Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12](O)[CH2:11]2)=[CH:5][CH:4]=1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12]([N:32]([C:28]3[CH:27]=[C:26]4[C:31](=[CH:30][CH:29]=3)[N:22]=[CH:23][CH:24]=[CH:25]4)[S:33]([CH3:36])(=[O:34])=[O:35])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CS(=O)(=O)Nc1ccc2ncccc2c1
Agent: Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(c1ccc2ncccc2c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
reaction of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol hydrobromide with N-quinolin-6-ylmethanesulfonamide in the presence of DIAD and triphenylphosphine in toluene, to form N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-yl-methylsulfonamide (the reaction is preferably performed at a temperature of between 40 and 60° C.), and then
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:18][CH:17]([C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]4[CH:33]=[CH:34][N:35]=[C:29]4[CH:28]=3)=[O:24])=[CH:21][CH:20]=2)[CH2:16]1.[H-].[Na+].[CH3:40][CH:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>O1CCCC1>[N:35]1[CH:34]=[CH:33][N:30]2[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([CH:17]4[CH2:18][N:15]([S:43]([CH:41]([CH3:42])[CH3:40])(=[O:45])=[O:44])[CH2:16]4)=[CH:37][CH:36]=3)=[CH:28][C:29]=12
Reactant: CC(C)S(=O)(=O)Cl
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N1CC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1
Reaction time: 1 h

Procedure:
In a 4 mL vial was mixed 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide bis(2,2,2-trifluoroacetate) (60 mg, 0.112 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature. To this mixture was added in portions 60% sodium hydride in mineral oil (22.45 mg, 0.561 mmol). This heterogeneous mixture was stirred 1 hour. To this was added propane-2-sulfonyl chloride (0.015 mL, 0.135 mmol) at and reaction mixture was stirred for 3 hours. The mixture was quenched with water, and product was extracted with 10% methanol/dichloromethane. The organic layers were combined, concentrated and purified by normal phase chromatography to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (m, 1H), 8.47 (d, J=7.0 Hz, 1H), 7.90 (m, 3H), 7.48 (m, 3H), 7.37 (s, 1H), 6.84 (m, 1H), 4.50 (d, J=5.9 Hz, 2H), 4.22 (m, 2H), 3.93 (m, 3H), 3.48 (m, 1H), 1.25 (d, J=5.9 Hz, 6H); MS (ESI(+)) m/e 413 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH2:23]1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][CH:24]3[CH2:25][CH2:26][CH2:27][NH:22][CH2:23]3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCC1CCCNC1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCC2CCCNC2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-piperidin-3-ylpropanoyl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(3-piperidin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:10][CH:11]2[CH:15]([CH:16]=1)[CH2:14][C:13](=[O:17])[CH2:12]2)#[N:2].[OH-:18].[K+]>C(O)(C)(C)C>[O:17]=[C:13]1[CH2:12][CH:11]2[CH:15]([CH2:16][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]([NH2:2])=[O:18])[CH2:10]2)[CH2:14]1
Reactant: [OH-]
Reactant: N#Cc1ccccc1C1=CC2CC(=O)CC2C1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccccc1C1CC2CC(=O)CC2C1
Yield: 111 %

Procedure:
5-(2-Cyano-phenyl)-3,3a,4,6a-tetrahydro-1H-pentalen-2-one, ethylene ketal (0.25 g, 0.935 mmol) and powdered potassium hydroxide (0.5 g, 8.9 mmol) in t-butanol (5 mL0 were refluxed for 2 hours. After concentration, the reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 0.296 g (111%) 2-(5-oxo-octahydro-pentalen-2-yl)-benzamide, ethylene ketal as light yellow oil which solidified upon standing. A portion was triturated with hexanes to give a dull yellow solid which had the following properties: mp 111-1 12.5° C.; NMR (CDCl3) δ 7.66 (dd, J1=7.5 Hz, J2=1.5 Hz, 1H), 7.36-7.18 (m, 3H), 6.56 (br s, 2H),5.71 (t, J=2.1 Hz, 1H), 3.88-3.82 (m, 4H), 3.44-3.33 (m, 1H), 3.03-2.87 (m, 2H), 2.63-2.49 (m, 1H), 2.11-1.93 (m, 2H), 1.78-1.67 (m, 2H); 13C NMR (CDCl3) δ 171.65, 141.48, 136.24, 134.20, 133.69, 130.33, 129.10, 128.96, 127.33, 118.19, 64.43, 64.11, 49.78, 43.68, 42.80, 39.83, 39.19; IR(KBr) 3386, 3171, 2967, 2940, 2897, 1666, 1387, 1325, 1111, 781, 771, 631; Anal. calculated for C17H13NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.39; H, 6.85; N, 4.92.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+].[CH2:21]1COCC1>O.Cl>[CH3:21][CH:9]1[CH2:10][CH2:11][CH2:12][C:8]1([C:6](=[O:7])[NH:5][CH2:4][CH2:3][CH:2]([CH3:17])[CH3:1])[C:13]([OH:15])=[O:14]
Reactant: COC(=O)C1(C(=O)NCCC(C)C)CCCC1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCNC(=O)C1(C(=O)O)CCCC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of methyl 1-[N-(3-methylbutyl)carbamoyl]cyclopentanecarboxylate (820 mg, 3.4 mmol) in 25 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (260 mg, 6.12 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 700 mg (90%) of methyl 1-[N-(3-methylbutyl)carbamoyl]-cyclopentanecarboxylic acid as a white solid. MS [M+H]+ 228.
Reaction SMILES: [C:1]([CH:5]1[CH2:10]C[C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[C:23](=[O:26])(O)[O-:24].[Na+]>ClCCl>[C:1]([CH:5]1[CH2:10][O:24][C:23](=[O:26])[CH2:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C1CCCC(=O)OC1

Procedure:
This was prepared in the same manner as Lactone 1 except using 4-tert butylcyclohexanone (10 parts, 0.065 m ex. Aldrich), 3-chloroperoxybenzoic acid (17.5 parts, 0.0713M), sodium bicarbonate (11.5 parts, 0.143M) and dichloromethane (750 ml) in place of the 3-methyl cyclohexanone and amounts described for Lactone 1. The product was obtained as an oil (10.2 parts).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C@:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@]12CCCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC12CCCCC1CN(C(=O)OCc1ccccc1)C2
Yield: 6.2 %

Procedure:
The racemate (1R*,6S*)-8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (6.65 g, 17.8 mmol) was optically resolved by an optically active column (CHIRALPAK AD, 20 mm diameter×250 mm, hexane:isopropyl alcohol=95:5, flow rate=20 ml/min) to give optically active 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer A) (427 mg, 1.14 mmol, retention time=14.2 min) and its optically active enantiomer 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer B) (415 mg, 1.11 mmol, retention time=19.4 min).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][C:37]=4[CH3:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnccc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnccc3C)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M211) (304 mg, 0.545 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (177 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([N:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=1)=O.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[N:8]=2)=[O:27]
Reactant: CCC(=O)c1ccc(C(F)(F)F)nc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Yield: 53.6 %

Procedure:
In a 250 mL pear-shaped flask, N-phenyl-N-(3-propionyl-6-trifluoromethyl-pyridin-2-yl)-oxalamic acid methyl ester (1.74 g, 4.58 mmol) was combined with methanol (25 mL) to give a yellow solution. Potassium carbonate (3.8 g, 27.5 mmol) was added and the reaction mixture was refluxed for 2 hr. The reaction mixture was cooled, diluted with H2O (75 mL) and extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with brine (1×50 mL), dried over MgSO4, and concentrated in vacuo to give 1.7 g crude product as a yellow solid. The crude material was purified by flash chromatography (silica gel, 120 g, 20% to 50% ethyl acetate in hexanes) to give 3-methyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (0.89 g, 3.7%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 8.84 (d, J=8.2 Hz, 1H) 7.91 (d, J=8.2 Hz, 1H) 7.32-7.70 (m, 5H) 3.51 (s, 3H) 2.01 (s, 3H). MS calcd. for C18H13F3N2O3 [(M+H)+] 363.0, obsd. 363.0.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:18])[CH3:17]>CN(C=O)C>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][C:16](=[O:18])[CH3:17])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC12CC(N)(C1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC12CC(OC(C)=O)(C1)C2
Temperature: 25 °C

Procedure:
To a DMF (2 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol) is added sodium bicarbonate (3 mmol) and then acetyl chloride (1 mmol) by syringe at 0° C. The reaction is allowed to warm up to r.t. and monitored by LCMS. After LCMS analysis indicated consumption of starting material, the reaction is diluted with water and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(=O)OC(C)(C)C)[C:10](=[O:32])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:20]=[C:19]4[NH:29][CH:30]=[CH:31][C:18]=34)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][N:20]=[C:19]3[NH:29][CH:30]=[CH:31][C:18]=23)[CH2:13][CH2:12]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-oxo-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-2-ylcarbamate (0.020 g, 0.036 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.015 g, 79% yield) as the dihydrochloride salt. MS ESI (+) m/z 460 detected.
Reaction SMILES: [C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([O:4][C:5]1[C:12]([O:13][CH3:14])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2]
Reactant: COc1cccc(C=O)c1OC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c([N+](=O)[O-])ccc(C=O)c1OC(C)=O
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
42 (42.0 g, 0.22 mol) was added portionwise as a finely ground powder over 1 h to a solution of concentrated sulphuric acid (28 mL) in 100% nitric acid (140 mL) at −20° C. During the addition, the reaction temperature was maintained at around −15° C. The reaction mixture was stirred at −5° C. for a further 40 min, then poured into to ice/water (1 L) and extracted rapidly with toluene (2×). The organic phase was washed successively with 0.25 M NaHCO3 aq. water and brine, dried (Na2SO4) and evaporated to dryness to give crude product (19.8 g) as a yellow oil, which was shown by NMR to contain ˜60% nitro-compounds. Purification of 8 g of this material by column chromatography (three times, SiO2, first eluting with 1:9 EtOAc:cyclohexane, then with 3:7 EtOAc:cyclohexane and finally with 1:1 EtOAc:cyclohexane) gave 43 (2.53 g) in (˜80% purity) together with 2-hydroxy-3-methoxy-4-nitrobenzaldehyde (˜10%). The product was used as such in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][OH:13].Cl.C([O-])([O-])=O.[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CCO.O>[OH:13][NH:12][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(C(=O)O)cc1
Yield: 55 %

