Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[N:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C>CCOCC>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([CH:20]=[O:21])=[CH:7][N:6]=1
Reactant: COc1ncc(Br)nc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ncc(C=O)nc1OC
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.85 gm of 2-bromo 5,6-dimethoxypyrazine in 80 ml of dry ether under N2 at -35° C. was added dropwise 14.5 ml of n butyllithium (1.6 N in hexanes). After stirring for 0.5 hours at -35° C. 5.74 ml of dry DMF was added dropwise to the reaction mixture. This dark brown homogeneous solution was stirred at -20° C. for 1 hour and at 25° C. for 0.5 hours, then was quenched with an aqueous solution of NH4Cl. The reaction mixture was extracted with methylene chloride, and the organic fractions were washed with water, brine and dried over MgSO4, and filtered and evaporated to give a red oil. Chromatography on a short silica gel column provided 1.5 gm of a mixture of the title aldehyde and its hydrate which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].CCCCCC>C(OCC)(=O)C>[C:2]1([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1N
Reactant: Brc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1Nc1ccccc1
Yield: 69.7 %

Procedure:
Following the general procedure, bromobenzene (55 μL, 0.5 mmol) was coupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reaction time of 15 h. Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 74 mg (70%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:38])[CH:20]([CH3:39])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1)C(C)C

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-(6-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow gum.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C@H:9]([NH:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)=[O:26])[C:10](=[O:23])[NH:11][C:12]([CH3:22])([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]([C:25]([NH:24][C@H:9]([C:10](=[O:23])[NH:11][C:12]([CH3:22])([CH3:21])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[O:26])=[CH:32][CH:31]=1
Reactant: CC(C)(Cc1ccc(F)cc1)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(Cc1ccc(F)cc1)NC(=O)[C@H](CCC(=O)O)NC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a suspension of Compound 5 (100 g) in toluene (325 ml) were added trifluoroacetic acid (TFA, 313 g) at 5 to 20° C. The resulting solution was stirred at ambient temperature until the reaction was completed (4 to 6 h). TFA was removed by vacuum distillation, the solution diluted with ethyl acetate, washed with aqueous potassium acetate, and crystallization was affected by adding heptane to afford Compound 6 as white solid (82.7 g, yield 92%; Purity—99.8% (HPLC area %); Strength—98.0%; ee—99.0%). NMR data: 1.37, 1.45-s, 6H, CH3; 2.10-m, 2H, CH2; 2.35-2.60-m, 2H, CH2; 2.80-3.10-d, 2H, CH2; 4.80-q, 1H, CH; 6.80-7.80-m, 13H, Ph; 7.90-s, 2H, NH.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18]OS(C)(=O)=O)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:24].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][I:24])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cc2c(cc1OCc1ccccc1)CCO2
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: ICc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
A flame dried, N2 purged 1-liter, 3-neck round bottom flask equipped with an internal thermometer and mechanical stirrer was charged with 5-benzyloxy-6-(methanesulfonyloxymethyl)-2,3-dihydrobenzofuran (30.60 g, 0.10 moles) and anhydrous acetone (250 ml). The resultant solution was cooled to 0° C. and with efficient stirring sodium iodide (59.90 g, 0.40 moles) in acetone (150 ml) was added in one portion. The reaction mixture was stirred at room temperature for 72 hours and then suction filtered through a bed of celite. The filtrate was concentrated in vacuo to afford the crude product. This was dissolved in ethyl ether (400 ml) and water (200 ml), the layers partitioned, and separated. The organic phase was washed with saturated NaHS03 solution (2×200 ml) and water (1×200 ml), dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield 5-benzyloxy-6-iodomethyl-2,3-dihydrobenzofuran as a yellow solid (33.0 g, 98%).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][NH:18][C:19]1[S:20][CH:21]=[N:22][N:23]=1)C>Cl.C(O)C.O>[ClH:1].[S:20]1[CH:21]=[N:22][N:23]=[C:19]1[NH:18][CH2:17][CH:16]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CCOC(CNc1nncs1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1nncs1)NCC2
Yield: 33.5 %

