Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CC(OC)(C)C.C(#N)C>[CH2:1]([CH2:8][NH:9][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCl
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: OCCCCCCCCNCCc1ccccc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 96.5 %

Procedure:
A 2-L flask was charged with benzylmethylamine (270 g, 2.23 mol), sodium carbonate (157 g, 1.48 mol), sodium iodide (11.1 g, 0.074 mol), 8-chlorooctanol (122 g, 0.74 mol) and ACN (1000 mL) and the resulting suspension was stirred at 80° C. for 20-30 hours. The reaction mixture was then concentrated to a volume of about 500 mL and water (600 mL) and MTBE (1000 mL) were added. The MTBE layer was then separated and washed with water (500 mL). The MTBE solution was concentrated under vacuum and the resulting oil was then further concentrated by distillation under high vacuum to remove excess benzylmethylamine. N-methyl-2-pyrrolidone (300 mL) was then added to the remaining oil and this solution concentrated by distillation under high vacuum to provide an oil. The oil was dissolved in MTBE (1000 mL) and the resulting solution was washed with water (2×500 mL), brine (500 mL), dried with sodium sulfate (100 g), filtered and concentrated by distillation to afford the title compound as an oil (178 g, 96% yield, >95% purity).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>[Pd].C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)c1ccc(O)cc1

Procedure:
The title compound was prepared as described in General Method 3 from 1-(4-hydroxy-phenyl)-3-phenyl-prop-2-en-1-one (16.5 g, 74.0 mmol), 5% Pd on BaSO4 (1.0 g), and THF (400 mL). The product was recrystallized from 50% EtOH to give the title compound, m.p. 102°-105° C. 1H NMR (CDCl3) δ 3.02 (t, 2 H), 3.22 (t, 2 H), 5.83 (s, 1 H), 6.84 (d, 2 H), 7.15-7.28 (m, 5 H), 7.88 (d, 2 H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=2[CH:20]=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:13]=3[CH:20]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(COc2ccc(C=O)cc2C=O)n1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Temperature: 130 °C
Reaction time: 27 h
Yield: 1232.1 %

Procedure:
A mixture of 4-tert-butyl-2-(2,4-diformylphenoxymethyl)thiazole (0.95 g) and acetic anhydride (12.9 ml) in dried xylene (100 ml) was stirred at 130° C. for 27 hours. After being cooled, the resulting mixture was concentrated in reduced pressure to give a residue. The residue was crystallized with diisopropyl ether. The resulting crystals were collected by filtration and washed with diisopropyl ether to give 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (11.01 g).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].O.NN.Cl>CN(C=O)C.CS(C)=O>[CH3:18][O:17][CH2:16][CH2:15][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:4][C:2]1=[O:3]
Reactant: COCCBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: NN
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COCCN1C(=O)Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a solution of isatin (2.94 g, 20 mmol) in DMF (40 mL) at 0° C. was added 60% NaH (1.00 g, 25 mmol) portionwise. After addition, the resulting mixture was stirred for 15 min at 0° C., then 1-bromo-2-methoxyethane (2.35 mL, 25 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 10 min at 0° C., then 0/N at rt, then cooled to 0° C., and quenched with saturated NH4Cl, ice, and H2O. The product was extracted with EtOAc (150 mL×2) and dried (Na2SO4). Removal of solvents gave a dark orange red liquid which was redissolved in DMSO (10 mL). Hydrazine hydrate (2 mL) was added dropwise over 7 min. After addition, the reaction mixture was stirred for 5 min at rt, then 2 h at 140° C. (oil temp.) before cooling to rt. Ice/H2O (20 mL) was added, followed by 6 M HCl (7 mL, 42 mmol), and the resulting mixture was stirred for 30 min at rt. Additional ice/H2O (40 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). Purification by flash chromatography (gradient: 0 to 40% EtOAc in hexane) afforded the title compound (orange liquid, 2.32 g, 61% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.26-7.20 (m, 2H), 7.03 (d, J=8.0 Hz, 1H), 6.98 (t, J=7.4 Hz, 1H), 3.82 (t, J=5.6 Hz, 2H), 3.55 (s, 2H), 3.52 (t, J=5.8 Hz, 2H), 3.22 (s, 3H); MS ESI 191.8 [M+H]+, calcd for [C11H13NO2+H]+ 192.1.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>N1C=CC=CC=1>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: O=C(Cl)CF
Reactant: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 96.1 %

