Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:17][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[CH:13][CH:14]=[C:15]([C:19]([C:24]2[N:25]=[CH:26][N:27]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:28]=2)([OH:23])[CH:20]([CH3:21])[CH3:22])[CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1cccc(-c2ccc(Cl)cc2Cl)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 75.7 %

Procedure:
By the reaction in the same manner as in Example 1-(i) using 2,4-dichlorophenylboronic acid (0.55 g) and 1-(3bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.00 g), the amorphous title compound (0.85 g) was obtained.
Reaction SMILES: [CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-])=O)[C:12]=1[OH:21])(=[O:10])=[O:9])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd]>[CH2:1]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:21])(=[O:9])=[O:10])[C@@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)NC[C@H]2CCCO2)c1O
Yield: 93.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-((2R)-tetrahydrofurfuryl)-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (660 mg, 1.96 mmol) was reduced with hydrogen and Pd/C (303 mg) to form the desired product (563 mg, 94%). EI-MS mn/z 305(M-H)−.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 62% of theory, C33H31N7O4 (589.7); Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=590; (M+Na)+=612.
Reaction SMILES: [H-].[Na+].Cl.Cl.[NH2:5][C@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[C:14](Cl)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[Cl-].[Na+].O>[CH2:17]([O:16][C:14](=[O:15])[NH:5][C@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Product: O=C(N[C@@H]1CN2CCC1CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (dispersion 55%) 0.33 g (7.5 mmol) is washed with petrolether and the solvent is removed by separation (decantation). Then, the sodium hydride is carefully suspended in dimethylformamide (12.5 ml). To this suspension (S)-(−)-3-aminoquinuclidine dihydrochloride 0.50 g (2.5 mmol) is added. The initially exothermic reaction is then stirred at room temperature for one hour and then carbobenzoxy chloride 0.39 ml (2.75 mmol) is added to the reaction mixture within 15 minutes. The again initially exothermic reaction is stirred at room temperature for 90 minutes then the mixture is poured into 10% brine (NaCl/water solution) and then four-times extracted with toluene. The combined organic phases are dried and evaporated. The crude oily residue is dissolved in dioxane (5 ml) and 0.31 ml of a 4 M hydrochloric acid is added. The mixture is then stirred at room temperature till the product precipitates. The crystals are filtered, washed with dioxane and ether and dried to give the title product. Mp=221-223° C. Optical rotation −8.0° (c=0.5, water).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][N:19]4[C:27]5[C:22](=[C:23]([O:28][C:29]6[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=6)[CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17](=[O:38])[CH2:18][N:19]4[C:27]5[C:22](=[C:23]([O:28][C:29]6[CH:37]=[CH:36][C:32]([CH2:33][OH:34])=[CH:31][N:30]=6)[CH:24]=[CH:25][CH:26]=5)[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc(Oc2cccc3c2CCN3CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)nc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CN1CCc2c(Oc3ccc(CO)cn3)cccc21)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
6-{1-[2-(4-Benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)-2-oxoethyl]-2,3-dihydro-1H-indol-4-yloxy}nicotinic acid (0.789 g, 1.53 mmol) was suspended in THF (15 mL). To the suspension were added triethylamine 0.234 mL, 1.68 mmol), then ethyl chloroformate (0.161 g, 1.68 mmol) under cooling in an ice-salt bath, and the resulting mixture was stirred for 30 minutes at the same temperature. The reaction mixture was filtered, and to the filtrate was added 80% solution of sodium borohydride (0.289 g, 7.64 mmol) in methanol (20 mL) under cooling with ice, and then the solution was stirred for 30 minutes at the same temperature. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (50 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to yield 0.671 g of the title compound as a pale brown amorphous powder.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])=[CH:27][C:26]=1[F:38].Cl>CN(C=O)C.O>[Cl:24][C:25]1[C:26]([F:38])=[CH:27][C:28]([C:32]2([C:34]([F:37])([F:35])[F:36])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:33]2)=[CH:29][C:30]=1[F:31]
Reactant: C=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(F)c(Cl)c(F)c4)(C(F)(F)F)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 34.4 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (200 mg, 0.98 mmol) in DMF (7 mL) at rt was added NCS (157 mg, 1.17 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. This mixture was added dropwise to a solution of 2-chloro-1,3-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (237 mg, 0.98 mmol) and TEA (218 mg, 2.16 mmol) in DMF (7 mL) at 0° C. The mixture was stirred at this temperature for 1 h, and then at rt overnight. The mixture was acidified with 3 N HCl to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, yield 35%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.82-7.73 (m, 3H), 7.71-7.60 (m, 2H), 4.50 (d, J=18.3 Hz, 1H), 4.44 (d, J=18.3 Hz, 1H), 1.51 (s, 3H), 1.50 (s, 3H) ppm; HPLC purity: 95.5% at 214 nm and 97.8% at 254 nm; MS: m/z=446 (M+1, ESI+).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]([P:32](Cl)(Cl)=[O:33])([CH3:31])([CH3:30])[CH3:29]>CCCCCC.C1CCCCC1>[C:28]([P:32]1(=[O:33])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][N:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)(C)P(=O)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC(C)(C)P1(=O)c2ccccc2CN1c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 8.2 %

