Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[C:3]([CH:10]=[CH2:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1ncc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ncc(Cl)cc1Cl
Yield: 84 %

Procedure:
20.06 g of 3,5-dichloro-2-fluoropyridine (0.110 mol), 30.46 ml of tributyl-vinyl-stannane (0.103 mol), 6.00 g (0.00518 mol) of Pd(PPh3)4 are refluxed in 400 ml of toluene for five hours. The reaction mixture is washed thrice with a saturated aqueous solution of potassium fluoride 200 ml), once with water (300 ml), once with brine (300 ml). The combined aqueous phases are extracted with 100 ml of toluene. After separation, the combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 15.05 g of 3,5-dichloro-2-vinylpyridine (62%) with 75% purity.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Cl[C:31]1[CH:36]=[N:35][CH:34]=[C:33]([Cl:37])[N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[N:35][CH:34]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(Cl)n3)c(=O)c2)cc1

Procedure:
4-{3-[1-(6-chloro-pyrazin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,6-dichloropyrazine for the iodobenzene in Step 3.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([CH2:13][O:14][CH3:15])=[N:9][O:10][C:11]=1[CH3:12].C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1.O>[CH3:15][O:14][CH2:13][C:8]1[C:7]([B:20]([OH:21])[OH:19])=[C:11]([CH3:12])[O:10][N:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCc1noc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCc1noc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 15 h
Yield: 26 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 2.20 mmol) was added dropwise to 4-bromo-3-methoxymethyl-5-methyl isoxazole (412 mg, 2.00 mmol) in THF (8 mL) at −78° C. under nitrogen. After stirring at −78° C. for 30 min triisopropylborate (564 mg, 3.00 mmol) was added dropwise. The temperature was maintained at −78° C. for 2 h then the reaction was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was poured into a mixture of 1N hydrochloric acid and water (1:1, 100 mL) and stirred rapidly for 1 h. The organic layer was separated and the aqueous layer was extracted with ether (3×25 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with hexanes (30 mL) then dried under high vacuum to provide 89 mg (29% yield) of 3-methoxymethyl-5-methyl isoxazole-4-boronic acid as a waxy tan solid which was immediately carried forward to the next reaction: 1H NMR (300 MHz, CDCl3) δ ppm 4.74 (s, 2H), 3.37 (s, 3H), 2.74 (s, 3H), 2.60 (s, 2H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].C1(C)C=CC=CC=1.[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH2:20]([O:27][C:28]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[N+:3]([O-:5])=[O:4])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCc1ccccc1
Reaction time: 0.17 h

Procedure:
1.89 g of sodium hydride (60% content) was suspended in 23.76 g of tetrahydrofuran and cooled with ice. To the obtained suspension, 23.1 g of a tetrahydrofuran solution containing 3.00 g of 2-nitroaniline was dropwise added over 1 hr, stirred for 10 minutes, allowed to stand at room temperature and stirred for 30 minutes. To the obtained mixture, 11.12 g of a 33% toluene solution containing benzyloxycarbonyl chloride was added dropwise over 1 hr at room temperature and stirred for 2 hours. To the reaction mixture, water was added at room temperature and extracted, and separated. The obtained organic layer was washed with water and analyzed by high performance liquid chromatography to find the yield of the desired product was 90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][C:6]=2[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>C(O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:7][C:6]=2[C:17]=1[O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Brc1ccc2c(c1Oc1ccccc1)N=C(c1ccccc1)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Brc1ccc2c(c1Oc1ccccc1)NC(c1ccccc1)CO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A suspension of 6-bromo-5-phenoxy-3-phenyl-2H-1,4-benzoxazine (0.0692 g, 0.182 mmol) in ethanol (1.20 mL) and water (0.240 mL) was treated with sodium tetrahydroborate (13.8 mg, 0.364 mmol) and stirred at 90° C. for 2 h. The reaction mixture was diluted with water and ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (67.3 mg, 97%) as a colorless oil. LCMS calculated for C20H17BrNO2 (M+H)+: m/z=382.0, 384.0. found: 382.0, 384.0.
Reaction SMILES: C1[CH:6]=[C:5]([S:7][S:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)N=CC=1.[ClH:15].SCC[NH2:19]>CO>[ClH:15].[N:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:8][S:7][CH2:5][CH2:6][NH2:19]
Reactant: NCCS
Reactant: c1ccc(SSc2ccccn2)nc1
Agent: Cl
Solvent: CO
Product: NCCSSc1ccccn1
Yield: 84.3 %

