Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O:12]1[CH2:16][CH:15]([CH2:17][C:18](OCC)=[O:19])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2.[OH-].[Na+]>O>[OH:19][CH2:18][CH2:17][CH:15]1[CH2:16][O:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]1=2
Reactant: CCOC(=O)CC1COc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1COc2ccccc21
Temperature: 22 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred 0° C. solution of THF (~50 mL) containing LAH (0.86 g, 22.6 mmol) under N2 atmosphere was added dropwise a THF solution of ethyl 2,3-dihydrobenzo[1,2-b]furan-3-acetate (2.50 g, 11.3 mmol). After complete addition the reaction was allowed to warm to 22° C. and stand for two h. The reaction was cooled to 0° C. and treated sequentially with water (0.9 mL), 15% NaOH (0.9 mL), and water (2.7 mL). After stirring for 2 h the reaction was filtered through Celite and the filter cake washed with THF and Et2O. The organic filtrate was dried with anhydrous MgSO4, filtered, and concentrated in vacuo to afford a the title compound (1.85 g, >99%) as a yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:16][NH:17][CH3:18]>I>[CH3:16][N:17]([CH3:18])[C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)nnc(-c2ccccc2)c1C
Reactant: CNC
Agent: I
Product: Cc1c(-c2ccccc2)nnc(N(C)C)c1C

Procedure:
A 1.5 g sample of 3-chloro-4,5-dimethyl-6-phenylpyridazine is placed in a 6 oz. glass pressure bottle and covered with 15 mL of condensed dimethylamine. To this mixture is added several drops of HI. The bottle is then closed, fitted with a pressure guage and heated for 50 hours at 90°-100° C. and 85-100 psig pressure. The mixture is cooled, excess dimethylamine is evaporated, and the residue partitioned between CH2Cl2 and water. The organic layer is separated and dried over MgSO4. Removal of the drying agent and concentration of the solvent in vacuo leaves a brown solid (1.7 g). The crude solid is boiled in cyclohexane, filtered; the filtrate diluted with hexane and chilled. The product (0.7 g) is isolated as a mustard-colored solid which melts at 86°-89° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=[O:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.[CH3:43][Mg]Br>C1COCC1.C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]([OH:33])[CH3:43])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1
Reactant: O=Cc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(O)c1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde (75 mg, 0.12 mmol) in THF (0.6 mL) at −78° C. under N2, add methylmagnesium bromide (120 μL, 3.0 M in Et2O). Allow the reaction to warm to 0° C. and stir for two h., then quench the reaction with a saturated solution of NH4Cl (1 mL). Dilute the mixture with CH2Cl2 (1 mL), wash with H2O (1 mL) and brine (1 mL). Pass the organic layer through a Varian ChemElute® drying cartridge and concentrate. Purify the residue by chromatography on silica gel using a gradient of 10:1 Hex/EtOAc to 2:1 Hex/EtOAc to afford the title compound (4.3 mg, 6%). MS/ES (M+1)=620.9.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][C:18]([C:20]([O:22]C)=[O:21])=[CH:19][C:11]=3[O:10][C:9]=2[CH2:8]1)=[O:6])[CH3:3].C1COCC1.CO.[Li+].[OH-]>O>[CH3:3][C:2]([CH3:24])([O:4][C:5]([N:7]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:11]=3[O:10][C:9]=2[CH2:8]1)=[O:6])[CH3:1]
Reactant: COC(=O)c1ccc2c3c(oc2c1)CN(C(=O)OC(C)(C)C)CC3
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(C(=O)O)ccc23)C1
Temperature: 30 °C

Procedure:
A solution of 11-11 (0.79 g, 2.38 mmol) in 1:1 THF/MeOH (30 mL) was treated with LiOH (0.95 g, 23.8 mmol) in 10 mL of H2O and heated to 30° C. overnight. The solvents were removed under vacuum and the residue was dissolved in H2O and acidified with 10% KHSO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to give 11-12 as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][NH:18][CH:19]([CH3:21])[CH3:20])[CH2:15][N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[O:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOCC.O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([O:31][CH3:30])=[C:33]([O:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH:34]=2)[CH2:15][N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: CC(C)NC[C@H]1CN(Cc2ccccc2)C[C@H]1CN(C(=O)OC(C)(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CN(C(=O)OC(C)(C)C)C(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(3S*,4S*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-isopropyl-carbamic acid tert-butyl ester (0.32 g, 0.55 mmol), 4-methoxy-3-(3-methoxy-propoxy)-benzoic acid (0.23 g, 0.96 mmol), DMAP (0.12 g, 0.96 mmol), and triethyl-amine (0.56 mL, 0.96 mmol) in DMF (10 mL), is added EDCl-HCl (0.19 g, 0.96 mmol) at 0° C. The reaction mixture is stirred overnight at room temperature. Water and Et2O are added, the layers are separated and the aqueous one is extracted twice with Et2O. The combined organic extracts are dried (MgSO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 90:10) to give the title product. TLC, Rf (CH2Cl2/MeOH 9:1)=0.72. MS (LC-MS): 626.4 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.28 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl>>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1cccc(Br)c1
Product: COCOc1cccc(Br)c1
Yield: 107.9 %

Procedure:
In a manner similar to that of Example 7(a), by reaction of 100.00 g (577.9 mmol) of 3-bromophenol with 48.28 g (635.8 mmol) of chloromethyl methyl ether, 135.32 g (100%) of the expected product are obtained in the form of a pale beige oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CCOCC>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NC1CCCC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1CCCC1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a chilled (0°-5° C.) and stirred ethereal solution (500 ml) containing cyclopentyl amine (75 g, 0.88 mol) and triethyl amine (101 g, 1.0 mol) was added t-butyl bromoacetate (136.5 g, 0.7 mol) in ether (300 ml). The reaction mixture was stirred overnight. The ethereal mixture was then concentrated and the residue redissolved in methylene chloride (750 ml). This solution was washed with saturated aqueous sodium bicarbonate (1000 ml), water (2×3000 ml), and brine (2000 ml). The organic portion was separated, dried over MgSO4, filtered and evaporated yielding N-cyclopentylglycine t-butyl ester (92 g, 66%) as a brown oil which slowly crystallized on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[C:25]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:26]=1
Reactant: OB(O)c1cc(F)ccc1OCc1ccccc1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCc3ccccc3F)n2)c1

Procedure:
Example 30 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {5-fluoro-2-[(2-fluorobenzyl)oxy]phenyl}boronic acid (Combi-Blocks Inc.). The batch was purified by preparative TLC. 1H NMR (400 MHz, CDCl3, 300K) δ=8.84 (s, 1H), 7.79 (br, 1H), 7.63 (m, 2H), 7.48 (m, 2H), 7.37 (m, 1H), 7.27 (m, 1H), 7.09 (m, 5H), 5.22 (s, 2H), 4.23 (s, 2H), 2.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].Cl.C[NH:32]C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]([NH2:32])=[O:29])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CNC
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CC(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CC(N)=O)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (4-{3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (10.0 mg, 0.0231 mmol), dimethylamine hydrochloride (9.41 mg, 0.115 mmol), TBTU (14.8 mg, 0.0462 mmol), DIPEA (0.021 mL, 0.115 mmol) and DCM (3 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.99 (s, 3 H), 3.14 (s, 3 H), 5.16 (s, 2 H), 5.29 (q, J=7.3 Hz, 1 H), 7.13-7.23 (m, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.63 (s, 1 H), 7.81 (s, 1 H), 8.34 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 460.02 (100) [MH+]. HPLC: tR=3.26 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCCc1ccccc1)Oc1ccccc1
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (3.29 g, 21.0 mmol.) and pyridine (1.74 g, 22.0 mmol.) were added to a solution of 3-phenylpropylamine (2.7 g, 20.0 mmol.) in abs. DCM (50 ml), and stirring was carried out for 24 h at RT. For working up, the mixture was washed in succession with water (2×20 ml), 1M HCl (2×20 ml) and 1N NaOH (2×20 ml) and then the organic phase was dried, filtered and concentrated. (3-Phenylpropyl)carbamic acid phenyl ester was obtained in a yield of 4.11 g by recrystallisation from EE/hexane (1:1) (white solid, m.p. 55–56° C.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:41]([CH3:43])[CH3:42])[C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39])=[O:31])=[O:27].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:24][O:25][C:26]([NH:28][C@@H:29]([CH:41]([CH3:43])[CH3:42])[C:30]([N:32]1[C@@H:36]([CH3:37])[CH2:35][CH2:34][C@H:33]1[C:38]([O:40][CH2:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:39])=[O:31])=[O:27]
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (750 mg, 2.02 mmol) in MeCN (20 mL) was added (2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid (600 mg, 2.09 mmol) and DIPEA (0.35 mL, 2.02 mmol) and the solution was heated to 60° C. After stirring for 4 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 80% EtOAc/hexanes) to afford (2S,5S)-2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (1.16 g, quant.).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].N[C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:20]=[CH:21][C:22]=1[F:27])#[N:25]
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: N#Cc1cc(N)ccc1F
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(C#N)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-cyano-4-fluoroaniline [Aldrich, product #639877] as the starting materials. LCMS for C13H14FN7NaO4S (M+Na)+: m/z=406.0. 1H NMR (400 MHz, DMSO-d6): δ 11.65 (s, 1H), 9.08 (s, 1H), 7.35 (m, 1H), 7.18 (m, 3H), 6.56 (m, 1H), 6.23 (m, 1H), 6.24 (s, 2H), 3.32 (m, 2H), 3.14 (m, 2H), 2.89 (s, 3H).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: O=S(=O)(NC1CCN(CCc2c[nH]c3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
Using an analogous procedure to Example 1 3-[2-(4-amino-1-piperidyl)ethyl]indole monohydrate may be reacted with p-chlorobenzenesulphonyl chloride to give the title compound.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[NH4+].[OH-].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([N+:36]([O-])=O)=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19].C1COCC1>O>[NH2:36][C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[F:11])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=1
Reactant: O=C(c1ccccc1F)N1CCN(c2ncc([N+](=O)[O-])c3ccccc23)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(N2CCN(C(=O)c3ccccc3F)CC2)c2ccccc12
Yield: 65.1 %

