Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>C(OCC)C.O>[Cl:14][C:15]1[N:20]=[C:19]([N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: O=C1OCCC1CNC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C1OCCC1CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 1.67 g (0.009 mole) of 3-cyclopentylaminomethyl-dihydro-furan-2-one in 25 mL of ethyl ether was added 15 mL of ice-water followed by 1.68 g (0.0087 mole) of 2,4-dichloro-5-nitro-pyrimidine. A solution of 1.36 g (0.014 mole) of potassium bicarbonate in 5 mL of water was added over 20 minutes. The mixture was stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure to remove the ethyl ether and the mixture then filtered, washing with water and then water-acetonitrile. The solid was purified by recrystallization from hexanes-ethyl acetate (1:1) to give 2.2 g of (rac)-3-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-dihydro-furan-2-one (IV-49).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17]O)=[C:4]([S:8][CH2:9][C:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.O=S(Cl)[Cl:21].ClC1C=NC=C(Cl)C=1CCl>>[Cl:1][C:2]1[C:3]([CH2:17][Cl:21])=[C:4]([S:8][CH2:9][C:10]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)N(C)C(=O)CSc1cncc(Cl)c1CO
Agent: ClCc1c(Cl)cncc1Cl
Product: CC(C)N(C)C(=O)CSc1cncc(Cl)c1CCl

Procedure:
2-(5-Chloro-4-hydroxymethyl-pyridin-3-ylsulfanyl)-N-isopropyl-N-methyl-acetamide (7.5 mg, 0.026 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine to give the title compound. MS (m/z): 307.0 [M+H+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.[C:31](O)(=[O:34])[CH2:32][OH:33]>>[OH:34][CH2:31][C:32]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:27])[F:28])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:5][CH2:6]1)=[O:33]
Reactant: O=C(O)CO
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Product: O=C(CO)N1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1

Procedure:
Following the procedure for 116, 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with glycolic acid to give 151 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.21 (s, 1H); 7.73 (d, J=2.16 Hz, 1H); 7.29 (dd, J=8.37, 2.17 Hz, 1H); 7.21 (d, J=8.32 Hz, 1H); 6.97 (s, 1H); 5.72 (q, J=8.78 Hz, 2H); 4.55-4.43 (m, 4H); 4.13-4.05 (m, 2H); 3.79 (d, J=13.44 Hz, 1H); 3.23-3.15 (m, 3H); 3.09 (t, J=12.91 Hz, 1H); 2.91-2.82 (m, 1H); 2.77-2.65 (m, 1H); 1.86 (d, J=12.87 Hz, 2H). LCMS: RT=9.76 min, M+H+=477
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10]Br.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][N:14]1[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]1[CH3:12]
Reactant: N#Cc1ccc(Br)c(CBr)c1
Reactant: C[C@H]1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1Cc1cc(C#N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-(bromomethyl)benzonitrile (0.9 g, 3.27 mmol) in DMF (13.09 ml) was added (S)-3-methylmorpholine (0.541 g, 3.93 mmol) and potassium carbonate (0.995 g, 7.20 mmol). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was poured onto water and extracted with EtOAc (×2). The organic extractions were combined, washed with brine (×3), dried (MgSO4) and evaporated to give the sub-title compound as a yellow oil. Yield: 0.75 g
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[CH2:20][CH2:21][C:22](=[O:23])[C:12]1=2>C(Cl)Cl>[Cl:5][CH2:6][C:7]([C:16]1[CH:17]=[CH:18][C:19]2[N:11]([CH3:10])[C:12]3[C:22](=[O:23])[CH2:21][CH2:20][C:13]=3[C:14]=2[CH:15]=1)=[O:8]
Reactant: Cn1c2c(c3ccccc31)CCC2=O
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c2c(c3cc(C(=O)CCl)ccc31)CCC2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
Aluminum chloride (8.5g) was suspended in CH2Cl2 (20 ml) at 0° C., chloroacetyl chloride (7.2 g) was slowly added and the mixture was stirred for 5 minutes. This mixture was added dropwise to a stirred solution of 1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (6.0 g) in 100 ml CH2Cl2 at 0° C. The mixture was stirred at 0° C. for 45 minutes and thereafter an additional equivalent of preformed solution of aluminum chloride and chloroacetyl chloride in methylene chloride was introduced in a dropwise manner. After 30 minutes the reaction mixture was slowly poured into a stirred ice/water mixture. The layers were separated and the CH2Cl2 layer was washed with NaHCO3, dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography on silica gel eluting with hexane/acetone provided 7-chloroacetyl-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (4.5 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 95 °C
Yield: 11.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine(0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 10 mg (11 %) of the title compound as an orange crystalline solid.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].[NH2:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1)=[O:4]
Reactant: NCCC1OCCO1
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCC1OCCO1)C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 69.63 g of 2-chloro-3-(phenylmethoxy)propanoyl chloride (prepared according to the procedure described in Inorg. Chem., 31. 2422, 1992) (0.299 mol) in 90 ml of CHCl3 was added to a solution of 35.49 g of 2-(2-aminoethyl)-1,3-dioxolane (prepared according to the procedure described in EXAMPLE 4) (0.303 mol) and to 60.3 g of triethylamine (83 ml; 0.596 mol) in 100 ml of CHCl3 under inert atmosphere, keeping the temperature at 0°-5° C. The reaction mixture was stirred for 5 h at 25° C., then was washed with H2O. The organic phase was dried and evaporated to dryness, the residue was purified by flash chromatography. 61.68 g of the desired product (0.197 mol) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:26](O)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][N:17]=2)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Reactant: O=C(O)c1nccc2ccccc12
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2nccc3ccccc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with isoquinoline-1-carboxylic acid. LC-MS (acidic): tR=1.04 min; [M+H]+=368.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[S:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[S:31]>C(O)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[C:35]2[S:29][C:30](=[S:31])[NH:32][C:33]2=[O:34])=[CH:22][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2Cc2ccccc2)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2Cc2ccccc2)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(2-benzylphenyl)methoxy]benzaldehyde (4.5 g, 14.9 mmol), sodium acetate (4.27 g, 52 mmol), and rhodanine (1.98 g, 14.9 mmol) were dissolved in 75 ml of acetic acid. The reaction solution was then heated to reflux and maintained at this temperature for about three days.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(F)c1F)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(F)c1F

