Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:23]([N:26](CC2C=CC(OC)=CC=2OC)[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:24])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(C#N)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 70.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using 3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (195 mg, 0.32 mmol) prepared in Example 55a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (102 mg, 70%) as a colorless solid.
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[CH3:13][N:14]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20](O)=[C:19](O)[CH:18]=1)[NH2:15]>>[CH3:13][N:14]([C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:19]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=1)[NH2:15]
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: CN(N)C(=O)c1ccc(O)c(O)c1
Product: CN(N)C(=O)c1ccc([Si](C)(C)C)c([Si](C)(C)C)c1
Temperature: 50 °C

Procedure:
9.53 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.051 mol) was added to a suspension of 4.2 g of 3,4-dihydroxybenzoic acid, 1-methylhydrazide (0.023 mol). After warming the suspension to 50° C. for one hour, a clear solution of 3,4-bis(trimethylsilyl)benzoic acid, 1-methylhydrazide was obtained.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][C:20]#[N:21])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C1COCC1.CO>C1COCC1>[NH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([C:2]2([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][S:8]([CH:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCC#N)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 27.6 %

Procedure:
Into a 50 mL 3 neck flask with stirrer, borane-THF complex (2 mL, 1M solution) was added syringe wise to 2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclopentyl)phenoxy]ethanenitrile (125 mg, 0.37 mmol) in THF (10 mL) while stirring at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred overnight. 3 mL of 1:1 THF/Methanol solution was then added by syringe with severe foaming. After the foaming subsided, the solution was concentrated under reduced vacuum to yield 85 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron® and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 9:1 to yield the intermediate title compound (35 mg) as an oil. Ion spray M.S. 341.4 (M*−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH2:13]([S:29](Cl)(=[O:31])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>N1C=CC=CC=1>[CH2:13]([S:29]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)(=[O:31])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 51.4 g (0.33 mole) 8-amino-2-naphthol in 500 ml pyridine was cooled to 0° and treated with 108.0 g (0.33 mole) hexadecanesulfonyl chloride. The mixture was stirred briefly at 0° C. and overnight at room temperature, then poured into ice water containing 500 ml concentrated hydrochloric acid. The solid was collected, washed, dried, and recrystallized from benzene to give 100 g of product, m.p. 103.5°-107° C.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O:12]CC)=[O:11].[OH-].[Na+:16]>O1CCCC1>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][C:2]=1[C:10]([O-:12])=[O:11].[Na+:16]
Reactant: CCOC(=O)c1nc2ccncc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl thiazolo[5,4-c]pyridine-2-carboxylate (J. Heterocyclic Chem., 27, 563(1990) (0.61 g) was dissolved in tetrahydrofuran (12 ml). To the resulting solution, a 1N aqueous sodium hydroxide solution (3 ml) was added, followed by stirring at room temperature for 30 minutes. The insoluble matter was collected by filtration. Without purification, it was provided for the subsequent reaction as it was.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[F:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:50]([C:49]1[CH:53]=[CH:54][C:46]([F:45])=[CH:47][CH:48]=1)=[O:51]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C(O)(=O)COCCOCC(O)=O.C(Cl)(=O)C(Cl)=O.N[C:20]1[C:33]2[C:34]3=[C:35]4[C:30](=[CH:31][CH:32]=2)[CH:29]=[CH:28][CH:27]=[C:26]4[CH:25]=[CH:24][C:23]3=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:27]1[C:26]2[C:35]3=[C:34]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:33]4[CH:32]=[CH:31][C:30]3=[CH:29][CH:28]=1
Reactant: Nc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)COCCOCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
3,6-dioxaoctanedioic acid (0.28 mmol) was dispersed in 100 ml of dichloromethane (CH2Cl2) in which 0.1 ml of oxalyl chloride ((COCl)2) and 15 μl of DMF were added, to prepare a solution. After the solution was stirred at ambient temperature for 4 hours, volatiles were removed from the solution and the residue was re-dissolved in a small amount of dichloromethane. After the solution was added slowly to dichloromethane solution in which 152 mg (0.70 mmol) of 1-aminopyrene and 0.2 ml (1.4 mmol) of triethylamine were dissolved, the solution was reacted at ambient temperature for 4 hours and the volatiles were removed. And then, the resulting product was partitioned between water and dichloromethane and the organic phase was separated and washed with water; the solvent was removed from the obtained organic phase; and then, re-crystallization was carried out with a solvent combination of dichloromethane and methanol. The target product, a pyrene compound of 3,6-dioctanedioic acid was obtained (reddish green solid, yield: 65%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:14]([O-])=[O:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.C(OC(Cl)=O)C>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@@H:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][OH:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CC(=O)[O-])NC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@@H](CCO)NC(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.05 h