Procedure:
4.2 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-bromoaniline, 1.42 g of pyridine and 1.74 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 4.73 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-bromoaniline are obtained as colorless needles.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([CH2:24][CH3:25])=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[N:6]=[CH:13][C:14]2[C:15]([CH2:24][CH3:25])=[N:16][O:17][C:18]=2[C:19]=1[OH:20])=[O:9])[CH3:12]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(CC)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2c(CC)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-ethyl-isoxazole-5-carboxylate (0.88 g, 2.03 mmol) was dissolved in 40 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (4.1 mL, 4.1 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was cooled in an ice bath and quenched with 50 mL of 1M HCl. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 0.8 g of crude oil. The crude intermediate was dissolved in 12 mL of CH2Cl2. Thionyl chloride (0.23 mL, 3.09 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. The volatiles were evaporated and the residue was partitioned between CH2Cl2 (50 mL) and saturated sodium bicarbonate solution (50 mL). To the vigorously stirring biphasic mixture was added 4M hydrochloric acid until pH was 2. The aqueous layer was extracted with additional CH2Cl2 and the combined organic layer was dried over MgSO4 and concentrated. The crude residue was purified by chromatography (0-100% CH2Cl2/hexanes) to give 440 mg of the title compound. MS: (+) m/z 237.29 (M+1).
Reaction SMILES: [OH:1][CH:2]1[C:7](OC)([O:8]C)[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.9 %

Procedure:
tert-Butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate from Example 44A (5.24 g, 20.1 mmol) was dissolved in acetone (100 mL), and p-toluene sulfonic acid (173 mg, 1.00 mmol) was added. The mixture was stirred at rt for 3 days, then filtered, and the filtrate was concentrated. The residue was dissolved in tert-butyl methyl ether and extracted with satd. aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo to yield 4.67 g of an oil (64% purity, 69% yield), which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH:18]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:2]1[N:1]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[CH:18][C:9]3=[C:10]2[C:5](=[CH:6][CH:7]=[CH:8]3)[CH2:4][CH2:3]1
Reactant: O=CNc1ccccc1N1CCCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C1=Nc2ccccc2N2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a stirred solution of 32.8 g of N-[2-(1,2,3,4-tetrahydro-1-quinolinyl)phenyl]formamide in 500 ml of dry toluene was added 99.6 g of phosphorus oxychloride. The initial solution was heated under nitrogen for 5 hours at 75° and thereafter stirred at room temperature overnight. The solvent and excess phosphorus oxychloride were removed at aspirator pressure with mild heating. The residue was washed twice with ether and twice with hexane to remove traces of phosphorus oxychloride. The residue was triturated and heated with 25 ml of ethanol. The ethanol was removed on a rotary evaporator and the resulting material was treated with 1 liter of ethyl acetate and 50 ml of dilute sodium hydroxide solution. The two phases were stirred vigorously until the residue was dissolved (except for some interfacial material). The dark aqueous layer was separated and back-extracted with 250 ml of ethyl acetate. The combined organic extracts were filtered, washed four times with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to leave 25.2 g. A part of this material (20 g) was purified further by chromatography on 500 g of silica gel (column packed in dichloromethane) using dichloromethane as eluant. The appropriate fractions were combined and concentrated to afford 9.1 g of crystalline product. This material was recrystallized from a small volume of toluene to provide 4.9 g, m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH:23]([OH:43])[C:24]2[N:28](COCC[Si](C)(C)C)[C:27]3[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=3[N:25]=2)=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2)C>>[CH2:1]([C:3]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH:7]=[CH:6][C:5]=2[C:4]=1[C:23]([C:24]1[NH:28][C:27]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:26]=2[N:25]=1)=[O:43])[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: CCc1cc(C)c2[nH]ccc2c1C(=O)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compounds was synthesized as in Example 25A and 25-B from (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 70-A). 1H NMR (400 MHz, ACETONITRILE-d3 with about 5 μL TFA) δ ppm 9.42 (br. s., 1H), 8.12 (dd, J=0.76, 1.39 Hz, 1H), 7.79 (dd, J=0.76, 8.59 Hz, 1H), 7.62 (dd, J=1.50, 8.60 Hz, 1H), 7.22 (dd, J=2.90, 3.03 Hz, 1H), 6.99 (s, 1H), 6.06 (dd, J=2.02, 3.03 Hz, 1H), 2.63 (q, J=7.58 Hz, 2H), 2.55 (d, J=0.88 Hz, 3H), 1.14 (t, J=7.58 Hz, 3H). HRMS calcd. for C20H16N4O (M+H)+ 329.1397. found 329.1327.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[N+:31]([C:27]1[CH:26]=[C:25]([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[CH:30]=[CH:29][CH:28]=1)([O-:33])=[O:32]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc(-c2cccc([N+](=O)[O-])c2)c1
Product: O=[N+]([O-])c1cccc(-c2cccc(Nc3cc(C(F)(F)F)nc(-c4cccnc4)n3)c2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-3′-nitrobiphenyl (83 mg, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (65 mg, 77%). 1H NMR (DMSO-d6): 13.00 (s, 1H), 11.94 (s, 1H), 11.23 (d, J=4.5 Hz, 1H), 11.11 (d, J=8.1 Hz, 1H), 10.97 (s, 1H), 10.78 (s, 1H), 10.75 (s, 1H), 10.69 (d, J 8.1 Hz, 1H), 10.35-10.28 (m, 2H), 10.14-10.04 (m, 3H), 9.67 (s, 1H).
Reaction SMILES: [C:1]1([C:9]([O:11]CC)=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.[OH-].[K+]>C(O)C.O>[CH2:7]([O:6][C:4]([C:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of diethyl cyclopropane-1,1-dicarboxylate (4.77 g, 25.6 mmol) in ethanol (40 mL) was added KOH (1.43 g, 25.6 mmol) in H2O (8 mL), and the reaction mixture was stirred at room temperature overnight. The ethanol was removed under reduced pressure. The residue was neutralized with HCl (6 mL, 5 mol/L), then extracted with EtOAc (100 mL×3). The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (3.58 g, 88.4%).
Reaction SMILES: [CH:1]([O:4][NH2:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl.[Cl-].[Na+].O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([NH:5][O:4][CH:1]([CH3:3])[CH3:2])=[O:15])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)ON
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)ONC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To as solution of the crude O-isopropyl-hydroxylamine (200 mg) from above in CH2Cl2 (5 ml) was added Et3N (0.30 ml, 2.16 mmol) and 4-nitrophenyl chloroformate (430 mg, 2.13 mmol) and the mixture stirred at room temperature for 30 min. before diluting with CH2Cl2 (20 ml) and brine (15 ml). The aqueous layer was extracted with CH2Cl2 (1×15 ml) and the combined organic extracts dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 4:1) to afford N-(4-nitrophenoxycarbonyl)isopropoxylamine (290 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-:18].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]([Br:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
To a solution of 1.89 g of (+/-)-1-(3,5-bis(trifluoromethy)-phenyl)-1-hydroxyethane prepared as in Example 5, Step A in 50 mL of acetonitrile at room temperature was added 5.15 g of triphenylphosphine dibromide. After 1.5 h, the reaction was partitioned between ether and water and the ether layer was washed with brine, dried with sodium sulfate and evaporated. The product was triturated with hexanes, filtered to remove the solid and reconcentrated. The residue was purified by flash chromatography using hexanes to provide 1.75 g of title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:45][N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: NN1CCOCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NN2CCOCC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with N-aminomorpholine (38.2 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (46 mg, 61% of theory).
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([NH2:14])=[O:13])[C:4]=2[CH:3]=[CH:2]1>C(O)(=O)C.[C].[Pd]>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)/C=C/c1nccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)CCc1nccc2c1CCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 41.4 %