Procedure:
2,2′-dipyridyldisulfide (13.2 g) was dissolved in 100 ml of methanol. Under vigorously stirring, 3.4 g of 2-mercaptoethylamine hydrochloride in 30 ml of methanol was added dropwise thereto. The reaction mixture was stirred for 1 hour and 40 minutes and the solvent was distilled off. Ethyl acetate was added to the resulting residue for crystallization and crystals were collected by filtration. Crude crystals thus obtained were recrystallized from methanol-ether. The mother liquor was concentrated and crystallized again from ether to obtain 5.62 g of S-(2-pyridylthio)-2-mercaptoethylamine hydrochloride (hereinafter referred to as Compound (2)) (yield 84%). The chemical formula of Compound (2) is shown below.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(NS(C)(=O)=O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(NS(C)(=O)=O)c1
Temperature: 80 °C
Yield: 23 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (117 mg, 0.38 mmol), 4-amino-6-chloro-N-(3-methoxy-5-(methylsulfonamido)phenyl)pyrimidine-5-carboxamide (266 mg, 65% purity, 0.46 mmol), DIEA (404 μl, 2.32 mmol) and cesium fluoride (175 mg, 1.14 mmol) were suspended in tert-butanol (12 ml) and the mixture was heated at 80° C. in a sealed tube for 3 days. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 54 mg (23% yield) as a solid. Purity 97%.
Reaction SMILES: [CH2:1](/[C:4](=[CH:8]\[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])/[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[H+].[B-](F)(F)(F)F.F[B-](F)(F)F>C(Cl)Cl>[N:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([S:9]([CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:7])=[O:6])(=[O:11])=[O:10])=[CH:17][CH:16]=2)=[O:19])=[CH:21][CH:22]=1
Reactant: CCC/C(=C\S(=O)(=O)c1ccc(C(=O)c2ccncc2)cc1)C(=O)O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: CCCC(CS(=O)(=O)c1ccc(C(=O)c2ccncc2)cc1)C(=O)O
Reaction time: 16 h
Yield: 83 %

