Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[CH:8])(=[O:4])[CH:2]=[CH2:3].[C:9]1([N:15]=[N+:16]=[N-:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C.O>[C:9]1([N:15]2[CH:8]=[C:7]([CH2:6][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[N:17]=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#CCOC(=O)C=C
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)OCc1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
Propargyl acrylate (13.5 g, moles), phenyl azide (12.5 g, moles) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (0.84 g, 2.3 mmoles) are dissolved in DMF (100 ml) and stirred at room temperature under nitrogen for 24 hours. The reaction mixture is poured in water and the product is extracted with ethyl acetate. The solvent is distilled under reduced pressure, and mixed with diethyl ether wherefrom the product crystallized as an off-white, crystalline solid (23 g; yield 89%; mp 55-56° C.). 1H NMR (CDCl3, δ ppm) 8.08 (s, 1H), 7.72 (d, 2H), 7.51 (t, 2H), 7.44 (q, qH), 6.48 (d, 1H), 6.17 (q, 1H), 5.88 (d, 1H), 5.50 (s, 2H). 13C NMR (CDCl3, δ ppm) 165.9, 143.4, 136.8, 131.5, 129.7, 128.8, 127.8, 122.1, 120.5, 57.5.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[C:31]([F:38])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[Cl-].[Na+].O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:34]5[C:29]([F:28])=[N:30][C:31]([F:38])=[CH:32][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Reactant: OB(O)c1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(F)nc4F)cc3c12
Reaction time: 3 h

Procedure:
A sealed tube was charged with the intermediate from Example 1 Step E (230 mg, 0.52 mmol), (2,6-difluoropyridin-3-yl)boronic acid (580 mg, 3.6 mmol), and bis(triphenylphosphine)palladium(n) chloride (73 mg, 0.1 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed toluene (3.0 mL) and ethanol (3.0 mL) were added, followed by the addition of 2.0M aqueous sodium carbonate solution (2.6 mL, 5.2 mmol). The tube was sealed, placed in an oil bath at 90° C., and stirred for 3 hours. The reaction mixture was then cooled and poured into a mixture of ethyl acetate and brine. The aqueous layer was extracted twice with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo. Purification via flash chromatography (silica, 0-20% methanol/dichloromethane) was followed by purification via preparative chiral HPLC (AD column, 25% ethanol/heptane isocratic) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 11.75 (s, 1H), 10.57 (s, 1H), 8.49 (broad s, 1H), 8.43 (q, 1H), 7.92 (d, 1H), 7.72-7.69 (m, 1H), 7.62-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.37 (dd, 1H), 7.27 (broad s, 1H). Imidazole proton was not observed [M+H]+ 476. τR: 9.44 min (analytical chiral HPLC, AD column, 0.46 cm×25 cm, 25% ethanol/heptane, isocratic, flow rate=0.75 mL/min).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:22][CH2:23][OH:24]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: OCCNCCO
Product: COC(=O)c1cc([N+](=O)[O-])c(N(CCO)CCO)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
A solution of methyl 4-chloro-3,5-dinitrobenzoate (XIV) (10.0 g, 0.036 mol) and diethanolamine (7.66 g, 0.073 mol) in ρ-dioxane (60 mL) was stirred at 50° C. for 5h. Volatiles were removed under reduced pressure, and the residue was adsorbed directly onto silica gel and chromatographed. Elution with EtOAc/petroleum ether (1:10) gave foreruns, and subsequent elution with EtOAc/petroleum ether (3:2) gave methyl 4-[N,N-bis(2-hydroxyethyl)amino]-3,5-dinitrobenzoate (XV: X=OH, Z=OMe) (9.61 g, 80%), mp (CHCl3 /petroleum ether) 101°-103° C. 1H NMR (CDCl3) δ8.52 (s, 2H, ArH-2,6), 3.97 (s, 3 H, COOCH3), 3.76 (dxt, J=6.5, 4.7 Hz, 4H, CH2OH), 3.26 (t, J=4.7 Hz, 4H, NCH2), 2.76 (t, J=6.5 Hz, 2 H, OH). 13C NMR δ163.14 (COOCH3), 145.50 (C-4), 142.54 (C-3,5), 131.19 (C-2,6), 123.59 (C-1), 59.16 (CH2OH)1, 54.58 (CH2N), 53.14 (OCH3). Anal. (Cl12H15N3O8) C,H,N.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[OH:17])=[N:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.Cl[CH:33]([F:35])[F:34]>O>[F:34][CH:33]([F:35])[O:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:18][C:7]=2[N:8]=1
Reactant: FC(F)Cl
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.50 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol, 1.23 g of potassium carbonate and 14 ml of DMF was stirred while heating at 70° C. for three hours with chlorodifluoromethane gas injected. By stopping injection of gas, the mixture was cooled to room temperature and allowed to stand overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 2-(3-difluoromethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 126”).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=O.Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC>[NH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)C(=O)Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A stirred solution of 0.35 g (1.07 mmol) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K2CO3. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg (92%) of 2'-amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. 1H NMR (300 MHz , CDCl3) δ7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C8H4NOClF4 (M+): 240.9918, found: 240.9914. 19F NMR (282 MHz , CDCl3) δ-132.7(s, 1F), -70.6(s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:4](=[O:5])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[S:14][C:15]=2[CH:21]=1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
At 0 to 5° C., 2-chloro-6-fluorobenzoyl chloride (1.93 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), pyridine (30 ml) and 4-dimethylaminopyridine (0.1 g). The reaction mixture was stirred at room temperature (20 to 30° C.) for one day, and then the pyridine was evaporated. Water was added to the residue, and the mixture was stirred. The resulting crystals were collected by filtration, and thoroughly washed with water. Recrystallization from ethanol gave the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2-chloro-6-fluorobenzamide (2.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[OH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[OH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:28][CH:27]=1
Reactant: NCc1ccc(CCO)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(CCO)cc4)cc3)c2)o1

