Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCBr
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(F)cc1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To 2-chloro-4-fluorophenol (52, 2.40 mL, 0.0213 mol) in N,N-dimethylformamide (30.0 mL), 1-bromo-2-methoxy-ethane (2.00 mL, 0.0213 mol) and potassium carbonate (3.00 g, 0.0217 mol) were added under an atmosphere of nitrogen. The reaction was stirred at 80° C. for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (122, 1.50 g, 34.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]([CH2:24][C:25]3([C:28]([F:31])([F:30])[F:29])[CH2:27][CH2:26]3)[CH2:22][NH2:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([C:18]1[CH:19]=[N:20][C:15]([CH:12]2[CH2:13][CH2:14]2)=[CH:16][CH:17]=1)[CH2:24][C:25]1([C:28]([F:29])([F:30])[F:31])[CH2:27][CH2:26]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=457.1, tR (minutes, Method G)=1.96
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][CH:6]=[C:7]([CH:8]=[O:9])[C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[CH:22][CH:21]=1)#[N:18]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)ccc(C=O)c1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(C=O)c1F

Procedure:
According to general procedure B (RS)-(2,6-difluoro-3-formyl-phenyl)-ethoxy-acetic acid was reacted with 4-aminomethyl benzonitrile to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-3-formyl-phenyl)-2-ethoxy-acetamide. Amorphous off-white solid. MS 359.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccnc(-c2cc(C=O)ccn2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccnc(-c2cc(C(=O)O)ccn2)c1
Reaction time: 8 h
Yield: 77 %

Procedure:
A suspension of 4′-methyl-2,2′-bipyridine-4-carboxaldehyde (3.5 g, 15 mmol) in 95% EtOH (150 ml) was added a solution of AgNO3 (3.15 g) in water (32 ml). The suspension was stirred rapidly and 1M NaOH (79 ml) solution was added dropwise over 20 min to form Ag2O. The dark black solution was stirred for an additional 15 hrs. EtOH was removed by rotary evaporator and filtred to remove Ag2O and unreacted metallic Ag. The residue was washed with 1.3M NaOH (2*20 ml) and H2O 20 ml. The combined basic filterate was extracted with DCM to remove unreacted aldehyde and adjusted to pH 3.5 with 1:1(v/v) 4N HCl/AcOH to afford white compound. After keeping overnight at −10° C. the compound was collected and dried to afford pure compound 2.9 g (77%). Mass Spect. (FAB) MW 215 [M+]; NMR assigned.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:12](=[O:13])[C:11]2[C:10]([Cl:9])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(Cl)cccc2Cl)n1
Yield: 66.5 %

Procedure:
Using a method similar to Preparation 48, using 2,6-diaminopyridine (2.6 g, 24 mmol), dioxane (75 mL), and 2,6-dichlorobenzoyl chloride (1.68 g, 8 mmol)(stir at 25° C. for 16 hr.) gives the title intermediate (1.5 g, 66% yield): mass spectrum (ion spray): m/z=282.0 (M+1)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11])=[O:3].[N:12](OCCCCC)=[O:13].Cl.[OH-].[Na+]>C(OCC)C>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[N:12][OH:13]
Reactant: CCCCCON=O
Reactant: CC(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(C=NO)c1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
2,3-Dichloroacetophenone (20.00 g, 0.104 mol) was dissolved in dry diethyl ether (200 ml) and hydrogen chloride bubbled through the solution for half an hour. Amyl nitrite (24.36 g, 0.238 mol) was added dropwise, with stirring, so that the solution was maintained at a gentle reflux. The solution was then gently refluxed for 3 hours with continued passage of hydrogen chloride. The solution was allowed to stand at room temperature overnight. The reaction mixture was poured into 2N sodium hydroxide solution (200 ml) with extreme caution (very vigorous reaction), and separated. The organic phase was extracted with 2N sodium hydroxide solution (2×100 ml). The alkaline phases were combined, poured onto ice (200 ml) and Concentrated hydrochloric acid (100 ml) added with stirring. The resulting acid mixture was allowed to stand at room temperature overnight and the precipitate which formed was filtered at the pump. 2,3-Dichlorophenylglyoxal aldoxime was afforded as a cream solid (10.4 g, 46% yield). T.l.c. (SiO2CHCl3) showed no impurities, therefore no further purification was attempted.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:23]1[C:24]([CH3:46])=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29]>COCCOC.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>[CH3:46][C:24]1[C:23]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[CH:37][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])=[C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:25]=1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1-c1cnn(C)c1

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (86 mg, 0.42 mmol), palladium tetrakis (26.1 mg, 0.02 mmol) and Na2CO3 (0.75 ml, 0.75 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 5; 150 mg, 0.38 mmol) in 1,2-dimethoxyethane (3 ml).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[CH3:23][N:24]([CH3:30])[C@@H:25]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:26]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-N,N-dimethylpyrrolidin-3-amine (1.2 equiv) to give 210 (M+1 410.0)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1.[C:25](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:9]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:20])[F:21])[CH3:25])[C:5]([Cl:23])=[C:4]([Cl:24])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Nc2c(Cl)c(Cl)nc(Cl)c2Cl)c(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(c1ccc([N+](=O)[O-])cc1C(F)(F)F)c1c(Cl)c(Cl)nc(Cl)c1Cl
Reaction time: 2 h

