Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][OH:21]>O1CCCC1>[OH:21][CH2:20][CH2:19][N:18]([CH3:17])[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1)=[O:12]
Reactant: CNCCO
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CN(CCO)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 71.1 %

Procedure:
To a solution of 46.4 g (0.2 mol) of 4-nitro-3-(trifluoromethyl)phenyl isocyanate in 200 ml of tetrahydrofuran was added dropwise with stirring and external cooling 15.2 g (0.2 mol) of 2-(methylamino)ethanol. This addition was exothermic. The solution was concentrated under reduced pressure, washed with water, acidified with hydrochloric acid and extracted with ether. Crystallization of the ether extract gave 43.69 g (71% yield) of the desired product as a tan solid; m.p. 180°-181° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[CH:15]=[C:14]([CH2:16][N:17]3[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]3)[CH:13]=[CH:12][N:11]=2)=[CH:4][C:3]=1[O:24][CH3:25].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:5]4[CH:4]=[C:3]([O:24][CH3:25])[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=4)[CH:15]=3)[CH2:18][CH2:19]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1Cl
Product: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(Cl)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (690 mg) and p-anisidine (283 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H-].[Na+].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>CN(C=O)C>[CH3:13][O:12][C:10]([C:7]1[S:6][C:5]2[CH:14]=[CH:15][C:2]([O:1][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH2:28][C:19]4[CH:20]=[CH:21][C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:18]=4)[CH:31]=3)=[CH:3][C:4]=2[C:8]=1[CH3:9])=[O:11]
Reactant: COC(=O)c1sc2ccc(O)cc2c1C
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 5-hydroxy-3-methyl-benzo(b)thiophene-2-carboxylate (878.6 mg, 3.96 mmol) in dry DMF (20 ml) at room temperature is added sodium hydride (158 mg, 3.95 mmol) as a 60% dispersion in mineral oil. After 30 minutes of stirring 3-(2-quinolinylmethoxy)benzyl chloride (1.02 g, 3.60 mmol) is added. The solution is stirred at room temperature for 4 hours and quenched with ice-water. Extraction with ethyl acetate, washing with aqueous sodium carbonate, water and brine is followed by drying (MgSO4) and concentration. The residue is subjected to flash chromatography on silica gel. Elution with 25% ether in hexane affords methyl-3-methyl-5-[3-(2-quinolinylmethoxy)benzyloxy]benzo(b) -thiophene-2-carboxylate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:21][C@H:11]1[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Mg]Br)[CH:23]=1>>[CH2:14]([O:13][CH2:12][C@@H:11]([CH2:31][C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)[C@@H:10]([OH:21])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(C[Mg]Br)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H]1COCc1ccccc1
Product: Cc1cccc(C[C@H](COCc2ccccc2)[C@@H](O)CO[Si](C)(C)C(C)(C)C)c1

Procedure:
325 mg of (2S,3S)-4-benzyloxy-2,3-epoxy-1-butanol tert-butyldimethylsilyl ether obtained in Example 53, was subjected to Grignard reaction in the same manner as in Example 53 by using 3-tolylmethyl magnesium bromide (0.8M diethyl ether solution). The product was purificated by silica gel column chromatography to obtain 210 mg of (2R,3R)-4-benzyloxy-1-tert-butyldimethylsilyloxy-3-(3-tolylmethyl)-2-butanol as colorless oily substance.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH3:28])[CH:22]=1.Cl>O1CCCC1.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:22][C:23]=1[CH3:28]
Reactant: Cc1cc(-c2oncc2CCl)ccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2oncc2CCC(=O)O)ccc1Cl
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
To a solution of diethyl malonate (5.82 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.32 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-chloro-3-methylphenyl)isoxazole (4.00 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (2.56 g, yield 58%) of 3-[5-(4-chloro-3-methylphenyl)-4-isoxazolyl]propionic acid. melting point: 158–159° C.
Reaction SMILES: [F:1][C:2]1[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[C:14]([F:20])[C:13]([F:21])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:22]([O-])([O-])[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>>[CH2:24]([O:23][CH:22]=[C:6]([C:4](=[O:5])[C:3]1[CH:12]=[C:13]([F:21])[C:14]([F:20])=[C:15]([O:16][CH:17]([CH3:18])[CH3:19])[C:2]=1[F:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:25]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(C)C)c1F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC(C)C)c1F