Procedure:
Add Na2S2O4 (60.87 g, 39.4 mmol) followed by NH4OH 32% (15 mL) to (2-fluoro-phenyl)-[4-(4-nitro-isoquinolin-1-yl)-piperazin-1-yl]-methanone (3 g, 7.89 mmol) in 170 mL of 1:1 mixture of THF:H2O and stir for 90 min. Dilute with water and extract with AcOEt several times. Combine organics and wash with saturated aq. sodium chloride, dry over Na2SO4 and evaporate under reduced pressure to give 1.8 g of the title compound as a solid. LCMS ES+ (m/z) 351.2 [M+H].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[NH:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[CH:27]1>>[NH:26]1[CH:30]=[C:29]([S:31]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[N:12]=[C:11]([CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH:25]=[N:24][N:23]=[N:22]5)=[N:19][CH:20]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:33])=[O:32])[N:28]=[CH:27]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Agent: Cl
Product: O=S(=O)(c1c[nH]cn1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and 1H-imidazole-4-sulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 12.89 (1H, bs), 10.07 (1H, s), 8.41 (1H, d), 7.99 (1H, d), 7.92 (1H, s), 7.86 (2H, m), 7.79, (1H, dd), 5.32 (2H, s), 4.59 (1H, m), 3.62 (2H, m), 2.77 (2H, m), 2.17 (2H, m), 1.95 (2H, M).
Reaction SMILES: IC.[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[OH:18])[N:5]=1.[OH-].[K+].[CH3:21]S(C)=O>O>[Cl:3][C:4]1[N:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[O:18][CH3:21])[N:5]=1
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccc(-n2cnc(Cl)n2)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
Iodomethane (0.860 mL, 13.82 mmol) was added to a mixture of 2-(3-chloro-1H-1,2,4-triazol-1-yl)-5-nitrophenol (1.33 g, 5.53 mmol), potassium hydroxide (0.388 g, 6.91 mmol), and DMSO (25 mL). The mixture was left to stir at rt for 24 h. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified using silica gel column chromatography (0-1% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min). The pure fractions were combined and concentrated to afford 3-chloro-1-(2-methoxy-4-nitrophenyl)-1H-1,2,4-triazole (0.924 g, 3.63 mmol, 65.6% yield) as a light yellow solid. LC-MS (M+H)+=255.0. 1H NMR (500 MHz, CDCl3) δ ppm 8.35 (s, 1H) 7.36 (d, J=8.55 Hz, 1H) 6.29-6.34 (m, 2H) 3.80 (s, 3H) 2.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[O-]CC.[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CCOC(=O)CCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)c(OCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,5-dimethylphenol (24.5 g, 0.2 mol) was dissolved in 125 ml of anhydrous ethanol. To the solution was added 75 ml of 21 wt % sodium ethoxide solution in ethanol (0.2 mol). The mixture solution was stirred at room temperature for 10 min. Ethyl 4-bromobutyrate (40 g, 0.205 mol) was then added to the solution. The reaction mixture was refluxed at 80° C. for 24 h. The precipitate was filtered off. The filtrate was then mixed with a solution of sodium hydroxide (10 g, 0.25 mol) in 150 ml of water. The mixture was stirred at 70° C. for about 2 hours, monitored with HPLC. It was diluted with 150 ml of water and acidified to pH 1. Oily precipitate formed immediately. It was collected by decanting the supernatant and washed with water twice (100 ml×2). The oily precipitate solidified after kept in water at room temperature overnight.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42](OC)[O:43]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:42]=[O:43])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (1.5 g), Amberlyst (registered trade mark) 15 ion exchange resin (0.35 g), acetone (30 mL) and water (0.15 mL) was stirred at room temperature for 18 hr. Amberlyst (registered trade mark) 15 ion exchange resin was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.4 g, yield: 100%) as a pale-yellow amorphous solid. MS: 645 (MH+).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[CH:29](COC1C=CC(C(C)(C)C)=CC=1)[CH2:30]NC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:29][CH3:30])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CCc1cccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)c1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15,0.6), 237(16), 236 (100), 163 (5), 121 (21), 114 (6), 105 (5), 90 (6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1

Procedure:
70.4 mg of the target compound (0.21 mmol, 47.7%) was obtained using 1-(4-methylphenyl)piperazine (155 mg, 0.88 mmol), biphenyl-2-carbaldehyde (80 mg, 0.44 mmol) and NaBH(OAc)3 (284 mg, 1.32 mmol) according to the synthesis method of Compound 1.