Procedure:
N-[4-(2-Hydroxyethyl)benzyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(2-hydroxyethyl)benzylamine using method H. NMR; δH [2H6]—DMSO 9.11,(1H, t), 7.99,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.56-7.51,(3H, m), 7.24,(2H, d), 7.16,(2H, d), 4.62,(1H, t), 4.46,(2H, d), 3.55,(2H, q), 2.69,(2H, t), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.00 min, MH+ 428.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][CH:3]([CH:2]([CH3:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CC(C)C(Cl)C[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 67.9 %

Procedure:
After dissolving 2.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 15 ml of toluene, 4.1 g of thionyl chloride and two drops of N,N-dimethylformamide were added thereto, and the solution was stirred for 2.5 hours at 80° C. The solution was cooled to room temperature and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane (yield: 72.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=O.[C:23]([CH2:25]P(=O)(OCC)OCC)#[N:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]=[CH:25][C:23]#[N:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=CC#N)c2)c1=O
Reaction time: 20 h

Procedure:
3.3 g of 3-(4-chloro-3-formylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 30 ml of dimethylformamide were added dropwise to a suspension of 1.8 g of diethyl cyanomethylphosphonate and 1.5 g of potassium carbonate in 120 ml of dimethylformamide, and stirring was carried out for 20 hours at room temperature. Thereafter, 150 ml of water were added and the precipitate which had separated out was isolated, washed with water and petroleum ether and dried.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH:13]([N:21]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]([NH:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[Cl:12][CH:13]([N:21]1[CH:24]([S:25]([CH2:26][C:27]#[C:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:9])[CH:23]([NH:36][C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:22]1=[O:56])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#CCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (30mg) in ethanol-free chloroform (3ml) was added in 10 minutes to a stirred solution of 1-(1-chloro-1-t-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylthio)-3-(triphenylmethylamino)azetidin-2-one (99mg) in ethanol-free chloroform (3ml) at 0°C. The mixture was stirred for a further 30 minutes at 0°C. The reaction mixture was diluted with ethanol-free chloroform (10ml) and washed successively with saturated sodium bicarbonate solution (5ml) and brine (2 × 5ml). The dried(MgSO4) organic layer was evaporated to give a gum which upon re-evaporation from dry ether gave 1-(1-chloro-1-tert-butoxycarbonylmethyl)-4-(4-phenylbut-2-ynylsulphinyl)-3-triphenylmethylamino-azetidin-2-one as a solid foam (92mg, 91%)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:6]1([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:2](=[O:3])[O:4][CH3:5])=[CH:21][CH:22]=3)[N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(-c2noc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Nc1ccc(-c2noc(-c3ccccc3)n2)cc1

