in water (200 mL) and ethyl acetate (150 mL). The organic phase was successively washed with water (2×200 mL) and brine (150 mL), dried with magnesium sulfate and concentrated. The resulting residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 1-(4-bromophenyl)-3-methyl-5-phenyl-4,5-dihydro-1H-pyrazole (4.05 g, 0.0129 mol) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][N:28]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:27])([F:26])[F:1])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Reactant: C1COCCN1
Product: O=C(c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2)N1CCOCC1

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and morpholine gave 123. MS: (ESI+)=449.1. 1H NMR (400 MHz, DMSO) δ 8.42 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.6 Hz, 2H), 7.40 (dt, J=21.4, 10.7 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 5.89 (q, J=8.8 Hz, 2H), 4.57 (s, 4H), 3.61 (s, 4H), 3.52 (s, 4H)
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further agitated with 2.9 g of cyclohexanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.24 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [K].[O-]CC.[K+].[CH3:6][CH:7]([CH3:16])[CH:8]([C:14]#[N:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[CH:18]([CH:24]([CH3:26])[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.O.C(OCC)C.C(O)C>[CH:7]([C:8]([C:14]#[N:15])([CH:18]([CH:24]([CH3:26])[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:6])[CH3:16]
Reactant: CCOC(=O)C(C#N)C(C)C
Reactant: CCOC(=O)C(Br)C(C)C
Agent: CC[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C(C)C)C(C#N)(C(=O)OCC)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 0.37 g of metallic potassium was added into 40 ml of absolute ethanol, to prepare potassium ethoxide. The prepared potassium ethoxide was added dropwise into a 100 ml flask containing 1.48 g of ethyl 3-methyl-2-cyanobutyrate. The reaction mixture was stirred at room temperature for 1 h, and then evaporated off the solvent to afford white solids. The white solids were dissolved in 25 ml of tetrahydrofuran, and then the resultant solution was slowly added dropwise into a solution of 2.2 g of ethyl 2-bromoisopentanoate in 30 ml of tetrahydrofuran, and the reaction mixture was heated to reflux for 9 h. Then the solvent was evaporated, to afford a mixture of yellow sticky liquid and pale yellow solids. To this mixture were added with 75 ml of diethyl ether and 20 ml of water, and an organic phase was separated. The organic phase was washed with 20 ml of 10% aqueous NaHCO3 solution twice, and then with water until the organic phase was neutral. The organic phase was dried over anhydrous magnesium sulfate over night, filtered, and evaporated off the solvent, to afford a yellow clear liquid. The yellow clear liquid was separated on a silica chromatographic column (eluent: petroleum ether and chloroform), to afford a pale yellow clear liquid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([S:5]([CH2:8][CH2:9]Cl)(=[O:7])=[O:6])[CH3:4]>C1(C)C=CC=CC=1>[CH3:1][NH:2][CH2:9][CH2:8][S:5]([CH2:3][CH3:4])(=[O:7])=[O:6]
Reactant: CN
Reactant: CCS(=O)(=O)CCCl
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)CCNC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Gaseous methylamine is passed to saturation (about 30 min) into a solution of 15.7 g of chloroethyl ethyl sulfone in 100 ml of toluene at an internal temperature of 50° C. The mixture is stirred at 50° C. for 3 h, the precipitate is filtered off with suction, and the filtrate is concentrated in a rotary evaporator. The remaining yellow mobile liquid (12.3 g) is reacted without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH3:14][S:15]([O:18][C:19]1[C:27]([CH2:28]/[CH:29]=[C:30](/[Cl:33])\[CH2:31]Br)=[C:26]([O:34][CH3:35])[C:25]([CH3:36])=[C:24]2[C:20]=1[C:21](=[O:37])[O:22][CH2:23]2)(=[O:17])=[O:16]>C1COCC1>[CH3:14][S:15]([O:18][C:19]1[C:27]([CH2:28]/[CH:29]=[C:30](/[Cl:33])\[CH2:31][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[C:26]([O:34][CH3:35])[C:25]([CH3:36])=[C:24]2[C:20]=1[C:21](=[O:37])[O:22][CH2:23]2)(=[O:16])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1c(C)c2c(c(OS(C)(=O)=O)c1C/C=C(/Cl)CBr)C(=O)OC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C/C(Cl)=C\Cc1c(OC)c(C)c2c(c1OS(C)(=O)=O)C(=O)OC2)C(=O)OCC