Procedure:
29.23 g of N-[(phenylmethoxy)carbonyl]-D-aspartic acid, 1,1-dimethylethyl ester, prepared as in Example C, in 120 mL dry tetrahydrofuran at -10° C. was treated with 10 mL N-methylmorpholine. The mixture was stirred for 3 min and 8.7 mL ethylchloroformate was added dropwise. The mixture was warmed to 23° C. over 15 min and filtered. The filtrate was added dropwise over 30 min to a vigorously stirred mixture of 7.7 g sodium borohydride in 60 mL water at 3° C. The cooling bath was removed, the mixture stirred at 21° C. for 3 h, then cooled to 0° C. and acidified to pH2 with concentrated HCl. The mixture was extracted with 3×200 mL ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to furnish a clear oil. Purification by silica chromatography using methylene chloride-acetone (9:1) as eluent gave the title compound as a clear oil; 21.6 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][C:40]1=[O:44].CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][C:40]3=[O:44])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: NCCN1CCCC1=O
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(NCCN3CCCC3=O)n2)s1
Temperature: 50 °C
Yield: 68 %

Procedure:
A mixture of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.28 mmol), 1-(2-aminoethyl)-2-pyrrolidinone (0.18 g, 0.83 mmol) and DIEA (0.10 ml, 0.56 mmol) in MeOH (0.5 ml) was heated at 50° C. for 2 h. LCMS analysis indicated that the reaction was proceeding very slowly, another equivalent amine and DIEA was added and the reaction was heated overnight. LCMS analysis indicated the reaction had still not progressed sufficiently so the reaction was heated overnight again. LCMS analysis indicated the reaction had progressed sufficiently so the reaction mixture was concentrated onto silica gel and purified by flash chromatography to afford a colourless foam. The product was dissolved in DCM and washed with HCl (10% Aq.) to remove some residual DIEA and the organics were dried over MgSO4, filtered and the filtrate was concentrated in vacuo to afford the title compound (0.12 g, 67% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.22-7.65 (m, 7H), 3.21-3.45 (m, 6H), 2.11-2.22 (m, 2H), 1.82-1.93 (m, 2H), 1.41 (s, 9H). MS (ES+): 631 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([NH:5][C:6]1[C:7]([NH2:16])=[CH:8][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 103.7 %

Procedure:
A mixture of 5.25 g of N-tert-butyl-2-nitro-4-trifluoromethylaniline, 20 ml of ethyl acetate and 5% palladium charcoal was stirred for 9 hours at room temperature under a hydrogen atmosphere of about 1 atm. The reaction mixture was filtrated through Celite (registered trademark). The filtrate was washed with water, dried over sodium sulfate, then, concentrated under reduced pressure to obtain a residue. The resultant residue was subjected to silica gel chromatography to obtain 4.82 g of N1-tert-butyl-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[N:28]1([CH2:27][CH2:26][NH:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(NCCN3CCCCC3)cc2)OC1(C)C

Procedure:
N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.219 g, 1 mmol), potassium iodide (0.006 g, 0.03 mmol), potassium carbonate (0.060 g, 0.4 mmol) and 1-(2-chloroethyl)-piperidine (0.050 g, 0.3 mmol) in MeCN (2 ml) to 110° C. by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the product as a white solid (0.009 g, 0.027 mmol). LCMS (3) 2.50 min; m/z (ES+) 331.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:22][S:23](O)(=[O:25])=[O:24].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([S:23]([Cl:22])(=[O:25])=[O:24])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)N1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
4-(4Fluoro-phenyl)-piperidine hydrochloride (1.0 g; 4.64 mmol) and Et3N (1.9 ml; 13.9 mmol) was dissolved in DCM (20 ml) and cooled to 0° C. using an ice/water bath. ClSO3H (309 ul; 4.6 mmol) was slowly added droppwise due to highly exothermic reaction. After addition was compleat the mixture was allowed to reach room temperature and stirred over night. The clear yellow solution of the intermediate sulfonicacid derivative was evaporated and dry Toluene (20 ml) was added to form a slurry. To this slurry was added PCl5 (1.06 g; 5.1 mmol) in portions, the mixture was heated on an oil bath to 75° C. for 2 h, and then left over night in room temperature before filtration. The filtercake was washed with Toluene and the filtrate was evaporated. EtOAc was added and precipitating salts was removed by filtration. The crude product was purified on 70 g Si-60 gel using flash chromatography with a gradient 100% Heptane to 100% DCM. Gradient time was 35 min and flow of solvent was 20 ml/min. Fractions containing product was evaporated to give the title compound as a slightly yellow oil that crystallises upon standing. Obtained 0.94 (70% yield) of the title compound.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1>[Fe].C(O)(=O)C>[NH2:26][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C

