Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH3:14])[CH2:7][CH2:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1.Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[Na+].C1COCC1>CN(C=O)C.O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][CH:6]([CH3:14])[CH2:7][CH2:8][C:9]1[NH:13][N:12]=[N:11][N:10]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(CCc1nnn[nH]1)Oc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(CCc1nnn[nH]1)Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 2.34 g (0.01 mol) 5-[3-(3-hydroxyphenoxy)butyl]tetrazole, 2.13 g (0.01 mol) 2-chloromethylquinoline hydrochloride and 12 ml (2N, NaOH) in 20 ml DMF and 20 ml THF is heated over a steam bath for a period of 24 hours. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethyl acetate (3:1) as eluent. Evaporation of eluent gives 5-[3-(3-(2-quinolylmethyloxy)phenoxy)butyl]tetrazole. (M.P. 147°-149° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.8 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 68%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([NH:31][CH:32]([CH2:36][C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[C:24]([O:28][C:29](=[O:30])[NH:31][CH:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=1)[C:33]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:34])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: Cc1cccc(CC(NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CC(NC(=O)OC(C)(C)C)C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (400 mg, 1.15 mmol), 2-tert-butoxycarbonylamino-3-m-tolyl-propionic acid (334 mg, 1.2 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 50 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 218 mg, 1.15 mmol), and DMF (5 mL) was shaken at room temperature for 8 hours. The reaction mixture was poured into 20 mL of ethyl acetate, washed with 5 mL of 2N HCl solution, saturated NaHCO3 (20 mL), water (10 mL), and brine (10 mL). The organic layer was concentrated under vacuum and purified by column (silica gel, EtOAc/hexane 1/1) to afford the intermediate [2-{4-[cyclopropyl-(3-trifluoromethylbenzenesulfonyl)-amino]piperidin-1-yl}-1-(3-methylbenzyl)-2-oxo-ethyl]carbamic acid tert-butyl ester as colorless oil (600 mg, yield 85%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:16])[C:10](=[O:15])[N:11]2[OH:14])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>P([O-])(O)(O)=O.[K+].C(O)C>[CH2:17]([O:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:13]=2)[NH:8][C:9](=[O:16])[C:10]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)n(O)c2c1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
7-Carboxy-1-hydroxyquinoxaline-2,3(1H,4H)-dione (2.22 g, 10 mmol) was dissolved in a mixture of 50 ml of 1M potassium dihydrogen phosphate buffer (pH 7.4) and 25 ml of ethanol by gently heating. To the cooled mixture was added 1.19 ml (10 mmol) of benzylbromide and the mixture was stirred overnight at room temperature. The precipitate was isolated by filtration and washed with ethanol. The crude product was triturated with 4M hydrochloric acid and washed with water and dried in vacuo to give 1.56 g (50%) of the title compound. 1H-NMR (DMSO-d6): 5.22 (s, 2H, CH2), 7.2-7.9 (m, 8H, ArH), 12.35 (s, 1H, exchangeable), 13.05 (br.s, 1H, exchangeable).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]4[C:25]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31][C:26]=5[N:27]([CH3:30])[C:28]=4[CH:29]=3)[C:17](=[O:36])[CH:16]=2)=[N:11][CH:12]=1.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][C:25]2[C:24]3[CH:23]=[CH:22][C:21]([N:18]4[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:10]5[CH:9]=[CH:8][C:7]([F:6])=[CH:12][N:11]=5)=[CH:16][C:17]4=[O:36])=[CH:29][C:28]=3[N:27]([CH3:30])[C:26]=2[CH2:31][CH2:32]1)(=[O:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CCNCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccc(F)cn5)cc4=O)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
AcCl (0.01 mL, 0.2 mmol) was added to a solution of 4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (49 mg, 0.11 mmol), DMAP (3 mg, 0.03 mmol), and Et3N (0.03 mL, 0.3 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. H2O was added and the resulting phases were separated. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded 39 mg (78%) of the title compound as a white solid as a mixture of rotomers: mp 88-94° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.84 (ddd, J=9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J=8.5, 4.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.38 (dd, J=3.0, 1.5 Hz, 1H), 6.92-6.88 (m, 1H), 6.12 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t J=5.5, 1H), 3.05-2.98 (m, 2H), 2.93 (t, J=5.5, 1H), 2.13 (s, 1.5H), 2.08 (s, 1.5H); ESI MS m/z 461 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([B:13]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=2[CH3:31])[C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[CH:10]=[C:9]([B:32]([C:42]2[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=2[CH3:50])[C:33]2[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=2[CH3:41])[CH:8]=1.[CH3:51][Si:52](I)([CH3:54])[CH3:53]>CCCCCC.C1COCC1.O>[C:15]1([CH3:22])[CH:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:14]=1[B:13]([C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])[C:11]1[CH:12]=[C:7]([Si:52]([CH3:54])([CH3:53])[CH3:51])[CH:8]=[C:9]([B:32]([C:42]2[C:43]([CH3:50])=[CH:44][C:45]([CH3:49])=[CH:46][C:47]=2[CH3:48])[C:33]2[C:34]([CH3:41])=[CH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])[CH:10]=1