Procedure:
N-(2,3,5,6-Tetrachloro-4-pyridyl)-N-(4-nitro-2-trifluoromethylphenyl)amine (2.0 grams; 0.005 mole), 30 ml. of acetone, 6.0 grams of sodium carbonate and 6 ml. of dimethyl sulfate were mixed and refluxed. After 2 hours, TLC showed no evidence of product. After 8 hours, TLC showed evidence of some product formation. After about sixteen hours, the reaction mixture was quenched by adding water, heating for one hour, and then allowing to cool. Product precipitated and was separated by filtration. It was purified by passing it through a silica gel column with toluene as eluent. Yield was 0.31 gram, m.p. 152°-155° C. Elemental analysis showed
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([O:20]C(=O)C)([CH2:14][CH2:15][C:16]([F:19])([F:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][CH2:15][C:16]([F:19])([F:18])[CH3:17])([OH:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC1(CCC(C)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(F)(F)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl-4-acetoxy-4-(3,3-difluorobutyl)piperidine-1-carboxylate (100 mg, 0.426 mmol) in MeOH (10 mL) and H2O (2 mL) was added NaOH (145 mg, 8.45 mmol). The resulting mixture was stirred at 40° C. for 4 h. After cooling to room temperature, the mixture was acidified with 2N HCl solution. After removal of MeOH, the resulting solution was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure to give the crude product which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])O.[Na+]>O>[CH2:21]([N:27]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 20 g, 67.2 mmol) in hexylamine (36 ml, 270 mmol) was added sodium hydrogen carbonate (5.64 g, 67.2 mmol), and the mixture was heated at 100° C. for 16 h. The rmixture was cooled, diluted with water (80 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of 2:1 to 1:2 hexane/ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (14.2 g, 67%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(O)[CH2:9]1.O>O1CCOCC1>[CH3:6][NH:7][CH:8]1[CH:9]=[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14]1
Reactant: CNC1CCc2ccccc2C(O)(c2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CNC1C=C(c2ccccc2)c2ccccc2CC1
Yield: 76.6 %

Procedure:
9.2 ml of 18 N sulfuric acid were added to a refluxing solution of 4.62 g of the product of Step A in 90 ml of dioxane and the mixture was refluxed for 15 minutes and was then cooled. The mixture was poured into iced water and was extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 2-8-1 benzene-ethyl acetate-triethylamine mixture and then a 95-5-1 chloroform-methanol-triethylamine mixture to obtain 3.3 g of 7-methylamino-9-phenyl-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=1>C1COCC1>[Cl:43][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Dissolved 336 mg (4.00 mmol) 2-butynoic acid in 20 ml of THF and chilled to 0° C. under N2. Added 520 μl (4.00 mmol) isobutyl chloroformate and 440 μl (4.00 mmol) N-methylmorpholine and stirred for 10 minutes. Added a solution of 500 mg (1.60 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile, stirred for 15 minutes at 0° C. and then at 25° C. overnight. Stripped solvent, washed with water, collected and dried in vacuo. Recrystallized from ethyl acetate, giving 148 mg of a yellow solid: mass spectrum (electrospray m/e): M+H=379.1, 381.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:6]=[CH:5]2
Reactant: NC1CCCCC1
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(NC2CCCCC2)ccc2cc(Br)ccc12
Temperature: 120 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of 6-bromo-2-methoxy-1-nitronaphthalene (10.0 g, 35.6 mmol) and 8 ml of cyclohexylamine in 50 ml of dry N,N-dimethylformamide was heated with stirring at 120° C. for 17 h. The mixture was evaporated to dryness and the residue was triturated with 50 ml of ethanol at 0° C. The solid was isolated by filtration and washed with light petroleum to give 10.4 g (84%) of 6-bromo-2-cyclohexylamino-1-nitronaphthalene. The crude product was suspended in 150 ml of 96% ethanol and hydrogenated at room temperature and 40 psi over Ni/Raney. After the hydrogen uptake was completed, the reaction mixture was filtered into 50 ml of 4M hydrochloric acid and concentrated to dryness. Crude 1-amino-6-bromo-2-cyclohexylaminonaphthalene hydrochloride (9.8 g, 27.6 mmol) was taken up in 80 ml of dry tetrahydrofuran. Dry triethylamine (7.7 ml, 55.3 mmol) was added, followed by the dropwise addition of ethyloxalyl chloride (3.1 ml, 27.7 mmol) with stirring at 0° C. The mixture was stirred over night at room temperature and finally at reflux for 4 h. The cooled mixture was filtered and the solid was washed with water and ethanol affording 5.2 g (51%) of the title compound. M.p. 347.0° C. (N,N-dimethylformamide, DSC); IR (KBr): 1700 cm-1 ; 1H-NMR (DMSO-d6) 1.13-2.93 (m, 10H, 5CH2), 4.33-4.90 (m, 1H, NCH), 7.47-8.67 (m, 5H, ArH), 12.1 (broad s, 1H, NH); MS (m/z): 372 (M+, 17%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N+:20]([O-])=O)[C:14]=2[OH:23])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=2[OH:23])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NCCN2CCOCC2)c1O
Yield: 108.9 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, crude N-[2-(morpholinyl)ethyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (300 mg) was reduced with hydrogen and 10% Pd/C (80 mg) to form the crude product (300 mg) which was carried onto the urea step without purification. EI-MS (m/z) 338.93, 340.98 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:31]=[CH2:32].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:32]=[CH:31]/[CH2:30][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.184 mmol) in MeCN (5 mL) in a pressure vessel is added allylbenzene (22 mg, 0.184 mmol), Pd(OAc)2 (3 mg) and triethylamine (186 mg, 1.84 mmol) and the mixture is heated at 100° C. for 10 h. The solvent is evaporated and the residue is purified by flash chromatography using a gradient of 10% to 40% EtOAc/hexane as eluent to give the title compound as a yellow foam.
Reaction SMILES: Cl[C:2]1[CH:7]=C(CC2C=C3C(=C4C=CC=CC=24)N=CN([C@H]2CCOC[C@@H]2O)C3=O)[CH:5]=[CH:4][N:3]=1.[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35](Cl)[CH:34]=1>>[Br:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[N:3]([CH2:4][CH3:5])[CH:2]=[CH:7][C:34]=12
Reactant: Clc1cc(CBr)ccn1
Reactant: O=c1c2cc(Cc3ccnc(Cl)c3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Product: CCn1ccc2c(CBr)ccnc21

