Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.[C:27]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Reactant: O=C1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCC2)CC1
Yield: 122.1 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide (100 mg, 0.205 mmol), cyclopentanone (0.091 mL, 1.02 mmol), and sodium cyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl, 60 mg (60%) of the title compound as a hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11].C1C=CN/C(=C\N=O)/C=1>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2ccccc2o1
Agent: O=N/C=C1/C=CC=CN1
Solvent: ClCCl
Product: C(#Cc1ccccn1)CCc1nc2ccccc2o1
Reaction time: 8 h
Yield: 79.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (746 mg, 4.67 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (800 mg, 4.67 mmol). Reaction time: 3 hours. The crude residue was dissolved in DCM, syn-2-pyridinecarboxaldoxime (684 mg, 5.60 mmol) was added and the reaction mixture was stirred overnight. The solvent was evaporated and the resulting crude product was purified by flash chromatography (DCM/MeOH 99:1) to yield 923 mg (3.72 mmol, 79%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=O)[N:7]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:17]=1.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:17]=1
Reactant: COCCCN1C(=O)COc2ccc(Br)cc21
Solvent: CO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(Br)cc21
Temperature: 65 °C
Reaction time: 1 h

Procedure:
The solution of 2.85 g of 6-bromo-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one in 50 ml of tetrahydrofuran is admixed with 48 ml of 1M borane-tetrahydrofuran complex and stirred at 65° C. over 1 hour. The reaction mixture is cooled to room temperature and then admixed cautiously with 100 ml of methanol. After 10 minutes, the mixture is concentrated to dryness and the title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (1:2 EtOAc-heptane). Rt=4.89 (gradient I).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C)C=O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(F)cc1)Nc1ccccc1C(=O)O
Temperature: 0 °C
Yield: 104.1 %

Procedure:
N(chloroacetyl)anthranilic acid 4.0 g (8 mmol) and p-fluoroaniline 5.3 ml (56 mmol) were dissolved in 4 ml of dimethylformamide and heated at 80° to 90° C. for 4 hours. The reaction solution was poured into ice water and deposited crystals were collected by filtration. These crystals were washed with ether and recrystallized from ethanol to obtain N-[(4-fluorophenylamino)acetyl]anthranilic acid (melting point: 217° to 219° C.) 2.4 g (yield: 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-:29].[K+]>CS(C)=O.C1COCC1>[Br:29][C:10]1[C:9]2[C:4](=[C:5]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: Cc1cc(C)c(-c2cccc3c(OS(=O)(=O)C(F)(F)F)cc(C)nc23)c(C)c1
Reactant: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cccc3c(Br)cc(C)nc23)c(C)c1
Temperature: 120 °C
Yield: 105.2 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-yl ester (426 mg, 1 mmol) and potassium bromide (KBr) (809 mg, 1.1 mmol) in a mixture of 1 ml of dry DMSO and 3 ml of dry THF was heated in 120° C. oil bath for 3 hours. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried and concentrated to give 358 mg of the title compound as an off-white solid. 1H NMR (CDCl3) δ 8.16 (m,1H), 7.59 (m,1H), 7.56(s,1H), 7.48(m,1H), 6.97(s,1H), 2.53(s,3H), 2.37(s,3H), 1.87(,6H) ppm.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[F:17][C:18]([F:25])([CH3:24])[C:19](OCC)=[O:20].[Cl-].[NH4+].Cl>C1COCC1>[F:17][C:18]([F:25])([CH3:24])[C:19](=[O:20])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(C)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)(F)F
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Lithium hexamethyldisilazide (150 ml of a 1M solution in THF, 0.15 mol) was cooled in an argon atmosphere to −78° C. and ethyl acetate (15 ml, 0.14 mol) was added dropwise with stirring. Stirring was continued for one hour at −78° C., then ethyl 2,2-difluoropropionate (12 g, 0.089 mol) was added dropwise with stirring. Stirring was continued for four hours at −78° C., then a saturated solution of ammonium chloride (175 ml) was added dropwise. The mixture was allowed to reach room temperature, acidified with 1M HCl (50 ml) and left standing overnight. The phases were separated. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with 1M HCl, brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by vacuum distillation (54 mbar, 130° C.) to yield 12.4 g (0.068 mmol, 77%) of a colourless liquid that was used directly in the next step.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[N:16]=[N:17][C:18]([Cl:24])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=2)=[C:9]([Cl:25])[CH:8]=1)=[O:5].[OH-].[Na+]>CO>[Cl:13][C:11]1[CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:26])=[O:2])[CH:8]=[C:9]([Cl:25])[C:10]=1[O:14][C:15]1[N:16]=[N:17][C:18]([Cl:24])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1
Reactant: COC(=O)C(=O)Nc1cc(Cl)c(Oc2cc(C(C)C)c(Cl)nn2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cc(Oc2c(Cl)cc(NC(=O)C(=O)O)cc2Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A suspension of N-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-oxalamic acid methyl ester (27) (1.87 g, 4.47 mmol) in methanol (35 mL) at 0° C. was treated with a 1N aqueous sodium hydroxide solution (8.95 mL, 8.95 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The solvent was concentrated under vacuum. The residue was diluted with water (500 mL), and the mixture was made acidic to pH=1-2 by the addition of a 1N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate (2×250 mL). The organic layer was separated, dried with magnesium sulfate, filtered and concentrated. The resulting solid was dried on high vacuum overnight to afford N-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-oxalamic acid (28) (1.77 g, 98%) as a white solid; EI(+)-HRMS m/z calcd for C15H12Cl3N3O4 (M+H) 403.9966, found 403.9968. Molecular Weight=404.6396; Exact Mass=402.9893
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3Cl)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3ccccc3Cl)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(2-chlorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.062 g, 0.18 mmol) in tetrahydrofuran (3 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.22 mL, 0.22 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (0.056 g), which was used directly in next step. C15H15ClN3OS (M+H)+: m/z=320.1. Found: 320.0.
Reaction SMILES: [CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+:34]>C(Cl)Cl>[CH:1]1([O:6][C:7]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1.[Na+:34]
Reactant: COc1cc(C(=O)O)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C(=O)[O-])ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Yield: 78 %