Procedure:
Under a static nitrogen atmosphere at 26° C., a solution of n-butyllithium (3.93 g, 7.13 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. The reaction mixture was cooled to 0° C. and then a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2.5 hours at 26° C. and then cooled to 0° C. A solution of t-butylphosphonic dichloride (5.6 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension and the resulting mixture was stirred for 1.5 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 10 ml. of a saturated solution of ammonium chloride. The resulting mixture was concentrated in vacuo and the residue was partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then with water, dried over sodium sulfate and concentrated in vacuo to yield a red oil. The red oil was separated on a silica gel column using ethyl acetate as the eluant. Fractions containing the benzazaphosphole were combined and concentrated in vacuo to produce a crude product. The crude product was triturated with isopropyl ether and petroleum ether to yield a white solid. The white solid was recrystallized from isopropyl ether to yield 1-(t-butyl)-2-pheny-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 8% yield) as colorless needles having a melting point of 171°-172° C. and the following analysis:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(N)cc2)C1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
2-(4-Nitro-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.440 g, 1.08 mmol) was dissolved in Methanol (40 mL) and transferred to a Parr bottle containing 5% Platinum on Carbon, Sulfided (0.5%) (65 mg, 0.017 mmol). The mixture was shaken under an atmosphere of Hydrogen (10 psi) for 2 h, then filtered and conc. in vacuo to afford 2-(4-Amino-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.37 g, 91%). 1H-NMR (DMSO-d6): 6.88 (d, 2H, J=8.0 Hz), 6.51 (d, 2H, J=8.0 Hz), 5.00 (m, 3H), 4.26 (m, 1H), 3.77 (m, 2H), 3.16 (m, 1H), 2.84 (m, 2H), 1.39 (s, 9H), 1.35 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.O.OC1C2N=NNC=2C=CC=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][CH2:30][C:31](O)=[O:32].C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:31](=[O:32])[CH2:30][CH2:29][C:25]1[S:24][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: O=C(O)CCc1cccs1
Reactant: COc1ccc2c(c1)CCNC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C(=O)CCc1cccs1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6-methoxyisoquinoline (3.29 g), hydroxybenzotriazole monohydrate (5.72 g) and 3-(2-thienyl)propanoic acid (3.31 g) in 280 ml of dry tetrahydrofuran (THF) at 0° C. was added DCC (4.37 g) in one portion. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was filtered and concentrated. The residue was taken up into 200 ml of ethyl acetate (EtOAc) refiltered, washed with 5% aq. HCl (50 ml), 5% aq. NaCl (50 ml), 10% aq. KOH (50 ml), dried (MgSO4), filtered, and concentrated. Chromatography on silica gel (elution with 20% EtOAc:hexanes) afforded 4.54 g of the desired product.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[CH3:17]>CO>[CH3:17][N:8]1[CH:7]([CH2:6][CH2:5][OH:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:16]
Reactant: COC(=O)CC1c2ccccc2C(=O)N1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)c2ccccc2C1CCO
Reaction time: 8 h
Yield: 52.5 %

Procedure:
Sodium borohydride (4.1 g, 109.4 mmol) is added to a solution of 2,3-dihydro-2-methyl-3-oxo-1H-isoindole-1-acetic acid methyl ester (Synthesis, 1986:755) (4.8 g, 21.9 mmol) in 50 mL of MeOH at room temperature and stirred overnight. The reaction is quenched by addition of 100 mL of 2.0 N NaOH, and the MeOH is evaporated. The solution is extracted with CH2Cl2 (3×100 mL). The extracts are combined and dried over Na2SO4 and evaporated to give 2.2 g (52% yield) of 1,3-dihydro-2-methyl-3-(2-hydroxyethyl)-2H-isoindol-1-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>C1COCC1>[C:25]([O:24][C:22]([C:19]1([CH3:29])[N:16]2[C:17](=[O:18])[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:13][N:14]=[C:15]2[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 160.9 %

