Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]#[C:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:31])[C@@H:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH2:13]2)=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([NH:32][C:2]2[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]#[C:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19](=[O:31])[C@@H:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH3:21])[CH2:13]3)=[CH:4][N:3]=2)=[CH:34][CH:35]=1)#[N:38]
Reactant: COc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccc(N)cc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1nc(Nc2ccc(C#N)cc2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl ((S)-1-(((1S,3R)-3-((2-chloro-4-methoxypyrimidin-5-yl)ethynyl)cyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (Q4, 32 mg) in N-methylpyrrolidone (0.5 mL), 4-aminobenzonitrile (42 mg) and (1S)-(+)-10-camphorsulfonic acid (81 mg) were added at room temperature, and the mixture was stirred at 60° C. for 7 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 88 to 25% hexane in ethyl acetate) to obtain tert-butyl ((S)-1-(((1S,3R)-3-((2-((4-cyanophenyl)amino)-4-methoxypyrimidin-5-yl)ethynyl)cyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (Q5, 11 mg).
Reaction SMILES: [CH:1]([C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[S:6][C:5]=2[CH:4]=1)=[O:2].[OH-].[K+].CO.Cl>O>[CH:1]([C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[S:6][C:5]=2[CH:4]=1)=[O:2]
Reactant: COC(=O)c1cc2c(cc(C=O)c3ccccc32)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cc2sc(C(=O)O)cc2c2ccccc12

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added methyl 5-formylnaphtho-[2,1-b]thiophene-2-carboxylate (7A, 9.75 g, 36 mmol), KOH (85%, Mallinckrodt Co., St. Louis, MO 63147, 18.0 g, 320 mmol), CH3OH (40 mL) and H2O (80 mL). The mixture was refluxed for 1.5 h, cooled and neutralized with 3N HCl (500 mL). A yellow solid formed which was filtered and washed with H2O (3×300 mL) and dried in a vacuum oven overnight to give crude 5-formylnaphtho-[2,1-b]thiophene-2-carboxylic acid in quantitative yield. This material was then slurried with quinoline (Mallinckrodt, 60 mL) and cuprous oxide (MCB, 6.2 g, 43.3 mmol) and heated to 185° in an oil bath for 1 h. The reaction mixture was allowed to cool to RT then partitioned between Et2O (500 mL) and concentrated HCl (200 mL) containing saturated NH4Cl (100 mL). The layers were separated and the aqueous layer extracted with additional Et2O (500 mL). The Et2O layers were combined and washed in succession with 1N HCl (300 mL), H2O (2×300 mL) and saturated NaCl solution (2×300 mL), dried (MgSO4), filtered and concentrated to give a light brown crude solid. After chromatography on SiO2 using CHCl3 /hexane as the eluting solvent and crystallization (CHCl3 /cyclohexane) there was obtained 4.98 g (65.2% yield) of naphtho[2,1-b]thiophene-5-carbaldehyde, mp 101°-102°, (C,H,S).
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].C(O)(=O)C.[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][NH:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([N:22]1[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[C:26](=[O:32])[N:25]([CH3:33])[C:24]2[CH:34]=[C:35]([CH2:38][N:39]([CH2:2][CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH2:40][C:41]3[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=3)[CH:36]=[CH:37][C:23]1=2)[CH3:21]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccncc3)ccc21
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
5-(2,2-Dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.21 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (15 ml) of 1-ethyl-3,3,5-trimethyl-7-{[(pyridin-4-ylmethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.38 g), and the mixture was stirred for 30 minutes at room temperature. Sodium triacetoxy borohydride (0.42 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→4:1). The purified product was condensed under reduced pressure, and the residue was recrystallized from ether to give the title compound (0.47 g) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3.5 h
Yield: 116.5 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (402 g) in acetone (2.5 l) were added 1-methylpiperazine (225 g) and potassium carbonate (415 g). The resulting mixture was refluxed with stirring for 3.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with acetone (500 ml). The filtrate and washing were combined and evaporated under reduced pressure. The remaining starting materials in the residnal oil were azeotropically removed with benzene to give an oil of N-[3-(4-methyl-1-piperazinyl)propyl]phthalimide (502 g). I.R. (Film): 1770,1700 cm-.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)c1ccc(C2c3ccc(O)cc3OC2(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)OC(C)(C)C3c2ccc(C(C)C)cc2)cc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 179.0 mg, 4.48 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-ol (1.12 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (636.8 mg, 4.07 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (1.19 g, yield 74%).
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][PH:17](=[O:23])[O:18]CC(C)C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C1COCC1.Cl>[C:24]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][PH:17](=[O:18])[OH:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)CO[PH](=O)Cc1ccccc1P(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=[PH](O)Cc1ccccc1P(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
0.30 g (7.6 mmol) of NaOH in 5 ml of water are added dropwise at 23° C. to a solution of 1.50 g (3.8 mmol) of isobutyl (2-diphenylphosphinophenyl)methylphosphinate in 5 ml of THF. After refluxing for 6 hours, the mixture is diluted with a further 5 ml of THF, 3.0 ml of 2N hydrochloric acid are added dropwise at 23° C. and the mixture is stirred for 20 min at 23° C. After phase separation, the aqueous phase is extracted twice, each time with 20 ml of dichloromethane, and the combined organic phases are washed with 20 ml of water. After drying over Na2SO4, complete evaporation under reduced pressure and drying in high vacuum, 1.17 g of (2-diphenylphosphinophenyl)methylphosphinic acid (92% of theory) are obtained in the form of a pale yellow solid having an m.p. of 167° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:4][CH2:3][CH2:2][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCCCc1ccccc1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CCCN2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 0.2 h

