Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:5][CH2:6]2.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>C(#N)C>[OH:1][C@H:2]1[C@H:7]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@@H](Sc2ccccc2)[C@H](O)C1
Temperature: 25 °C

Procedure:
40 g (0.146 mol) of the 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine obtained according to Example 12 are dissolved, together with 32 g (0.29 mol) of thiophenol and 146 ml (0.29 mol) of 2 N sodium hydroxide solution, in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 4 hours, then cooled to room temperature and concentrated to about 1/3 of the original volume under a water pump vacuum. The solution is then diluted with 900 ml of water and extracted by shaking with 3 times 1,000 ml of methylene chloride; the combined organic phases are washed twice with 0.1 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oil which remains is dissolved in 50 ml of benzene and the solution is filtered through a layer of silica gel. Trans-3-hydroxy-4-phenylthio-1-(β,β,β-trichloroethoxycarbonyl)-piperidine is isolated in the form of a slightly orange coloured oil by elution with a benzene/ethyl acetate mixture (4:1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1.[CH3:22][N:23]=[C:24]=[O:25].O>N1C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][CH:5]=[C:6]([CH2:8][C:9](=[O:21])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]=1)[C:24]([NH:23][CH3:22])=[O:25]
Reactant: CN=C=O
Reactant: CNc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)N(C)c1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Yield: 47.7 %

Procedure:
A solution comprising 12.7 g (0.04 mole) of 2-methylamino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole, 3.1 g (0.054 mole) of methyl isocyanate in 40 ml of pyridine was heated at about 45° for 24 hours. The reaction solution was poured into water and the crude product was collected. Two recrystallizations from isopropanol-heptane yielded 7.1 g of desired product, m.p. 125°-27°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 2.8 (CH3, doublet), 3.5 (CH3, singlet), 3.8 (CH2), 6.9 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=O).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]([OH:15])=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:17]1([O:6][C:5](=[O:7])[C:4]2[C:8]([OH:15])=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=[C:2]([Br:1])[C:3]=2[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Oc1ccccc1

Procedure:
From 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzoic acid, phenol and phosphorus oxychloride in toluene; amber oil; 1H NMR (CDCl3): δ 11.10 (s, 1H), 7.64 (s, 1H), 7.50-7.42 (m, 2H), 7.36-7.28 (m, 1H), 7.22-7.17 (m, 2H), 2.74 (s, 3H), 1.40 (s, 9H); LC-MS: Major component: m/z 269/270 (acylium ion), 363/365 (M+H), 385/387 (M+Na); Rt=2.95 min. The crude product was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:28][CH2:27][C:17]2([C:20]3[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][CH2:19][C:14]([F:13])([F:29])[CH2:15][CH2:16]2)=[O:6])=[C:2]([F:1])[CH:10]=1)#[N:12]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Product: N#Cc1ccc(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c(F)c1

Procedure:
From 2-fluoro-4-cyanobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=392.1, tR (minutes, Method D)=0.68
Reaction SMILES: [Li+].[Cl-].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12]C)[CH:11]=1)[C:7]#[N:8].CCOC(C)=O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:7]#[N:8]
Reactant: COc1cc(Cl)cc(C#N)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(O)cc(Cl)c1
Temperature: 180 °C
Yield: 84.7 %

Procedure:
To a stirred solution of LiCl (84 g, 1980 mmol) in DMF (500 mL) was added 3-chloro-5-(methyloxy)benzonitrile (167 g, 1000 mmol). The reaction mixture was heated to 180° C. for 12 h. The reaction mixture was poured into ice (300 g) and EtOAc was added. The organic layer was separated, dried over MgSO4 and evaporated to dryness. The solid was recrystallized from EtOAc and petroleum ether (1:5) to afford the title compound (130 g, 67%) as a solid.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:15]=[C:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:9][C:2]=12
Reactant: CNc1cccc(Br)c1
Reactant: OB(O)c1ccc2nonc2c1
Product: CNc1cccc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and (3-bromo-phenyl)-methyl-amine. Yellow powder. MS(ES+): 226 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:18]([S:25](Cl)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([S:25]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:27])=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Yield: 53.9 %

