Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].[CH3:20][C@H:21]1[CH2:23][C@@H:22]1[CH2:24]Br.O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C[C@H]1C[C@@H]1CBr>[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH2:20][C@H:21]2[CH2:23][C@@H:22]2[CH3:24])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: C[C@H]1C[C@@H]1CBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (3.94 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) was further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][CH2:48][CH2:49]O)([CH3:46])([CH3:45])[CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:49][CH2:48][O:47][C:43]([CH3:46])([CH3:45])[CH3:44])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 73, Step 6) (0.167 mmol) in dichloromethane (20 mL), add 2-tert-butoxy-ethanol (0.835 mmol) and triphenylphosphine (0.501 mmol). To this solution, add diethyl azodicarboxylate (0.501 mmol) dropwise at room temperature. After stirring for 12 h, remove the solvent under vacuum. Chromatograph the intermediate over silica gel, eluting with ethyl acetate/hexane (2-35%) to afford the title compound as an oil. MS (ES+): 699 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([CH3:23])([CH3:22])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:22])[CH3:23])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CNCCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.73 mmol) was dissolved in 4M HCl/Dioxane (2 ml, 8 mmol). The solution was stirred at room temperature for about 4 hours. The solvent was removed in vacuo. The residue was quenched with aqueous sodium hydroxide, extracted with ethyl acetate, and the organic layers were dried over sodium sulfate and evaporated in vacuo to yield the title compound as a yellow solid. The mixture was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[NH:11][C:12](=[O:21])[C:13]([OH:20])=[C:14]([C:16](OC)=[O:17])[N:15]=1>C1COCC1>[CH3:1][NH:2][C:16]([C:14]1[N:15]=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:11][C:12](=[O:21])[C:13]=1[OH:20])=[O:17]
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
A sealed tube containing 2M solution of methylamine (2 ml, 4 mmol) in THF and methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.05 g, 163 μmol, Eq: 1.00) was heated at 150° C. in a microwave oven for 15 min, cooled and filtered. The solid was stirred in MeOH, in the presence of Amberlyst 15 IE resin, at 60° C. for 5 min and then at room temperature for 1 h, filtered, evaporated to dryness and triturated with Et2O to give the title compound as a white solid (0.015 g; 27%). LCMS: m/z=336 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.CN([CH:21]=[O:22])C>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([C:5]([Cl:8])=[CH:6][CH:7]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 169 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50° C. The resulting solution was then warmed to −20° C. and cooled again to −50° C. A solution of DMF (14.6 g, 0.20 mol) in THF (50 mL) was slowly added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic phases were dried and concentrated. The product was recrystallized from hexane to give 3-bromo-6-chloro-2-fluorobenzaldehyde (40.0 g, 0.169 mol): mp 92-93° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH:28]([CH:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)[OH:29])[CH:25]=[CH:24][CH:23]=1>>[O:37]=[S:33]1(=[O:36])[CH2:34][CH2:35][CH:30]([CH:28]([OH:29])[C:26]2[N:27]=[C:22]([NH:1][C:2]3[S:3][C:4]([C:10]4[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=4[F:20])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:23]=[CH:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=S1(=O)CCC(C(O)c2cccc(Br)n2)CC1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)C4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.14 g, 0.47 mmol) and (6-bromopyridin-2-yl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanol (0.15 g, 0.46 mmol) as the starting materials.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([O:17][C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=O)C(=O)C1.CO.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>O>[OH:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: O=C(CCc1ccc(O)cc1)ON1C(=O)CCC1=O
Reactant: NCCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCc1ccc(O)cc1)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
β-Phenylethylamine is derivatized with Bolton-Hunter reagent as follows. β-Phenylethylamine and Bolton-Hunter reagent were mixed in equimolar quantities in a 1:1 solution of methanol and sodium phosphate buffer (1M, pH 8). After 30 minutes, an excess of water was added. A crystalline solid was collected, washed with water and dried in vacuo giving 1-[3-(4-hydroxyphenyl)-propionylamino]-2-(phenyl) ethane in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=1[NH2:7].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCCC1.N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:6]=1[NH:7][S:29]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=1)(=[O:31])=[O:30]
Reactant: COc1cccc(Cc2c(F)cccc2F)c1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Reaction time: 18 h
Yield: 73 %

