Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2](=[O:5])([O-])[O-].[K+].[K+].[CH3:8][C:9]1[C:18]([C:19]([C:21]2C=[N:23][N:24]([CH2:27][CH3:28])[C:25]=2O)=[O:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][S:14]2(=[O:30])=[O:29].[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:8][C:9]1[C:18]([C:19]([C:21]2[C:2]([O:5][S:37]([C:34]3[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=3)(=[O:39])=[O:38])=[N:23][N:24]([CH2:27][CH3:28])[CH:25]=2)=[O:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][S:14]2(=[O:29])=[O:30]
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)CCCS3(=O)=O)c1O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCn1cc(C(=O)c2ccc3c(c2C)CCCS3(=O)=O)c(OS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
5 ml of dichloromethane, 5 ml of water and 0.10 g (0.72 mmol, 1 equivalent) of potassium carbonate were added to 0.26 g (0.75 mmol) of 5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide in a 30-ml eggplant type flask. While the mixture was stirred at room temperature, a solution of 0.16 g (0.82 mmol, 1.1 equivalents) of p-toluenesulfonyl chloride in 1 ml of dichloromethane was dropwise added at room temperature. 5 mg of benzyltriethyl-ammonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.24 g of a crude product, and the crude product was recrystallized from ethanol to give 0.14 g (yield 92%) of 5-methyl-6-(1-ethyl-p-toluenesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 59).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]([C:23](Cl)=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:8]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]([CH2:23][NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1c2ccccc2CCc2ccccc21
Reactant: Nc1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)CCc1ccccc1C2CNc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.4 %

Procedure:
A solution of 4.7 grams (50 milliliters) of 4-aminopyridine in 50 cc of dry pyridine was treated dropwise at room temperature with a solution of 6.6 grams of 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylcarbonyl chloride (M. A. Davis, Stanley O. Winthrop, J. Steward, F. A. Sunahara, and F. Herr, J. Medicin. Chem. 1963, 6, 251-5) in 50 cc of toluene. After the exothermic reaction subsided the mixture was stirred at room temperature for 4 hours and was then poured into 30 cc of water. 100 milliliters of toluene were added and the phases were separated. The toluene phase was washed once with 100 cc of water, then the combined aqueous phases were back-extracted with toluene (3×100 cc). The combined toluene solutions were dried(MgSO4) and evaporated, leaving an oily residue which was evaporated several times with further toluene and finally once with ethanol to remove residual pyridine, giving 8.45 grams of a yellow solid. This solid was crystallised from toluene (charcoal) giving off-white crystals (4.78 g, 61%), mp 145°-6° ; second crop, off-white crystals (0.96 g, 12%), mp 145°-7.5° .
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH2:25])[CH:16]=[CH2:17]>C(O)(C)C>[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH:25][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([C:10](=[O:11])[NH2:12])[CH:13]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1ccccc1OCC(O)CN
Reactant: NC(=O)c1cc(OCCBr)ccc1O
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CNCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
A mixture of 6.5 g of 5-(2-bromoethoxy)salicylamide and 8.9 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol is melted in an oil bath at 100° and stirred for 1 hour using a magnetic stirrer. The working up is carried out analogously to Example 11 and yields 1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-propan-2-ol having a melting point of 147°-148° (from isopropanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[OH:10])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([Br:11])=[CH:8][C:9]=1[O:10][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])[CH3:20])=[O:4]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(Br)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(Br)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 98.2 %

Procedure:
5-Bromo-3-hydroxy-thiophene-2-carboxylic acid methyl ester (1.67 g, 7/04 mmol, 1.0 Eq.), 1-(2-Chloro-phenyl)-ethanol (1.43 g, 9.16 mmol, 1.3 Eq.) and triphenylphosphine (2.40 g, 9.16 mmol, 1.3 Eq.) were dissolved in anhydrous THF (30 mL) under nitrogen. The resultant solution was cooled to 0° C. and DEAD (1.4 mL, 9.16 mmol, 1.3 Eq.) was added dropwise. The reaction was warmed to ambient temperature and stirred for 4.5 hours. The crude reaction was purified by column chromatography (10% EtOAc/petroleum ether) to give the sub-title compound as a yellow solid (2.60 g, 6.92 mmol, 98%); 1H NMR (400 MHz, CDCl3) δ 1.68 (3H, d), 3.88 (3H, s), 5.71 (1H, q), 6.65 (1H, s), 7.23-7.33 (2H, m), 7.37 (1H, dd), 7.66 (1H, dd).
