Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[CH3:6].[Cl-].[NH4+].[N-:39]=[N+:40]=[N-:41].[Na+].O>CN(C)C=O>[CH3:36][C:23]([NH:22][CH2:21][C@@H:2]([OH:1])[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[NH:41][N:40]=[N:39][N:20]=2)=[CH:17][CH:18]=1)[CH3:6])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2′-[1-[(2R)-2-Hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carbonitrile (500 mg) obtained in Step 2 was dissolved in N,N-dimethylformamide (6.0 ml), ammonium chloride (535 mg) and sodium azide (676 mg) were successively added and the mixture was stirred overnight at 115° C. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was dissolved in methanol, water was added and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound (280 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1>C(Cl)(Cl)Cl>[CH2:12]1[O:35][C:34]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:31])(=[O:9])=[O:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of 0.65 g (3.8 mmol) of m-chloroperbenzoic acid in 20 ml of chloroform was dropped into a solution of 1.00 g (2.98 mmol) of the 4-(3,4-methylenedioxybenzyl)amino-6-methylsulfinylquinazoline prepared in Example 137 under stirring at room temperature. The obtained mixture was stirred at room temperature for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate) and recrystallized from chloroform/n-hexane to give 0.85 g of the title compound as a yellow crystal.
Reaction SMILES: [K].Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][N:4]=1.ClC1C2C(=CC=C(Cl)C=2)C=C(C)N=1.[C:28]([N:32]1[CH2:36][CH:35]([CH2:37][OH:38])[O:34][CH:33]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:31])([CH3:30])[CH3:29]>C(O)(C)(C)C>[C:28]([N:32]1[CH2:36][CH:35]([CH2:37][O:38][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)[C:6]([CH3:14])=[CH:5][N:4]=2)[O:34][CH:33]1[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Reactant: Cc1cnc(Cl)c2cc(Cl)ccc12
Agent: Cc1cc2ccc(Cl)cc2c(Cl)n1
Agent: [K]
Solvent: CC(C)(C)O
Product: Cc1cnc(OCC2CN(C(C)(C)C)C(c3ccccc3)O2)c2cc(Cl)ccc12

Procedure:
0.74 g of Potassium is dissolved in 15 ml of absolute tert.-butanol and 4.0 g of 1,7-dichloro-4-methylisoquinoline [m.p. 90°-92°: preparable in manner analogous to that described in Helv. Chim. Acta 52 (1969) 1755-1762 for the preparation of 1,7-dichloro-3-methylisoquinoline] and 4.4 g of 3-tert.-butyl-5-hydroxymethyl-2-phenyloxazolidine are added. The solution is heated to 50° for 1 hour, whereupon it is evaporated to dryness. The product is digested in water, extracted with ether, the ether phase dried and the ether distilled off. 1-(3-tert.-Butyl-2-phenyl-5-oxazolidinyl-methoxy)-7-chloro-4-methylisoquinoline is obtained as an oil.
Reaction SMILES: [H-].[Na+].C(NC(C)C)(C)C.[C:10]1([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C([Li])CCC.CCCCCC.[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:10]1([O:20][CH:21]([CH2:45][CH2:44][CH2:43][CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:22]([OH:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCc1ccccc1
Reactant: O=C(O)COc1cccc2ccccc12
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CCCCc1ccccc1)Oc1cccc2ccccc12
Temperature: 50 °C
Yield: 23.6 %

Procedure:
To a mixture of 5 ml of dry tetrahydrofuran and 0.26 g of 50% sodium hydride (suspension in oil) were added 0.7 ml of diisopropylamine and 1.0 g of 1-naphthoxyacetic acid with stirring under an argon atmosphere under ice-cooling. The mixture was heated for 30 minutes at 50° C., and then heated under reflux for 15 minutes. After cooling below 5° C., to the reaction mixture was added dropwise 3.5 ml of n-butyllithium (as a 1.6 mole hexane solution), the mixture was stirred below 10° C. for 20 minutes, and then warmed for 20 minutes at 30° C. After cooling below 5° C. again, 1.00 g of 4-phenylbutyl bromide was added to the reaction mixture. The mixture was stirred for 30 minutes at below 5° C., and then warmed for 1 hour at 30° C. with stirring. After cooling, the reaction mixture was washed with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene) to obtain 0.37 g of (±)-2-(1-naphthoxy)-6-phenylhexanoic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:5]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/S(C)(=O)=O)c(OCCc2cccc(C)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCS(C)(=O)=O)c(OCCc2cccc(C)c2)c1
Yield: 99.5 %