Procedure:
The title compound was prepared by the procedure described for the synthesis of 6-[(2-chloropyridin-4-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one in Example 15, substituting 4-(bromomethyl)-1-ethyl-1H-pyrrolo[2,3-b]pyridine for 4-(bromomethyl)-2-chloropyridine. The resultant orange solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 455.2087 for [M+H]+ [Calc'd for C27H27N4O3, [M+H]+=455.2078]: 1H NMR (400 MHz, d6-DMSO) δ 9.01-8.98 (m, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 2H), 8.01 (s, 1H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 6.74-6.72 (m, 1H), 6.59 (s, 1H), 5.31 (d, J=5.5 Hz, 1H), 4.80 (s, 2H), 4.63 (br s, 1H), 4.28 (q, J=7.2 Hz, 2H), 4.18-4.15 (m, 1H), 3.99-3.92 (m, 1H), 3.42 (t, J=11.1 Hz, 1H), 3.14 (t, J=10.4 Hz, 1H), 2.26 (br s, 1H), 1.91-1.89 (m, 1H), 1.38 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH-].[Na+].O.[F:4][C:5]([F:26])([F:25])[CH:6]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][O:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][CH:11]=1>CO>[F:4][C:5]([F:25])([F:26])[CH:6]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:7][CH2:8][O:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1
Reactant: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(CCOc1ccc(C(=O)O)cc1)C(F)(F)F
Yield: 90 %

Procedure:
In a round-bottomed flask, 0.27 g of sodium hydroxide and 1 ml of water were placed, 3 ml of methanol was added and then 0.7 9 of ethyl p-(3-trifluoromethylheptyloxy)benzoate was added thereto, followed by 4 hours of reaction at 50° C. Then, water was added to the system, and methanol was distilled off, followed by addition of 6N-hydrochloric acid to recover a precipitated crystal. The crystal was dried in a desiccator to obtain 0.55 g of p-(3-trifluoromethylheptyloxy)benzoic acid 4 (Yield: 90%)
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:33][CH:34]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-(4-trifluoromethoxy-phenyl)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.2041 g, 0.0003768 mol) was dissolved in ethanol (4.00 mL, 0.0685 mol) in a capped 40 mL EPA vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (2.00 mL, 0.00840 mol) was added and the mixture was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The product was partitioned between water and methylene chloride. The combined organic phase was dried over MgSO4, filtered, concentrated and purified by flash chromatography [0-50% of 2M NH3 solution in MeOH (10% in methylene chloride) and methylene chloride to give the title compound in 69% yield. MS: m/z=499.23 [M-NH2]+. 1H NMR (MeOD) δ: 7.93-7.96 (m, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.47-7.52 (m, 1H), 7.38-7.45 (m, 6H), 4.06-4.16 (m, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 1.99-2.07 (m, 2H), 1.76-1.84 (m, 2H), 1.51 (s, 3H), 0.91-1.24 (m, 5H), 0.86 (s, 9H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Reactant: OC1CCNCC1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCC(O)CC3)nc2)o1
Yield: 7 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) was converted using 4-hydroxypiperidine instead of morpholine to the title compound (17 mg, 7%) which was obtained as a light yellow solid. MS: m/e=404.5 [M+H]+.