Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:35])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:38][C@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][N:40]1[C:45]1[N:49]2[CH:50]=[C:51]([O:54][C@H:55]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C@@H:58]([NH2:65])[CH2:57][CH2:56]3)[CH:52]=[CH:53][C:48]2=[N:47][N:46]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:65][C@@H:58]2[C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@H:55]([O:54][C:51]3[CH:52]=[CH:53][C:48]4[N:49]([C:45]([N:40]5[CH2:41][CH2:42][CH2:43][CH2:44][C@@H:39]5[CH3:38])=[N:46][N:47]=4)[CH:50]=3)[CH2:56][CH2:57]2)=[O:35])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CO)(C(C)C)C(C)C
Yield: 57.3 %

Procedure:
A solution of Intermediate 61d (173 mg, 0.29 mmol), Intermediate B (100 mg, 0.27 mmol) and DIPEA (58 μL, 0.33 mmol) in 1,4-dioxane (2.9 mL) was stirred at 70° C. for 42 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM, to give the title compound as a cream colored glass (127 mg, 58%). LCMS (Method 3): Rt 4.97 min, m/z 821 [MH+].
Reaction SMILES: [OH-].[K+].O.COC(=O)[NH:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH:16]([CH3:18])[SeH:17])[N:9]=1.Cl>CO>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH:16]([CH3:18])[SeH:17])[N:9]=[C:8]([NH2:7])[N:13]=1
Reactant: COC(=O)Nc1nc(OC)cc(C(C)[SeH])n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(C)[SeH])nc(N)n1
Temperature: 0 °C

Procedure:
To a stirring solution of potassium hydroxide (15.6 mmol) in H2O (77.5 mmol) and 50 ml of methanol was added methyl[4-methoxy-6-(methylselenylmethyl)pyrimidin-2-yl]carbamate (5.2 mmol). The solution was heated to the reflux point for 3 hours, then cooled to 0° C. The solution was neutralized to pH7 with concentrated HCl and then the solvent was removed under reduced pressure. The resulting residue was washed with THF to afford 1.3 g, m.p. 88°-91° C.; NMR (200 MHz, CDCl3): δ 2.01 (s, 3H); 3.48 (s, 2H); 3.85 (s, 3H); 5.1 (br. s, 2H); 5.99 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:11][N:10](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[C:27]([OH:30])(=[O:29])[CH3:28]>C(O)C.[Pd]>[C:27]([OH:30])(=[O:29])[CH3:28].[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CNC1

Procedure:
A suspension of 14 (4.6 g, 13.6 mmol) and 10% Pd/C (2.0 g) in 200 ml of 10:2:1 ethanol:water:acetic acid was hydrogenated at 50 psi for 24 hours. The suspension was subsequently filtered through celite and the solvents removed in vacuo to give the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[C:30]1([C:36]2[N:37]=[CH:38][NH:39][C:40]=2[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C:36]2[N:37]=[CH:38][N:39]([CH2:6][CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]4[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][CH:21]=4)=[CH:13][CH:14]=3)[C:40]=2[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3cnc(-c4ccccc4)c3-c3ccccc3)cc2)co1)\c1ccccc1
Yield: 53 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with 4,5-diphenylimidazole to give 4-[4-[3-(4,5-diphenyl-1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 137-138° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O.[S:43]1[C:51]2[C:46](=[N:47][C:48]([CH2:52][CH2:53]O)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1>C1COCC1>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:53][CH2:52][C:48]3[N:47]=[C:46]4[CH:45]=[CH:44][S:43][C:51]4=[CH:50][CH:49]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: OCCc1ccc2sccc2n1
Reactant: O=c1[nH]ncc2scc(Br)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Br)csc2cnn1CCc1ccc2sccc2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one (100 mg, 0.433 mmol) from Example 3.3 and triphenylphosphine (227 mg, 0.866 mmol) in THF (2 mL) was added (E)-diethyl diazene-1,2-dicarboxylate (151 mg, 0.866 mmol) dropwise at 0° C. After the addition, the mixture was stirred for 1 h at 0° C. Then 2-(thieno[3,2-b]pyridin-5-yl)ethanol from Example a3 (78 mg, 0.433 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at room temperature overnight. The solution was filtered to obtain the title compound (80 mg, yield 47.1%).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O[CH:24]([CH3:34])[CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:28][C:27]([NH:26][CH2:25][CH:24]([O:1][C:2]1[C:7]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:34])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OC(C)CNC(=O)OC(C)(C)C)c2c1C