Procedure:
0.70 g of iron powder was added to a suspension of 7.5 mL of methanol and 7.5 mL of acetic acid containing 1.5 g of tert-butyl 4-((E)-2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate, and the resulting mixture was heated to reflux for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the obtained residue and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=4:1] to obtain 0.44 g of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate as white solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.F[C:20]1C=CC=C(C)C=1B(O)O>>[F:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:20])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: Cc1cccc(F)c1B(O)O
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: Cc1cccc(F)c1-c1nc(C(=O)O)cs1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-fluoro-6-methylphenyl)boronic acid gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:17].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][I:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICc1ccc(OCc2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.0 g (4.3 mmol) of 4-benzyloxybenzyl chloride (Fluka; Buchs/Switzerland) in 8 ml of acetone is stirred at RT with 3.13 g (20.9 mmol) of sodium iodide. After 90 min, a gas chromatogram of the reaction mixture indicates that the reaction is complete; the reaction mixture is therefore poured onto ether, and this mixture is washed with 10% sodium thiosulfate solution and saline. Drying the organic phase with Na2SO4, and evaporating, yields the title compound: 1H-NMR (200 MHz, CDCl3 : 4.48 (s, 2H), 5.06 (s, 2H), 6.85-6.95 (m, 2H), 7.25-7.48 (m, 7H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>C[C@@H](CC)CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH2:12][C@@H:2]([CH3:7])[CH2:3][CH3:4])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(O)cc1
Agent: CC[C@H](C)CO
Product: CC[C@H](C)COC(=O)C(C)c1ccc(O)cc1
Yield: 90 %

Procedure:
A mixture of MHPP (2.0 g, 12 mmole) and tetra-(n-butyl)titanate (2 drops) in (S)-2-methylbutanol (5 ml) was stirred at reflux for 16 hours after which excess alcohol was allowed to distill, out and the residual product recovered by distillation (yield 90%; bp 155°-60° C.; SOR: +5.4°,c=3). The results of IR, 1H-NMR and mass spectroscopy and elemental analysis were consistent with the assigned structure.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:50])[C:7](=[O:8])[N:6]([C@@H:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:10][NH:11][C@H:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14]([O:16]CC)=[O:15])[C:5](=[O:29])[N:4]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])=[O:39])=[C:33]([O:48][CH3:49])[CH:32]=1>Cl.C1COCC1>[ClH:1].[CH3:50][C:3]1([CH3:2])[C:7](=[O:8])[N:6]([C@@H:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:10][NH:11][C@H:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13][C:14]([OH:16])=[O:15])[C:5](=[O:29])[N:4]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])=[O:39])=[C:33]([O:48][CH3:49])[CH:32]=1
Reactant: CCOC(=O)C[C@H](NC[C@H](CC(C)C)N1C(=O)N(Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)C(C)(C)C1=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CN2C(=O)N([C@H](CN[C@@H](CC(=O)O)c3ccccc3)CC(C)C)C(=O)C2(C)C)ccc1NC(=O)Nc1ccccc1C
Yield: 19.7 %

Procedure:
A solution of 100 mg (0.149 mmol) of the compound of example 9 in 6N hydrochloric acid and THF was heated at 60° C. for 4 h. The THF was removed in vacuo and the residue was freeze-dried. Following purification by means of preparative HPLC, chromatography over silica gel using dichloromethane/methanol/acetic acid/water (9.5/0.5/0.05/0.05), concentrating the product fractions and freeze-drying in the presence of 2N hydrochloric acid, 20 mg (21%) of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([CH3:25])[CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:14])[CH3:2]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.9 %

Procedure:
To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfonyl-2-propanone (7-2-1) (0.30 g) were added under a nitrogen atmosphere and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: acetone=3:1) to give 0.25 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8](OC)OC.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:14]([CH:8]=[C:7]([OH:13])[N:6]=[CH:5]2)=[CH:15][CH:16]=1
Reactant: COC(OC)C(=O)NCc1cccc(F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1cc2ccc(F)cc2cn1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Into a RBF was added N-(3-Fluorobenzyl)-2,2-dimethoxyacetamide (1.53 g, 6.73 mmol) and sulfuric acid (18M; 3.4 mL, 61 mmol); this mixture was stirred at 85° C. for 5 min. Ice water was added and stirred, and then solid NaHCO3 was carefully added until the solution was neutralized. The aqueous layer was extracted with DCM. The DCM layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. It was carried onto the next step without any further purification. HPLC: tR=2.13 min. (ZQ2, polar—5 min.). MS (ES+): m/z=164.69 (100) [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[F:29][C:30]1([F:35])[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[F:29][C:30]1([F:35])[CH2:33][CH:32]([NH:34][C:24]([C:21]2[O:22][C:23]3[C:15]([N:12]4[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=2)=[O:26])[CH2:31]1
Reactant: NC1CC(F)(F)C1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Agent: Cl
Agent: [Li+]
Product: O=C(NC1CC(F)(F)C1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and 3,3-difluorocyclobutanamine hydrochloride (48 mg, 0.34 mmol). Yield: 63 mg (64%).