Procedure:
To 4-cyanobenzoic acid (5 g, 34.0 mmol) in EtOH (150 mL) were added NH2OH.HCl (4.96 g, 71.4 mmol) in water (15 mL) and K2CO3 (7.51 g, 54.4 mmol) in water (30 mL) then 8-hydroxyquinoline (0.064 g, 0.442 mmol). The reaction was stirred at reflux temperature for 4 h. The solvent was removed in vacuo. Water (150 mL) was added and the pH adjusted to 3 using 2M HCl. The white precipitate was filtered off and washed with water to yield E-50734-EXPO37 (3.37 g, 18.71 mmol, 55.0% yield) as a white solid. The mother liquor was extracted with ethyl acetate (75 mL) twice. The combined organics were dried, filtered and condensed in vacuo to obtain: 571 mg (2.54 mmol, 8.0%, 80% purity) as green solid.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH2:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:20]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Product: Fc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 3,4-difluorobenzylamine (0.5 ml) as described above; yield: 0.049 g (15.8%); MS m/z: 312.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 5.36 (s, 2H); 6.81-6.84 (m, 1H); 7.13-7.19 (m, 1H); 7.29-7.36 (m, 1H); 7.59 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 7.82 (d, 1H, 3J=8.7 Hz); 7.88 (d, 1H, 4J=1.7 Hz); 8.77 (s, 1H); 9.03 (s, 1H); HPLC (METHOD [A]): it 8.82 min (95.6%)
Reaction SMILES: [O:1]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14](C)=[O:15].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[O:1]([CH:8]([CH3:12])[CH2:9][C:10]([O:15][CH2:14][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCO)Oc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCOC(=O)CC(C)Oc1ccccc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 3.15 g of the crude alcohol 27 (prepared in 30-(3)) in 80 ml of acetone is added 10 ml of 8N Jones' reagent at 20° C. to 30° C. dropwise. The mixture is stirred for additional 10 minutes, and 3 ml of isopropyl alcohol is added thereto. The resulting mixture is stirred for 10 minutes and acetone is evaporated under reduced pressure. Water is added to the residue, and the residue is extracted with ethyl acetate twice. The organic layer is washed with water and then extracted with 1N aqueous solution of sodium hydroxide. The aqueous layer is acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate again. The ethyl acetate extract is washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is dissolved in 50 ml of ether and an ethereal solution of diazoethane is added at 0° C. until the orange color persists. The reaction mixture is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (50 of silica gel, ethyl acetate-n-hexane=1:19) to give 2.35 g of the desired ethyl ester 28 as an oil in 67.0% yield from the compound 26.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CC(N(C)C)=O.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](Cl)=[O:25]>O>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([C:24]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Under ice-cooling, 660 mg (3.56 mmol) of methyl 2-amino-5-chlorobenzoate was added to a DMAc (10 mL) solution comprising 1.00 g (3.62 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was stirred for a short time. Thereafter, the precipitates were collected by filtration, washed with water, and then air-dried, thereby giving methyl 2-({[3,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-5-chlorobenzoate (yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a solution of 0.16 g of ethyl (E)-3-[3-(3-fluorophenyl)-1H-5-indazolyl]-2-propenoate in methanol was added 1 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with diluted hydrochloric acid to be acidic and was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 90 mg of the title compound as a colorless powder.
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:16]1([Mg]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C1COCC1>[CH:16]1([C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)C1CCCCC1
Temperature: 25 °C
Yield: 24.9 %

Procedure:
To a tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (400 mg, 1.83 mmol) in THF (10 mL) was added cyclohexylmagnesium chloride (4.12 mL, 8.24 mmol) portionwise at room temperature under N2 atmosphere. As addition of the Grignard reagent was completed, the reaction mixture was stirred and heated to reflux for an hour. Then the mixture was allowed to cool down to room temperature. The reaction was quenched by adding water (10 mL) slowly. 1N HCl solution (30 mL) was added to the mixture, and extracted with EtOAc (20 mL×3). The combined organic layers were collected and evaporated in vacuo. The crude material was purified by column chromatography (hexane: EtOAc=10:1 to 5:1) to yield the desired product (110 mg, 25%).