Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(C)cc2)CC1
Product: Cc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (30%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=2)[CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(N(CC)CC)C>[CH2:18]([NH:20][C:21]([N:6]1[C:2]([CH3:1])=[CH:3][C:4]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][N:9]=2)=[N:5]1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2cc(C)c([N+](=O)[O-])cn2)n[nH]1
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2cc(C)c([N+](=O)[O-])cn2)cc1C
Yield: 19.3 %

Procedure:
Reaction of 5-methyl-3-(4-methyl-5-nitropyridin-2-yloxy)pyrazole with ethyl isocyanate was carried out in the presence of triethylamine in the same manner as in Example 130, to give a yellow viscous substance of N-ethyl-5-methyl-3-(4-methyl-5-nitropyridin-2-yloxy)pyrazole-1-carboxamide (yield: 19.3%). 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.65 (d, J=0.7 Hz, 3H), 2.70 (s, 3H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.03 (q, J=0.7 Hz, 1H), 6.95 (s, 1H), 6.99 (br s, 1H), 8.92 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.C[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](=O)[O-:13]>>[C:4]1([NH:1][C:12]([NH:11][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CN(C(=O)[O-])c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1
Temperature: 135 °C
Reaction time: 5 h

Procedure:
The experiment as described in Example 10 was repeated at a temperature of 110° C. using nitrobenzene (7.5 ml) and aniline (4 ml) as feed. Gas-liquid chromatography indicated that the initial amount of aniline had been converted completely and that 1,3-diphenylurea had been formed in high yield (90%, based on aniline. Methyl carbanilate had been obtained in 60% yield, based on nitrobenzene with a nitrobenzene conversion of about 70%). The reaction temperature was then raised to 135° C. and the reaction was allowed to proceed at that temperature for another 5 hours. The total conversion of nitrobenzene amounted to 90% and more methylcarbanilate had been formed, corresponding to the amount of 1,3-diphenylurea converted.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[O:10])=[CH:7][C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]1[CH3:23].II>C(Cl)(Cl)Cl>[Br:1][C:7]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH3:23])[N:4]([CH3:3])[C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)c1cc(C(=O)c2ccc(C)cc2)n(C)c1C
Reactant: BrBr
Agent: II
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(Br)c(C(=O)c2ccc(C)cc2)n(C)c1C
Temperature: 0 °C

Procedure:
A solution of 27.4 ml (0.538 mole) of bromine in 150 ml of chloroform is added to a refluxing solution of 152.6 g. (0.538 mole) of ethyl 1,2-dimethyl-5-(p-toluoyl)pyrrole-3-carboxylate in 1500 ml of chloroform containing a few iodine crystals over a period of 45 min. The solution is heated under reflux for 10 min. and is then poured into ice water. The organic layer is separated and washed with sodium bicarbonate solution, sodium bisulfate solution, and brine. It is then dried over sodium sulfate and the solvent is evaporated in vacuo. After recrystallization of the product from methanol, it is extracted in a Soxhlet extractor with about one liter of diethyl ether and then crystallized from the cooled ether to yield ethyl 4-bromo-1,2-dimethyl-5-(p-toluoyl)pyrrole-3-carboxylate; m.p. 122°-125° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd](Cl)Cl.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>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3×10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4) The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s), 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.25 (1H, d, J~1.8 Hz), 7.30 (1H, d, J~8.2 Hz). MS exact mass, m/1 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11](O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:61]=[N+:62]=[N-:63])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: -10 °C
Reaction time: 6 h

Procedure:
To a cooled (−10° C.) and stirred solution under Ar of (trans-4-hydroxy-cyclohexyl)carbamic acid tert-butyl ester (10.0 g) (H. Noguchi, T. Aoyama, T. Shioiri, Heterocycles 2002, 58, 471-504) and PPh3 (18.3 g) in THF (250 ml) was added diethyl azodicarboxylate (12.1 g). After 5 min a solution of diphenylphosphoryl azide (19.2 g) in THF (250 ml) was slowly added from a dropping funnel. The reaction mixture was stirred 6 h at −10° C. and stirring was continued over night at RT. After dilution with Et2O the mixture was washed with H2O. The aqueous layer was washed with one more portion of Et2O. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. Chromatography (silica, CH2Cl2 to CH2Cl2/5% MeOH) afforded 12.0 g (quant.) of product still contaminated by side products. This material was used as this in the following step. Light yellow semisolid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1.[O:16]1CCOCC1>O>[CH:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[N:3]=1)=[O:16]
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc2ccc(C)nc2c1
Solvent: O
Product: COC(=O)c1ccc2ccc(C=O)nc2c1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
To a solution of methyl 2-methylquinoline-7-carboxylate (0.99 g, 4.92 mmol) in dioxane (60 mL) and water (0.6 mL) was added SeO2 (0.66 g, 5.90 mmol) and the mixture was stirred at reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:4 hexane/ethyl acetate) to give methyl 2-formylquinoline-7-carboxylate (0.75 g, 70.8%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:15]2[CH2:16][C@H:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH2:13][C@H:14]2/[CH:17]=[CH:18]\[C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/C=C\[C@@H]2C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)CN2S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a suspension of (2S,4R)-4-(4-chlorophenyl-sulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (11.5 g) in dichloromethane (200 ml) were added triethylamine (3.80 ml) and 4-chlorobenzenesulfonyl chloride (5.77 g) under ice bath cooling and the mixture was stirred at room temperature for 1 hour. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residual solid was collected by filtration to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-2-(4-methoxycarbonylphenyl)vinyl]pyrrolidine (15.71 g) as a white powder
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]OS(CC1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[I:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:1][CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: Cc1ccc(CS(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(C#N)ccc1I
Temperature: 50 °C
Reaction time: 16 h

