Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C@H:11]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:16][C:17]1[C:22]([CH2:23][CH3:24])=[N:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[C:19]([CH2:34][CH3:35])[N:18]=1)[CH3:9]>>[CH2:8]([O:10][C@H:11]1[CH2:15][N:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:13][C@H:12]1[NH:16][C:17]1[C:22]([CH2:23][CH3:24])=[N:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[C:19]([CH2:34][CH3:35])[N:18]=1)[CH3:9]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Reactant: Brc1ccccn1
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrzin-2-amine but substituting 2-bromopyridine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.31, 2.14, 2.49, 2.71, 3.42, 3.54, 3.78, 3.85, 4.07, 4.28, 4.92, 5.21, 6.50˜6.66, 6.79, 6.84, 7.12, 8.20; IR (diffuse reflectance) 2969, 2405 (w), 2351 (w), 2337 (w), 2212 (w), 2015 (w), 1599 (s), 1560, 1482 (s), 1474 (s), 1442 (s), 1392, 1385, 1242, 769 cm−1 HRMS (ESI) calcd for C27H35N5O2+H1 462.2869. found 462.2859.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH:9]1[S:13][C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:23]([CH3:32])[S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])=[N:11][CH2:10]1)#[N:8].[OH-].[Na+]>O1CCCC1>[NH2:8][CH2:7][CH:9]1[S:13][C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:23]([CH3:32])[S:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)(=[O:26])=[O:25])=[N:11][CH2:10]1
Reactant: CN(c1cccc2cc(C3=NCC(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CN)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
To a suspension of lithium aluminum hydride (0.015 g) in tetrahydrofuran (2 ml) was added dropwise a solution of N-[2-(5-cyano-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.080 g) in tetrahydrofuran (3 ml) under ice-cooling, and the reaction mixture was stirred at 0° C. for 2 hr. 1N Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=80:20-100:0), and recrystallized from hexane-ethyl acetate to give the title compound (0.029 g, yield 36%) as colorless crystals.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.N([O-])=O.[Na+].[BrH:18]>C(O)(=O)C.O>[Br:18][C:6]1[CH:8]=[CH:9][C:3]([S:2]([F:13])([F:12])([F:11])([F:10])[F:1])=[CH:4][CH:5]=1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FS(F)(F)(F)(F)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 4-pentafluorosulfanylaniline were dissolved in 20 ml of acetic acid and, at 0° C., a saturated aqueous HBr solution was added. Then at 0° C., a solution of 1.9 of NaNO2 in 5 ml of water was slowly added dropwise over the course of 5 minutes. The reaction mixture was stirred at 0° C. for 10 minutes and then added in portions to a suspension of 6.5 g of CuBr in 20 ml of a half-saturated aqueous HBr solution at 0° C. Nitrogen is liberated during this. The mixture was stirred at 0° C. for 30 minutes and then at RT for 1 h. It was subsequently extracted 3 times with 100 ml of HEP each time, and then the HEP was washed twice with 50 ml of a saturated aqueous Na2CO3 solution each time. The residue after drying over MgSO4 and removal of the solvent in vacuo was chromatographed on silica gel with HEP. 1.8 g of a colorless oil were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[C:7]([NH2:16])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.B(Br)(Br)Br.O>ClCCl>[NH2:16][C:7]1[C:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[OH:2])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: COc1ccccc1Cc1cc2ccccc2nc1N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Nc1nc2ccccc2cc1Cc1ccccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-(2-Methoxybenzyl)quinolin-2-amine (53 mg, 0.2 mmol) was mixed with boron tribromide solution in dichloromethane (1M, 0.4 mL, 0.4 mmol) in dichloromethane [sic; duplication] at −78° C. After thawing, the mixture was stirred for 12 hours at room temperature. The batch was mixed with water, extracted with dichloromethane and the combined organic phases were washed with sodium hydroxide solution (1M), water and saturated saline solution until neutral. After drying (sodium sulfate), the crude product was stirred with methyl tert-butyl ether and recrystallized from methanol/water (yield: 28 mg, 56%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][NH:24][CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)C>C(#N)C>[C:6]([O:10][C:11]([N:13]1[CH:22]([CH2:23][N:24]([CH:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:4][CH2:3][O:2][CH3:1])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)NCC1Cc2ccccc2CN1C(=O)OC(C)(C)C