Procedure:
To a solution of (2E)-3-furo[3,2-c]pyridin-4-ylacrylamide (500 mg, 2.65 mmol) in acetic acid (5 mL) was added palladium-carbon powder (10 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=3/97→15/85) to give the title compound (211 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH2:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:8][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: NCCOc1cc(Cl)cc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 2-(3,5-dichloro-phenoxy)-ethylamine, Et3N, and methanesulfonyl chloride using the procedure described in Step 2 of Preparation A1. Recrystallization from EtOH provided the title compound. 1HNMR (400 MHz, CDCl3) δ 6.93 (m, 1H), 6.74 (m, 2H), 5.09 (m, 1H), 4.01 (t, 2H), 3.47 (q, 2H), 2.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:43](=[S:45])[NH2:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1)c1cc(F)ccc1F

Procedure:
The title compound was prepared from N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.5 g, 3.54 mmol), NBS (0.630 g, 3.54 mmol) and 4-morpholinecarbothioamide (0.517 g, 3.54 mmol) by a procedure analogous to Intermediate 9. The title compound was obtained as a yellow solid (1.8 g, 90% yield). ES-LCMS m/z 549.7 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])[CH2:8]1>>[S:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][OH:17])[CH2:8]1
Reactant: O=Cc1cccc(C2CCCSC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc(C2CCCSC2)c1
Yield: 14 %

Procedure:
Using lithium aluminium hydride, the resulting aldehyde compound was reduced in a customary manner to give 75 mg (yield 14%) of the captioned compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:22])=[O:23])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirred solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-(phenylsulfonyl)phenyl)propanoate (700 mg) in THF (15 mL) and water (10 mL) was added lithium hydroxide monohydrate (140 mg). The mixture was stirred at RT for 2 h. The mixture was partitioned between 0.1 N HCl(aq) and ethyl acetate, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to leave the subtitle compound (675 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:34])[C:8]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[C:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=3)[S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[S:10][C:11]3[C:6]([C:7](=[O:34])[C:8]=2[C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=3)=[CH:19][CH:18]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1ccc(Cc2sc3cc(OC)ccc3c(=O)c2-c2ccc(C(=O)OC)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(O)c1ccc(Cc2sc3cc(O)ccc3c(=O)c2-c2ccc(C(=O)O)cc2)cc1

Procedure:
To a solution of methyl 4-(7-methoxy-2-(4-(methoxycarbonyl)benzyl)-4-oxo-4H-thiochromen-3-yl)benzoate (105 mg, 0.23 mmol) in dry DCM (3 ml) was added BBr3 (0.2 ml, 2.23 mmol) at 0° C. with stirring. The mixture was stirred at room temperature for 40 hours and poured into 1 N icy HCl solution (1 ml) with stirring. The volatiles were evaporated and the residue was purified by prep-TLC (PE:EtOAc=1:1) to afford the desired product in Example 7 as a pink solid (15 mg, 16%).