Procedure:
Conc. hydrochloric acid (2 drops) was added to a solution of 3,4-dihydroxyphenethylamine hydrochloride (1.8 g.) and (1,3,4-thiadiazol-2-yl)aminoacetaldehyde diethyl acetal (3.1 g.) in a mixture of ethanol (60 ml) and water (15 ml.). The resulting mixture was refluxed for 18 hours. After cooling, the reaction mixture was allowed to stand at ambient temperature. Precipitating crystals were collected by filtration and washed with ethanol to give 1-(1,3,4-thiadiazol-2-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.0 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1)c1ccccc1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 4-chlorophenol (0.774 g) and phenacyl bromide (1 g) in N,N-dimethyl formamide (10 ml) potassium carbonate (3.5 g) was added. The mixture was refluxed with stirring for 2 h. After cooling the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried (MgSO4), and evaporated. The crude was purified by flash chromatography on silica gel (petrol ether/ethyl acetate 10:1) to give 2-(4-chlorophenoxy)-1-phenylethanone (1.22 g) as pale yellow solid.
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Br:32][C:33]1[CH:34]=[C:35]([CH:39]=O)[CH:36]=[N:37][CH:38]=1>O1CCCC1>[Br:32][C:33]1[CH:38]=[N:37][CH:36]=[C:35]([CH:39]=[CH2:2])[CH:34]=1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cncc(Br)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: C=Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyltriphenylphosphine bromide (3.16 g, 8.87 mmol) in tetrahydrofuran (20 mL) is added sodium hexamethyldisilazane (1M solution in THF, 9.67 mL, 9.67 mmol) dropwise. The reaction mixture is stirred at room temperature for 30 min, whereupon 5-bromo-pyridine-3-carbaldehyde (1.5 g, 8.06 mmol) is added. The reaction mixture is allowed to stir at room temperature for 1 h. The mixture is concentrated and the residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 7:3) to afford 3-bromo-5-vinyl-pyridine as a colorless oil. MS (ESI) m/z 185.91 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:12][CH:13]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:9]=1)#[CH:15]
Reactant: COCCOCOc1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1cccc(OCOCCOC)c1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
[3-(2-Methoxy-ethoxymethoxy)-phenylethynyl]-trimethyl silane (0.57 g, 2 mmol, example 97) and 1.0 M tetrabutylammonium fluoride (2.1 mL, 2 mmol) are added to THF (10 mL) and acetic acid (0.13 g, 2 mmol) is added and this mixture is stirred at 20° C., under nitrogen. After 15 minutes, the solvent is removed in vacuo and the residue is azeotroped with benzene and purified by flash chromatography (silica, 20% ethyl acetate, 30% dichloromethane in hexanes) to give 1-ethynyl-3-(2-methoxy-ethoxymethoxy)-benzene (0.28 g, 1.4 mmol) which is dissolved in THF (8 mL), cooled to −78° C., under nitrogen and to this solution is added 2.5M n-butyl lithium (0.56 mL, 1.4 mmol) dropwise over 30 seconds. After stirring for 15 minutes, 1.0M zinc chloride in ether (1.4 mL, 1.4 mmol) is added dropwise over 30 seconds and this mixture is stirred for 30 minutes. Bis-(dibenzylideneacetone) palladium (0.04 g, 0.07 mmol) and bis (diphenyl phosphino) ferrocene (0.04 g, 0.07 mmol) is added and to this mixture is added ethyl-2-methyl-6-trifluoromethanesulfonyloxy benzoate (0.44 g, 1.4 mmol, 95) in THF (2 mL). The cooling bath is removed and the reaction allowed to warm to room temperature. Then the reaction mixture is heated in an oil bath at 65° C. overnight. The reaction is then diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride and brine and then dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography (silica, 10% ethyl acetate, 25% dichloromethane in hexanes) to give the title compound. MS (ESI) 369 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[N:4][C:3]=1[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH:30]1([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[N:4][C:3]=2[NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH2:32][CH2:31]1
Reactant: OB(O)C1CC1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(C3CC3)nc2C(N)=O)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid (18 mg), tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115° C. overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1). The resulting residue was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)[CH2:3][CH3:4].[ClH:40]>C(O)C>[ClH:40].[ClH:40].[OH:1][CH:2]([C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:16]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)=[O:17])[CH2:10]1)[CH2:3][CH3:4]
Reactant: CCC(O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCC(O)[C@H]1CNC[C@@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3R, 5S)-3-(1-hydroxypropyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (200 mg) in ethanol (1 ml) was added 12M hydrochloric acid (0.30 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethanol, and ethanol was evaporated under reduced pressure. This operation was repeated twice to give the object product (140 mg).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](C4C=C5C(C=NN5C)=CC=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)(=O)C(C)(C)C.C(OC[C@@H](OC(C)(C)C)C1C(C)=CC2N=C([C:64]3[CH:65]=[C:66]4[C:70](=[CH:71][CH:72]=3)[N:69]([CH3:73])[N:68]=[CH:67]4)SC=2C=1C1C=CC(Cl)=CC=1)(=O)C(C)(C)C.CO.[OH-].[Na+]>C(OCC)(=O)C>[C:44]([O:43][C@@H:9]([C:10]1[C:34]([CH3:35])=[CH:33][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:64]4[CH:65]=[C:66]5[C:70](=[CH:71][CH:72]=4)[N:69]([CH3:73])[N:68]=[CH:67]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[CH2:8][OH:7])([CH3:46])([CH3:47])[CH3:45]
Reactant: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2nc(-c3ccc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 55 °C