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CC#N
Product: COCCN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of methoxyacetaldehyde (0.15 gm, 2.03 mmol), 3-{[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethylamino]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester from preparation 3BC Step C (0.31 gm, 0.68 mmol) in acetonitrile was added sodium triacetoxyborohydride (0.72 gm, 3.38 mmol). After stirring overnight under a nitrogen atmosphere at r.t., additional acetaldehyde (0.25 gm) dissolved in acetonitrile and sodium triacetoxyborohydride (0.21 gm) was added, and the mixture was stirred for about 8.5 hours. The mixture was quenched at r.t. with 5N NaOH (5 mL). The aqueous phase was separated from the organic and extracted with ethyl acetate (4×). The combined organics were washed with a brine solution, and then dried, filtered and concentrated. Chromatography (gradient of ethyl acetate in hexane, 0 to 12%) gives about 0.23 g of 3-{[[2-(4-Chloro-phenyl)-1-methoxycarbonyl-ethyl]-(2-methoxy-ethyl)-amino]-methyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as a yellow oil (70%). MS (m/z, ES+): 517.2.
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C4C=CC(S(=O)(=O)NC)=CC=4)[CH2:23][CH2:22][C:21]([C:36](O)=[O:37])=[CH:20][C:19]=3[CH:39]=2)=CC=1)CCC.C(Cl)(=O)C(Cl)=O.C[N:47](C=O)C>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:39][C:19]=2[CH:20]=[C:21]([C:36]([NH2:47])=[O:37])[CH2:22][CH2:23]1
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(=O)(=O)NC)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)C1=Cc2ccccc2NCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (7 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.4 g). Under ice-cooling, to the solution were added oxalyl chloride (0.19 ml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, and the solution was added dropwise to a suspension of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.28 g) and triethylamine (0.5 ml) in THF (5 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with basic silica gel column chromatography (ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-N-[4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 48) (0.28 g) as pale yellow crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl-].C[Al+]C.CO[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)OC
Reactant: CNOC
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of N,O-dimethylhydroxylamine hydrochloride(13.3 g, 136.3 mmole, 6.0 eq) in dry CH2Cl2(250 ml) at 0° C. was treated dropwise with neat dimethylaluminum chloride (12.7 ml, 136.3 mmole, 6.0 eq) and the resulting mixture stirred at 0° C. for 2 hours then allowed to warm to RT. To this mixture was added dropwise a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methyl ester (5.98 g, 22.71 mmole, 1.0 eq) in CH2Cl2 (20 ml). The yellow mixture was then stirred at room temperature under nitrogen for one hour and re-cooled to 0° C. The mixture was quenched slowly by adding 2.0N NaOH dropwise, warmed to room temperature, and extracted with two portions of CH2Cl2. The organic phase was washed successively with 1.0N NaOH and brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with (4:1) hexanes-ethyl acetate to give 6.5 g (97%) of the title compound as a yellow waxy crystalline solid. 1H NMR (CDCl3): δ 3.35 (s, 3H), 3.5 (s, 3H), 3.7 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I:13][C:14]1[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=1.C(O)(=O)C.O>O1CCCC1.ClC(OCC(C)C)=O.CN1CCOCC1.C(OCC)(=O)C>[I:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH:21][C:16]=2[CH:15]=1
Reactant: Nc1ccc(I)cc1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1nc2ccc(I)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
To a solution of N-Boc-glycine (129 mg) in tetrahydrofuran (3.5 mL), isobutyl chloroformate (97 μL) and N-methylmorpholine (81 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, 4-iodobenzene-1,2-diamine (200 mg) synthesized according to the method described in WO2010/065668 A1 was added under ice cooling, and the mixture was stirred at room temperature for 1 hour, and then acetic acid (3.5 mL) was added, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 0% hexane in ethyl acetate) to obtain tert-butyl ((6-iodo-1H-benzo[d]imidazol-2-yl)methyl)carbamate (G4, 216 mg).
