Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:26]3[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc3nc(N)nc(N)c3n2)ccc1O
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (378 mg, 1.93 mmole), K2CO3 (1075 mg, 7.78 mmole) and 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (599 mg, 2.32 mmole) in 1,4-dioxane (29 ml) and water (6 ml) was purged with a nitrogen stream for 30 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmole) was added and purging with N2 was continued for 15 minutes. The reaction mixture was then heated at reflux under a N2 atmosphere for 2 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and brine and the organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. Purification of the residue by silica gel flash chromatography with 10% methanol and 1% Et3N in CH2Cl2 as mobile phase, afforded the pure title compound (375 mg, yield 69%) which was characterized by its mass spectrum as follows: MS (m/z): 284 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O-:15])=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([Cl:26])=[O:15])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1nnnn1Cc1ccccc1
Temperature: 15 °C

Procedure:
The potassium salt produced in Example 2, and pyridine are stirred at 6° C. in benzene followed by rapid addition of oxalyl chloride. After stirring one half hour at 15° C. the mixture is stripped at 15° C., and scrubbed with two portions of benzene at 15° C. to yield 1-benzyl-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: CO[C:3](=[O:22])/[C:4](/[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5](\O)/[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH3:24][C:25]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH2:26][C:27](=[NH:29])[NH2:28].C[O-].[Na+].Cl>CO.O>[CH2:15]([O:14][C:4]1[C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[N:28][C:27]([CH2:26][C:25]([CH3:30])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:24])=[N:29][C:3]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: CC(C)(CC(=N)N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 42.4 %

Procedure:
4-tert-Butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (4) (652 mg, 2.12 mmol, Eq: 1.5,) and 3-methyl-3-phenylbutanimidamide hydrochloride (54) (300 mg, 1.41 mmol, Eq: 1.00) were stirred in methanol (7.2 ml). The reaction mixture was cooled to 0° C. and sodium methoxide (229 mg, 4.23 mmol, Eq: 3) (powdered, Aldrich) was added. The reaction mixture was stirred at room temperature. The reaction mixture is a suspension. It was stirred overnight. 5 ml 1N aqueous HCl was added and the mixture was diluted with water, filtered through a sintered glass funnel. The solid was washed with water. The solid was placed under high vacuum to dry to give tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate as a yellow solid (260 mg, 21%) as a 1:1 mixture of tert-butyl 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylate (55) and 3-methyl-3-phenylbutanimidamide. The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[CH3:11].[C:12]1(=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]1.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:11])=[CH:5][C:6]([NH:7][C:12]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13]2)=[CH:8][C:9]=1[CH3:10]
Reactant: CCOC(=O)C=C1CCC1
Reactant: COc1c(C)cc(N)cc1C
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(Nc2cc(C)c(OC)c(C)c2)CCC1
Yield: 10.4 %