Procedure:
A solution of 1-chloro-3-phenylpropane (5.4 g) in toluene (10 ml) was added to a stirred solution of piperazine (15.0 g) and triethylamine (3.5 g) in toluene (20 ml) at 100° C. The reaction mixture was heated with stirring at 100° C. for 0.2 hours and then heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was evaporated and the residual oil was purified by column chromatography, eluting with dichloromethane/methanol (19:1), then methanol, to give 1-(3-phenylpropyl)piperazine as an oil.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[CH2:17][C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40](=[O:41])[CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccccc1)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.7 g, 4.3 mmol) was added to a stirred suspension of 3-[4-(aminomethyl)-1-oxo-1,3-dihydro-isoindol-2-yl]piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, phenylacetyl chloride (0.4 g, 2.3 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed and the residue was stirred with water (40 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-phenyl-acetamide (0.41 g, 54%) as a white solid: mp 236-238° C.; 1H NMR (DMSO-d6) δ 1.94-1.98 (m, 1H, CH2), 2.15-2.19 (m, 1H, CH2), 2.49-2.63 (m, 1H, CH2), 2.85-2.99 (m, 1H, CH2), 3.47 (s, 2H, CH2), 4.23-4.43 (m, 4H, 2CH2), 5.07-5.14 (dd, J=5.1 and 13.2 Hz, 1H, CH), 7.18-7.33 (m, 5H, Ar), 7.46-7.64 (m, 3H, Ar), 8.61 (t, J=5.6 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.14, 42.23, 46.08, 51.47, 121.70, 126.34, 128.22, 128.95, 130.73, 131.69, 134.49, 136.16, 140.09, 167.99, 170.18, 170.87, 172.81; Anal. calcd. for C22H21N3O4+0.07H2O: C, 67.29; H, 5.43; N, 10.70. Found: C, 66.94; H, 5.22; N, 10.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:35]([NH:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)=[O:41])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: Nc1nccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nccs4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 132.2 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (84 mg) was dissolved in chloroform (2.5 ml) and triethylamine (0.25 ml) to prepare a solution. A solution of triphosgene (38 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-aminothiazole (28 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated and was evaporated to dryness. Next, diethyl ether was added to the solid, and the solid was then collected by filtration. Further, the collected solid was washed with methyl alcohol to give the title compound (77.5 mg, yield 66%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.O.B1([O-])O[O:34]1.O.O.O.O.[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][CH2:22][OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-]B1OO1
Reactant: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCO)N(Cc2ccccc2)C1
Yield: 82.3 %

Procedure:
To a solution of (2S,4R)-1-benzyl-2-vinyl-4-(t-butyldimethylsilyloxy)pyrrolidine (24.03 g) in tetrahydrofuran (120 ml) was added 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (318 ml) at 0°~5° C. with stirring and then stirred at ambient temperature for 4 hours. To the reaction mixture were added water (200 ml) and sodium perborate tetrahydrate (87 g) at ambient temperature with stirring vigorously and then the mixture was stirred at the same temperature for 12 hours. The insoluble material was filtered off, and the filtrate was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of n-hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-benzyl-2-(2-hydroxyethyl)-4-(t-butyldimethylsilyloxy)pyrrolidine (20.89 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][CH:3]=1.O=S(Cl)[Cl:16]>>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(Cl)c[nH]c2c1

Procedure:
3-Chloro-1H-indole-6-carboxylic acid (200 mg) was mixed with 3 mL of SOCl2. The mixture was refluxed for 1 h and evaporated to dryness. Benzene (2 mL) was added and evaporated twice in order to eliminate residual SOCl2. The dark oil was triturated in ether/CH2Cl2 to yield 3-chloro-1H-indole-6-carbonyl chloride as a dark solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1>CCCCCC.C(O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@H:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1.[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCCCC1c1nc2cc(Br)sc2c(=O)[nH]1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCCC[C@@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Product: CC(C)(C)OC(=O)N1CCCCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1