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])[CH3:4]>C(O)C>[CH2:3]([O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]=[C:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3-c3ccccc32)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCC=C2c3ccccc3-c3ccccc32)cc1)C(=O)O

Procedure:
Lithium hydroxide (1M, 1.0 ml, 1.0 mmol) was added to a suspension of ethyl 2-ethoxy-3-[4-(2-fluoren-9-ylidene-ethoxy)-phenyl]-propionate (0.214 g, 0.5 mmol) in ethanol (5 ml) and the resulting mixture heated to gentle reflux for 30 min. The cooled mixture was partitioned between water (30 ml) and dichloromethane (20 ml), acidified to pH 1 by adding 1N hydrochloric acid (3 ml), and the organic phase collected. The aqueous phase was further extracted with dichloromethane (3×20 ml) and the combined organics were washed with brine, dried (MgSO4) and evaporated to give a yellow gum. The product was purified by column chromatography on silica gel (3% methanol in dichloromethane eluent) to give 2-ethoxy-3-[4-(2-fluoren-9-ylidene-ethoxy)-phenyl]-propionic acid, as a yellow solid; 0.104 g (51%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2'-cyanophenyl)benzoic acid methyl ester (0.428 g, 1.804 mmol) in tetrahydrofuran (14.3 mL) at 0° C. was added 1.0 M lithium aluminum hydride in tetrahydrofuran (3.61 mL, 3.61 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, then warmed to 45° C. for 3 hours, cooled and quenched by dropwise addition of saturated Na2SO4 (0.46 mL). The reaction was diluted with diethylether, Na2SO4 was added, the mixture filtered through a pad of Celite and the filtrate evaporated in vacuo to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(#N)C>ClCCl>[CH3:32][S:29]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:31])=[O:30]
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15 %

Procedure:
To a solution of 3-[1-(1,2,3,6-tetrahydro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino]-propan-1-ol as prepared in example 27 (50.0 mg; 0.132 mmol; 1 eq) in anhydrous dichloromethane (660 μL) are successively added N,N′-dimethylaminopyridine (16.1 mg; 0.132 mmol; 1 eq) and mesyl chloride (10.3 μL; 0.132 mmol; 1 eq). The solution is allowed to stir at room temperature for 17 hours after which period the reaction is almost complete. The reaction mixture is concentrated under vacuum and the resulting residue is taken-up with ethyl acetate (10 mL). The organic solution is washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. Two successive column chromatography on silica gel (eluent column 1: ethyl acetate/methanol/triethylamine 8:2:0.2; eluent column 2: dichloromethane/methanol 95:5) and one column chromatography on reversed-phase (C18, acetonitrile) affords the title compound as a white solid (9 mg; 0.020 mmol; 15%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl.O.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][CH2:43][C:38]1[CH:39]=[C:40]([CH:41]=[CH:42][C:37]=1[O:36][CH2:32][CH:33]([CH3:35])[CH3:34])[C:8]([C:7]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])=[CH:14][C:6]=1[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH3:49]
Reactant: CC(C)COC(=O)c1ccc(C(=O)O)c(OCC(C)C)c1
Reactant: CCOC(=O)CCc1ccccc1OCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(C(=O)OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
In 18 ml of methylene chloride is dissolved 1.8 g of 2-isobutoxy-4-(isobutoxycarbonyl)-benzoic acid. After adding 0.7 ml of oxalyl chloride and subsequently 20 μl of N,N-dimethylformamide at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 1.6 g of aluminum chloride and subsequently 1.8 g of ethyl 3-(2-isobutoxyphenyl)propanoate are added at 5-10° C., and the resulting mixture is stirred at ambient temperature for one hour. The reaction mixture is added to a mixture of chloroform and water and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 2.1 g of isobutyl 4-[3-(3-ethoxy-3-oxopropyl)-4-isobutoxybenzoyl]-3-isobutoxybenzoate as a colorless oily product.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.CC1C=C(O)C=CC=1C.[O:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:36][C:29]1([C:9]2[C:8]([OH:11])=[CH:7][C:6]3[O:1][CH2:2][O:3][CH2:4][C:5]=3[CH:10]=2)[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH2:26][C@H:22]2[CH2:23][CH2:24][CH2:25][O:21]2)[C:28]1=[O:37]
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: Oc1ccc2c(c1)OCOC2
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C1(O)c1cc2c(cc1O)OCOC2

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 4H-benzo[d][1,3]dioxin-7-ol to replace 3,4-dimethylphenol, and (R)-1-((tetrahydrofuran-2-yl)methyl)indoline-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (62%) as a colorless solid: MS (ES+) m/z 366.2 (M−17).