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethyl pivalate and (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-indazol-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate was telescoped into the subsequent reaction. To the previous reaction mixture, methanol and 2M NaOH were added and reaction mixture was heated at 55° C. overnight. Reaction mixture was cooled to rt, diluted with ethyl acetate and washed with brine. The organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (Hex/EtOAc) to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-5-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethanol.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@:14]2([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1>[ClH:31].[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[C@:14]12[CH2:16][NH:17][CH2:18][C@H:13]1[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N:15]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccs2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1=N[C@@]2(c3cccs3)CNC[C@H]2CS1)c1ccccc1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of tert-butyl(4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.3 g, 2.93 mmol) in 1,4 dioxane (60 mL) is added drop wise 4 N hydrogen chloride in 1,4 dioxane (14.6 mL, 58.6 mmol). The reaction is stirred for 4 hours. The solution is concentrated to give the title compound (1.1 g, 99%). ES/MS (m/e): 344 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>CN(C=O)C.[Pd].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.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>[CH2:26]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1)[CH:25]=[CH2:24]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1ccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc2c1
Temperature: 120 °C
Yield: 0.6 %

Procedure:
To a solution of 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.025 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.083 g, 0.025 mol) and degassed the reaction mixture for the 10 minutes. Tetrakis (triphenylphosphine) Palladium (0) (0.029 g, 0.0025 mol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere, then cooled to r.t. Water was added to the reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was crystallized with ethyl acetate/hexane to give the title compound as brown solid (0.050 g, 55%). 1H NMR (DMSO-d6, 400 MHz): δ 3.52 (d, 2H, J=6.4 Hz), 5.07-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m, 1H), 7.10 (dt, 1H, J=8.4 Hz (o-coupling), 7.31 (d, 1H, J=8.4 Hz (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.05 (d, 1H, J=8.4 Hz (o-coupling), 8.17 (broad s, 1H) MS ES+ (361.05), HPLC (method 5) Rt=16.74 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[CH:57]=[CH:56][S:55][C:54]=1[C:58](Cl)=[O:59])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43].P([O-])([O-])([O-])=O>COCCOC>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[CH:57]=[CH:56][S:55][C:54]=1[C:58]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:59])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccsc1C(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCOP(=O)(OCC=C)OCc1ccsc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (699.1 mg, 1.29 mmol) described in Reference example 1 in 1,2-dimethoxyethane (10 ml) was cooled to 0° C., and sodium hydride (55% dispersion in mineral oil; 67.5 mg, 1.55 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. To the mixture was added a solution of the crude 3-[[bis(allyloxy)phosphoryl]oxymethyl]-2-thenoyl chloride obtained above in 1,2-dimethoxyethane (2 ml), and the mixture was stirred at room temperature for 20 minutes and cooled to 0° C., then a phosphate buffer solution (pH 7) was added to the reaction mixture to stop the reaction, and the product was extracted with ethyl acetate. The crude product was subjected to chromatography on a silica gel (40 g) column (eluent; ethyl acetate:hexane=3:2˜5:1) to give the title compound (520.6 mg, 48% yield) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7](OS(C(F)(F)F)(=O)=O)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22](=[O:24])[NH2:23].[O:25]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:32]3[CH2:33][CH2:34][C:29]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:30][CH2:31]3)=[CH:8][C:9]=2[S:11]([CH3:13])=[O:12])[S:4][C:3]=1[C:22]([NH2:23])=[O:24]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2sc(C(N)=O)c(N)c12
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)c1cc(N2CCC3(CC2)OCCO3)nc2sc(C(N)=O)c(N)c12
Temperature: 70 °C
Yield: 42.4 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-amino-2-carbamoyl-4-methanesulfinyl-thieno[2,3-b]pyridin-6-yl ester (3.00 g, 7.44 mmol) in DMF (100 mL) was added 1,4-dioxa-8-azaspiro[4,5]-decane (2.20 g, 15.4 mmol). The mixture was heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with H2O, and washed with CH2Cl2. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 1.25 g (42.2%) of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methanesulfinyl-thieno[2,3-b]pyridine-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[CH3:21][NH:22][C:23]([NH2:25])=[S:24]>>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[N:25]=[C:23]([SH:24])[N:22]([CH3:21])[C:11]=2[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Reactant: CNC(N)=S
Product: COc1ccc(-c2nc(S)n(C)c2-c2ccc(OC)cc2)cc1

Procedure:
13.6 g (50 mmol) of p-anisoin and 6.8 g (75 mmol) of N-methylthiourea were reacted as in example 10. The yield was 7.4 g.