Procedure:
2.0 g (8.16 mmol) of 3-hydroxy-4-iodobenzonitrile was dissolved in 20 ml of DMF. 5.8 g (16.3 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine and 3.37 g (24.4 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 50° C. for 16 hours. 1.5 g (4.2 mmol) of 1-t-butoxycarbonyl-(2R)-2-(p-tolylmethanesulfonyloxymethyl)pyrrolidine was added to the obtained mixture, and they were stirred at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38].C(N(CC)CC)C>CN(C=O)C>[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][N:43]([C:33]([CH:31]2[CH2:30][C:29](=[O:28])[CH2:32]2)=[O:35])[CH2:42][CH2:41]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(C(=O)C2CC(=O)C2)CC1
Temperature: 0 °C

Procedure:
BOP (4.43 g, 10 mmol) was poured some more to a solution of 3-oxo-cyclobutanecarboxylic acid (1.14 g, 10 mmol), intermediate 35, 1-(Methanesulphonyl)piperazine (1.64 g, 10 mmol), and triethylamine (4.1 mL, 30 mmol) in DMF (10 mL) in argon under stirring at 0° C. The mixture was stirred for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was subjected to chromatography on SiO2 (200 g, 40-63 μm, CHCl3/hexane 8:2, 9:1, 9.5:0.5→CHCl3→CHCl3/i-PrOH 99:1→95:5) to give the title compound as white crystals in 2.2 g yield. GCMS data: M+ 260 (Calculated for C10H16N2O4S 260.31), 93.5%, r.t. 14.64 min. 1H-NMR data (dmso-d6): 3.56-3.64 (m, 4H), 3.50 (ddd, 1H, J=7.1 Hz, J=9 Hz, J=15 Hz), 3.20-3.29 (m, 4H), 3.08-3.15 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:26])=[C:5]([C:10]2[NH:11][C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[F:22][C:21]([F:23])([F:24])[C:18]1[CH:19]=[CH:20][C:15]([N:13]2[C:12](=[O:25])[NH:11][C:10]([C:5]3[C:4]([CH3:26])=[C:3]([CH:8]=[CH:7][C:6]=3[CH3:9])[CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(CN)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 19.5 %

Procedure:
To a solution of 5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-66, 0.050 g) in dry THF (5 mL), TEA (3 mL) was added and stirred the reaction mixture for 20 minutes. The reaction mixture was cooled to 0° C. and pivaloyl chloride (0.05 g, 0.563 mmol) was added and stirred for 3 h at RT. After completion of the reaction, the reaction mass was quenched with water, extracted with DCM:MeOH. The organic layer was separated, concentrated, and purified by column chromatography to afford 0.012 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.15 (s, 9H), 2.18 (s, 3H), 2.22 (s, 3H), 4.24 (d, J=12.6 Hz, 2H), 7.19 (d, 1H), 7.25 (d, 1H), 7.84 (d, J=5.7 Hz, 2H), 8.0 (t, 1H), 8.20 (d, J=6.4 Hz, 2H), 12.30 (br s, 1H); MS (m/z): 447.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:4][C:3]=1[CH3:12].C1N=CN([C:18](N2C=NC=C2)=[S:19])C=1.O>CN(C=O)C>[CH3:12][C:3]1[S:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[C:2]=1[NH:1][C:18](=[S:19])[NH:7]2
Reactant: COC(=O)c1sc(C)c(N)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C)c2[nH]c(=S)[nH]c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3,4-diamino-2-methylthiophene-5-carboxylate (1.0 g) and N,N'-thiocarbonyldiimidazole (1.1 g) in DMF (5 ml) was stirred at 50° C. for one hour. To the reaction mixture was added water to give crystals. Recrystallization from DMF-water afforded colorless prisms (1.2 g, quantitatively), m.p. 285°-288° C. (dec.)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11]Br>C(O)(=O)C.O>[Br:11][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: OCCc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: OCCc1ccc(O)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol 9.50 g in acetic acid 60 ml is dropped bromine 3.54 ml over a period of 10 minutes on a water bath, and the mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is dissolved in methanol 120 ml and thereto is added potassium carbonate 25 g. The mixture is stirred at room temperature for 5 hours. and then diluted with water and with ethyl acetate. The solution is acidified with concentrated sulfuric acid. The organic layer is extracted with ethyl acetate, washed, dried and concentrated in vacuo. The residue is crystallized from chloroform to give 2-bromo-4-(2-hydroxyethyl)phenol as a slightly brown crystalline powder 9.37 g. mp 83-85° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([CH2:18][C:19]#[N:20])[C:12]=1[O:21][CH3:22].Cl>CN(C)C=O.O>[C:19]([C:18]1([C:13]2[CH:14]=[C:15]([Br:17])[CH:16]=[C:11]([Br:10])[C:12]=2[O:21][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:20]
Reactant: COc1c(Br)cc(Br)cc1CC#N
Reactant: BrCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)cc(Br)cc1C1(C#N)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7 g) in dry dimethylformamide (200 ml) was added a solution of 1,5-dibromopentane (20 ml) and the product of stage (d) in dimethylformamide (40 ml), keeping the temperature at 20°-30° C. The mixture was stirred for 30 minutes, water was added cautiously, and was then poured into ice water. Hydrochloric acid was added and the mixture was extracted with dichloromethane, washed with water and brine, dried over magnesium sulphate and filtered, and the solvent was removed to give a pale brown oil which slowly crystallised. Recrystallisation from ethanol gave the title product as yellow crystalls, mp 100°-102° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][OH:17].C[O-].[Na+]>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:17][CH3:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(SCc2ccccc2)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(SCc2ccccc2)n1
Yield: 86 %