Procedure:
To a solution of intermediate 1g (200 mg, 0.519 mmol) in 5 mL THF at −78° C., was added a 1M solution of LIHMDS in THF (1.09 mL, 1.09 mmol). The mixture was stirred for 5 min, then MeI (162 mL, 2.60 mmol) was added. The mixture was stirred with warming to −30° C. over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc and washed with H2O and brine, dried (Na2SO4), and concentrated. The resultant residue was combined with additional crude material from another batch for purification by flash chromatography (stepwise gradient, 40 to 45 to 50% EtOAc/hexanes) to afford 59 mg of intermediate 19a (18%, based on 0.835 mmol of starting material). LR MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=C(O)C=CC=1C.[F:18][C:19]([F:38])([F:37])[C:20]1[O:24][C:23]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:28]2([OH:35])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]([CH2:25][C:23]3[O:24][C:20]([C:19]([F:38])([F:37])[F:18])=[CH:21][CH:22]=3)[C:27]2=[O:36])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 4-bromophenol to replace 3,4-dimethylphenol, and 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one was obtained (62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.49-7.37 (m, 2H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.25-7.17 (m, 1H), 7.03 (d, J=7.9 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.74-6.68 (m, 1H), 6.38-6.32 (m, 1H), 5.00-4.81 (m, 2H), 4.09 (s, 1H); MS (ES+) m/z 449.9 (M−17), 451.3 (M−17).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][N:4]1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[NH2:16])[CH3:2].C(OC([NH:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38](O)=[O:39])=O)(C)(C)C>>[NH2:24][C:25]1[S:29][C:28]([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=2[F:37])=[N:27][C:26]=1[C:38]([NH:16][C:11]1[CH:12]=[N:13][N:14]([CH3:15])[C:10]=1[N:4]1[CH2:5][CH2:6][N:7]([CH3:9])[CH2:8][C@H:3]1[CH2:1][CH3:2])=[O:39]
Reactant: CC[C@@H]1CN(C)CCN1c1c(N)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC[C@@H]1CN(C)CCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Yield: 28 %

Procedure:
Following the procedure for Example 110, (R)-5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-amine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 176 as a white solid (47 mg, 28% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.87 (s, 1H), 7.37-7.25 (m, 1H), 7.01 (t, J=8.8 Hz, 2H), 6.17 (s, 2H), 3.76 (s, 3H), 3.33 (t, J=11.3 Hz, 1H), 3.22 (t, J=9.2 Hz, 1H), 2.97 (t, J=12.7 Hz, 2H), 2.79 (d, J=11.0 Hz, 1H), 2.41-2.22 (m, 4H), 1.96 (t, J=10.2 Hz, 1H), 1.41-1.33 (m, 1H), 1.28-1.13 (m, 1H), 0.80 (t, J=7.5 Hz, 3H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:5][CH:4]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=3)[CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(Oc3ccc(C=O)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a solution of 56 (1.20 g, 6.0 mmol) and 4-fluorobenzaldehyde (745 mg, 6.0 mmol) in DMF (25 mL) was added cesium carbonate (3.90 g, 12.0 mmol). After stirring for 1 h at 100° C., the product was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was dissolved in dichloromethane and adsorbed onto silica gel and purified by flash chromatography using hexanes-ethyl acetate (6:1) to yield 57 (1.23 g, 67%) as a white solid after solvent removal.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10]CCSC)(=[O:4])[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=O)C=1>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][S:9][CH3:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCSCCCSC
Agent: O=C(OO)c1cccc(Cl)c1
Product: C=CC(=O)OCCCSC

Procedure:
Compound 4,8-dithianonyl acrylate (21) (4.86 g, 20.7 mmol), and mCPBA (9.34 g, 41.4 mmol) were reacted as described in Example 18. The crude product was obtained as a clear oil that was purified by column chromatography (silica gel, 20 wt % acetone/ether, 50 wt % acetone/ether, acetone) to furnish a colorless oil that solidified upon standing in the refrigerator (3.4 g, 27 wt % over three steps from 5) to give compound 24, methyl 3-(acryloyloxy) propyl sulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:20]=[O:21])[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:25]([O:19][C:13]1[C:12]([CH:20]=[O:21])=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([CH:22]([CH3:24])[CH3:23])[O:10]2)=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1oc2c(C=O)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2c(C=O)c(OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-4-oxo-4H-chromene-8-carbaldehyde (7.95 g, 23.2 mmol) and benzyl bromide (7.93 g, 46.4 mmol) in N,N-dimethylformamide (200 ml) is added K2CO3 (9.61 g, 69.5 mmol), and the reaction mixture is stirred at room temperature for 96 h. The mixture is poured into ice/water, extracted with CH2Cl2, dried (MgSO4) and concentrated in vacuo. The resulting solid residue is stirred with hexane/ethyl acetate for 1 h, the solvent is decanted, and the solid is stirred with hexane/diethyl ether for 16 h. The title compound is collected by filtration and washed with hexane to afford a pale brown solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([F:30])[CH:21]=2)[C:8]1=[O:33])[CH3:6])=[N+]=[N-].C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:1][CH2:4][C@H:5]([N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:32])[C:13]=2[NH:17][C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[C:22]([F:30])[CH:21]=2)[C:8]1=[O:33])[CH3:6]
Reactant: Cc1ccc2c(=O)n([C@H](C)CN=[N+]=[N-])ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(=O)n([C@H](C)CN)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A solution of (R)—N-(2-(1-azidopropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamide (0.6 g, 0.001 mol) in ethanol (50 mL, 0.8 mol) was heated at 85° C. A solution of ammonium chloride (0.6 g, 0.01 mol) in water (15 mL, 0.83 mol) was added followed by iron powder (0.6 g, 0.01 mol). The mixture was stirred at the same temperature for 3 hours and poured onto dichloromethane (200 mL) and extracted. The residue was purified by reverse phase HPLC to afford the desired product as a white solid (232 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:35]/[OH:36])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2-chloro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI−): m/z=469.1 ([M−H]−).