Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC2C3N(CC(C)C)C(CCCC)=NC=3C=[N:9]C=2C=1.COC1C=C(OC)C=CC=1B(O)O.[CH2:36]([C:40]1[N:41]([CH2:63][CH:64]([CH3:66])[CH3:65])[C:42]2[C:51]3[CH:50]=[CH:49][C:48]([C:52]4[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=4[O:60][CH3:61])=[CH:47][C:46]=3[N:45]=[CH:44][C:43]=2[N:62]=1)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([C:40]1[N:41]([CH2:63][CH:64]([CH3:65])[CH3:66])[C:42]2[C:51]3[CH:50]=[CH:49][C:48]([C:52]4[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][C:53]=4[O:60][CH3:61])=[CH:47][C:46]=3[N:45]=[C:44]([NH2:9])[C:43]=2[N:62]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Reactant: CCCCc1nc2cnc3cc(-c4ccc(OC)cc4OC)ccc3c2n1CC(C)C
Agent: COc1ccc(B(O)O)c(OC)c1
Product: CCCCc1nc2c(N)nc3cc(-c4ccc(OC)cc4OC)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinoline and 2,4-dimethoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The resulting 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline was oxidized and then aminated according to the general procedures described in Parts H and I of Example 1 and purified by chromatography on silica gel (8% methanol in CH2Cl2 to 10% methanol in CH2Cl2 gradient) followed by recrystallization from 1/1 ethyl acetate/hexane to afford 2-butyl-7-(2,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a pale orange solid, m.p. 187–189° C.
Reaction SMILES: [OH-:1].[Li+].[S].[Se].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6].[O:14]1[CH2:19][CH2:18]OC[CH2:15]1>CO.C(O)(=O)C>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6].[NH2:5][C:15]([O:14][CH2:19][CH3:18])=[O:1]
Reactant: [OH-]
Reactant: C1COCCO1
Agent: [Li+]
Agent: [S]
Agent: [Se]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CO
Product: CCOC(N)=O
Reaction time: 0.75 h

Procedure:
0.29 gram of lithium hydroxide, 0.72 gram of acetic acid, 0.25 gram of sulfur, 0.25 gram of selenium metal, 10 milliliters of nitrobenzene, 15 milliliters of methanol and 15 milliliters of dioxane were charged into a 110 milliliter autoclave maintained under an initial carbon monoxide pressure of 2600 psig and at a temperature of 200° C. for 45 minutes. A nitrobenzene conversion of 98 per cent and a urethane product yield of 88.4 per cent were obtained as determined by gas chromatographic analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Yield: 74 %

Procedure:
A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine, 200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed with N,N-dimethylacetamide. The filtrate is poured onto water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine; mp. 191.8° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>N1C=CC=CC=1.C(Cl)(=O)CCCC>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:21](=[O:24])[CH2:20][CH2:19][CH2:18][CH3:15])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCC)cc3)s2)cc1
Temperature: 0 °C
Yield: 170.8 %

Procedure:
To a solution of 0.60 g (1.78 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole in 10 ml of pyridine, 0.36 ml (3.03 mM) of pentanoyl chloride was added on an ice water bath under stirring, followed by further stirring for 2 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and dissolved in toluene, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent of toluene-methanol to obtain 0.64 g of 2-(4-hexylphenyl)-5-(4-pentanoyloxyphenyl)thiazole (Yield: 85.4%). ##STR38## SmC: smectic C phase, and N: nematici phase.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11]1
Reactant: Brc1ccc(Br)nc1
Reactant: CN1CCCC(O)C1
Product: CN1CCCC(Oc2ccc(Br)cn2)C1

Procedure:
Prepared from 2,5-dibromopyridine and N-methylpiperidin-3-ol by the method of Example 10 (b).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([OH:25])=[O:24])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Yield: 89.1 %

Procedure:
(2R,5S)-4-Benzyloxycarbonylmethyl-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (39 g, 84.6 mmol) in EtOH (200 mL) was hydrogenated (1 atmosphere H2) in the presence of Pd/C (8.9 g) at room temperature for 2 h. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound (28 g) as a pale yellow solid. 1H NMR (CDCl3): 4.21-4.05 (1H, m), 4.05-3.83 (3H, m), 3.83-3.55 (4H, m), 3.55-3.27 (4H, m), 3.27-3.13 (1H, m), 3.05 (1H, s), 2.87 (1H, s), 2.64 (1H, dd), 2.50 (1H, d), 1.48 (9H, s), 1.37-1.06 (6H, m). MS: [M+H]+=372.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=O)[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:14])[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)C1C(=O)NCC1C
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=S)NCC1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 146.6 %

Procedure:
2.5 g of ethyl 4-methyl-2-oxopyrrolidine-3-carboxylate and 3.4 g of phosphorus pentasulfide were added to 50 ml of benzene and stirred at 50° C. for 1 hour. After cooling, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by silica gel chromatography to thereby give 2.1 g of the title compound as an oily product.
Reaction SMILES: [Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][N:9]2C(OC(C)(C)C)=O)=[O:5].CO.Cl>O1CCOCC1>[Cl:1][C:2]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][C@@H:10]2[CH2:12][C@H:7]1[CH2:8][NH:9]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cccc(Cl)c1Cl)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 5.5 g of tert-butyl (1S,4S)-5-(2,3-dichlorobenzoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 10 ml of methanol was added hydrochloride in 1,4-dioxane solution (4 mol/l, 20 ml) followed by stirring for 1.5 hour at room temperature. The reaction mixture was concentrated in vacuo and then the resulting residue was suspended with diethylether. The precipitate was filtered and dried to give a crystal of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=[S:12].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[N:34][S:35][CH:36]=2)=[CH:28][CH:27]=1)=O>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:21])([C@H:10]([C:11]1[S:12][CH:23]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:33]=[N:34][S:35][CH:36]=3)=[CH:30][CH:31]=2)[N:13]=1)[CH3:14])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C[C@@H](C(N)=S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(CBr)c1ccc(-c2csnn2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](c1nc(-c2ccc(-c3csnn3)cc2)cs1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutyramide (19.7 mg) and 2-bromo-1-[4-(1,2,3-thiadiazol-4-yl)phenyl]ethanone (27.4 mg) in acetonitrile (3.0 ml) was stirred at room temperature for 1.0 hour. The solution was diluted with ethyl acetate (10 ml), washed with saturated sodium hydrogen carbonate solution (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified by silica gel column chromatography developed by hexane-ethyl acetate (1:1) to give (2R,3R)-2-(2,4-difluorophenyl)-3-{4-[4-(1,2,3-thiadiazol-4-yl)phenyl]thiazol-2-yl}-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as a pale yellow solid (14.1mg). EI-MS: m/z 497 (M+); 1H-NMR (CDCl3): δ 1.26(3H, d, J=6.9 Hz), 4.10(1H, q, J=6.9 Hz), 4.31(1H, d, J=14.3 Hz), 4.92(1H, d, J=14.3 Hz), 6.04(1H, s), 6.76˜6.87 (2H, m), 7.48˜7.58(1H, m), 7.58(1H, s), 7.68(1H, s), 7.92(1H, s), 8.06(2H, d, J=8.4Hz), 8.16(2H, d, J=8.4 Hz), 8.73(1H, s).
Reaction SMILES: [CH2:1]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:28][CH2:29][C:30](OC)=[O:31]>CO.C[O-].[Na+]>[Cl:28][CH2:29][C:30]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:31]
Reactant: COC(=O)CCl
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCNC(=O)CCl
Yield: 94 %

Procedure:
A four-necks-flask equipped with a stirrer, a temperature gage, a dehydrating pipe and a dropping funnel was charged with 383.69 g of 3-docosyloxypropylamine obtained in the same manner as in Example 24, 1000 g of methanol and 9.6 g of a methanol solution of 28% sodium methylate as a catalyst. 113.9 g of methyl chloroacetate was added to the mixture in one hour while the mixture was kept at 20 to 30° C. and the resulting mixture was reacted for 24 hours. After the reaction was completed, the precipitated crystal was filtered. The crystal was washed with 1000 g of methanol and then dried to obtain 432.6 g of 2-chloro-N-(3-docosyloxypropyl)-acetamide as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1)#[N:15]
Reactant: CNC(=S)NCCCSc1ncco1
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCCSc1ncco1)NC#N