Procedure:
Ethyl 2,4,5-trifluoro-3-isopropyloxybenzoylacetate (2.9 g) was stirred together with ethyl orthoformate (2.4 g) and acetic anhydride (2.8 g) at 140° C. for 1 hour while removing distillate. The reaction mixture was concentrated under reduced pressure at the same temperature. After the residue was allowed to cool, a process of adding toluene (10 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-isopropyloxybenzoyl)acrylate obtained as the residue was dissolved in chloroform (20 ml). N-(tert-Butoxycarbonyl)-2,4-difluoro-m-phenylenediamine (900 mg) was added to a half of this solution. The resultant mixture was concentrated under reduced pressure. Anhydrous potassium carbonate (1.3 g) and N,N-dimethylformamide (2.5 ml) were added to the resultant residue, and the mixture was stirred at 90° C. for 10 minutes. The reaction mixture was allowed to cool, and chloroform (50 ml) and distilled water (300 ml) were added to conduct liquid separation. A chloroform layer was washed twice with distilled water (300 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol to obtain the title compound (1.18 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(=O)=O.C(OCC)C>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(CBr)cc2)c1

Procedure:
A mixture of 28.4 g. (0.1 mole) of 4'-methyl-2,5-diacetoxy-1,1'-biphenyl prepared in section (a) of this Example, 18.7 g. (0.105 mole) of N-bromosuccinimide, and 0.25 g. (0.001 mole) of dibenzoyl peroxide in 250 ml. of carbon tetrachloride was heated at reflux for about 6 hours. The mixture was cooled and the precipitated succinimide was removed by filtration. The filtrate solvent was removed on a rotary evaporator yielding about 42 g. of a syrupy residue. The residue was mixed with 80 ml. of low boiling petroleum ether, the mixture heated to reflux with stirring, and the petroleum ether decanted. This extraction process was repeated twice more yielding 35.5 g. of a syrupy residue. This residue was then dissolved in 180 ml. of diethylether and the solution diluted with 120 ml. of n-hexanes. Cooling of the solution in dry-ice and scratching the sides of the container induced crystallization of the product. A first crop of 17.2 g. of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl was obtained. The mother liquor was concentrated and crystallization induced as above to yield an additional 6.5 g. of product. The procedure was repeated once again to yield a third crop of 8.3 g. Total yield was thus 32.0 g. Nuclear magnetic resonance analysis of the combined product in deuterochloroform was consistent with the structure of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl. The melting range of the product was 51°-53° C.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[C:20]([Cl:30])[CH:19]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[C:15]([C:18]1[CH:19]=[C:20]([Cl:30])[C:21]([NH:25][C:26](=[O:29])[CH2:27][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[C:22]([Cl:24])[CH:23]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2C)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 12 parts of (1,1-dimethylethyl) 3-methyl-1-piperazinecarboxylate, 18.7 parts of N-(4-acetyl-2,6-dichlorophenyl)-2-chloroacetamide, 11.8 parts of N,N-diethylethanamine and 230 parts of N,N-dimethylformamide was stirred first for 8 hours at 70° C. and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The desired fraction was collected and the eluent was evaporated, yielding 27 parts (100%) of (1,1-dimethylethyl) 4-[2-[(4-acetyl-2,6-dichlorophenyl)amino]-2-oxoethyl]-3-methyl-1-piperazinecarboxylate as a residue (int. 21).
Reaction SMILES: [F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:3]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[F:1][C:2]1[C:11]2=[CH:12][C:13]([F:15])=[CH:14][C:9]3=[C:10]2[C:4](=[N:5][NH:6][C:7]2[C:8]3=[CH:16][N:17]([CH3:26])[CH2:18][C:19]=2[C:20]2[CH2:21][CH2:22][N:23]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:24][CH:25]=2)[CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CN1C=C2C(=C(C3=CCNCC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C=C2C(=C(C3=CCN(CC(=O)N(C)C)CC3)C1)NN=C1C=C(F)c3cc(F)cc2c31
Temperature: 70 °C

