Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]I.[OH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[CH2:13][CH2:14][CH2:15]C(O)=O.[Cl-].[NH4+].[CH2:21]1CCCCC1.CC[O:29][CH2:30][CH3:31]>>[OH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[CH2:13][CH2:14][CH2:15][C:30]([CH3:31])([OH:29])[CH3:21]
Reactant: Cc1cc(C)c(CCCC(=O)O)c(O)c1
Reactant: C1CCCCC1
Reactant: CCOCC
Agent: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C)c(CCCC(C)(C)O)c(O)c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
A 3M ethereal solution of methylmagnesium iodide (8 ml, 24 mM) was added dropwise to a stirred solution of the lactone (C) (1.8 g, 9.5 mM) in ether (42 ml) at 5° C. Stirring was continued at ambient temperature for 12 hours. The mixture was then cooled to 5° C., treated with excess saturated ammonium chloride solution and extracted with ether. The combined extracts were washed with brine, dried (Na2SO4) and the solvent removed by evaporation. The residual oil was purified by flash chromatography, eluting with dichloromethane/ethyl acetate (9:1 v/v increasing in polarity to 8:2 v/v) to give 5-(2-hydroxy-4,6-dimethylphenyl)-2-methylpentan-2-ol (D) (1 g, 48% yield), m.p. 128° C. (after recrystallisation from cyclohexane); NMR (d6 -DMSO): 0.95(6H,s), 1.33(4H,m), 1.97(3H,s), 2.01(3H,s), 2.37(2H,s), 6.24(1H,s), 6.28(1H,s); microanalysis, found: C, 75.6; H,10.2%; C14H22O2 requires: C,75.6; H,10.0%.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCCCCCCCCCCCNC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 600g 2-chloro-5-nitrobenzoic acid, 900g methyltetradecylamine (84%, tertiary amines as impurities) and 500 ml triethylamine was heated on a steam bath for 7 hours and then poured into 2 liters of water and made acid with HCl. The reaction product was filtered, air dried and then recrystallized from methanol and then from petroleum ether. Yield: 820g, m.p. = 100°-101°.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+].CO.Cl>O>[C:3]1([CH:8]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CC(=O)c1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 4.02 g (29.5 mmol) of 2'-hydroxyacetophenone, 1.94 g (14.5 mmol) of 1,3-benzodicarboxaldehyde, 6.67 g NaOH (in 15 mL of water) and 100 mL MeOH was stirred for 21 hours before the solution was poured into 800 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystallization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 20 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 17% overall yield. MP: 316°-318° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.2. Extinction coefficient εmax (M-1 cm-1) 26,000. λmax (abs)=345 nm and λmax (em)=525 nm.
Reaction SMILES: [NH2:1][S:2](C1C=C(C2C=CC=CC=2)C=CC=1C(OC)=O)(=[O:4])=[O:3].C1N2CCN(CC2)C1.C([N:33]=[C:34]=[O:35])CCC.[C:36](Cl)(Cl)=[O:37]>>[S:2]([N:1]=[C:36]=[O:37])([N:33]=[C:34]=[O:35])(=[O:3])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: CCCCN=C=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Product: O=C=NS(=O)(=O)N=C=O

Procedure:
The sulfonamide of Example 5 (5.0 g) was stirred in 75 mL dry xylenes with 0.1 g DABCO® and 1.9 mL n-butylisocyanate, then heated to reflux (138°) with a dry ice condenser in place. Phosgene gas was introduced into the vessel above the liquid level until the reaction temperature dropped below 130°. As phosgene was absorbed by the reactants, a gradual rise in reaction temperature was observed. Heating was continued until the reaction temperature remained constant, indicating complete consumption of the sulfonamide starting material (ca. 2 hrs). Evaporation of the xylenes after filtration under nitrogen to remove traces of solid gave crude sulfonyl isocyanate as a viscous oil, IR (neat) 2250 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)CC1(N)CCCC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC1(NCc2ccc(F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A solution of (1-amino-cyclopentyl)-acetic acid methyl ester (318 mg, 2.02 mmol) in anhydrous methanol (10 mL) was treated with 4-fluoro-benzaldehyde (0.27 mL, 2.56 mmol) and stirred at 25° C. under a nitrogen environment. After 10 min, glacial acetic acid (0.384 mL, 6.71 mmol) and sodium triacetoxyborohydride (1.1 g, 5.05 mmol) were added sequentially, and the resulting mixture was stirred at 25° C. for 18 h. The reaction was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (270 mg, 50%) as a colorless oil. LC-MS (ESI) calculated for C15H20FNO2: 265.3, found 266.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([CH2:10][CH3:11])[CH:3]1[CH2:12][CH2:13][CH3:14].[C:15]([OH:18])(=[O:17])[CH3:16]>O>[C:15]([O-:18])(=[O:17])[CH3:16].[CH3:1][N+:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCC1C(CC)=CC(CC)=CN1C
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)[O-]
Product: CCCc1c(CC)cc(CC)c[n+]1C
Yield: 96 %

Procedure:
A sample of 38.6 g of 1-methyl-2-propyl-3,5-diethyl 1,2-dihydropyridine was added to a mixture of 12 grams of acetic acid and 26 grams of water. The mixture was stirred and air was introduced for 18 hours. The resulting aqueous phase was evaporated under diminished pressure to yield 48.2 grams of 1-methyl-2-propyl-3,5 diethylpyridinium acetate, identical to the product described in example 1.
Reaction SMILES: [CH2:1]=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].N>CO.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:1])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: C=O
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(C2CCN(C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.042 ml) at 0° C. was added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (178 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Then sodium triacetoxyhydroborate (121 mg) was added and the mixture was stirred for 5 minutes at 25° C. A solution of ammonia in methanol 7N (2 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness, then the resulting solid was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (125 mg) as a solid; NMR Spectrum: (DMSOd6) 1.88-2.11 (m, 6H), 2.21 (s, 3H), 2.33 (s, 3H), 2.81-2.93 (m, 2H), 3.97-4.11 (m, 1H), 7.38-7.50 (m, 2H), 7.65 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+: 389
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38]CC3C=CC=CC=3)=[C:22]([C:24]3[NH:25][C:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[C:27](Cl)[N:28]=3)[N:23]=[C:12]21)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([OH:38])=[C:22]([C:24]3[NH:28][CH:27]=[C:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[N:25]=3)[N:23]=[C:12]21
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(-c2nc(Cl)c(Cc3ccc(F)cc3)[nH]2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NC12CCC(CC1)Cn1c2nc(-c2nc(Cc3ccc(F)cc3)c[nH]2)c(O)c1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1H-imidazol-2-yl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 6 (60 mg, 0.092 mmol) in MeOH (3 mL) was added formic acid (0.100 mL, 2.65 mmol) followed by 10% Pd/C (98 mg, 0.092 mmol) and the mixture stirred at 40° C. for 3 h. After cooling to room temperature, the mixture was filtered through a pad of celite and concentrated. The mixture was then treated with sat. NaHCO3, extracted with dichloromethnae (×4), dried (Na2SO4), filtered and concentrated to afford the title compound (30 mg, 83% yield) as a light purple solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.53-1.60 (m, 2H), 1.73-1.81 (m, 6H), 2.37 (br. s., 1H), 2.51-2.54 (m, 2H), 3.93-3.99 (m, 2H), 4.01 (d, J=3.66 Hz, 2H), 7.10-7.17 (m, 3H), 7.30 (dd, J=8.24, 5.80 Hz, 2H). LCMS (M+H)=396.13.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:35][N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[C:21]2[C:25]=1[N:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:23]=[CH:22]2.[NH:42]1CCNC[CH2:43]1.C[Si](C#N)(C)C>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:35]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:43]#[N:42])=[C:21]2[C:25]=1[N:24]([S:26]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH:23]=[CH:22]2
Reactant: COc1ccc(CN2CCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c12
Reactant: C1CNCCN1
Agent: C[Si](C)(C)C#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(C#N)N2CCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c12

Procedure:
1-Benzenesulfonyl-7-methoxy-1H-indole-4-carbaldehyde (50 mg, 0.2 mmol, prepared as in Example 79), piperazine (28 mg, 0.3 mmol) and methanol (0.5 mL) was charged into a tube suitable for microwave irradiation. The mixture was heated at 100° for 1 min in the microwave oven. Trimethylsilyl cyanide (21 μl, 0.2 mmol) was added and the heat treatment, 100° 1 min, was repeated. LCMS indicated the formation of expected product. The crude product was purified using prep LC on a YMC column (24-52% MeCN over 16 min). Obtained 26.2 mg (40%). MS ESI+ for C16H13NO4S, m/z 325 (M-piperazine)+, m/z 384 (M-nitrile)+, m/z 411 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(=O)[NH:11]C(=O)C2=CC=CC=C12.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([CH2:28]Cl)[C:20]=1[Cl:30]>>[Cl:30][C:20]1[C:19]([Cl:18])=[CH:24][CH:23]=[C:22]([N+:25]([O-:27])=[O:26])[C:21]=1[CH2:28][NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NCc1c([N+](=O)[O-])ccc(Cl)c1Cl
Yield: 75 %

Procedure:
Potassium carbonate and 2 equivalents of phthalimide are ground together and heated to reflux with 2 equivalents of 1,2-dichloro-3-chloromethyl-4-nitrobenzene for three hours. Upon cooling, the substituted benzylphthalimide crystallizes and is filtered in 60-80% yield. 2,3-Dichloro-6-nitrobenzylamine is obtained in a 75-95% yield with acid hydrolysis using hydrochloric acid from the substituted benzylphthalimide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([N:31]1[CH:35]=[N:34][C:33]([C:36](O)=[O:37])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:33]1[N:34]=[CH:35][N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1)=[O:37])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=C(O)c1ncn(Cc2ccccc2)n1
Product: CCOC(=O)C(C(=O)c1ncn(Cc2ccccc2)n1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (1.1 g, 50%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid. MS: 517.2 (MH+).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])=[CH:4][C:3]=2[O:2]1.C(O)(=O)C.COCCOC>[H][H].[Pt](=O)=O>[CH3:16][C:11]([NH2:13])([CH3:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: COCCOC
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc2c(c1)OCO2
Yield: 72.2 %

Procedure:
A mixture of 0.8 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane, 100 mg of platinum dioxide, one ml of acetic acid and 20 ml of 1,2-dimethoxyethane is shaken at 60°-70° C. for 18 hours in hydrogen gas atmosphere under elevated pressure (initial pressure: 80 atmospheric pressures). After the reaction, the insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is extracted with 5% hydrochloric acid. The extract is alkalized with potassium carbonate, and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. The residue (oil) is distilled at 100°-120° C. (bath temperature) under reduced pressure (0.04 mm Hg). 0.5 g of α,α-dimethyl-3,4-methylenedioxyphenethylamine are thereby obtained as an oil.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22](=O)[CH3:23]>C(#N)C>[CH3:23][C:22]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: CC(=O)c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1sc2ccncc2c1C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol) and triethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at room temperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g, 0.042 mol). The reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature, the solvent was evaporated and the residue obtained partitioned between ethyl acetate and water. The organic layer was dried over anhydrous NaHSO4, filtered and concentrated. The oily residue was passed through a pad of silica (ethyl acetate/hexane: 5/1) to afford ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g, 22%). LCMS (FA) ES+ 222; 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH2:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:30][CH2:29][C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(=O)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NCc1ccc(Cl)cc1Cl)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step C in 100 mL of dichloromethane was added 1.41 mL (12.0 mL) of 1-(2,4-dichlorophenyl)methanamine, followed by 2.54 g (12.0 mmol) of sodium triacetoxyborohydride, and 0.960 mL (16.0 mmol) of acetic acid. After 16 h at ambient temperature, the reaction was quenched with an equal volume of saturated aqueous NaHCO3. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried (Na2SO4), and concentrated in vacuo, affording a yellow solid. Purification by flash chromatography (15% EtOAc in hexane) afforded the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[NH:18][CH2:17][CH2:16][S:15]1)=[O:13].[OH:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[N+:5]([O-:35])[CH:6]=[C:7]([Cl:34])[C:8]=1[CH2:9][C@@H:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[C:21]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)[CH:20]=1)[O:11][C:12]([C@H:14]1[N:18]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[C:37]([OH:36])[CH:38]=2)[CH2:17][CH2:16][S:15]1)=[O:13]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide hydrochloride (I5, 300 mg, 0.52 mmol) in DCM (2 mL) was added 3-hydroxybenzaldehyde (172 mg, 1.2 mmol) followed by glacial AcOH (0.11 mL, 2.08 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (500 mg, 2.26 mmol) was added and the reaction was stirred at room temperature for 4 h. DCM (50 mL) and 1 N HCl (20 mL) were added to quench the reaction. The layers were separated and the organic layer washed with 1 N HCl (2×20 mL), passed through a hydrophobic fit and the solvent was removed in vacuo to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH2:21])[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:30]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH:21][S:43]([C:40]1[CH:39]=[CH:38][C:37]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:12][C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H](CC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCOCC1)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of the title B compound, (2R)-amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride (420 mg, 1.28 mmol) in 5 mL of dichloromethane is treated with triethylamine (345 mg, 2.82 mmol) followed by a solution of 4-phenoxybenzenesulfonyl chloride (345 mg, 1.28 mmol) in 2 mL of dichloromethane. The reaction is stirred for 16 h, then partitioned between dichloromethane and water. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated. Chomatography on silica gel (eluant; 3% MeOH in dichloromethane) affords 430 mg (64%) of (2R)-(4-phenyloxybenzenesulfonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>CCO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:27]=[CH:26][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]([NH:28][OH:29])=[NH:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a stirred suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 57) (355 mg, 1 mmol) in EtOH (60 mL) was added at 23° C. over 6 h 50% aqueous hydroxylamine solution (3.48 mL, 60 mmol) in 6 portions. The mixture was cooled in the ice-bath, diluted with H2O (100 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with water and Et2O, and triturated with ethyl acetate to give the title compound as light yellow solid (336 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20]Br>CN(C)C=O>[Br:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxybenzaldehyde (11.5 g, 0.52 mol) in dimethylformamide (220 ml) was added cesium carbonate (50.7 g, 1.56 mol). The mixture was stirred at ambient temperature for 30 min, then 1,2-dibromoethane (12.76 g, 0.68 mol) were added. After heating at 80° for 4 h, the dimethylformamide was removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried. The crude product was purified by flash column chromatography (silica gel, 4:1 hexane:ethyl acetate) to give the desired compound as an off-white solid (9.57 g, 75%).