Procedure:
Reaction of N-methyl-N'-[3-(2-oxazolyl)thiopropyl]thiourea with lead cyanamide by the procedure of Example 121 gives the title compound.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27]O)=[CH:24][C:23]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)=[O:30])=[C:22]2[CH3:42])=[C:17]([CH3:43])[CH:16]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([CH2:26][CH2:27][F:11])=[CH:24][C:23]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)=[O:30])=[C:22]2[CH3:42])=[C:17]([CH3:43])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1-n1c(CCO)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1-n1c(CCF)cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of bis(2-methoxyethyl)aminosulfur trifluoride (11 ml, 61 mmol) in dichloromethane (200 ml), a solution of the above 1-(4-chloro-2-methylphenyl)-5-(2-hydroxyethyl)-2-methyl-N-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carboxamide (6.8 g, 15 mmol) in dichloromethane (200 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to a saturated aqueous sodium hydrogencarbonate solution cooled to 0° C., and the mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated brine, and after it was dried with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=4:1) to give the title compound (3.8 g, 56%) as a solid.
Reaction SMILES: Cl[C:2]([CH3:12])([CH3:11])[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[C:13]([NH2:16])(=[S:15])[CH3:14]>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[S:15][C:13]([CH3:14])=[N:16][C:3]=1[CH:2]([CH3:12])[CH3:11])=[O:7])[CH3:10]
Reactant: CC(N)=S
Reactant: CCOC(=O)CC(=O)C(C)(C)Cl
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1C(C)C
Yield: 62.9 %

Procedure:
To a solution of ethyl 2-chloroisobutyrylacetate from step A (1.58 g, 8.2 mmol, ˜66% pure) in ethanol (20 mL) at 25° C. was added thioacetamide (617 mg, 8.2 mmol) and the reaction mixture was stirred at reflux for 24 h. After the solvents were removed under reduced pressure, the residual oil was diluted with ethyl acetate (100 mL), washed in turn with water (75 mL) and brine (75 mL), then was dried (MgSO4), filtered and concentrated in vacuo. The residue was flash chromatographed over silica gel (5% diethyl ether in hexanes) to yield 4-(1-methylethyl)-2-methylthiazole-5-carboxylic acid ethyl ester (1.1 g, 63% yield) as a yellow oil.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[C:19]=1[O:28][CH3:29]>C(Cl)Cl.CCOC(C)=O>[CH3:16][O:17][C:18]1[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]([O:24][CH3:25])=[CH:22][C:23]=1[CH:9]=[O:10]
Reactant: COc1ccc(OC)c(OC)c1OC
Reactant: CN(C=O)c1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.7 %

Procedure:
Following the procedure by Syper et al.,19 N-methylformanilide (1.0 mL, 8.1 mmol) was added to a flame dried 10 mL round bottom flask under argon and a drying tube. POCl3 (1.0 mL, 11 mmol) was added at room temperature and the Argon line was removed. After 5 minutes 18 (1.067 g, 5.38 mmol) was dissolved in CH2Cl2 (2.0 mL) and added at room temperature. The reaction was stirred at room temperature under a drying tube for 48 hrs and monitored by 1H NMR. When complete the reaction was diluted with EtOAc, washed with saturated brine, dried over MgSO4, filtered, and condensed. The resulting product was separated from remaining N-methylformanilide using flash chromatography (1:4 Et2O:hexanes) to provide 19 (1.141 g, 5.04 mmol, 94%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18](O)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([NH2:24])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(N)=O)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (100 mg, 0.33 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (64 mg, 0.39 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (490 μL, 3.3 mmol) and stirred for 1 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 1:1) afforded the title compound (84 mg, 84%) as an off white solid. MS: m/e=306.1 [M+H]+.
Reaction SMILES: O[C:2]1([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH2:10][CH2:9][CH2:8][C:7]2[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[N:5]=[CH:4][C:3]1=2.OC1(C2C=CC(C#N)=CC=2)CCCC2C1=CN(S(C1C=CC(C)=CC=1)(=O)=O)N=2.Cl.O1CCOCC1>>[N:6]1[NH:5][CH:4]=[C:3]2[C:7]=1[CH2:8][CH2:9][CH:10]=[C:2]2[C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3(O)c2ccc(C#N)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3(O)c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(C2=CCCc3n[nH]cc32)cc1
Temperature: 80 °C
Yield: 67 %