Procedure:
3.8 g of 2-(2,6-difluorobenzyl)-6-methoxyaniline are dissolved in 36 ml of tetrahydrofuran and 1.2 ml of pyridine, and then 4.06 g of 3,4-dimethoxybenzene-sulfonyl chloride are then added. After 18 hours at room temperature, the reaction medium is taken up in ethyl acetate and then hydrolyzed, the organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is solidified in a toluene/ethyl acetate mixture (9/1) (v/v) in order to obtain 5 g of expected product.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7](/[CH:10]=[CH:11]/[C:12]3[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CO[C:21]1[CH:32]=[C:25]2[CH2:26][C:27]([O:29][C:30](=[O:31])[C:24]2=[CH:23][CH:22]=1)=[O:28].C1(C)C=CC=CC=1.[O:40]1CCC[CH2:41]1>>[CH3:41][O:40][C:22]1[CH:21]=[CH:32][C:25]([CH2:26][C:27]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12](/[CH:11]=[CH:10]/[C:7]3[S:8][CH:9]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:6]=3)[CH:13]=2)=[O:28])=[C:24]([CH:23]=1)[C:30]([OH:29])=[O:31]
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)CC(=O)OC2=O
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)c(C(=O)O)c1

Procedure:
A solution of 0.4 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.4 g of 5-methoxyhomophthalic anhydride, 50 ml of toluene and 10 ml of tetrahydrofuran was heated to reflux for 0.5 hr. The solvents were removed by rotary evaporation and the residual materials were triturated with ethanol to yield (E)-5-methoxy-2-[2-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid, m.p. 190°-191° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:19]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C#CC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (4.7 mL) was dissolved in dichloromethane (75 mL), and the solution was cooled to 0° C. To this solution was added dropwise a solution (10 mL) of ethyl propiolate (1.55 mL) in dichloromethane, and acetic acid (0.1 mL) was further added. The mixed solution was stirred for 4 hr while gradually warming to room temperature. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the object product as a pale-yellow oil (1.37 g). The obtained compound was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Reaction time: 3.5 h
Yield: 140.9 %

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (3.2 g) in ethyl acetate is treated with 2.0 g of diphenyldiazomethane in ethyl acetate. After 3.5 hours, the reaction mixture is partitioned between ethyl acetate and water. The layers are separated and the organic portion is washed with saturated sodium bicarbonate, 5% potassium bisulfate, brine and dried (MgSO4). The solvent is stripped leaving 6.1 g of residue which is chromatographed on 180 g of silica, eluting with ethyl acetate to yield 3.4 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].[OH2:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1>CC(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][C:4]([C:12]1[CH:13]=[CH:14][C:9]([CH:19]=[O:8])=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)(C)CC=O
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)CC(=O)c1ccc(C=O)cc1
Yield: 650.9 %

Procedure:
Dissolve 144-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-one (3.49 g, 12.55 mmol) in acetone (50 mL) Add p-toluenesulfonic acid monohydrate (238 mg, 1.256 mmol). Heat the mixture under reflux for 3 h. Concentrate in vacuo and partition the residue between water and EtOAc. Extract the aqueous phase three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (1.67 g, 65%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C@H:15]1[C@H:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:19][CH2:18][CH2:17][O:16]1)(=[O:4])=[O:3].[S:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C1(C)C=CC=CC=1>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH2:22]([O:21][C@@H:20]1[CH2:19][CH2:18][CH2:17][O:16][C@H:15]1[CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N+:40]1[CH:41]=[CH:42][S:38][CH:39]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCOS(C)(=O)=O
Reactant: c1cscn1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCC[n+]1ccsc1
Product: CS(=O)(=O)[O-]
Reaction time: 120 h