Procedure:
Prepared analogously to example 9.1 using methyl 4-(2-hydroxypyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate and tert-butyl N-(2-hydroxypropyl)-carbamate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[C:4](=[O:9])[CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1ccc2[nH]ncc2c1
Temperature: 90 °C

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (3.75 g, 0.029 mol) and 5-aminoindazole (4.0 g, 0.03 mol) in water (70 ml) was heated at 90° C. under argon for 1 h. The mixture was cooled, decanted the supernatant and residue was triturated with ethanol, cooled and filtered the solid. It was washed with cold ethanol, and dried. 1H NMR (CD3OD/400 MHz) δ8.11 (s, 1H), 7.64 (m, 2H), 7.18 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2.0 Hz) 6.07 (m, 1H), 5.81 (d, 1H, J=2.8 Hz), and 1.94 (s, 3H); ES-HRMS m/z 242 0962(M+H calcd for C13H12N3O2 requires 242.0924).
Reaction SMILES: [CH:1]1([NH:7][C:8]2([CH2:13]O)[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl.[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>>[CH:1]1([N:7]2[C:8]3([CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:13][S:31][C:30]2=[N:29][C:21]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1(NC2CCCCC2)CCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCCC1
Yield: 17 %

Procedure:
1-(Cyclohexylamino)-1-(hydroxymethyl)cyclopentane (Method B4a; 1.89 g, 9.59 mmol) was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to yield 1-cyclohexyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane (0.44 g, 17%): CI-MS m/z 374 ((M+H)+).
Reaction SMILES: CS(O)(=O)=O.[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[N:10]=1)(=O)[CH3:7].BrBr.C(=O)([O-])O.[Na+].[NH2:28][C:29]([NH2:31])=[S:30]>O1CCOCC1.CO>[NH2:31][C:29]1[S:30][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[N:10]=2)[N:28]=1
Reactant: NC(N)=S
Reactant: CCC(=O)NCc1cccc(C(C)=O)n1
Agent: BrBr
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CO
Product: CCC(=O)NCc1cccc(-c2csc(N)n2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
Methanesulfonic acid (18.6 g) was added to a solution of 2-acetyl-6-(propionylaminomethyl)pyridine (40.0 g) in dioxane (800 ml) at room temperature. The mixture was stirred at room temperature for 15 minutes. Bromine (34.1 g) was added slowly to the mixture at room temperature. The mixture was heated at 50° C. for 3 hours. To the mixture sodium hydrogencarbonate (65.2 g), thiourea (17.7 g) and methanol (800 ml) was added. The mixture was heated at 50° C. for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water (700 ml). The mixture was extracted with a mixture of ethyl acetate (700 ml) and tetrahydrofuran (700 ml). The extract was dried with magnesium sulfate and then was evaporated. The residue was crystallized from acetone to afford 2-amino-4-(6-propionylaminomethylpyridin-2-yl)thiazole (26.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH3:24][N:25]=[C:26]=[S:27]>C(Cl)CCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:26]([NH:25][CH3:24])=[S:27])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CN=C=S
Solvent: ClCCCl
Product: CNC(=S)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) and methyl isothiocyanate (54.8 mg) in ethylene chloride (4 ml) was stirred for 2 hours at ambient temperature and then gently refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[4-(methyl)thiosemicarbazido]quinoline (213 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][C:3]=1[CH3:18].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(-c2cn3cccc(C)c3n2)ccc1O
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn3cccc(C)c3n2)ccc1OCCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step B (6.0 g) in N, N-dimethylformamide (200 mL) was added to a suspension of 60% sodium hydride (2.0 g) in N, N-dimethylformamide (200 mL). The mixture was stirred at ambient temperature for 1 hour and then treated with 1-bromo-3-chloropropane (30 mL). The mixture was stirred at ambient temperature for 18 hours and partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate, filtered and evaporated to give the title compound (6.2 g).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3]1.[N:13]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[N:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH2:28]([O:27][C:25]([N:13]([C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1CC(=O)NC1=O
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (3.92 g) in ethyl acetate (60 ml) was added dibenzyl azodicarboxylate (7.27 g), followed by potassium carbonate (317 mg) at room temperature. After this mixture was stirred at room temperature for 1 hour, the mixture was filtered through a Celite pad. The filtrate was concentrated and the resulting residue was purified by a flash column chromatography (hexane:ethyl acetate=2:1) to give the ethyl 3-[N,N′-bis(benzyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxylate (10.1 g, 94%) as amorphous.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[OH2:14]>C(O)(=O)CCCCCCCCCCC.[OH-].[Na+]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:14])[OH:4]
Reactant: O
Reactant: CCCCCCCCOCC1CO1
Agent: CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCC(O)CO
Temperature: 157 °C
Yield: 86 %

Procedure:
The crude octyl glycidyl ether (175 g), water (110 g; 6.111 mol), lauric acid (7.10 g; 0.033 mol) and sodium hydroxide (0.71 g; 0.018 mol) were placed in a 2-l autoclave, and the mixture was heated up to 157° C. while stirring it. The mixture was stirred for 5 hours as it was, and was then allowed to cool down to room temperature. The mixture was extracted with ethyl acetate (500 ml), and the extract was washed twice with water (300 ml). The solvent was then distilled off to obtain 165 g of crude monooctyl glyceryl ether. This crude product was purified by vacuum distillation (0.4-0.5 mmHg, 120-123° C.) to obtain 124 g of monooctyl glyceryl ether as a colorless transparent oil (total yield: 75%). Quenching of a proton signal (methylene in an epoxy ring) at δ=2.65, 2.80 was observed by 1H-NMR (200 MHz), thereby identifying the compound. The purity of the compound was found to be 99% by GLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O1CCOCC1>[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)[O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: COC(=O)C(O)C1CC1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)C(Oc1c(Cl)nc(Cl)nc1Cl)C1CC1
Reaction time: 6 h
Yield: 57.5 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidin-5-ol (250 mg, 1.25 mmol), cyclopropyl-hydroxy-acetic acid methyl ester (245 mg, 1.88 mmol) and triphenylphosphine (493 mg, 1.88 mmol) in THF (12 mL) was added DIAD (370 μL, 1.88 mmol) dropwise. The resultant suspension was stirred for 18 hours before the addition of dioxane (10 mL) and the reaction stirred for a further 6 hours. The heterogeneous mixture was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, gradient 0-30% ethyl acetate in cyclohexane) affording Cyclopropyl-(2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid methyl ester as a white solid (224 mg, 32%). LCMS: RT=3.66 min, [M+H]+=311/313/315.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:29]([C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:30])[CH:16]=1
Reactant: c1ccc2c(CCN=c3sc4ccccc4s3)c[nH]c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1ccc(Cl)cc1)n1cc(CCN=c2sc3ccccc3s2)c2ccccc21
Reaction time: 4 h

Procedure:
Sodium hydride (57% dispersion in mineral oil; 408 mg) is slurried in 10 ml of anhydrous 1,2-dimethoxyethane and treated dropwise with N-(1,3-benzodithiol-2-ylidene)-1H-indol-3-ethanamine (3g, prepared as described in Example 30) in 15 ml of anhydrous 1,2-dimethoxyethane. The reaction mixture is heated at reflux for two hours. A solution of p-chlorobenzoyl chloride (1.69g) in 10 ml of anhydrous 1,2-dimethoxyethane is added dropwise to the refluxing mixture. Refluxing is continued for an additional 4 hours. The reaction mixture is then poured into water (100 ml) and extracted with three 50 ml portions of dichloromethane. The combined dichloromethane extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (500 ml) eluting with dichloromethane/pentane (3:2). The fractions containing product with Rf =0.5 (silica gel; dichloromethane) are concentrated in vacuo. The solid thus obtained is recrystallized from hexane/dichloromethane to yield 2.1g of the title compound, melting point 135° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[S:9][C:8](/[CH:10]=[CH:11]/[C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][C:6]=2[CH3:22])=[O:4])[CH2:25][CH2:26]1
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCOCC2)s1
Yield: 75 %