Procedure:
250 mg of 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester were dissolved using 10 ml of methanol and hydrogenated under an 1.5 bar atmosphere of hydrogen using 50 mg of Pd/C (10%, 50% water) for 30 minutes. The catalyst was then removed by filtration and the solution evaporated to yield 250 mg of the title compound that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)=[CH:4][C:3]1=[O:21].[Cl-].[NH4+]>[Zn].CO>[NH2:18][C:14]1[CH:13]=[C:12]([C:5]2[C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[C:3](=[O:21])[CH:4]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cn1c(=O)cc(-c2cccc([N+](=O)[O-])c2)c2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cn1c(=O)cc(-c2cccc(N)c2)c2cccnc21
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Zinc (4.4 g, 67 mmol) was added to a mixture of 1-methyl-4-(3-nitrophenyl)-1,8-naphthyridin-2(1H)-one (0.95 g, 3.4 mmol) obtained in Example 12, methanol (20 ml) and an aqueous solution (20 ml) of ammonium chloride (3.6 g, 67 mmol) under ice-cooling, and the mixture was stirred for 4 hours under ice-cooling and then for 3 hours at room temperature. After removing insoluble matter by filtration, the filtrate was concentrated under reduced pressure, water was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give 4-(3-aminophenyl)-1-methyl-1,8-naphthyridin-2(1H)one (693 mg, 82%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.O[C:45]1[CH:60]=[CH:59][C:48]([C:49]([O:51][CH2:52][CH:53]([CH3:58])[O:54][CH2:55][CH2:56][CH3:57])=[O:50])=[CH:47][CH:46]=1>S(Cl)(Cl)=O.C1COCC1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:45]2[CH:60]=[CH:59][C:48]([C:49]([O:51][CH2:52][CH:53]([CH3:58])[O:54][CH2:55][CH2:56][CH3:57])=[O:50])=[CH:47][CH:46]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CCCOC(C)COC(=O)c1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)OCC(C)OCCC)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
2.9 g of 4-(6-acryloxyhexyloxy)benzoic acid was heat-refluxed for 2 hours in 10 ml of thionyl chloride in the presence of 2,6-di-t-butylphenol, followed by distilling-off of the thionyl chloride. Anhydrous THF and triethylamine were added to the reaction mixture, and a solution of 1.6 g of 2-methyl-2-propyloxyethyl 4-hydroxybenzoate in THF was added dropwise thereto at 0° C., followed by 4 hours of stirring at 50° C. The reaction mixture was subjected to extraction with ethyl acetate and column chromatography to obtain 1.8 g of the product. (Yield: 59 %)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[CH:13]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[C:14]([CH3:18])([CH2:16]Br)[S:15][C@H:11]12)=[O:8].N1C=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])=[C:14]([CH3:16])[CH2:18][S:15][C@H:11]12)=[O:8]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 56.5 %

Procedure:
2,2,2-trichloroethyl 6-[2-(thiophene-2-yl)acetamido]-2-methyl-2-bromomethylpenam-3-carboxylate (0.85 g.) was dissolved in benzene (12 cc), and thereto was added pyridine (0.24 g.). The mixture was refluxed for 2 hours, washed with water, dried and concentrated. Ether was added to the residue and the precipitate was collected by filtration to yield crystals (0.41 g.) of 2,2,2-trichloroethyl 7-[2-(thiophene-2-yl)acetamido]-3-methyl-3-cephem-4-carboxylate, m.p. 151°-152° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][CH:14]=[CH:13][C:12]2=O>>[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[Cl:3]
Reactant: O=c1cc[nH]c2c(Br)cccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2c(Br)cccc12

Procedure:
A suspension of 2-bromoaniline (20.9 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (22.6 g) in 2-propanol (240 ml) was heated to reflux for 1 hour. The reaction solution was cooled to 0° C., and the deposit was then filtrated to obtain a pale yellow solid (35.0 g). A suspension of the obtained pale yellow solid (10.0 g) in Dowtherm (100 ml) was heated at 210° C. for 1 hour. After cooling, hexane (100 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-bromoquinolin-4(1H)-one (6.3 g). Phosphorus oxychloride (5.9 ml) was added to 8-bromoquinolin-4(1H)-one (9 g), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and chloroform was added to the residue. The reaction solution was neutralized with an aqueous sodium hydroxide solution with cooling in an ice bath and partitioned into organic and aqueous layers. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 8-bromo-4-chloroquinoline (8.3 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:39])C(=O)C1>ClC(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16]2[C:17]3[C:24]([Br:39])=[C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)cc23)C1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H](Nc2ncnc3oc(-c4ccccc4)c(Br)c23)C1

Procedure:
Suspend 132 mg (0.312 mmol) of (+/−)-cis-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclo-hexyl}oxy)acetic acid tert-butyl ester in 0.3 ml of tetrachloromethane, add 61 mg (0.343 mmol) of NBS and heat to reflux. On completion of conversion (approx. 1 h), cool the reaction mixture and isolate the product directly by preparative RP-HPLC. 104 mg (66.4% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(=O)O)cc2)c(C)c1
Temperature: 110 °C

Procedure:
A solution of methyl 4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)benzoate (1.2698 g, 3.38 mmol) in tetrahydrofuran (THF) (8 mL) and water (2 mL), was prepared and treated with sodium hydroxide (1.015 mL, 10.15 mmol). The reaction was then heated by microwaves to 110° C., for 30 minutes. After cooling, the solution was neutralised with 2M HCl and concentrated in vacuo. The product was extracted into the organic phase of an aqueous work up between water and ethyl acetate. The organic phase was then separated (hydrophobic frit) and concentrated in vacuo to give the desired product, 1.063 g. LCMS (M+1) 362, RT 1.27 mins.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42]Br>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][CH2:41][O:40][CH3:39])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 46.9 %