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=N[CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=[O:3])[CH3:2].[CH:29](=O)C1C=CC=CC=1>>[C:1]([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=[CH:29][CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Product: CC(=O)N1c2ccccc2-n2cc(Cc3ccccc3)c(=O)c3cccc1c32
Yield: 36 %

Procedure:
According to Example 9<step 4>, the compound (5 g) produced in Example 9<step 3>was reacted with benzaldehyde (3 mL) to obtain the title compound (2.4 g; 36%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:11][O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][C:6]=1[F:9]
Reactant: Nc1nccc(F)c1O
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(F)c1OCc1c(F)cccc1F
Temperature: 50 °C

Procedure:
55 mg (0.43 mmol) of 2-amino-4-fluoropyridin-3-ol Example 267A, 98 mg (0.47 mmol) of 2-(bromomethyl)-1,3-difluorobenzene and 308 mg (0.95 mmol) of caesium carbonate were initially charged in 1 ml of dry DMF and heated for 15 min in an oil bath warmed to 50° C. The mixture was then filtered off and purified by preparative HPLC (Method 9). This gave 70 mg of the title compound (64% of theory).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:20])[C:9](=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])[C:10](O)=[O:11].[CH:21]([O-])([O-])OC.C([O-])(=O)C.[NH4+:30]>CO>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[C:9]2[C:8](=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:20]=[CH:21][NH:30][C:10]2=[O:11]
Reactant: COCCOc1cc(N)c(C(=O)O)cc1OCCOC
Reactant: COC([O-])[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COCCOc1cc2nc[nH]c(=O)c2cc1OCCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 g (2.8 mmol) of 4,5-bis(2-methoxyethoxy)anthranilic acid, 0.93 g (8.8 mmol) of methyl orthoformate, 0.67 g (8.8 mmol) of ammonium acetate, and 5.0 mL of methanol. The reaction was carried out at 95° C. for 8 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Then, the concentrate was recrystallized from 20 mL of methanol. The crystalline product was collected by filtration and dried under reduced pressure to give 0.85 g (isolated yield: 83%) of 6,7-bis(2-methoxyethoxy)quinazolin-4-one as a white crystalline product.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:22][C:21]=2[Br:33])([C:18]#N)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:34].[Na+].[OH2:36]>CCO>[CH:1]([N:14]1[CH2:17][C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:22][C:21]=2[Br:33])([C:18]([OH:36])=[O:34])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)c1ccc(C2(C#N)CN(C(c3ccccc3)c3ccccc3)C2)c(Br)c1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)c1ccc(C2(C(=O)O)CN(C(c3ccccc3)c3ccccc3)C2)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a suspension of 1-benzhydryl-3-(2-bromo-4-(diethoxymethyl)phenyl)-azetidine-3-carbonitrile (Preparation 16, 13.5 g, 26.7 mmol) in EtOH (150 mL) was added aq NaOH (85 mL of a 25% wt. solution). The reaction mixture was heated to reflux for 36 hours. Contents were concentrated under vacuum to remove EtOH to a concentration of ˜100 mL and solution became cloudy. The residue was placed in an ice bath and cooled. The pH of the residue was lowered to ˜5-7 by the slow addition of 3M HCl at which time a precipitate formed. Additional water was added and the mixture was stirred for 15 minutes and filtered. The precipitate was re-dissolved in EtOAc (250 mL) and washed with saturated NH4Cl and brine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH3:11][O:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31]
Reactant: COCOCCCCCCCCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCOCCCCCCCCCCCCCCCC=O
Reaction time: 0.17 h

Procedure:
To a solution of 1.23 ml of oxalyl chloride in 60 ml of dichloromethane was added dropwise at -78 ° C. a solution of 2.0 ml of dimethyl sulfoxide in 2 ml of dichloromethane. After stirring for 10 minutes, a solution of 2.13 g of 16-methoxymethoxyhexadecanol in 30 ml of dichloromethane was added dropwise and the mixture was allowed to slowly rise up to -20° C. and then stirred for 15 minutes. 5.9 ml of triethylamine was added and the mixture was stirred at 0° C. for one hour. To the reaction solution was added a saturated aqueous solution of ammonium chloride and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, distilled under reduced pressure and chromatographed over a silica gel column to afford the title compound as a colorless oily substance.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[F:14][C:15]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:16]=1[CH2:17][NH:18][C:19]1[C:24]([N+:25]([O-])=O)=[CH:23][N:22]=[C:21]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[N+:36]([O-])=O)[N:20]=1>O.C1COCC1>[F:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:15]([F:14])[C:16]=1[CH2:17][NH:18][C:19]1[C:24]([NH2:25])=[CH:23][N:22]=[C:21]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[NH2:36])[N:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NCc2c(F)cccc2F)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(F)cc1Nc1ncc(N)c(NCc2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
A freshly prepared solution of sodium hydrosulfite (tech, 100 mg) and sodium bicarbonate (50 mg) in H2O (5 mL) was added to a solution of N4-(2,6-difluorobenzyl)-N2-(5-fluoro-2-nitrophenyl)-5-nitropyrimidine-2,4-diamine (75) (24 mg) in THF (5 mL). The mixture was stirred vigorously for 30 min and extracted with DCM (3×). The combined organics were washed with brine, dried, filtered and concentrated to yield the intermediate N4-(2,6-difluorobenzyl)-N2-(2-amino-5-fluorophenyl)pyrimidine-2,4,5-triamine (76) for use in the next step. A catalytic amount of para-toluene sulfonic acid monohydrate was added to a solution of the intermediate and trimethyl orthoformate (1 mL) in MeOH (2 mL), after 2 hr conc. HCl (1 mL) was added and the mixture was heated at 50° C. for 4 hr. The reaction solvents were removed and the crude material was purified via preparative HPLC to give 9-(2,6-Difluorobenzyl)-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9H-purine (78) as the TFA salt in low yield (0.8 mg) MH+=404, 1H NMR (5% CD3OD/CDCl3) δ 9.1 (s, 1H), 9.0 (s, 1H), 8.3 (d, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 7.0 (t, 1H), 6.9 (m, 2H), 5.5 (s, 2H) ppm, 19F NMR δ−76.6 (s, TFA), −114.5 (m), −117.1 (m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.F[C:15](F)(F)C(O[Si](C)(C)C)=O.[Si]([N:29]=[N+:30]=[N-:31])(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O>[N:1]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)[CH:15]=[N:29][N:30]=[N:31]1
Reactant: CCOC(=O)Cc1ccc(N)nc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C[Si](C)(C)OC(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Reaction time: 0.08 h

Procedure:
A 1 L 3-neck flask was purged with nitrogen and charged with a solution of ethyl (6-aminopyridin-3-yl)acetate (31.7 g, 176 mmol) in EtOAc (317 mL) at +22° C. Then 30 mL of TMS trifluoroacetate was added (1.0 equiv) while cooling in a water bath. A mild exotherm to +25° C. and partial crystallization was observed. After 5 min, triethylorthoformate was added (44.0 mL, 264 mmol) followed by TMS-azide (28.0 mL, 211 mmol). The resulting suspension was stirred at +23° C. After 15 min, an additional 10 mL of TMS trifluoroacetate was added (0.30 equiv). A clear soln formed after ˜10 min. The mixture was stirred for 3 days at +20° C. whereupon a thin, light yellow suspension had formed. The mixture was cooled in an ice bath, and 200 mL of 1M aq K3PO4 was added while maintaining the temperature below +20° C. Then 465 mL EtOAc was added to solubilize the product. The layers were separated (pH of aq˜8), then the organic phase was washed with 2×250 mL water, and concentrated to a thick slurry. Then 400 mL of n-heptane was added to the concentrated organic phase over 20 min. After 30 rnM, the suspension was filtered to afford the title tetrazole product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Li]CCCC.[F:13][C:14]([F:42])([F:41])[O:15][C:16]1[CH:17]=[C:18]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)=[N:23][S:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:19]=[CH:20][CH:21]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:40][C:37]([F:38])([F:39])[O:36][C:32]1[CH:31]=[C:30]([C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:42])([F:41])[F:13])[CH:17]=2)=[N:23][S@@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH:35]=[CH:34][CH:33]=1.[CH3:29][C:26]([S:24]([NH:23][C:22]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:38])[F:39])[CH:31]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:42])[F:41])[CH:17]=1)[CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:25])([CH3:27])[CH3:28]