Procedure:
tert-Butyl 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane-1-carboxylate (772 mg) produced in Example 79, step A, was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (500/500), flow rate: 60 mL/min, column temperature: 30° C.). tert-Butyl(2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane-1-carboxylate (325 mg, >99.9% ee, retention time 11.2 min) and tert-butyl(2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)azepane-1-carboxylate (326 mg, >99.9% ee, retention time 13.7 min) were obtained under the above-mentioned high performance liquid chromatography conditions. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (500/500), flow rate: 0.5 mL/min, column temperature: 30° C., detection 220 nm). The absolute steric configuration after optical resolution was determined by an X-ray crystal structural analysis of the fraction at retention time 13.7 min.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[NH:36][C:37]([NH2:40])=[N:38][N:39]=2)[CH:32]=[CH:33][CH:34]=1>>[CH:1]1([CH2:4][S:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:40][C:37]2[NH:36][C:35]([C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=3)=[N:39][N:38]=2)=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cccc(-c2nnc(N)[nH]2)c1
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2nnc(NC(=O)C(C)(C)S(=O)(=O)CC3CC3)[nH]2)c1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Activation of 0.46 g (2.23 mmol) of 2-cyclopropylmethanesulfonyl-2-methyl-propionic acid as the corresponding acid chloride is achieved by treatment with thionyl chloride (5 mL, 69 mmol) at 70° C. for 2 h. The reaction is cooled to room temperature and excess thionyl chloride is removed under reduced pressure. The crude acid chloride is dissolved in THF (5 mL) and N,N-diisopropylethylamine (0.54 mL, 5.64 mmol) is added followed by 0.3 g (2.6 mmol) of 5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylamine. After complete addition the reaction is heated to 70° C. for 36 h. The reaction is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3 solution (20 mL). The aqueous layer is back-extracted with DCM (2×20 mL). The combined organic layers are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is slurried in DCM/ether (1/1, 10 mL) to yield 0.398 g of 2-cyclopropylmethanesulfonyl-N-[5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-2-methyl-propionamide. Yield: 46%; ES-MS: m/z 379 [M+H]
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:13]1[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=[C:15]([S:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=2[F:52])[N:14]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(C2C=CN=CC=2)(=O)=O)C=C(O[C@H](C)CO)N=1>>[C:1]([C:3]1[O:7][C:6]([S:8]([NH:11][C:13]2[CH:18]=[C:17]([O:19][C@H:20]([CH3:42])[CH2:21][O:22][C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:16]=[C:15]([S:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[F:52])[N:14]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: N#Cc1ccc(S(N)(=O)=O)o1
Agent: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccncc2)nc(SCc2cccc(F)c2F)n1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C#N)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-cyanofuran-2-sulfonamide (the product of step i) (0.29 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step (0.15 g) according to the procedure outlined in Example 1, step iv). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:4 to 2:3 gradient) to give the subtitle compound as a pale yellow solid. Yield: 0.25 g
Reaction SMILES: C1(OC)C=CC=CC=1.COC1C=CC(C[N:16]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26](=[O:40])[C:27]3[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[CH:29][C:28]=3[N+:37]([O-:39])=[O:38])[N:18]=[N:17]2)=CC=1.COC1C=CC(CN2C(C(=O)C3C=C(OC)C(OC)=CC=3[N+]([O-])=O)=C(C(OCC)=O)N=N2)=CC=1>FC(F)(F)C(O)=O>[CH3:36][O:35][C:30]1[C:31]([O:33][CH3:34])=[CH:32][C:27]([C:26]([C:19]2[NH:18][N:17]=[N:16][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:40])=[C:28]([N+:37]([O-:39])=[O:38])[CH:29]=1
Reactant: CCOC(=O)c1c(C(=O)c2cc(OC)c(OC)cc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1nn[nH]c1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 10 h
Yield: 95.2 %

Procedure:
Anisole (1 ml) was added to a solution of an about 1:1 mixture (4.4 g) of ethyl 1-(4-methoxybenzyl)-4-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (Synthesis Example 1, b-1) and ethyl 1-(4-methoxybenzyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (Synthesis Example 1, b-2) in trifluoroacetic acid (10 ml), and the mixture was stirred at 60° C. for 10 hr. After the mixture was allowed to stand for cooling, the solvent was evaporated under reduced pressure, followed by azeotropic evaporation using toluene. The resultant crystal was collected by filtration, washed with diethyl ether, and then dried to give ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1H-1,2,3-triazole-4-carboxylate (3.12 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1cccc(-c2nc(C)cc(Cl)n2)c1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2cc(C)nc(-c3cccc(C)c3)n2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) and p-anisidine (56 mg, 0.457 mmol), similar to Example 11 as a pale green solid (39 mg, 28%). 1H NMR (DMSO-d6): 8.04 (s, 1H), 8.01–7.99 (m, 1H), 7.56–7.51 (m, 4H), 7.04 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.79 (s, 3H), 2.44 (s, 6H).