Procedure:
A mixture of 306 mg. 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic acid in 4 ml. methanol and 6 ml. methylene chloride was treated with 0.75 ml. of 1 M sodium hydroxide solution. After 15 minutes the mixture was evaporated and the residue was recrystallised from ether/methylene chloride/methanol to give sodium 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoate in 78% yield as a solid, m.p. >280° C. (d); microanalysis, found: C,59.80; H,5.06; N,9.20%; C22H22H3O5Na.0.5H2O requires C, 59.99; H,5.26; N,9.54%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH2:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc(CN2CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.5 %

Procedure:
A solution of 5 g (41.96 mmol) of indoline in DMF was treated with 5.8 g (41.96 mmol) of K2CO3 and then at 0° C. dropwise, under intense stirring, with 5.5 mL (46.2 mmol) of benzylbromide. The mixture was stirred at RT for 10 hrs and then for 2 hrs at 60° C. The resulting thick pulp was distributed between a saturated aqueous solution of NH4Cl and Et2O. Drying of the combined organic phases over Na2SO4 and evaporation of the solvent yielded 6.1 g (69%) of N-benzylindoline MS: 210 (MH+).
Reaction SMILES: Cl.[CH2:2]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11]C)=[O:10])[C:5]=1[CH3:13])[CH3:3].CC(C)([O-])C.[K+].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.[Li+].[OH-].Cl>C(O)C.O>[CH2:2]([C:4]1[N:8]([CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[CH3:13])[CH3:3]
Reactant: CCc1[nH]nc(C(=O)OC)c1C
Reactant: Cc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCc1c(C)c(C(=O)O)nn1Cc1ccc(C)cc1
Temperature: 60 °C
Yield: 17.6 %

Procedure:
To a mechanically stirred solution of methyl 5-ethyl-4-methyl-1H-pyrazole-3-carboxylate hydrochloride (Step 1, 825 mg, 4.03 mmol) in dry ethanol (20 mL) was added potassium tert-butoxide (1.18 g, 10.5 mmol) and a solution of 4-methylbenzyl bromide (1.12 g, 6.05 mmol) in dry ethanol (20 mL). The reaction mixture was stirred at 60° C. over night. After being cooled to rt, LiOH (0.5N aq., 40.3 mL, 20.1 mmol) was added, and the mixture was stirred at 40° C. for additional 3 h. After being cooled to RT again, the reaction mixture was diluted with water (200 mL) and acidified with HCl (2N aq., 12.1 mL, 24.2 mmol). Extraction with dichloromethane, drying over anhydrous magnesium sulfate, filtration, evaporation of the solvent and subsequent purification by preparative HPLC afforded the title compound as a white solid (183 mg, 18%): 1H NMR (400 MHz, CDCl3) δ 7.12 (d, 2H), 7.01 (d, 2H), 5.30 (s, 2H), 2.53 (quart, 2H), 2.32 (s, 3H), 2.22 (s, 3H), 0.98 (t, 3H); ES-MS m/z 259 (MH)+; HPLC RT (Method D) 2.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:6]=1)=[O:4].[ClH:25]>C(O)C.O1CCOCC1>[ClH:25].[ClH:25].[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COC(=O)c1ccnc(NC2CCNCC2)n1