Procedure:
To a suspension of Example 48 (100 mg, 0.284 mmol) in N,N-dimethylformamide (4 mL) was added triethylamine (0.237 mL, 1.703 mmol) and 2-chloro-N,N-dimethylacetamide (41.4 mg, 0.341 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 10-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.57-2.62 (m, 2H), 2.79 (t, J=5.04 Hz, 2H), 2.84 (s, 3H), 2.89 (s, 3H), 3.03 (s, 3H), 3.30-3.37 (m, 4H), 4.07 (s, 2H), 5.85 (s, 1H), 7.26-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.62-7.66 (m, 1H), 8.24 (d, J=5.19 Hz, 1H), 11.62 (s, 1H). MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:31]=[C:30]([CH3:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(NS(C)(=O)=O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.1 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (141 mg, 45% purity, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (50 to 100%, hexane-ethyl acetate) phase using SP1® Purification System to give 42 mg (55% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:44](=[O:46])[CH3:45])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([O:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(OCc4ccccc4)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
A mixture of 3.75 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 23 ml of acetic anhydride and 8 ml of pyridine is treated in the same manner as described in Example 1-(2). 4.18 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-benzyloxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([CH2:23][PH:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)CC)C>C(#N)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>[CH2:27]([O:26][P:24]([CH2:23][P:18]([O:17][CH2:15][CH3:16])([O:19][CH2:20][CH3:21])=[O:22])([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])=[O:25])[CH3:28]
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(CP(=O)(OCC)c1ccc2c(c1)C(C)(C)CC(=O)O2)OCC
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A mixture of 6-bromo-4,4-dimethylchroman-2-one (3.5 g, 9.7 mmol), diethyl(ethoxyphosphinyl)methylphosphonate (1.7 g, 9.7 mmol), triethylamine (4.1 mL, 29 mmol) and Pd(PPh3)4 (0.56 g, 0.48 mmol) in acetonitrile (20 mL) was heated to 100° C. for 18 hr. The reaction mixture was cooled and diluted with acetonitrile (50 mL) followed by washing with aqueous HCl (10%), water and saturated aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% methanol in CH2Cl2) on a Biotage™ flash chromatography system, resulting in 120 as pale yellow oil (3.0 g, 73%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.2, 3H), 1.30-1.37 (m, 6H), 1.40 (s, 6H), 2.61 (dd, J=1.7, 17.2, 20.7, 2H), 2.66 (s, 2H), 3.95-4.08 (m, 2H), 4.11-4.21 (m, 4H), 7.16 (dd, J=3.1, 8.3, 2H), 7.73 (dd, J=3.1, 8.3, 2H): 31P (162 MHz, CDCl3) δ 20.07 (d, J=7.7, 1 P), 33.74 (d, J=7.7, 1 P).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([OH:7])=O.C(OC(=O)[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:5]([C:4]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[O:7])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COc1cccc(OC)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OC)c1C(=O)N1CCC[C@@H](N)C1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
A mixture of 0.143 g (0.786 mmol) 2,6-dimethoxybenzoic acid (commercially available), 0.15 g (0.749 mmol) (R)-piperidin-3-yl-carbamic acid tert-butyl ester (commercially available), 0.264 g (0.824 mmol) TBTU and 0.145 g (1.123 mmol) DIPEA in 9.2 mL DMF was stirred at room temperature over night. DMF was evaporated and the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated and the residue was treated with 4N HCl in dioxane and stirred at 50° C. over night. The mixture was evaporated to dryness and treated with NaHCO3 aq. and DCM. The organic layer was separated, dried with MgSO4 and evaporated to yield 22 mg (11%) of the title compound as colourless oil. (MH+) 265.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([C@H:66]([NH2:68])[CH3:67])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@@H:66]([CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: C[C@@H](N)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then (1R)-1-cyclohexylethanamine (60.9 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water and dried to give the title compound (196 mg) as a yellow solid. LC-MS (ES) m/z=465 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([NH:22][C:23]1[S:27][C:26]2[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[C:32]([NH2:34])=[O:33])=[O:21]>CN(C=O)C.O>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:19][C:20]([NH:22][C:23]2[S:27][C:26]3[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[C:32]([NH2:34])=[O:33])=[O:21])[N:2]=1)#[N:11]
Reactant: N#Cc1n[nH]c2ccccc12
Reactant: NC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)c2ccccc12
Temperature: 60 °C
Yield: 13 %

Procedure:
To a solution of 1H-indazole-3-carbonitrile (11 mg, 0.077 mmol) in DMF (500 μL) was added potassium carbonate and the whole was stirred at RT for 30 min before 2-(2-bromoacetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (24 mg, 0.077 mmol) was added. The reaction mixture was heated to 60° C. and this temperature was maintained for 1.5 h before the reaction mixture was cooled to RT, then diluted with water (5 mL). The organics were extracted with diethyl ether (10 mL), EtOAc (10 mL) and DCM (10 mL), then combined and the suspension concentrated to dryness. The residue was dissolved in DMSO (1 mL) and purified by preparative reverse phase HPLC to give the title compound as a white solid (4 mg, 0.01 mmol, 14%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])[CH3:17]>C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:7][NH:8][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:18]=1[CH2:16][CH3:17])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCc1c(OC)cccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCc1c(OC)cccc1C(=O)NNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Tert-butylcarbazate (80.0 g, 605 mmol) was stirred in 800 mL methylene chloride and cooled to 0° C. To this was added the potassium carbonate solution (937 g, 847 mmol). 2-Ethyl-3-methoxybenzoyl chloride (132 g, 666 mmol) was dissolved in 400 mL of methylene chloride and added to the reaction mixture dropwise over 15 minutes. The mixture was stirred at 0° C. for 15 min, then at room temperature for 18 hours. The reaction was diluted with more methylene chloride and water. The aqueous phase was separated. The remaining organic phase was washed with 1N HCl, water, saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with hexane to give a white solid, N′-(2-ethyl-3-methoxy-benzoyl)-hydrazinecarboxylic acid tert-butyl ester (167 g, 567 mmol) in 94% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.4 (br s, 1H), 7.22 (t, 1H), 7.03 (br d, 1H), 6.95 (d, 1H), 6.65 (br, 1H), 3.84 (s, 3H), 2.8 (q, 2H), 1.51 (s, 9H), 1.2 (t, 3H).