Procedure:
To a solution of 4-methoxy-3,5-dimethylaniline (5 g) and ethyl 2-cyclobutylideneacetate (10 g) in 6 mL toluene, under nitrogen was added by syringe 1mL HCl (4M in dioxane). After refluxing the solution for 3 days, the mixture was concentrated, water was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude compound was purified by column chromatography (10% ethyl acetate/hexane), giving ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)-cyclobutyl)acetate (1 g) as a while solid. 1H-NMR (300 MHz, CDCl3) δ=6.21 (s, 2H), 4.10(q, 2H), 3.67 (s, 3H), 2.90 (s, 2H), 2.33 (m, 2H), 2.19 (m, 8H), 1.95 (m, 2H), 1.24 (t, J =6.9 Hz, 3H) ppm. MS: m/z 293 (100, M+H)+
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13].[OH-].[NH4+:35].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:35][C:20]1[C:19]2[N:28]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:29][C:30](=[O:33])[CH2:31][CH3:32])[C:18]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(=O)CC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(=O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
mCPBA (2.11 g, 8.57 mmol) was added to a solution of 1-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one (1.96 g, 6.59 mmol) in chloroform (30 mL) at room temperature. The reaction mixture was stirred for 1 hour, then was cooled to 0° C. Concentrated ammonium hydroxide (10 mL) and p-toluenesulfonyl chloride (1.38 g, 7.25 mmol) were added. The mixture was stirred at 0° C. for 1 hour, then was filtered. The filtrate was diluted with dichloromethane (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield a brown solid. The solid was purified by chromatography on a HORIZON High-Performance Flash Chromatography (HPFC) instrument (available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-35% of a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH (CMA) in chloroform) to afford a tan solid that was recrystallized from chloroform/hexanes. The crystals were isolated by filtration and dried in a vacuum oven at 80° C. to afford 0.718 g of 1-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butan-2-one as pale pink needles, mp 187-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:32])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-:31])=[O:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1[N+](=O)[O-])S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1[N+](=O)[O-])c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
A mixture 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (580 g, 1.02 mmol) in 4 M HCl in dioxane (15 mL), and water (5 mL) was heated at 100° C. for 8 h and then at room temperature for 10 h. The reaction mixture was concentrated to dryness under reduced pressure and it was treated with aqueous NaHCO3 to adjust pH to 5-6 and extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide the desired product 4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 11.06 (s, 1 H), 8.23 (d, J=2.4 Hz, 1 H), 8.18 (d, J=2.4 Hz, 1 H), 8.14 (dd, J=8.0, 1.4 Hz, 1 H), 8.07 (d, J=2.4 Hz, 1 H), 8.00 (dd, J=8.4, 2.0 Hz, 1 H), 7.80-7.77 (m, 1 H), 7.70-7.66 (m, 2 H), 7.45 (dd, J=8.0, 1.6 Hz, 1 H); Mass spectrum m/z: 520.2 (M+H).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:13]1([CH2:1][C:3]2[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1csc(C=O)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-formyl-1,3-thiazole-4-carboxylate (315 mg) in anhydrous DCM (25 ml) was added morpholine (0.164 ml) and the mixture stirred under nitrogen for 3 h at RT. Sodium triacetoxyborohydride (759 mg) was added and the mixture stirred at RT for 16 h. Sodium bicarbonate (50 ml) and DCM (50 ml) were added and the aqueous layer was extracted with DCM (2×25 ml) using a hydrophobic frit. The solvent was removed in vacuo, the residue was dissolved in DCM (5 ml) and purified by chromatography on silica gel eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. The solvent was removed in vacuo to give a white solid. The solid was dissolved in methanol (15 ml) and loaded onto an SCX SPE cartridge (50 g), which was preconditioned with methanol and allowed to stand for 15 min. The column was washed with methanol (50 ml) and elution with 2M ammonia in ethanol gave the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: BrCCc1cccc2ccccc12
Product: O=S(=O)(O)c1ccc(CCBr)c2ccccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(2-bromoethyl)naphthalene (120 g) was stirred in an ice bath while fuming sulfuric acid (50 g) was slowly added dropwise. After the dropwise addition, the mixture was stirred at 0° C. for 24 hours, whereby 4-(2-bromoethyl)naphthalenesulfonic acid was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=O.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([CH2:25][C:26]2[O:18][C:5]3[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][C:4]=3[C:2]=2[CH3:1])=[CH:23][CH:22]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3ccc(OCc4ccccc4)cc3c2C)cc1
Yield: 93.2 %