Reaction SMILES: Cl[C:2]1[N:3]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[S:4](=[O:11])(=[O:10])[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O-:20])=[O:19].N1C=CC=CC=1>C(Cl)Cl.C1COCC1.C>[CH:12]1([N:3]2[C:2]([O:27][C:24]3[CH:25]=[CH:26][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)=[N:7][C:6]([O:8][CH3:9])=[N:5][S:4]2(=[O:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC1=NS(=O)(=O)N(C2CCCCC2)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(Oc2ccc([N+](=O)[O-])cc2)=N1

Procedure:
A solution of the chlorothiatriazine obtained in Step 3. above (92.3 g) in methylene chloride (250 ml) is added dropwise to a stirred solution of para-nitrophenol (49.4 g) and pyridine (70.2 g) in methylene chloride (500 ml) and refluxed for 3 hours. The reaction mixture is washed with 3N HCl and sodium bicarbonate solution. The methylene chloride layer is dried, filtered, washed and evaporated yielding a solid which is dissolved in hot THF with charcoal, filtered and evaporated. The resulting solid is washed with diethyl ether, dissolved in methylene chloride, filtered through silica gel, washed with methylene chloride, filtered through Celite®, evaporated, and triturated with diethyl ether affording a yellow solid. The solid is recrystallized from hot THF, yielding the desired product as a solid used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([NH2:6])[CH2:2]1.C([O-])(=O)C.[Na+].[Si:12]([O:19][CH2:20][CH:21]=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl.CO.C(OC)(C)(C)C.O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][NH:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: NC1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OCCNC1CCOC1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of tetrahydrofuran-3-amine (see WO98/08855, 0.500 g, 4.04 mmol) and sodium acetate (0.331 g, 4.04 mmol) in a 1:3 mixture of methanol and tetrahydrofuran (60 ml) was stirred at room temperature. To this was added (tert-butyl-dimethylsilanyloxy)acetaldehyde (2.112 g, 12.12 mmol) followed by glacial acetic acid (1.456 g, 24.24 mmol) and then sodium triacetoxyborohydride (2.568 g, 12.12 mmol) was then added in 5 portions over 3 minutes (CAUTION: vigorous effervescence) and the resulting suspension was left to stir at room temperature for 4 hours. The mixture was evaporated under reduced pressure to leave a thick brown paste which was dissolved in dichloromethane (20 ml) and to this was added a solution of ammonia in methanol (7M solution, 25 ml). The mixture was stirred for 10 minutes and then evaporated under reduced pressure to leave an orange paste which was triturated with dichloromethane (50 ml) and filtered through Celite. The mixture was evaporated under reduced pressure to leave a brown gum which was dissolved in methyl tert-butyl ether (3 ml) and then purified by silica gel chromatography using methyl tert-butyl ether as eluent to give N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)tetrahydrofuran-3-amine (0.446 g, 48% yield) as a brown oil: