Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13](=[O:15])[CH3:14])[NH2:12])=[C:7]([N+:16]([O-])=O)[CH:6]=1)=[O:4].[H][H]>[Pd].COC(O)C>[NH2:16][C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][C:8]=1[N:11]([C:13](=[O:15])[CH3:14])[NH2:12]
Reactant: COC(=O)c1ccc(N(N)C(C)=O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Product: COC(=O)c1ccc(N(N)C(C)=O)c(N)c1
Yield: 85.6 %

Procedure:
2.5 g of 10% palladium-on-carbon catalyst were added to a solution of 25.3 g of 4-methoxycarbonyl-2-nitro-N-acetylphenylhydrazine in 380 ml of methoxyethanol and the mixture was hydrogenated in a shaking equipment until the hydrogen uptake ceased. After filtering off the catalyst, the filtrate was evaporated under reduced pressure and the residue was mixed with 100 ml of water. The separated crystals were filtered by suction, washed with water and dried at 80° C. Thus, 19.1 g (85.6%) of 2-amino-4-methoxycarbonyl-N-acetylphenylhydrazine were obtained as a beige crystalline solid, m.p.: 175°-178° C. After recrystallization from methanol, the m.p. was raised to 180°-182° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(C(C)C)c(C)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C(C)C)cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
1-(2-Hydroxy-5-isopropyl-4-methyl-phenyl)-ethanone (13 mg), 4-chloro-6,7-dimethoxyquinoline (30 mg), and 4-dimethylaminopyridine (25 mg) were suspended in o-dichlorobenzene (3 ml) to prepare a suspension which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (2 mg, yield 7%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)[CH:18]=1)[C:3]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:30]N1C(=O)CCC1=O>>[Cl:30][C:27]1[CH:28]=[C:19]([C:17]2[CH:18]=[C:13]([CH2:12][N:2]([CH3:1])[C:3]([C:5]3[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][N:6]=3)=[O:4])[CH:14]=[N:15][CH:16]=2)[CH:20]=[C:21]2[C:26]=1[NH:25][C:24](=[O:29])[CH2:23][CH2:22]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl
Product: CN(Cc1cncc(-c2cc(Cl)c3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 203, 3-chloro-pyridine-2-carboxylic acid methyl-[5-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 215) was reacted with N-chloro-succinimide to give the title compound as a light brown solid. MS: 441.5 (M+H+).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([OH:31])=O)[CH2:24]4)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.ClCCl>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:31])[CH2:24]4)[CH2:21][CH2:22]2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1c2ccccc2cc2ccccc12)N1CCC(N2CCC[C@@H](C(=O)N3CCOCC3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude (3R)-1′-(anthracene-9-carbonyl)-[1,4′]bipiperidinyl-3-carboxylic acid as prepared above (approx 22 mmol) was heated under reflux in a mixture of chloroform (75 mL, Aldrich, amylenes-stabilized) and thionyl chloride (10 mL, 0.137 mmol) until all the solid had dissolved. The mixture was diluted with toluene, evaporated to dryness under vacuum and anhydrous dichloromethane (40 mL) added. A mixture of morpholine (21 mmol, 1.81 mL) and triethylamine (62 mmol, 8.7 mL) in anhydrous dichloromethane (40 mL) was added and the solution was stirred for 16 hr at ambient temperature. The mixture was washed with ice-cold 0.1M sodium hydroxide solution, dried over anhydrous sodium sulfate, diluted with toluene and evaporated to dryness. The residue was purified by chromatography on 240 g silica gel eluting with a 4%-7%-10% methanol-dichloromethane gradient to give the title compound as a pale yellow glassy foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([OH:17])[CH:3]=1.Br[CH2:19][CH2:20][CH2:21]Br.[OH-].[Na+]>C(#N)C.ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:19][CH2:20][CH2:21][O:17][C:4]=2[CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1O)c1ccccc1
Reactant: BrCCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1ccccc1)N1CCCOc2cc(Cl)ccc21
Temperature: 60 °C
Yield: 83 %

Procedure:
N-(4-Chloro-2-hydroxy-phenyl)-benzamide from Example E25.1 (1.0 g, 4 mmol) was dissolved in acetonitrile (10 ml) and dichloromethane (15 ml). 1,3-Dibromopropane (3.26 g, 16 mmol), aliquat 336 (170 mg, 0.4 mmol) and sodium hydroxide (750 mg, 16 mmol) were added and the mixture was heated at 60° C. for 3 h. The solid was filtered off and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane) to yield the title compound (783 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5](=[NH:9])OCC.[NH3:15].[ClH:16]>C(O)C.C(OCC)C>[ClH:16].[CH3:1][O:2][C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([NH2:9])=[NH:15]
Reactant: CCOC(=N)c1cccc(C)c1OC
Reactant: N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1c(C)cccc1C(=N)N
Reaction time: 72 h

Procedure:
Ethyl 2-methoxy-3-methylbenzimidate borofluoride (28 g.) was mixed with a saturated anhydrous solution of ammonia in ethanol (46 ml.), the mixture was kept at room temperature in a stoppered vessel for 3 days and then evaporated to dryness in vacuo. The residue was dissolved in water (25 ml.) and treated with 5N sodium hydroxide solution (50 ml.). The solution was saturated with sodium chloride and extracted with diethyl ether. The extract was dried over potassium hydroxide and evaporated to give crude 2-methoxy-3-methylbenzamidine, m.p. 72°-74° C. This was dissolved in anhydrous ethanol (40 ml.) and the solution treated with a saturated anhydrous solution of hydrogen chloride in diethyl ether (100 ml.), and diluted with anhydrous diethyl ether (100 ml.). The solid which separated was filtered off and washed with anhydrous diethyl ether to give 2-methoxy-3-methylbenzamidine hydrochloride (17.8 g.), m.p. 208°-209° C. (with decomposition).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Ba+2:5].[C:6]([O-])(=O)C.C([O-])(=O)C.[Sr+2:14].C([O-])(=O)C.C(O)(=O)C.CC(C)[O-].[Ti+4:27].CC(C)[O-].CC(C)[O-].CC(C)[O-]>O>[CH3:6][CH:1]([CH3:2])[O-:4].[Ti+4:27].[CH3:6][CH:1]([CH3:2])[O-:4].[CH3:6][CH:1]([CH3:2])[O-:4].[CH3:6][CH:1]([CH3:2])[O-:4].[O-2:3].[O-2:3].[O-2:3].[O-2:3].[Ti+4:27].[Sr+2:14].[Ba+2:5]
Reactant: CC(=O)[O-]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Ba+2]
Solvent: O
Solvent: CC(=O)O
Product: [O-2]
Temperature: 85 °C

Procedure:
Equal molar amounts of barium acetate (1.57 g) and strontium acetate (3.51 g) were combined with acetic acid (5.6 ml) and the mixture heated at 85° C. for 1 hour to dissolve the salts. Titanium isopropoxide (3.51 g) was then added to the mixture. The resulting mixture had the desired a Ba:Sr:Ti molar ratio of 1:1:2. Deionized water (18 megohm) was added to achieve a water:titanium isopropoxide molar ratio of 1000:1 and form a barium strontium titanate sol.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](Cl)=[O:15].C(Cl)(Cl)Cl.[NH2:21][C:22]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:37]=[N:38][C:39]([C:42]3[N:46]=[C:45]([CH3:47])[O:44][N:43]=3)=[CH:40][CH:41]=2)=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>O>[CH3:47][C:45]1[O:44][N:43]=[C:42]([C:39]2[N:38]=[CH:37][C:36]([O:35][C:32]3[CH:33]=[CH:34][C:22]([NH:21][C:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=4)=[O:15])=[C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][C:26]4=[O:30])[CH:31]=3)=[CH:41][CH:40]=2)[N:46]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1nc(-c2ccc(Oc3ccc(N)c(CN4CCCC4=O)c3)cn2)no1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccc(Oc3ccc(NC(=O)c4ccccn4)c(CN4CCCC4=O)c3)cn2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
With cooling with ice, 0.33 ml of triethylamine and 210 mg of picolinic acid chloride were added to a chloroform (2 ml) solution of 144 mg of 1-(2-amino-5-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}benzyl)pyrrolidin-2-one, and stirred at room temperature for 1 hour. Water was added to it, extracted with chloroform, the organic layer was dried, the solvent was removed, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 2/8) to obtain 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide as a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:27]3[N:26]=[C:25]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:24]([CH2:37][CH2:38][CH2:39][CH:40]4[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[N:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][CH2:17][O:18][C:19]2[C:27]3[N:26]=[C:25]([CH2:28][O:29][C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[N:24]([CH2:37][CH2:38][CH2:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCCCN4CCCCC4CCN4CCCCC4)cccc32)CC1
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCCCN4CCCCC4CCN4CCCCC4)cccc3n2CCCC2CCNCC2)cc1

Procedure:
The title compound was prepared from (RS) 4-[3-[2-[2-(piperidin-1-yl)ethyl]piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]benzimidazole using trifluoroacetic acid deprotection as described supra.
Reaction SMILES: [NH:1]([C:35]([CH3:37])=[O:36])[C@H:2]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH:1]([C:35]([CH3:37])=[O:36])[C@H:2]([C:14]([N:16]1[CH2:34][CH2:33][CH2:32][C@H:17]1[C:18]([NH:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:19])=[O:15])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](CCCN)C(=O)N1CCC[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of Ac-Orn(Boc)-Pro-Gly-OBzl are dissolved in 5 ml of trifluoroacetic acid, and the solution is stirred at room temperature for 1 hour. After evaporation under high vacuum, 2.1 g of the trifluoroacetate of Ac-Orn-Pro-Gly-OBzl remain. Rf (system 2)=0.3; MS (FAB): 419 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][O:45][NH2:46]>>[CH3:44][O:45][N:46]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:43]=[CH:42][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CON
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Oc1ccccc1
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)Oc2ccccc2)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([O:18][CH:19]([O:27][CH2:28][CH3:29])[CH2:20][N:21]1[CH:25]=[C:24](I)[N:23]=[CH:22]1)[CH3:17].CC(OC)(C)C>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:24]3[N:23]=[CH:22][N:21]([CH2:20][CH:19]([O:27][CH2:28][CH3:29])[O:18][CH2:16][CH3:17])[CH:25]=3)[S:10][C:3]=12
Reactant: CCOC(Cn1cnc(I)c1)OCC
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(Cn1cnc(-c2cc3nccc(Cl)c3s2)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (9.26 g, 54.6 mmol) in THF (88 mL) at −15° C. was added n-BuLi (21.84 mL, 54.6 mmol). After 30 min, a solution of ZnCl2 0.5M in THF (109 mL, 54.6 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.841 g, 0.73 mmol) and iodide 260 (11.29 g, 36.4 mmol) in THF (33 mL) was added and the mixture was heated to reflux for 3 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 100/0 over 20 CV) to produce a material that upon trituration with. MTBE afforded the title compound 261 (1.2 g, 3.41 mmol, 9% yield) as light-brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][NH:16][C@@H:17]([CH3:27])[C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[OH:19])=[CH:11][CH:10]=2)O1.Br[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]=1[CH2:41][CH3:42].[F-].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH2:41]([C:33]1[CH:34]=[C:35]([C:36]([OH:38])=[O:37])[CH:39]=[CH:40][C:32]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][C@@H:17]([CH3:27])[C@H:18]([OH:19])[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[CH:28][CH:29]=1)[CH3:42]
Reactant: CCc1cc(C(=O)O)ccc1Br
Reactant: C[C@H](NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCc1cc(C(=O)O)ccc1-c1ccc(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)cc1
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
A mixture of 4-((1R,2S)-2-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethylamino}-1-hydroxypropyl)phenol (0.04 g), 4-bromo-3-ethylbenzoic acid (0.044 g), tetrakis(triphenylphosphine)palladium (0.011 g), cesium fluoride (0.088 g), 1,4-dioxane (0.6 mL), ethanol (0.12 mL) and water (0.2 mL) was stirred at 140° C. for 5 min in a sealed tube. After being cooled to room temperature, the reaction mixture was purified by SCX ion exchange column chromatography (2 g, preconditioning: tetrahydrofuran, washing solvent:tetrahydrofuran, eluent:2 mol/L ammonia in methanol), followed by reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 120 Å, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.010 g) as a white amorphous. The structure and physical data were shown in table 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[N+:17]([O-])=O)[CH3:2].[H][H]>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 12 h

Procedure:
Subsequently, crude 2-nitro-5-piperidin-1-yl-benzoic acid ethyl ester (3.8 g) was dissolved in methanol (35 ml), and platinum oxide (300 mg) was added to the solution at room temperature. The air in the reaction system was replaced by hydrogen, and the mixture was then stirred for 12 hr. After the completion of the reaction, the atmosphere in the reaction system was replaced by nitrogen, and the reaction solution was then filtered through Celite to remove platinum oxide, and was then concentrated under the reduced pressure to give crude 2-amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) as a useful intermediate (3.4 g, crude yield 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[NH:5][N:4]=1.C(O)C.N>O>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][N:4]=[C:3]2[NH:2][CH3:1]
Reactant: CNc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: N
Solvent: O
Solvent: CCO
Product: CNc1n[nH]c2ccc(N)cc12
Yield: 23.7 %

Procedure:
5-Amino-3-methylamino-1H-indazole can be obtained as described in Example 4 from 0.5 g of 3-methylamino-5-nitro-1H-indazole, 25 ml of ethanol, 5.2 g of ferrous sulfate, 8 ml of water and 6.2 ml of 32% aqueous ammonia. 0.1 g of 5-amino-3-methylamino-1H-indazole is thus obtained in the form of a cream powder melting at 215° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[C:18]#[N:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(N)ccc1C#N
Yield: 92.4 %

Procedure:
To a mixture of (2-cyano-5-nitrobenzyl)carbamic acid t-butyl ester (2.39 g) and ethanol (180 mL) there were added water (12 mL), saturated aqueous ammonium chloride (5 mL) and iron powder (2.02 g), under a nitrogen atmosphere. The mixture was heated to reflux for 2 hours and then filtered through Celite to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure to obtain a residue. The Celite and filtered substance were washed with ethyl acetate (400 mL) and water (200 mL) in that order, and this washed solution was combined with the previous residue. After sufficiently shaking the mixture, the organic layer was separated off and the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (1.97 g) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([O:17][CH3:18])(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.COCCOCCN(CCOCCOC)CCOCCOC>[CH3:1][N:2]([CH3:7])[S:3]([O:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=1[C:8]([O:17][CH3:18])=[O:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
Dimethylaminosulphonyl chloride (17.2 g)was added to a mixture of methyl salicylate (15.2 g) and potassium carbonate (27.6 g) in acetonitrile. The mixture was stirred at room temperature for 1 hour. TDA-1 (2.0 g) was added and the mixture stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in dichloromethane, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether. The solid was filtered off and purified by chromatography eluted with dichloromethane to give methyl 2-(dimethylaminosulphonyloxy)benzoate (17.4 g) as a white solid m.p. 75.5°-76.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][CH3:12])[C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24](OC)=[O:25])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]2[C:5]([CH:6]=[C:23]([C:17]3[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)[C:24](=[O:25])[N:11]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNc1c(C=O)cnc(Cl)c1C
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)c(C)c3n(C)c2=O)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 6-chloro-5-methyl-4-(methylamino)nicotinaldehyde (3.11 g, 16.8 mmol), methyl 2-(3,5-dimethoxyphenyl)acetate (4.25 g, 20.2 mmol) and potassium carbonate (2.8 g, 20.3 mmol) in N,N-dimethylformamide (100 mL) was stirred at 105° C. overnight. LCMS monitored the reaction was completed. The reaction mixture was cooled to RT and quenched by water. The precipitate was filtered and dried to get the title compound (5.5 g, crude) as a yellow solid. MS (ES+) C18H17ClN2O3 requires: 344, 346. found: 345, 347 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1([OH:11])[CH2:10][CH2:9]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[OH:11][C:8]1([C@H:2]([NH:1][C:13]2[CH2:17][S:16][C:15](=[O:18])[N:14]=2)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH2:10][CH2:9]1
Reactant: CN(C)C(=O)[C@@H](N)C1(O)CC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C1(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of (2S)-2-amino-2-(1-hydroxycyclopropyl)-N,N-dimethylethanamide (60 mg) in ethanol (1 mL) was added 4-thioxothiazolidin-2-one (51 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (13 mg).