Procedure:
As described for example 93d, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (55 mg, 75%) which was obtained as a white solid. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]2=[N:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[CH:12]=[C:7]2[CH2:6][C:5]1=[O:16]>C(O)(=O)C>[Br:1][CH2:14][C:13]([C:11]1[CH:12]=[C:7]2[CH2:6][C:5](=[O:16])[N:4]([CH3:3])[C:8]2=[N:9][CH:10]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1cnc2c(c1)CC(=O)N2C
Solvent: CC(=O)O
Product: CN1C(=O)Cc2cc(C(=O)CBr)cnc21
Temperature: 80 °C
Yield: 60 %

Procedure:
Add 170 mg (1.05 mmol) of bromine dissolved in 1 ml of acetic acid dropwise to a solution of 200 mg (1.05 mmol) of 1,3-dihydro-1-methyl-5-acetyl-2H-pyrrolo[2,3-b]pyridin-2-one (obtained as described in Example 13 hereinafter) in 4 ml of acetic acid. After 6 hours' heating at 80° C., the acetic acid is removed under reduced pressure and the residue is taken up in water and then extracted with dichloromethane. The crude product obtained is purified by chromatography on silica gel (eluant ethyl acetate/petroleum ether/dichloromethane, 1/1/1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH2:37][C:38](=[O:44])[NH:39]2.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>O1CCCC1>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([O:32][CH2:33][CH2:34][C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][C:38](=[O:44])[NH:39]3)=[CH:49][CH:48]=1
Reactant: COc1ccc(O)cc1
Reactant: O=C1Cc2c(CCO)cccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCCc2cccc3c2CC(=O)N3)cc1
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
Diethyl azodicarboxylate (0.47 mL, 3 mmol) was added to a solution of triphenylphosphine (0.786 g, 3 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture was stirred for 15 minutes. To it was then added 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (0.53 g, 3 mmol) followed by 4-methoxyphenol (0.372 g, 3 mmol). The mixture was stirred at room temperature for 18 hours and the solvent was evaporated. The residue was dissolved in ethyl acetate (150 mL) and the organic solvent was washed with 2 N hydrochloric acid (3×30 mL), saturated sodium bicarbonate solution and brine. The residue was chromatographed on silica gel eluting with ethyl acetate:hexane 2:8 to give 0.14 g (16%) 4-[2-(4-Methoxy-phenoxy)-ethyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[S:13][CH:12]=[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:10]=2)=[O:8])=[CH:5][CH:4]=1>O=[Mn]=O.C1COCC1>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[S:13][CH:12]=[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1)=[O:1]
Reactant: NS(=O)(=O)c1csc(C(=O)c2ccc(CO)cc2)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1csc(C(=O)c2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30 mg (0.1 mmol) of 5-(4-hydroxymethylbenzoyl)-3-thiophene sulfonamide and 300 mg of MnO2 were added to 5 mL of THF. After stirring at rt for 30 min the mixture was filtered through a bed of celite and eluted with ethyl acetate. The filtrate was concentrated and the crude product subjected to flash chromatography utilizing 1:1 ethyl acetate/hexane as the eluent to recover 16 mg of 5-(4-formylbenzoyl)-3-thiophene sulfonamide as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH:2]=[CH2:3].[N:22]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]=[CH2:17])[C:11]([CH2:18][C:19]#[C:20][CH3:21])=[CH:10][C:6]=1[C:7]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:34][CH:33]=1)=[O:9])[CH:2]=[CH2:3]
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: C=CCOc1cc(OCC=C)c(C(=O)O)cc1CC#CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(OCC=C)c(C(=O)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Reaction time: 4 h
Yield: 86.8 %

Procedure:
2,4-bis-allyloxy-5 (but-2-ynyl)-benzoic acid (Example 1-4, IM07-c: 287 mg, 1 mmol) and 4-(morpholin-4-ylmethyl)-phenylamine (IM08-02: 193 mg, 1 mmol) were dissolved in dimethylformamide (4 mL) and mixed with 1-hydroxybenzotriazole monohydrate (176 mg, 1.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (249 mg, 1.3 mmol) at 0° C., and the resulting mixture was stirred for 4 hours under ice cold conditions. The reaction mixture was mixed with water (40 mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and then were concentrated. The residue was purified by silica gel column chromatography (hexane-ethylacetate=1:2-1:5) to obtain the title compound (F470-IM09: 0.40 g, yield 82%).