Procedure:
(E)-2-Propyl-3-[4-(pyridine-4-carbonyl)benzenesulfonyl]acrylic acid was converted into its HBF4 salt on treatment with 1 equivalent of HBF4 in DCM and evaporation to dryness. (E)-2-Propyl-3-[4-(pyridine-4-carbonyl)benzenesulfonyl]-acrylic acid hydrofluoroborate (0.22 g, 0.49 mmol) and [(R,R)-MeDuPHOS Rh (COD)]BF4 (6 mg, 0.49×10−2 mmol) were place in the pressure vessel under nitrogen, and then the bomb was degassed with hydrogen. Degassed methanol (10 ml) was added and the mixture was hydrogenated at 2070 kPa (300 psi) hydrogen for 16 hour at room temperature. The methanol was removed under reduced pressure. The product was treated with aqueous sodium bicarbonate and then citric acid was added until pH 4. The product was extracted into dichloromethane, which was dried over magnesium sulfate and then evaporated to give the title compound (0.15 g, 83% yield). E.e. was determined by chiral HPLC to be 96% e.e.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=[O:18])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:17]([C:14]1[C:15]([O:16][C:27](=[O:29])[CH3:28])=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[S:12][CH:13]=1)(=[O:18])[CH3:19]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C(C)=O)csc1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 2-(4-tert-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (137 mg, 0.5 mmol) in THF (2 mL) were added triethylamine (105 μL, 0.75 mmol) and acetyl chloride (53.3 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 0.5 h. After removing solvent, the residue was diluted with AcOEt, washed with a saturated aqueous NH4Cl solution, dried over MgSO4 and concentrated to give product as a brown oil (146 mg, yield 92%).
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[C:4](=[O:8])[O:3][C:2]2=[O:9].C(N(CC)CC)C.[CH3:17][OH:18]>>[CH3:17][O:18][C:4]([CH:5]1[CH2:6][CH2:7][CH:1]1[C:2]([OH:9])=[O:3])=[O:8]
Reactant: O=C1OC(=O)C2CCC12
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of 3-oxabicyclo[3.2.0]heptane-2,4-dione (1 g), triethylamine (1.36 ml) and MeOH (20 ml) was stirred at room temperature over weekend. The mixture was quenched with 1 M HCl, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo to give the title compound (1.18 g) as a colorless oil.
Reaction SMILES: C1(C2ON=C(C(O)=O)C=2)C=CC=CC=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.C(OC(=O)CN)C.C([O:56][C:57](=[O:73])[CH2:58][NH:59][C:60]([C:62]1[CH:66]=[C:65]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:64][N:63]=1)=[O:61])C.O[Li].O>CN(C=O)C.O.C1COCC1.CO>[C:67]1([C:65]2[O:64][N:63]=[C:62]([C:60]([NH:59][CH2:58][C:57]([OH:73])=[O:56])=[O:61])[CH:66]=2)[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(=O)CN
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a stirred solution of 5-phenyl-isoxazole-3-carboxylic acid (1 g, 0.00529 mol) in DMF (5 mL) was added DIPEA (2.73 g, 0.0211 mol), HOBt (0.89 g, 0.006078 mol) and EDCI.HCl (1.266 g, 0.00661 mol) at ambient temperature. After 2 minutes glycine ethyl ester hydrochloride (0.811 g, 0.00581 mol) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the resulting precipitate was isolated by filtration and dried to afford 0.744 g (56%) of 5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid ethyl ester. LCMS: 275.1 (M+1)+, 94%. To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid ethyl ester (0.74 g, 0.00270 mol) in a mixture of THF (5 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.34 g, 0.00809 mol) and the resulting mixture was stirred at ambient temperature for 1 hour. Volatiles were then evaporated and the resulting residue was diluted with water and acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 0.57 g (76%) of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid. LCMS: 247.06 (M+1)+, 98.18%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].CC1N=C(C2C=N[C:30]([C:33](F)([F:35])[F:34])=[CH:31]C=2)SC=1CO.BrC(F)(F)C=C.[In]>CN(C)C=O>[F:34][C:33]([F:35])([CH:30]=[CH2:31])[CH:7]([C:6]1[S:5][C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)=[N:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1C=O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)nc2)sc1CO
Agent: C=CC(F)(F)Br
Agent: [In]
Solvent: CN(C)C=O
Product: C=CC(F)(F)C(O)c1sc(-c2ccc(C(F)(F)F)nc2)nc1C
Reaction time: 3 h

Procedure:
To a solution of 5.0 g 4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carbaldehyde (derived from [4-Methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol according to the method described for 4-Methyl-2-(trans-1,4-trifluoromethyl-cyclohexyl)-thiazole-5-carbaldehyde) and 4.33 g 3-bromo-3,3-difluorpropene in 25 ml dimethylformamide. 2.11 g Indium were added and the resulting suspension was stirred in an ultrasonic bath for three hours. Then 20 ml 1N HCL were added and the mixture stirred at room temperature for thirty minutes. The mixture was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 4.67 g 2,2-Difluoro-1-[4-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-but-3-en-1-ol as a colorless lyophilisate.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=O)[CH2:16][CH2:15]1>C(Cl)Cl>[C:1]([N:5]=[N:6][C:14]1[CH2:20][CH2:19][CH2:17][CH2:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N=NC1=CCCCC1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 11 g. (0.125 m.) tert.-butylhydrazine in 80 ml. of methylene chloride containing 2 g. anhydrous sodium sulfate, was added 6.8 g. (0.052 m.) alpha-chlorocyclohexanone. The addition was carried out dropwise and the reaction temperature was maintained at 20° C.±5° by an ice bath. The solution immediately turned yellow, but the reaction was stirred for an additional 1 hour after the addition was complete before filtering it. The filtered methylene chloride solution was washed with 100 ml. water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off. A viscous, gelatinous liquid remained. The material was cooled in the freezer and then filtered. A white solid, 0.1 g., remained on the filter. The filtrate weighed 8.4 g. (97% yield) and its infra-red spectrum was consistent with the proposed structure. It showed the absence of N-H and carbonyl bands and the presence of a carbon-carbon double bond (1650 cm-1) and a conjugated azo bond (1510 cm-1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C(Cl)(=O)OCC.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:25][CH2:24]2)=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)O)N1
Reactant: NC1CCN(CCc2ccccc2)CC1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COc2c(cc(Cl)cc2C(=O)NC2CCN(CCc3ccccc3)CC2)N1