Procedure:
To a solution of tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate (3.04 g, 12.1 mmol) in pyridine (30 mL) cooled to 0° C. was added benzylsulfonylchloride (2.67 g, 15.1 mmol). While stirring of the reaction mixture the precipitate formed. After one hour the solvent was evaporated under reduced pressure and the product was partitioned between dichloromethane and 10% KHSO4 solution. The aqueous phase was extracted with dichloromethane twice. The combined organic phases were dried over a drying agent and the solvent was evaporated under reduced pressure. A brown-reddish product obtained was suspended in ethyl acetate and heated to reflux, then cooled and filtered to give 2.56 g (6.52 mmol) of a pink product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5](=[CH2:29])[CH2:6][C@H:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH3:29])[CH2:6][CH:7]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C(C)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid ethyl ester (2-a, R1=Boc, R2=H, R3=CO2Et) is added to ethanol (5 ml) at ambient temperature. Triethylamine (170 μl) is then added to the mixture. 50 mg Palladium on carbon (10%, 50% water-wet, Degussa E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is then stirred overnight at ambient temperature and pressure. The mixture is then filtered and concentrated under reduced pressure to afford 2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-a, R1=Boc, R2=H, R3=CO2Et) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid ethyl ester (1-b, R1=Boc, R2=H, R3=CO2Et). Spectroscopic data as in Example 63. Ratio of diastereomers 70:30 (1-a, R1=Boc, R2=H, R3=CO2Et:1-b, R1=Boc, R2=H, R3=CO2Et) as determined by hplc (hplc method as in Example 65)
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:29][OH:30]>C1(C)C=CC=CC=1>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:13](=[O:16])[CH2:14][C:29](=[O:30])[CH2:24][CH2:25][CH2:8][CH2:7][CH2:6][CH2:15][CH2:2][CH2:3][CH3:4])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CO
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)CC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 20 °C
Yield: 63 %

Procedure:
To a solution of 100 mg (0.30 mmole) of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) in 8 mL of toluene, magnetically stirred at 20° C., 103 mg of the compound of example 19 were added. The mixture was refluxed during 2.5 hours, and then allowed to cool to 20° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 79 mg (yield: 63%) of the desired product (formula below) as a red powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[CH:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 50 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (101 mg, 0.17 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methanesulfonamide (147 mg, 0.44 mmol), sodium carbonate (45 mg, 0.43 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (41 mg, 0.2 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 89 mg (50% yield, 69% purity) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH2:15])=[O:14])=[CH:7]2.[Cl:18][CH:19](Cl)[C:20](=O)[CH3:21]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:18][CH2:19][C:20]1[N:15]=[C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:12][CH:11]=3)[O:14][CH:21]=1
Reactant: CC(=O)C(Cl)Cl
Reactant: NC(=O)c1cc2cc(OC(F)(F)F)ccc2[nH]1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1

Procedure:
5-trifluoromethoxy-1H-indole-2-carboxylic acid amide (4.5 g, 18.43 mmol) and dichloro acetone (3.5 g, 27.63 mmol) in toluene/DMF (5:1, 30 ml) were kept at reflux temperature for 24 h with continuous removal of water by applying a Dean-Stark trap (a water separator used in chemical reactions). After removal of solvents in vacuo, the residue was intensively shaken with water, the precipitate was isolated by filtration and washed with water and brine. After evaporation of the solvents in vacuo chromatography on silica gel (iso-hexanes/ethyl acetate 3:1) yielded 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole as off white solid. Yield 2.6 g (44%)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C1COCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30](=[O:31])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (121.0 mL of a 2.0M solution, 0.243 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. 2,6-Dimethyl-7-octen-2-yl acetate (22.66 g, 0.114 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of 4-nitrobenzoyl chloride (20.00 g, 0.108 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (70 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([CH:33]1[CH2:35][CH2:34]1)[NH2:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)=[O:9])[CH2:11]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)C1CC1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 27.5 mg (0.275 mmol) of N′-hydroxycyclopropanecarboximidamide (Example 78A) were reacted according to the General Method 1. Yield: 51.8 mg (45% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[O:21]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc3c(c2)CCC3=O)c1
Yield: 52 %

Procedure:
Reaction of 5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with m-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave 3-methoxy-N-(1-oxo-indan-5-yl)-benzamide (73 mg, 0.26 mmol, 52% yield) as a yellow powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/10 to 1/9).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:16]
Reactant: Nc1ccc(F)cc1F
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(F)cc1F

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 2,4-difluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[CH:5]=O.[NH2:12]OS(O)(=O)=O>O>[Br:1][C:2]1[C:3]([F:11])=[C:4]([C:7]([Cl:10])=[CH:8][CH:9]=1)[C:5]#[N:12]
Reactant: NOS(=O)(=O)O
Reactant: O=Cc1c(Cl)ccc(Br)c1F
Solvent: O
Product: N#Cc1c(Cl)ccc(Br)c1F
Temperature: 50 °C
Yield: 100 %