Procedure:
A mixture of 4-[4-hydroxy-1-(p-tolylsulfonyl)-6,7-dihydro-5H-indazol-4-yl]benzonitrile and 4-[4-hydroxy-2-(p-tolylsulfonyl)-6,7-dihydro-5H-indazol-4-yl]benzonitrile (8.56 g, 21.7 mmol) is added to 4.0 M HCl in dioxane (20.0 mL, 80.0 mmol), heated to 80° C. for 2.0 h and concentrated to dryness. The residue is dissolved in dichloromethane/water, separated and the organics are dried over Na2SO4, filtered, and evaporated. The residue is purified by silica gel chromatography 80% ethyl acetate/hexanes to give the title compound (3.21 g, 67%). ES/MS m/z 222 (M+H), 220 (M−H).
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:16][SnH:17]([CH3:19])[CH3:18]>[Hg].C1(C)C=CC=CC=1>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH2:2][Sn:17]([CH3:19])([CH3:18])[CH3:16])(=[O:5])=[O:4])=[CH:7][CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[SnH](C)C
Reactant: C=CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Hg]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(S(=O)(=O)CC[Sn](C)(C)C)cc1
Yield: 68.9 %

Procedure:
An 80 ml, two-necked, pyrex glass Schlenk reaction tube containing a Teflon coated magnetic stir bar was swept thoroughly with nitrogen and maintained in an air-free condition. The tube was charged with 9.5 g (42.5 mmoles) of 4-t-butylphenyl vinyl sulfone, 7.0 g (42.5 mmoles) of trimethyltin hydride and 10 ml. of toluene, stoppered, and placed in a 20°C water bath. The tube was irradiated for 35 hours by a 100 watt mercury vapor lamp which was situated in a large test tube and placed in the same bath 5-10 cm. from the reaction tube. Solvent was stripped off at reduced pressure on a rotary evaporator. Recrystallization of the solid product from cyclohexane gave 11.4 g of 2-(4-t-butylphenylsulfonyl)ethyltrimethylstannane, m.p. 118°-120°C. The presence of both the sulfonyl and trimethyltin groups was indicated by the strong infrared absorption bands at 1310 cm-1, 1262 cm-1, 1145 cm-1 (--SO2 --) and 770 cm-1 ((CH3)3Sn) using a KBr disc. Nuclear magnetic resonance spectroscopy (NMR) showed the following:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH2:11])=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH:22]1[CH:21]=[C:20]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH2:11])=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:24]=[N:23]1
Reactant: Nc1nc2ccc(Br)nc2s1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2ccc(-c3cn[nH]c3)nc2s1
Temperature: 150 °C

Procedure:
To a microwave vial, 5-bromothiazolo[5,4-b]pyridin-2-amine (1B, 100 mg, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5A, 2.0 equivalent), Na2CO3 (4.0 equivalents), DMF (0.15 M) and H2O (0.73 M) were added. While mixture was under N2, Pd(PPh3)4 was added and the mixture was then heated in a microwave for 3 h at 150° C. The crude mixture was filtered, and purified by preparatory LCMS. Intermediate 5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine (5B) was obtained as a white solid. ESI-MS: m/z 218.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+].O>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:14][CH3:13])[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (6.54 g) in methanol (31.5 mL) was added sodium methoxide (28% methanol solution, 6.05 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature for 1.5 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=9/1) to give the title compound (5.7 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH2:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1)C.[NH3:23]>>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([NH2:23])=[O:3]
Reactant: N
Reactant: CCOC(=O)CCCOc1ccc(C)cc1Cc1ncc[nH]1
Product: Cc1ccc(OCCCC(N)=O)c(Cc2ncc[nH]2)c1
Reaction time: 6 h

Procedure:
A mixture of 4-[2-(1-imidazolylmethyl)-4-methyl-phenoxy]butyric acid ethyl ester (1.0 g) and 0.880 ammonia solution was stirred for 6 hours and allowed to stand for a further 36 hours. The solid was filtered off and crystallised from water to give 4-[2-(1-imidazolylmethyl)-4-methyl-phenoxy]butyramide (0.30 g), m.p. 114°-116° C. Found: C, 65.31, H, 7.23, N, 15.13. C15H19N3O2 requires: C, 65.91, H, 7.01, N, 15.37%.