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
Diethyl malonate (113 mg) was added to a suspension of 50% NaH (35 mg) in THF (3 ml) at 0° C. and the mixture stirred for 30 minutes. To this solution was added (E)-4-(1,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-bromo-2-chlorobut-2-ene (280 mg) in THF (10 ml). The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was added to water (30 ml), the aqueous and organic phases separated, and the aqueous phase was extracted once with ethyl acetate (20 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue passed through a short column (silica gel, hexanes-EtOAc 8:2) affording 190 mg of ethyl (E)-6-(4-methanesulfonyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-chloro-2-ethoxycarbonyl-4-hexenoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Reactant: Cc1ccc(Cl)c(OCC2CO2)c1
Product: Cc1ccc(Cl)c(OCC(O)CNCCOc2cccc(C3=NNC(=O)CC3C)c2)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-chloro-5-methyl-phenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[C:10]([C:16]([O:18][CH2:19][CH3:20])=C)[N:9]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+]>O.O1CCOCC1>[Cl:7][C:8]1[N:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:22])[C:11]([CH3:15])=[C:12]([Cl:14])[N:13]=1
Reactant: C=C(OCC)c1nc(Cl)nc(Cl)c1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1nc(Cl)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium metaperiodate (2.111 g, 9.87 mmol) was suspended in water (20 mL) and sonicated until a clear solution was obtained. 2,4-Dichloro-6-(1-ethoxyvinyl)-5-methylpyrimidine (1.15 g, 4.93 mmol) dissolved in 1,4-dioxane (40 mL) was added followed by potassium permanganate (0.117 g, 0.74 mmol). The mixture was stirred at rt for 2 h. The mixture was filtered. The filtrate was diluted with saturated solutions of sodium bicarbonate and sodium chloride and extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuum. Column chromatography on silica gel using a 0-30% gradient of ethyl acetate in heptane yielded the title product, 0.67 g (58%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]C)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([SH:18])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC(=O)C1=C(O)CC(c2ccc(S)cc2)CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5 g (0.0163 mol) of 2-propionyl-3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one in a flask cooled to in an ice-water bath was added 25 mL (0.177 mol) of trifluoroacetic anhydride dropwise over 5 minutes. The ice-water bath was removed and the solution stirred at ambient temperature for 3 hours. The solvent was removed in vacuo and the oil remaining was dissolved in 82 mL of 1N NaOH and the solution stirred at ambient temperature overnight. The mixture was diluted with 1200 mL of water, filtered and the filtrate acidified with 5 mL of concentrated HCl with the product precipitating as an oily solid. The product was dissolved in 150 mL of methylene chloride and the solution washed twice with 150 mL portions of water and dried over Na2SO4. Removal of the solvent in vacuo gave the above named product in a yield of 4.0 g (88.7 percent of theoretical).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][NH2:13])[C:6]=2[S:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>C(O)C>[CH3:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][N:13]=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[C:6]=2[S:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1csc2c(NN)ncnc12
Agent: Cl
Solvent: CCO
Product: Cc1csc2c(NN=Cc3cccnc3)ncnc12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A suspension of (7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (5, 1.7 g, 7.9 mmol) and 3-pyridinecarboxaldehyde(1.1 g, 10.3 mmol) in ethanol (30 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration and recrystallized from methanol to yield 3-pyridinecarboxaldehyde(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazone (1.5 g, 71% yield) as white needles.