Procedure:
A suspension of 3-bromo-6-chloro-2-fluorobenzaldehyde (9.0 g, 0.04 mol) and hydroxylamine-O-sulfonic acid (7.50 g, 0.07 mole) in water (300 mL) was heated at 50° C. for eighteen hours. The suspension was cooled and the solid was collected to give 3-bromo-6-chloro-2-fluorobenzonitrile (8.8 g, 0.04 mol): 1H NMR (CDCl3): δ 7.75 (m, 1H), 7.25 (m, 1H).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[F:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.3 %

Procedure:
To a solution of 0.704 g (5.67 mmol) of orcinol monohydrate and 1.00 g (5.15 mmol) of 3-fluorobenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.41 g of a pale amber-colored oil. This material was flash chromatographed on 65 g of silica gel with 3% ethyl acetate-dichloromethane to afford 935 mg (68%) of the desired product as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 7.66 (ddd, 1H, J=7.8, 1.7, 1.1 Hz), 7.55 (m, 2H), 7.38 (tdd, 1H, J=8.3, 2.6, 1.1 Hz), 6.56 (m, 1H), 6.40 (m, 1H), 6.33 (td, 1H, J=2.2, 0.5 Hz), 5.29 (s, 1H) and 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[C:11]([N+:24]([O-])=O)[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O>C(O)(=O)C.[Fe]>[NH2:24][C:11]1[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=[C:2]([F:1])[C:12]=1[N:13]1[C:21](=[O:22])[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]1=[O:23]
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c([N+](=O)[O-])c2N1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c2c(cc(F)c1N1C(=O)C3=C(CCCC3)C1=O)OCC(=O)N2
Yield: 104.7 %

Procedure:
2-[7-Fluoro-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.25 g) was dissolved in acetic acid (13 ml) and iron powder (0.77 g) was added with stirring. Solution was stirred at ambient temperature for 12 hr and water was added. Product was extracted with ethyl acetate to afford the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[C:4](C(O)=O)[NH:5][C:6]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])=[CH:4][NH:5][CH:6]=1
Reactant: O=C(O)c1[nH]c(C(=O)O)c(-c2cccc(Cl)c2Cl)c1Cl
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Clc1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 84.8 %

Procedure:
The mixture of 53 g of 4-chloro-3-(2,3-dichlorophenyl)pyrol-2,5-dicarboxylic acid, 2.65 g of cupric acid and 80 ml of quinoline was heated at 140°-150° C. for 30 minutes with stirring. To the resulting reaction mixture were added ethyl acetate, ice and concentrated hydrochloric acid which of molar amount was 1.1-time that of employed quinoline. The ethyl acetate layer was washed with successive, water, aqueous sodium carbonate and water. After dehydration, the ethyl acetate layer was evaporated to dryness under reduced pressure to obtain 33.1 g of brown product. The crude product was purified by silicagel chromatography and countercurrent distribution to obtain pale yellow oily substance. The oily substance was recrystallized from n-hexane to obtain 22.5 g of the desired product (colorless or pale yellow needles, m.p. 58°-59° C.).
Reaction SMILES: [H-].[Na+].[F:3][CH:4](P(=O)(OCC)OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH:6]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>CCCCC.C1COCC1>[F:3][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)[CH:6]=1)=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(OCC)C(F)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(F)c2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (166 mg, 6.92 mmol) under a N2 atmosphere was washed with n-pentane and dried blowing N2 gas. THF (5 mL) was added and the mixture was cooled to 0° C. Diethyl fluoro(3-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)methylphosphonate (940 mg, 2.3 mmol) was added as a solution in THF dropwise and the mixture was stirred for 30 min. tert-Butyl 4-oxopiperidine-1-carboxylate as a solution in THF was added dropwise and the reaction was stirred for 1 h. Excess NaH was quenched with water at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified by column chromatography to give the pure title compound (600 mg). 1H NMR (500 MHz, CDCl3): δ 1.4 (s, 9H), 2.0 (m, 2H), 2.4 (m, 2H), 3.4 (m, 2H), 3.5 (m, 2H), 7.0 (d, 1H, J=8.5 Hz), 7.1-7.2 (m, 4H), 7.4 (t, 1H, J=8 Hz), 7.9 (d, 1H, J=8.5 Hz), 8.4 (s, 1H).