Procedure:
A solution of 4.56 g of 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 100 ml of tetrahydrofuran and 10 ml of dimethylformamide is cooled to below 0° C. and 2.2 ml of triethylamine is added under stirring thereto. Further, 2.3 g of ethyl chlorocarbonate is added and the mixture is stirred at a temperature below 5° C. for an hour. To the resultant mixture is added 4.2 g of 4-amino-1-(2-phenylethyl)piperidine and the mixture stirred for 4 hours. After completion of the reaction, aqueous sodium hydrogen carbonate and ethyl acetate are added. The organic layer is separated, washed with water and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ethyl acetate-ethanol to give 6-chloro-3,4-dihydro-3-oxo-N-[1-(2-phenylethyl)-4-piperidyl]-2H-1,4-benzoxazine-8-carboxamide, melting at 233°-235° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8](CC1C=CC(C(OC)=O)=CC=1)[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34]>>[CH3:4][C:2]([O:5][C:6]([N:8]([CH2:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #54, replacing Methyl 4-(Bromomethyl)Benzoate with Methyl 3-(Bromomethyl)Benzoate
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:14]=[CH:13][N:12]=1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(OC2CCCCC2)ccn1
Yield: 88.9 %

Procedure:
Using the method of Example 3, Step A, cyclohexanol (948 mg, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(cyclohexyloxy)pyridine (1.78 g, 89% yield) as an oil. 1H NMR (CDCl3) δ 8.15 (d; 1H), 6.80 (s, 1H), 6.71 (d, 1H), 4.32 (m, 1H), 1.94-1.99 (m, 2H), 1.79-1.85 (m, 2H), 1.26-1-62 (m, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[C:9]([CH3:11])=O>O.C(O)C>[CH3:15][CH2:14][O:13][C:8]([C:9]1([CH3:11])[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)=[O:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCOC(=O)C(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Under an argon atmosphere, L-cysteine (10 g) was dissolved in pure water (150 ml), and ethyl pyruvate (19.7 ml) dissolved in ethanol (10 ml) at room temperature was gradually added to the solution. The mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The obtained solid was dissolved in pure water, and the solution was extracted with chloroform. The extract was dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The oil was recrystallized from chloroform/hexane to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (diastereomer mixture) (12.7 g, yield 70%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([OH:22])[C:6]=1[CH:23]=O)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[C:1]([C:5]1[C:6]([CH2:23][NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:7]([OH:22])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c(O)c1C=O
Product: CC(C)(C)NCc1c(C(C)(C)C)cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c1O

Procedure:
Using the procedure described in Step B of Example 8 above, the product of Step A and tert-butylamine were converted to the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][C@H:12](O)[CH3:13].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[C:3]([CH2:11][C@H:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:13])[C:4]=1[F:10]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)Cc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Cc1c(F)c(F)cc(F)c1F)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A solution of (2R)-1-(2,3,5,6-tetrafluorophenyl)-propan-2-ol (E-1) (1.9 g, 9.13 mmol) and Et3N (0.85 mL, 10.95 mmol) in 40 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (0.85 mL, 10.95 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (10 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4 and concentrated, and crystallized with DCM/hexane to give white solid (2.58 g, 99%). MS (ESI) m/z 309.0 [M+Na]+, 1H NMR (CDCl3, 500 MHz) δ 7.02 (m, 1H), 5.04 (m, 1H), 3.14˜3.07 (m, 2H), 2.90 (s, 3H), 1.49 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[CH:17]1([NH:23][CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[CH:17]1([N:23]([CH3:24])[C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Reactant: CNC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(c1ccc2c(n1)CC1CCCCC1C2=O)C1CCCCC1
Yield: 52 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 1.23 mmol) and cyclohexyl(methyl)amine (1.39 g, 12.3 mmol) was stirred at 110° C. for 9.5 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.2 g, 52%) as a colorless oil.