Reactant: Cc1cc(C)c(B(c2cc(Br)cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)c2)c2c(C)cc(C)cc2C)c(C)c1
Reactant: C[Si](C)(C)I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc(C)c(B(c2cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)cc([Si](C)(C)C)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 110.6 %

Procedure:
6.25 ml (0.01 mol) of a 1.6M solution of butyllithium in hexane are added at -78° C. to a solution of 6.53 g of (0.01 mol) of 1-bromo-3,5-bis(dimesitylboryl)benzene in 50 ml of THF. The mixture is stirred at -78° C. for 1.5 h, and then 2.0 ml (3.0 g; 0.015 mol) of trimethylsilyl iodide are added over the course of 10 minutes. After the mixture has been stirred again at -78° C. for one hour, it is allowed to warm up to room temperature and stirred for about 12 hours. It is then diluted with water and subjected twice to extraction with 50 ml of ethyl acetate each time. Drying over magnesium sulfate and concentration gives 7.15 g of a viscous oil. Following purification by chromatography (hexane, SiO2), 3.7 g (0.0058 mol, i.e. 58% of theory) of the title compound are obtained as a white solid. Physical data are given in Table 1.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].O.[NH2:14][NH2:15].C(O)C>CCCCCC>[Cl:10][C:8]1[CH:9]=[C:4]([C:3]([NH:14][NH2:15])=[O:2])[C:5]([OH:11])=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cc(Cl)ccc1O
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 5-chloro-2-hydroxybenzoic acid methyl ester (0.50 g, 2.7 mmol), hydrazine monohydrate (0.3 mL, 6.2 mmol) and ethanol (5 mL) was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, n-hexane was added and the separated crystal was filtered to give the title compound (395.9 mg, 79.2%) as a white crystal.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][OH:17])=[NH:15])=[CH:11][CH:12]=2)[C@H:7]([NH:18][C:19](=[O:24])[O:20][CH:21]([CH3:23])[CH3:22])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].N1C=CC=[CH:28][CH:27]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]([O:20][C:19](=[O:24])[NH:18][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:27]([CH3:28])[O:17][N:16]=3)[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:25])[CH2:6]1)[CH3:22]
Reactant: c1ccncc1
Reactant: CC(=O)N1c2ccc(C(=N)NO)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3noc(C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[(hydroxyamino)(imino)methyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation, see Intermediate 56) (130 mg, 0.373 mmol) in toluene (2 mL) and pyridine (2 mL) was added acetyl chloride (a solution 0.34 mL of acetyl chloride in 5 mL of toluene was made and 0.52 mL was used, 0.485 mmol) dropwise and the resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture was then warmed to 110° C. and stirred at this temperature for 16 h then cooled to room temperature. Most of the solvents were removed in vacuo and the residue was partitioned between AcOEt and water (acidified to pH 1 with a 2N HCl aqueous solution). The two layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phases were washed with a saturated NaHCO3 aqueous solution then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (120 mg, 0.322 mmol, 86% yield) as a white foam. LCMS (method A): Retention time 0.94 min, [M+H]+=373.05
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])[CH3:13]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:12][CH3:13])=[S:19])[N:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: COc1cc(OC)nc(N)n1
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
2-Amino-4,6-dimethoxypyrimidine (5.0 g, 36 mmol) was dissolved in dry tetrahydrofuran (THF, 35 mL), ethoxycarbonylisothiocyanate (6.4 mL, 54 mmol) was added and the solution was allowed to stir at room temperature. After 24 hours, the solvent is removed in vacuo and the residue was mixed with ether to form a crystalline solid. The solids were removed by vacuum filtration and dried to afford the product as a tan solid (8.9 g, 87%). mp 196-197° C. 1H NMR (CDCl3): δ13.2 (bs, 1H); 8.8 (bs, 1H); 5.80 (s, 1H); 4.32-4.25 (q, 2H, J=7.2); 3.93 (s, 3H); 1.30 (t, 3H, J=7.2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](SC)[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CSc1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: NCc1ccccc1
Solvent: CCO
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-Amino-4-benzo [1,3] dioxol-5-yl-6-methylsulfanyl-pyrimidine-5-carbonitrile and benzylamine in ethanol. ES-MS m/e (%): 346 (M+H+, 100).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>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>[C:26]([C:28]1[CH:33]=[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(C#N)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 301 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boronic acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 298 mg, 94%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]([CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:37][CH2:38][N:39]([C:44]1[CH:50]=[CH:49][C:47]([NH:48]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:46][CH:45]=1)[S:40]([CH3:43])(=[O:41])=[O:42])[CH3:36])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(CCN(c1ccc(N)cc1)S(C)(=O)=O)Cc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)Cc2ccccc2)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-aniline Rf value: 0.7 (silica gel, methylene chloride/methanol=10:1) C34H34N4O5S