Procedure:
A mixture of 2-hydroxy-5-benzyloxyacetophenone (93 g, 380 mmoles), p-methoxyphenacyl bromide (88 g, 384 mmoles) and potassium carbonate (106 g, 768 mmoles) in acetone (1.5 L) was refluxed for 46 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using 10% ethylacetate in hexane as eluent to yield (127 g, 89%) of 2-(p-methoxybenzyl)-3-methyl-5-benzyloxybenzofuran, E48.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]>N1CCCCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCC#Cc1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 10.0 g (54.05 mmol) of 3-bromo-benzaldehyde in 150 ml of piperidine was treated at RT with 1.029 g (5.40 mmol) of copper(I)iodide and 6.246 g (5.40 mmol) of tetrakis-(triphenylphosphine)-palladium and the mixture was then warmed up to 60° C. After 10 min, a solution of 9.30 ml=6.66 g (81.07 mmol) of hex-1-yne in 150 ml of piperidine was added drop by drop during 1 hour. After 30 min, the oil bath temperature was steadily increased to 80° C. The reaction mixture was then stirred at 80° C. for 15 hours and subsequently cooled down to RT. The solvent was evaporated and the residue poured into crashed ice, acidified with HCl (37%) to pH 2-3 and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 1:0 to 97:3) to give 8.78 g (87%) of the title compound as yellow oil. MS: 186.2 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[H-].[Na+].Cl[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=1>CN(C=O)C>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Treat [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (534.3 mg, 2.2 mmol) with NaH (80% in mineral oil, 78.0 mg (2.6 mmol) in anhydrous DMF (10 mL) at room temperature for 30 minutes. Add 6-chloronicotinamide (343.8 mg, 2.2 mmol) and heat the mixture at 80° C. overnight. Quench the reaction with H2O and concentrate to dryness, using xylenes to remove DMF as an azeotrope. Suspend the residue in MeOH and filter with thorough MeOH and CH2Cl2 rinse. Concentrate the filtrate and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH. Deprotect the BOC group with 1:1 TFA/CH2Cl2 (16 mL) at room temperature overnight. Concentrate and purify by an SCX column, washing with MeOH and then eluting with 2.0 M NH3 in MeOH: MS ES+ 297.9 (M+H+K)+, HRMS calcd for C14H16N3O2 258.1243 (M+H)+, found 258.1235 time 0.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.93 min. 100% purity.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[CH:20][C:19]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].II>CN(C)C=O.C(O)(C)(C)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[CH:20][C:19]=1[CH3:29]
Reactant: Cc1cc(C(CN)CN)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: Cc1cc(C2CN=C3c4ccccc4NC(=O)N3C2)ccc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=O)[N:10](C)[CH:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[CH:9]([NH:10][CH3:11])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CN1C(=O)OC(c2ccc(F)cc2)C1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Yield: 0.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (4.56 g, 12.9 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (8.07 ml) and the mixture was heated under reflux for 3 hrs. The reaction solution was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether-hexane to give (1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (3.34 mg, 79%).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:16]2[O:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12][C:11]=2[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=1>N1C=CC=CC=1>[OH:6][C:7]1[C:16]2[O:15][CH2:14][CH:13]([CH2:17][O:18][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:12][C:11]=2[CH:10]=[C:9]([O:19][CH3:20])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)c2c(c1)CC(CO)CO2
Solvent: c1ccncc1
Product: COc1cc(O)c2c(c1)CC(COS(C)(=O)=O)CO2
Reaction time: 1.5 h
Yield: 63.3 %

Procedure:
5.15 g of mesyl chloride was added to a solution of 6.30 g of 3,4-dihydro-8-hydroxy-3-hydroxymethyl-6-methoxy-2H-1-benzopyran in 90 ml of anhydrous pyridine, and the mixture was stirred for 1.5 hours. After the reaction, the solvent was distilled off. The residue was dissolved in 100 ml of ethyl acetate, and washed with water, 1 N hydrochloric acid and water in this order, and then dried. The solvent was distilled off, and the residue was purified by silica gel column chromatography to give 5.47 g (yield 63.3%) of 3,4-dihydro-8-hydroxy-3-mesyloxymethyl-6-methoxy-2H-1-benzopyran as a pale brown viscous oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12](=[O:47])[CH2:13][CH:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2)(=[O:24])=[O:23])[C:15](N(OC)C)=[O:16])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:47])[CH2:13][C@H:14]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][C:26]=1[O:34][CH2:35][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2)(=[O:24])=[O:23])[CH:15]=[O:16])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Temperature: -65 °C
Reaction time: 2 h

Procedure:
To a −65° C. solution of lithium aluminum hydride (0.51 mL, 1M in diethyl ether) in diethyl ether (5 mL) was added a solution of 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.10 g, 0.17 mmol) in diethyl ether (5 mL). The reaction was stirred at −65° C. for 2 h. The reaction was then diluted with ethyl acetate (100 mL) and washed with 10% potassium hydrogen sulfate and then saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester as a clear oil. MS(APCI) m/z 528.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:9]=2[CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:9]=2[CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:4][CH:3]=1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCOc1cccc(-c2ccc(Cl)cc2)c1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 199B (2 g) in dichloromethane (10 ml) was added trifluoroacetic acid (10 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was loaded onto a C18 column, and eluted with 0-50% 0.1% trifluoroacetic acid/water in acetonitrile. The title compound was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH2:19][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCCS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cool (ice-bath) a mixture containing the product of Step C (21.8 gm-0.078 mol), 250 ml CH2Cl2 and 9.7 ml pyridine (0.12 mol), add in a dropwise fashion (20 minutes) mesylchloride (6.65 ml-0.086 mol) in 6.6 ml CH2Cl2 and allow the mixture to warm to room temperature, stirring the mixture for 2 hours. Pour the resulting mixture into 200 ml CH2Cl2, wash with 500 ml 0.5N HCl, saturated NaHCO3, dry over MgSO4, evaporate (in vacuo) and flash chromatograph eluting from the silica gel with 25% EtOAc/hexane to obtain 10.7 g of desired product, Rf is 0.36 (silica gel plates eluted with 25% EtOAc/hexane).