Reactant: Cc1cc(C)on1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Product: Cc1cc(CC(NS(=O)C(C)(C)C)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)on1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(R)—N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide was prepared as described for Procedure 11. Under an Argon atmosphere, 3,5-dimethylisoxazole (0.20 mL) was stirred in anhydrous THF in an oven-dried round bottomed flask at −78° C. nBuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol) was added dropwise. The resulting yellowish solution was stirred at −78° C. for 2 h. N-(bis(3-(trifluoromethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (0.81 g, 1.8 mmol) in THF (2 mL) was added dropwise to the above stirred solution. The reaction mixture was stirred at −78° C. for 5 h, then slowly warmed up to room temperature overnight. Saturated NH4Cl was added, followed by the addition of EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes=0 to 100%, came out at 100% EtOAc) to give 2-methyl-N-(2-(3-methylisoxazol-5-yl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide as light tan viscous oil (0.14 g, yield: 13.5% with 0.55 g recovery of the starting material). LC-MS (ESI) 551.38 (M+H), retention time=3.98 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CDCl3) δ ppm 7.49-7.40 (m, 2H), 7.37-7.28 (m, 1H), 7.19 (d, J=6.57 Hz, 1H), 7.05-7.14 (m, 4H), 5.70 (s, 1H), 4.61 (s, 1H), 4.14 (d, J=14.40 Hz, 1H), 3.88 (d, J=14.40 Hz, 1H), 2.26 (s, 2H), 2.13 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 15b (0.14 g, 0.53 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 15c.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: CON(C)C(=O)c1cncn1C
Reactant: Cn1cncc1Br
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1cncn1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (1.2 g, 7.448 mmol) in DCM (10 mL) was added ethyl magnesium bromide (2.5 mL, 7.448 mmol; 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting pale yellow solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N,1-dimethyl-1H-imidazole-5-carboxamide (1.0 g, 6.206 mmol, Intermediate 39: step a) dissolved in DCM (3 mL) was added dropwise. The cold bath was removed and the reaction mixture stirred at room temperature for 48 hours. To the resulting yellow suspension was added water followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM (2×). The combined DCM extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The product was precipitated with Et2O, filtered and dried to provide the title compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[C@@H:55]([CH3:64])[C:56]([N:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)=[O:57])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH3:13][C@@H:12]([N:14]([CH2:22][C@@H:23]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][C:7]1[C:6]2[C:10](=[C:2]([O:1][C@H:55]([CH3:64])[C:56]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)=[O:57])[CH:3]=[CH:4][CH:5]=2)[NH:9][CH:8]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O)cccc12)c1cccnc1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H](C)C(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)c1cccnc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of tert-butyl (1R)-2-(7-hydroxy-1H-indol-3-yl)-1-methylethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)carbamate (300 mg, 0.570 mmol) in N,N-dimethylformamide-(1.0 mL) are added potassium carbonate (98.5 mg, 0.714 mmol), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonate (JP-A-2000-273085) (196 mg, 0.627 mmol), and the mixture is stirred at 50° C. for one hour. To the reaction solution are added potassium carbonate (45 mg), (1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzene-sulfonate (120 mg), and the mixture is stirred at 60° C. for 10 hours. After allowed to cool, to the reaction solution is added ethyl acetate (50 mL), and the mixture is filtered, washed with water and a saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (chloroform/methanol=100/1→20/1) to give tert-butyl (1R)-1-methyl-2-(7-(((1R)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)oxy)-1H-indol-3-yl)ethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)-ethyl)carbamate (209 mg, yield: 55%).