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 17 mg, 0.039 mmol) in DMF (1.0 ml) was reacted with K2CO3 (28 mg, 0.20 mmol), 2-bromoethyl methyl ether (18 μl, 0.20 mmol) to yield the title compound (9 mg, 49%).
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[Mg].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl>C1COCC1.O>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH2:4][CH3:5]
Reactant: CCC(C)Br
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.4 %

Procedure:
Add slowly a solution of 2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirring mixture of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. Heat the mixture at reflux for 30 min. Cool the mixture to room temperature and add 4-bromo-benzaldehyde (5.36 g, 29 mmol). After stirring for 5 min, cool the mixture in an ice-bath and acidify with 3N aqueous HCl (50 mL). Dilute the mixture with water and extract twice with diethyl ether. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 20:1 and 1:1) to provide the desired intermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[S:48]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=S)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide (Compound 149) (273 mg, 0.5 mmol) (i.e. the product of Example 6, Step D) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (202 mg, 0.5 mmol) (Lawesson's reagent) in 5 mL of toluene was heated at 100° C. for 3 days. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in 10 mL of dichloromethane and washed with 1 M aqueous solution of potassium carbonate, and dried over magnesium sulfate. The filtered residue was concentrated in vacuo and purified by medium-pressure liquid chromatography on silica gel using 50-100% of ethyl acetate in hexanes as eluant to give 70 mg of the title compound, a compound of the present invention as a white foam.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@H:26]([NH2:29])[CH2:27][OH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@H:26]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][OH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: OC[C@@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-phenyl-2-hydroxyethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): m/e 332.2 (M+1). 1H NMR (500 Mz, CD3OD): δ partial 8.58 (br s, 1H); 8.38 (s, 1H); 7.69 (d, J=7.3 Hz, 1H); 7.47 (d, J=7.3 Hz, 2H); 7.02 (d, J=5.5 Hz, 1H); 5.16 (s, 1H); 3.81-3.91 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@@:12]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]3[CH3:32])=[CH:22][N:21]=2)([C:15]([O:17]CC)=[O:16])[CH2:11][C@@H:10]1[F:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C:12]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[C:30]([CH3:31])=[CH:29][CH:28]=[C:27]3[CH3:32])=[CH:22][N:21]=2)([C:15]([OH:17])=[O:16])[CH2:11][C@@H:10]1[F:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@]1(c2cnc(-n3c(C)ccc3C)cn2)CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)n1-c1cnc(C2(C(=O)O)CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C2)cn1
Temperature: 30 °C
Reaction time: 16 h
Yield: 153.4 %

Procedure:
To a 1 L flask was added (1R,3S,4S)-ethyl 4-((tert-butyldimethylsilyl)oxy)-1-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazin-2-yl)-3-fluorocyclohexanecarboxylate (48 g, 67 mmol), ethanol (250 mL) followed by 11% aqueous NaOH solution (112 g, 300 mmol). The reaction mixture was stirred at 30±5° C. for 16 hours, and then was quenched with 10% aqueous HCl (70 mL) to pH=6˜7. After distillation of ethanol under reduced pressure (50±5° C., 50˜100 mbar), the pH of the resulting mixture was adjusted to between 4 and 5 with 10% HCl. The aqueous solution was extracted twice with IPAc (200 mL×2). The combined organic layers were washed with 10% brine (200 mL) and concentrated under reduced pressure (50±5° C., 50˜100 mbar) to give 46 g of (1RS,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-1-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazin-2-yl)-3-fluorocyclohexanecarboxylic acid which was used for next step without further purifications. HPLC retention time=7.390 min (Instrument: Agilent Technologies 1200 series. Column: Waters Xbridge C18, 150*3.0 mm, 3 um. Column temperature: 35° C. Flow rate: 0.70 mL/min. Detection: 210 nm/DAD. Mobile phase composition: A: 0.1% H3PO4 in water; B: acetonitrile. Gradient: 0 min: 90% A, 10% B; 5 min: 100% B; 11 min 100% B), LC-MS: [M+H]+=448.2415.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (135.0 g, 700 mmol) and K2CO3 (289.8 g, 2100 mmol) in DMF (1.5 L) was stirred at 70° C. for 0.5 h and then 2-bromo-propionic acid ethyl ester (136.3 mL, 1050 mmol) was added to the mixture. The reaction mixture was heated at 80° C. for 2 h then cooled to ambient temperature. The solvent was removed in vacuo and the residue was dissolved in water (600 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was concentrated, washed with brine (3×30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a brown liquid (185.0 g, 90%). 1H NMR (CDCl3, 400 MHz): δ 7.90 (dd, J=2.4 Hz, J=9.2 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 5.27 (q, J=7.2 Hz, 1H), 4.67 (d, J=15.2 Hz, 2H), 4.18 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H).