Procedure:
1.20 g of the methanesulfonate [prepared as described in step (a) above] and 1.56 ml of thiazole were dissolved in 3 ml of toluene, and the solution was stirrd on an oil bath kept at 70° C. for 5 days. At the end of this time, the mixture was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography through 40 g of silica gel. 0.741 g of the title compound was obtained as a viscous oil from the fractions eluted with a 60:35:5 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.COP([CH2:19][C:20]1[S:21][C:22]2[N:23]=[C:24]([N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[C:36]3[CH2:44][CH3:45])[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:27]=2[N:28]=1)(=O)OC.[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=O)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C1COCC1>[C:46]([O:50][C:51]([N:53]1[CH2:56][C:55](=[CH:19][C:20]2[S:21][C:22]3[N:23]=[C:24]([N:35]4[C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[N:37]=[C:36]4[CH2:44][CH3:45])[N:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:27]=3[N:28]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CP(=O)(OC)OC)sc2n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CN(C(=O)OC(C)(C)C)C3)sc2n1
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (200 μL, 1.42 mmol) in THF (0.5 mL) at −78° C. was added n-BuLi (556 μL, 1.42 mmol, 2.5 M in hexanes) and the resulting mixture stirred for 20 min. The resulting solution was added to a suspension of [5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]phosphonic acid dimethyl ester (620 mg, 1.27 mmol) in THF (11 mL) at −78° C. The resulting mixture was warmed to r.t. before a solution of 3-oxo-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.46 mmol) in THF (1.5 mL) was added. The resulting mixture was stirred at r.t. for 5 h then quenched with H2O. The mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was filtered through a pad of silica affording the title compound (493 mg, 73%). LCMS (method H): RT 3.72 min, [M+H]+ 534.3
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Br-:16].[Br-:17].[Br-:18].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([Br:18])[C:12]([Br:17])=[C:13]([Br:16])[C:8]=2[NH:7][C:6]1=[O:14].[Br:16][C:12]1[C:11]([Br:17])=[CH:10][C:9]2[N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6](=[O:14])[NH:7][C:8]=2[CH:13]=1
Reactant: CN(C)CCn1c(=O)[nH]c2ccccc21
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CN(C)CCn1c(=O)[nH]c2c(Br)c(Br)c(Br)cc21
Product: CN(C)CCn1c(=O)[nH]c2cc(Br)c(Br)cc21
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of 1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one (0.63 g) in acetic acid (20 ml) were added zinc chloride (1.33 g) and benzyltrimethylammonium tribromide (2.64 g). The reaction mixture was stirred at 70° C. for 24 hours, after which the solvent was distilled off under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=15:1) to give 0.31 g of 1,3-dihydro-1-(2-dimethylaminoethyl)-4,5,6-tribromo-2H-benzimidazol-2-one (Compound C) and 0.45 g of 5,6-dibromo-1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one (Compound D).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in toluene (25 mL). Thiomorpholine (2.4 mL, 23.4 mmol) was added and the mixture stirred overnight at 100° C. At 17 h, the mixture was distributed between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid.
Reaction SMILES: NC1C=C(C2[CH:22]=[CH:21][C:11]3[N:12]=C(NC(NCC)=O)SC=3C=2)C=CC=1.Br[C:24]1[CH:38]=[CH:37][C:27]2[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[S:30][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C[N:46](C=O)C.O>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>[NH:12]1[CH:11]=[C:21]([C:24]2[CH:38]=[CH:37][C:27]3[N:28]=[C:29]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[S:30][C:26]=3[CH:25]=2)[CH:22]=[N:46]1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: CN(C)C=O
Reactant: CCNC(=O)Nc1nc2ccc(-c3cccc(N)c3)cc2s1
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: O
Product: CCNC(=O)Nc1nc2ccc(-c3cn[nH]c3)cc2s1
Yield: 30 %

Procedure:
Similar to the synthesis of 1-(6-(3-aminophenyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 4-pyrazolylboronic pinacolate, 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, sodium carbonate, and Pd(PPh3)4 in DMF/water mixed solvent was reacted to give the desired compound 0.543 g (30%). LC/MS 288.2 (M+1); LC retention time 2.61 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])=[CH:6][N:7]=1.I([O-])(=O)(=O)=[O:31].[Na+].[OH2:36]>C(#N)C.[Ru](Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[O:4][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])=[CH:6][N:7]=1)(=[O:31])=[O:36]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cnc(SC)o1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1cnc(S(C)(=O)=O)o1
Reaction time: 6 h

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-methylsulfanyl-oxazol-5-yl)-propyl]-amide (0.1 g, 0.2 mmol) in a mixture of acetonitrile (25 mL) and water (5 mL) was added sodium periodate (0.155 g, 0.725 mmol) followed by ruthenium trichloride (5 mg, 0.02 mmol). After 6 hours, the mixture was filtered and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was dissolved in ethyl acetate and passed through a pad of silica. The material from the pad was crystallized from ethyl acetate-hexanes to afford the title compound.