Procedure:
1.4 g. (0.015 mole) of methyl chloroformate is added to a mixture of 2.4 g. (0.01 mole) of 5-phenyl-3-(4-aminophenyl)-1,2,4-oxadiazole, from part (b), and 2.1 g. of potassium carbonate in 50 cc. of dioxane. The resulting mixture is refluxed for 0.5 hours. It is then concentrated to dryness and the residue is crystallized from benzene to yield [4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]carbamic acid, methyl ester.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:16][C:17]1[N:18]([CH2:25][C@:26]2([CH3:29])[CH2:28][O:27]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1.CN(C=O)C>O>[Cl:16][C:17]1[N:18]([CH2:25][C@@:26]([CH3:29])([OH:27])[CH2:28][N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[N:21]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CC=C(c2ccccc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (0.495 g, 2.53 mmol) was added to a sodium hydroxide solution, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.5 g, 2.29 mmol) and DMF (5 ml) were added followed by stirring at 70° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)propan-2-ol (0.492 g, yield 57%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1csc(-c2ccncc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of the obtained ethyl 2-(4-pyridyl)-4-thiazolecarboxylate (1.5 g) in ethanol (10 ml) was added 1 N sodium hydroxide solution (10 ml), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (10 ml). The precipitate was filtered, washed with water and dried to give the title compound (1.264 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C.C(Cl)Cl>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a solution of 2.03 g (11.6 mmol) of 4-chloro-2-fluoro-nitrobenzene in DMF (12.0 mL) at rt was added 2.00 g (11.6 mmol) of ethyl 4-amino-1-piperidinecarboxylate. A yellow precipitate formed within 30 min and the reaction was further diluted with DMF (12.0 mL) and CH2Cl2 (5.0 mL) and was shaken at 300 RPM overnight. The solvent was removed under reduced pressure and the resulting solid was dried under vacuum. The crude product was purified by flash chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 2.83 g (81%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): m/z calculated for C14H18ClN3O4 [M++Na] 350.09, observed 350.0. 1H NMR (400 MHz, CDCl3): 8.13 (apparent d, J=9.1 Hz, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.62 (dd, J=9.4, 2.3 Hz, 1H), 4.15 (q, J=14.9, 7.3 Hz, 2H), 4.08 (br d, J=12.4 Hz, 2H), 3.70-3.58 (m, 1H), 3.17-3.05 (m, 2H), 2.07 (br dd, J=13.1, 3.1 Hz, 2H), 1.63-1.50 (m, 2H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([C:39]([F:50])([F:49])[CH2:40]OS(C(F)(F)F)(=O)=O)[CH:36]=[CH:37][CH:38]=1>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:40][C:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=3)([F:49])[F:50])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: O=S(=O)(OCC(F)(F)c1cccc(Cl)c1)C(F)(F)F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCC(F)(F)c3cccc(Cl)c3)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 5.8 %

Procedure:
To a mixture of 230 mg (0.67 mmol) of 2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester and 227 mg (1.62 mmol) of potassium carbonate in 6 ml of acetone and 1.7 ml of DMF was added slowly a solution of 437 mg (1.65 mmol) of the compound of step 2. The reaction mixture was stirred for 3 d at room temperature and then evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 20 mg of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:22](OC(OC(OC(C)(C)C)=O)=O)(C)([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[CH3:1][C@@H:2]1[O:3][C:4]2[CH:12]=[C:11]3[C:10](=[CH:9][C:5]=2[NH:6][C:7]1=[O:8])[C@H:13]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:24][CH2:22][CH2:23]3
Reactant: C[C@H]1Oc2ccc(CNCCCC(F)(F)F)cc2NC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1Oc2cc3c(cc2NC1=O)[C@H](NCCCC(F)(F)F)CCC3
Yield: 105.5 %

Procedure:
608 mg (2.014 mmol) of (2R)-methyl-3-oxo-6-(4,4,4-trifluorobutylamino-methyl)-3,4-dihydro-2H-1,4-benzoxazine is stirred with 439.9 mg (2.014 mmol) of di-tert-butyldicarbonate and 303 mg (2.995 mmol) of triethylamine in 15 ml of dichloromethane for four hours at room temperature. The batch is spun in until a dry state is reached, and the residue is put on a column on silica gel (mobile solvent: ethyl acetate/hexane). 727.6 mg (99%) of the desired compound is isolated.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](Cl)=[O:26])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2].[N+:29](=[CH2:31])=[N-:30]>C(OCC)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[C:18]([C:25](=[O:26])[CH:31]=[N+:29]=[N-:30])[N:17]=[CH:16]2)[C@@H:6]1[F:28])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)Cl)c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Solvent: CCOCC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@H](F)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
The reaction solution containing compound (19) was then added to a 0.2M diazomethane solution (20 ml) in diethylether and the mixture so obtained was allowed to react at room temperature for 1 hour. The resulting reaction solution was filtered and the filtrate was concentrated to give the titled compound (20) (55 mg) as a syrup.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:12][CH2:13][C:14](O)=O>>[Cl:12][CH2:13][C:14]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: O=C(O)CCl
Reactant: CC(C)Nc1ccccc1N
Product: CC(C)n1c(CCl)nc2ccccc21
Yield: 38 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-isopropylbenzene-1,2-diamine (3.88 g, 25.82 mmol)-1) and 2-chloroacetic acid (3.70 g, 39 mmol). The crude residue was purified over silicagel chromatography (prepacked 85 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 2.05 g of 2-(chloromethyl)-1-isopropyl-1H-benzo[d]imidazole (Yield: 38%) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-])=O)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:10]1[C:11]([F:13])=[CH:12][C:2]([Cl:1])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(N)c(F)cc1Cl
Temperature: 40 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Then, 60 g of iron powder and 500 ml of 10% acetic acid were mixed, and the mixture was heated to 40° C. Separately, 50 g (0.20 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate was dissolved in a mixed solution of 20 ml of acetic acid and 20 ml of ethyl acetate, and added dropwise to the above iron powder-acetic acid mixed solution. Then, the reaction mixture was stirred at 50° C. for 1 hour and filtered though celite. The filtrate was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution and saturated sodium chloride solution, and dried with magnesium sulfate. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded to 40 g (0.18 mol) of ethyl 5-amino-2-chloro-4-fluorobenzoate.