Procedure:
A solution of 2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester (0.48 g, 1.43 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 237.4 [M+H]+.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]([Cl:16])[CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](SC)[NH:9][CH:8]2[CH3:15].[O:17]([CH2:24][CH2:25][NH2:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].C(Cl)Cl>C(#N)C.OO>[Br:2][C:3]1[CH:4]=[C:5]([Cl:16])[CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([NH:26][CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:9][CH:8]2[CH3:15]
Reactant: CSC1=Nc2c(Br)cc(Cl)cc2C(C)N1
Reactant: NCCOc1ccccc1
Agent: I
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC1NC(NCCOc2ccccc2)=Nc2c(Br)cc(Cl)cc21
Temperature: 200 °C
Yield: 46.1 %

Procedure:
8-Bromo-6-chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (141 mg, 0.33 mmol) and 2-phenoxyethyl amine (53.5 mg, 0.39 mmol) were dissolved in acetonitrile (1 ml) and heated to 200° C. in a sealed tube in a microwave oven for 30 minutes. After cooling the reaction was treated with 1N aqueous sodium hydroxide solution, methylene chloride and 5 to 7 drops of 30% aqueous hydrogen peroxide solution. After the reaction has ceased the layers were separated and the aqueous phase was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, the solvent was evaporated and the residue was purified by column chromatography (CH2Cl2:MeOH:aq conc NH3=9:1:0.1) to yield the title compound as an off-white solid (60 mg, 47%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1C(O)=O>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:27]2[N:26]([CH3:25])[C:34]3[C:29]([CH:28]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:9][CH:10]=1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: Cn1c(N[C@@H](Cc2ccc(OCc3c(Cl)cccc3Cl)cc2)C(=O)O)cc2ccccc21

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 1-methylindole-2-carboxylic acid. Freeze drying afforded the title compound as a white amorphous solid (220 mg). δH (DMSO-d6) 11.7 (1H, br s), 8.66 (1H, d, J 8.3 Hz), 7.65 (1H, d, J 7.9 Hz), 7.53 (2H, app.d, J 8/1 Hz), 7.26 (1H, obscured m), 7.09 (2H, app.t, J 7.5 Hz), 6.96 (2H, d, J 8.5 Hz), 5.16 (2H, s), 4.64-4.54 (1H, m), 3.89 (3H, s), 3.16 (1H, dd, J 13.8, 4.3 Hz) and 3.00 (1H, dd, J 13.8, 10.4 Hz); m/z (ESI, 60V) 497 and 499 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[CH3:15])[CH:9]([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:17][O:18][NH3+:19].[Cl-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=[N:19][O:18][CH3:17])[CH3:15])[CH:9]([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: CC(=O)C(c1ccc(Cl)cc1)C(C)CC#N
Agent: [Cl-]
Solvent: c1ccncc1
Product: CON=C(C)C(c1ccc(Cl)cc1)C(C)CC#N

Procedure:
4-Chloro-γ-(1-oxoethyl)-β-methylbenzenebutanenitrile (4.4 grams) and methoxyamine.HCl (3.7 grams) in 80 ml of pyridine were stirred at ambient temperature. The mixture was then poured into ice containing sufficient concentrated HCl to neutralize the pyridine, stirred, and extracted with dichloromethane. The resulting dichloromethane solution was washed with water and a saturated solution of sodium chloride and was then dried over magnesium sulfate. Filtering and stripping resulted in a clear colorless gum which was shown by NMR and IR to be the desired product.
Reaction SMILES: C([Li])CCC.Cl.Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.CCOCC.[O:19]=[C:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>CCCCCC>[OH:19][C:20]1([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccncc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.600 M of n-Butyllithium in hexane (0.810 mL) was added to a solution of 4-bromopyridine hydrochloride (210 mg, 1.1 mmol) in ether (5 mL, 0.05 mol) at −78° C. The solution was stirred at −78° C. for 30 min. and then tert-butyl 3-oxopyrrolidine-1-carboxylate (200 mg, 0.001 mol) was added and the temperature was maintained at −78° C. for 3 hours. The reaction mixture was quenched with water, extracted with AcOEt. The organic layer was dried with MgSO4, and concentrated to afford the desired product.
Reaction SMILES: [Cl-].[NH4+].O.[Cl:4][C:5]1[CH:6]=[C:7]([C:27]([O:29][CH3:30])=[O:28])[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:9]([N+:17]([O-])=O)[C:10]=1[C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14]>>[NH2:17][C:9]1[C:10]([C:11]#[C:12][Si:13]([CH3:15])([CH3:14])[CH3:16])=[C:5]([Cl:4])[CH:6]=[C:7]([C:27]([O:29][CH3:30])=[O:28])[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c(N)c1-c1cccc(F)c1
Temperature: 60 °C
Yield: 83.1 %