Procedure:
2-(Benzylthio)-6-fluoropyridine (199 mg) and 28% sodium methoxide methanol solution (2 mL) were stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 182 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]3[CH3:20])[N:11]=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][C@H:22]3[CH3:27])[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([NH2:38])=[N:36][C:35](Cl)=[C:34]([Cl:40])[N:33]=1)=[O:31]>C(O)(C)C>[CH3:28][O:29][C:30]([C:32]1[N:33]=[C:34]([Cl:40])[C:35]([N:17]2[CH2:18][CH2:19][N:14]([C:12]3[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[C:10]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C@H:22]4[CH3:27])[N:11]=3)[CH:15]([CH3:20])[CH2:16]2)=[N:36][C:37]=1[NH2:38])=[O:31]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: CC1CNCCN1c1cc(-c2ccc(F)cc2)nc(N2CCOC[C@H]2C)n1
Solvent: CC(C)O
Product: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1N

Procedure:
Heat a mixture of 4-[4-(4-fluoro-phenyl)-6-(2-methyl-piperazin-1-yl)-pyrimidin-2-yl]-3-(R)-methyl-morpholine with 1.1 equivalents of 3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester (Cragoe et. al. J. Med. Chem., 1967, 10, 66-75) in isopropanol at 85° C. for 12 h. Concentrate the mixture under reduced pressure, and then partition between 10% NaOH and EtOAc. Dry the organic layer (Na2SO4) and concentrate under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([S:25][CH3:26])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:13]
Reactant: CSc1ccc(-c2ccc(C(=O)C=Cc3ccc(O)c(Cl)c3Cl)s2)cc1
Solvent: C1CCOC1
Product: CSc1ccc(-c2ccc(C(=O)CCc3ccc(O)c(Cl)c3Cl)s2)cc1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(methylthio)phenyl)thien-2-yl)propan-1-one is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(methylthio)phenyl)thien-2-yl)prop-2-en-1-one according to general procedure C in solution in tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]([CH3:10])[CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:9][CH2:8][CH:7]([O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:10])(=[O:23])=[O:22]
Reactant: CC(CO)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 51.5 g of 2-(p-chlorophenoxy)-1-propanol and 57.5 ml of triethylamine in 680 ml of dichloromethane is chilled to -10° C. To the solution is added dropwise with stirring 25.8 ml of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture is stirred for 1 hour at -7° C. to -10° C. and washed with ice cold water, saturated NaCl, saturated NaHCO3 and dried (MgSO4). The solvent is removed under reduced pressure to give 73 g of product as an oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[O:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:23][C:22]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=2)[N:10]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CS(=O)(=O)c1nccc(Oc2ccccc2)n1
Product: COc1cc(Nc2nccc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 1.7 %

Procedure:
2-Methylsulphonyl-4-phenoxypyrimidine (0.76 g, 3.04 mmol) and 3,4,5-trimethoxyaniline (0.56 g, 4.0 mmol) were heated as a melt at 140° for 2 h. On cooling the residue was partitioned between ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml), and the organic layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography [silica 20% ethyl acetate-hexane] to give the title compound (18 mg) as a white solid m.p. 149° after recrystallisation from ethyl acetate. δH (CDCl3) 8.26 (1H, d, J 5.6 Hz), 7.39 (2H, m), 7.26 (1H,m), 7.18-7.15 (2H, m), 6.73 (2H, s), 6.31 (1H, d, J 5.6 Hz), 3.77 (3H, s) and 3.64 (6H, s). MS m/z 354 (M+H)+.