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>CC(N(C)C)=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:18][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acetic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:37]([O:38][CH3:39])=[CH:36][C:6]2[N:7]([C:10]3[S:14][C:13]([C:15]([NH2:17])=[O:16])=[C:12]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23](NCC5CCNCC5)[C:22]=4[Cl:35])[CH3:20])[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.C=O.[C:42]([OH:45])(=O)[CH3:43].C(O[BH-](O[C:56](=O)[CH3:57])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[C:37]([O:38][CH3:39])=[CH:36][C:6]2[N:7]([C:10]3[S:14][C:13]([C:15]([NH2:17])=[O:16])=[C:12]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:45][CH2:42][CH:43]5[CH2:57][CH2:56][N:7]([CH3:8])[CH2:6][CH2:5]5)[C:22]=4[Cl:35])[CH3:20])[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: COc1cc2ncn(-c3cc(O[C@H](C)c4cccc(NCC5CCNCC5)c4Cl)c(C(N)=O)s3)c2cc1OC
Reactant: CC(=O)O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncn(-c3cc(O[C@H](C)c4cccc(OCC5CCN(C)CC5)c4Cl)c(C(N)=O)s3)c2cc1OC
Reaction time: 0.17 h
Yield: 1116.6 %

Procedure:
To a solution of 5-[5,6-bis(methyloxy)-1H-benzimidazol-1-yl]-3-[((1R)-1-{2-chloro-3-[(4-piperidinylmethyl)amino]phenyl}ethyl)oxy]-2-thiophenecarboxamide (Example 40, 86 mg, 0.015 mmol) in 2 mL of DCM and 1 mL of MeOH was added formaldehyde (23 μl, 0.30 mmol) and acetic acid (10 μl, 0.18 mmol). After 10 min, sodium triacetoxyborohydride (49 mg, 0.23 mmol) was added and the reaction was stirred for 16 h. The solution was diluted with DCM and washed with saturated NaHCO3 solution and water, dried over MgSO4 and concentrated to give 49 mg of the title compound (56%). 1H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 7.78 (br s, 1H), 7.28 (s, 1H), 7.13 (t, J=7.8 Hz, 1H), 7.07 (br s, 1H), 7.01-7.00 (m, 2H), 6.76 (d, J=7.6 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 5.92 (m, 1H), 5.39 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.95 (m, 2H), 2.65 (m, 2H), 2.06 (s, 3H), 1.70-1.56 (m, 7H), 1.12-1.09 (m, 2H). HRMS calculated C29H34ClN5O4S [M+H]+ 584.2098, found 584.2093.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:26]([Br:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[Br-:34].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:7]=1
Reactant: CCCCCCCCBr
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Product: CCCCCCCCn1cc[n+](CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1
Product: [Br-]

Procedure:
mp. 141.5°-143° C., from 1-[2,4dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole and n-octyl bromide after an overnight reflux.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][O:38][CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:39][O:38][NH:37][S:34]([C:30]1[CH:31]=[C:32]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:28][CH:29]=1)(=[O:36])=[O:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: CONS(=O)(=O)c1cccc(Br)c1
Product: CONS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)c2)c1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.20 g, 0.56 mmol) and 3-bromo-N-methoxy-benzenesulfonamide (example H.3) (0.149 g, 0.56 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 43%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[CH2:13][CH2:14][C:15](O)=O.[N:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]([NH:31][NH2:32])=O)=[CH:28][C:23]=2[NH:22][CH:21]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1.O=P(Cl)(Cl)Cl>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[CH2:13][CH2:14][C:15]1[S:42][C:29]([C:27]2[CH:26]=[CH:25][C:24]3[NH:20][CH:21]=[N:22][C:23]=3[CH:28]=2)=[N:31][N:32]=1
Reactant: O=C(O)CCc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(C(F)(F)F)c(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c1

Procedure:
The compound was synthesized starting from 3-(2,5-bis(trifluoromethyl)phenyl)propionic acid (287 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.013 g (2.9%); MS m/z: 443.4 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.36-3.40 (m, 2H); 3.51-3.55 (m, 2H); 7.82-7.85 (m, 2H); 7.92 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 7.97 (d, 1H, 3J=8.3 Hz); 8.06 (br s, 1H); 8.23-8.24 (m, 1H); 8.88 (s, 1H); HPLC (METHOD [A]): rt 16.42 min (96.7%)
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([NH2:40])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[C:42](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([NH:40][CH3:42])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:41])[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CO
Product: CNc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To 1.5 mL of a methanol solution containing 280 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.5 mL of water, 83 mg of sodium carbonate and 99 mg of dimethyl sulfate were added, and stirred at room temperature for 3 days. The insoluble material was filtered off, and the solvent was removed under reduced pressure, and purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=10:1], to give 65 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(N-methylamino)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.