Procedure:
The reaction mixture was treated with 5 M ammonium chloride in water (4.1 mL, 21 mmol) followed by methyl 4-chloro-3′-fluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (1.9 g, 4.8 mmol) and heated at 60° C. for 16 hours. The reaction mixture was filtered over celite, washed with methanol, and the filtrate was concentrated to a solid. The solid was diluted with ethyl acetate (200 mL) and saturated sodium bicarbonate (100 mL) and stirred for a few minutes. The organic layer was separated, washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-10%) gave the desired product (1.5 g, 86%). LCMS for C19H20ClFNO2Si (M+H)+: m/z=376.1; Found: 376.1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:8](=[O:15])([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Sc1ccccn1
Solvent: C1CCOC1
Product: O=C(Sc1ccccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
Following a standard procedure,16 a solution of 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) was treated with benzoyl chloride (4.21 g, 30.0 mmol) at room temperature with stirring for 30 min. The standard workup followed by precipitation afforded a pale yellow solid (5.67 g, 88%): mp 48-50° C. 1H NMR spectral data are consistent with reported values:15 1H NMR δ 7.31-7.37 (m, 1H), 7.46-7.53 (m, 2H), 7.59-7.65 (m, 1H), 7.71-7.83 (m, 2H), 8.00-8.06 (m, 2H), 8.66-8.71 (m, 1H); 13C NMR δ 123.7, 127.6, 128.9, 131.0, 134.0, 136.6, 137.3, 150.6, 151.4, 189.4. Anal. Calcd for C12H9NOS: C, 66.95; H, 4.21; N, 6.51. Found: C, 66.63; H, 4.12; N, 6.57.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([CH:38]=[O:39])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].CC(=CC)C.[O-:46]Cl=O.[Na+].Cl>C1COCC1.O.CCOC(C)=O.C(O)(C)(C)C>[CH:22]([C:20]1[CH:19]=[CH:18][C:17]([O:25][CH3:26])=[C:16]([C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[CH2:5][N:4]([CH2:27][C:28]2[CH:29]=[C:30]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[C:38]([OH:46])=[O:39])[C:3]([O:2][CH3:1])=[O:40])[CH:21]=1)([CH3:24])[CH3:23]
Reactant: [O-][Cl+][O-]
Reactant: COC(=O)N(Cc1cc(C=O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(Cc1cc(C(=O)O)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl[3-formyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (37.0 mg, 0.065 mmol) (Example 40) in THF (123 μL) was added t-butanol (360 μL), 2-methyl 2-butene (123 μL), and a solution of NaClO2 (12.9 mg, 0.014 mmol) and NaH2PO4 (19.7 mg, 0.014 mmol) in H2O (152 μL). The reaction was stirred vigorously for two hours at room temperature, diluted with EtOAc (30 mL), and poured into 1N HCl (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0.1% acetic acid in 8% MeOH/CH2Cl2 afforded 3-{[{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(methoxycarbonyl)amino]methyl}-5-(trifluoromethyl)benzoic acid. Rf=0.35 (10% MeOH/CH2Cl2). LCMS=584.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.28 (broad singlet, 1H), 8.04 (broad singlet, 1H), 7.68 (broad singlet, 1H), 7.37-7.34 (m, 2H), 7.07-7.05 (m, 2H), 6.87 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.43 (broad singlet, 2H), 4.41 (broad singlet, 2H), 3.40 (s, 3H), 3.29 (s, 3H), 2.75 (m, 1H), 1.17 (d, J=6.5 Hz, 6H).
Reaction SMILES: BrC1C=CC(S)=C(C(F)(F)F)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=O)=O)=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Agent: FC(F)(F)c1cc(Br)ccc1S
Product: Fc1ccc(S)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to Example 58, Intermediate 1, using 4-fluoro-2-trifluoromethyl-benzene sulfonyl chloride. Colorless liquid. MS (EI): 195.1 (M−H)−.