Procedure:
Tert-butyl 2-(2,3-difluoro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(2,3-difluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: -10 °C
Yield: 56.9 %

Procedure:
2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g) dissolved in methylene chloride (15 ml). To this solution was added aniline (0.28 g) under cooling at -10° C. and then silver fluoroborate (0.43 g), after which the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was washed with a dilute phosphoric acid aqueous solution and then with water, dried over magnesium sulfate, after which the solvent was distilled off. The residue was subjected to column chromatography on silica gel (20 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml. The second to seventh fractions were collected and the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.64 g), mp 148° to 149° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
1H-Benzimidazole (300 mg) was dissolved in N,N-dimethylformamide (6 ml), added with sodium hydride (60%, in oil, 122 mg) and stirred at room temperature for 1 hour. Subsequently, the reaction mixture was added with 1-(tert-butoxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine (1.08 g) and further stirred at room temperature for 23 hours and at 60° C. for 2 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 192 mg of the title compound. Yield: 25%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36][S-:37].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](=[O:15])[S:37][CH3:36])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1
Reactant: C[S-]
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CSC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Yield: 9.4 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.066 mmol) was treated with thionylchloride (1.5 mL) and stirred at reflux for 2 h. The mixture was concentrated under reduced pressure. The intermediate was treated with benzene (3×) and the benzene was evaporated to remove water. Then, the obtained mixture was dissolved in benzene (1.5 mL) and sodium methanethiolate (32.5 mg, 0.46 mmol) was added. The reaction mixture was stirred at reflux for 5 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example B-68) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%). Result of LC/MS MH+: 482.76; 1H NMR (CDCl3): 2.33 (t, 3H), 7.19 (t, 1H), 7.33-7.55 (m, 6H), 8.23 (s, 1H)
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>C(#N)CC.ClCCl>[Cl:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[N:21]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Solvent: ClCCl
Solvent: CCC#N
Product: COC(=O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Yield: 48.3 %

Procedure:
Methyl 4-chloro-3-oxobutanoate (4.32 ml, 37.44 mmol, 2 eq) is added to a solution of 4-(3-chloropropoxy)benzamide (4 g, 18.72 mmol, 1 eq) in propionitrile (50 ml). The mixture is heated at reflux for 48 h. The mixture is then diluted with dichloromethane and filtered. The solvent is removed under vacuum and the residue is purified on silica gel (eluent: ethyl acetate) to give 2.8 g methyl {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetate ax62 as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]2[CH2:34][CH2:33][CH2:32][C@H:27]2[C:28]([O:30][CH3:31])=[O:29])=[C:20]([F:35])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=[CH:36][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:25][N:26]2[CH2:34][CH2:33][CH2:32][C@H:27]2[C:28]([O:30][CH3:31])=[O:29])=[C:20]([F:35])[CH:19]=1
Reactant: COC(=O)[C@@H]1CCCN1SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
A solution of 2,6-difluorobenzoylisocyanate (2.8 g) in a 1:1 mixture of toluene and petroleum ether (10 ml) was added at room temperature over 30 minutes to a stirred solution of the compound of Example 4 (6.5 g) in the same solvent (20 ml). After stirring at room temperature for 3 hours, the solvent was stripped and the residue purified by chromatography over silica using dichloromethane as eluant, to give 5.5 g of the desired product, melting point 65°-68° C.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH:28]=[CH:27][N:26]=[CH:25]1.O>CN(C=O)C>[N:24]1([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cn2ccnc2)cc1)c1ccccc1
Yield: 90 %

Procedure:
Prepared from 3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone and 1.5 equivalents of 4-(imidazol-1-yl)methyl-aniline (melting point: 128-130° C.) in DMF (120° C., 1 hour), pouring into water and washing the precipitate with MeOH and ether. Yield: 90% of theory;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1cc(C=O)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C2N=C(c3cccs3)OC2=O)ccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of N-(2-thienylcarbonyl)glycine (454 mg, 2.45 mmol), 2-methoxy-4-pyridinecarboxaldehyde (370 mg, 2.7 mmol), sodium acetate (201 mg, 2.45 mmol) and acetic anhydride (3.0 mL) was stirred at 90° C. for 3 hours in a sealed tube. Thereafter, the temperature of the reaction solution was returned to room temperature, and water (15 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1 hour. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (50 mL) and was then dried under reduced pressure, so as to obtain 572 mg of the above-captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:19][OH:20])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29]>ClCCl>[CH:28]([NH:31][C:32](=[O:18])[OH:33])([CH3:30])[CH3:29].[CH:28]([NH:31][C:32](=[O:18])[OH:33])([CH3:30])[CH3:29].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[C:14](=[C:15]([CH2:19][OH:20])[C:16]=2[CH2:17][OH:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N=C=O
Agent: OCc1c(CO)c(-c2ccc(Cl)c(Cl)c2)n2c1CCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)O

Procedure:
A solution of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine (6.244 g, 0.02 mol) and triethylamine (0.5 mL) in dichloromethane (45 mL) was treated with isopropyl isocyanate (7 mL, ca. 10 equiv) and refluxed for 1.5 h. The mixture was concentrated to dryness in vacuo and the off-white residue was crystallized from ethyl acetate-isopropyl ether to give about an 81% yield of 2,3-dihydro-5-(3',4'-dichlorophenyl)-6,7-bis(hydroxymethyl)-1H-pyrrolizine Bis(isopropylcarbamate).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17].Cl>CC(OC)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CSc1ccc(C(C)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Product: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of ethyl trifluoroacetate (7.95 ml, 1.1 eq) in MTBE (125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml, 1.2 eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was added portionwise and the mixture stirred at ambient temperature overnight. 2N Hydrochloric acid (40 ml) was added cautiously and the organic phase separated, washed with brine and dried (Na2SO4) to give an orange solid. The orange solid was recrystallised from hot isopropanol to give the title compound as a yellow crystalline solid (11.25 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C:20]([C:22]2[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=2)=O)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=1[Cl:8].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCOCC1.CCOC(C)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:1][C:2]3[C:3]([N:19]=2)=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]=3[Cl:8])[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)cc(Cl)c3[nH]2)on1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (36.2 mg, 0.0825 mmol, prepared as described in STEP B above) in 1,4-dioxane (10 mL) was treated with (+)-10-camphorsulfonic acid (38.3 mg, 0.165 mmol), and the mixture was heated to 100° C. for 5 h. The cooled mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (20 mL). The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was purified on an 8-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-7-chloro-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 7.77 (d, J=7.8 Hz, 1H), 7.58-7.64 (m, 1H), 7.50-7.58 (m, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 1.88 (br. s., 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C20H16N4OClF3: 421.1 (M+H). Measured: 421.1.