Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].O>CN(C)C=O>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: Nc1ncccn1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNc1ncccn1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 2-aminopyrimidine (1.9 g.) in dried dimethylformamide (8 ml.) was dropwise added to a suspension of 50% sodium hydride (1.25g.) in dried dimethylformamide (2 ml.) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. Bromoacetaldehyde diethyl acetal (4.3 g.) and dried dimethylformamide (2 ml.) were added thereto, and the mixture was stirred for 2 hours and 20 minutes at ambient temperature and for 2.5 hours at 80° C. The reaction mixture was cooled to at ambient temperature and to the mixture was added water, and then the mixture was extracted 3 times with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on silica gel (25 g.) using chloroform as developing solvent to give 2-pyrimidinylaminoacetaldehyde diethyl acetal (1.4 g.), oil. This oil was allowed to stand to give crystals.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:11]Br>C(O)(=O)C.O>[Br:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: BrBr
Reactant: Cc1cccc(C=O)c1O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
The solution of 2-Hydroxy-3-methylbenzaldehyde (1.0 g, 7.35 mmole) in acetic acid (6 mL) was cooled to 0° C. (ice bath). Bromine (1.36 g, 8.52 mmole) was added dropwise and allowed to stir for 2 hours. The reaction was warmed to room temperature and diluted with water (100 mL) yielding a light orange precipitate. The solid was filtered and washed with water (10 mL). Dried on high vacuum to give a light brown solid (1.4 g, 88.6%). 1H NMR (CDCl3/400 MHz) 11.16 (s, 1H), 9.79 (s, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>COC(C)(C)C>[Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Dissolve (-)-cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g, 42.5 mmol) in anhydrous tert-butyl methyl ether (50 mL) and cool to -5° C. Treat the solution with methanesulfonyl chloride (3.6 g, 46.5 mmol, mesyl chloride), followed by triethylamine (7.2 mL, 51.7 mmol), at such a rate as to keep the temperature between -5° C. and -2° C. with an ice bath. The ice bath is removed and the solution is stirred for 2 hours. The mixture is then transferred to a separatory funnel and treated with brine/water (50 mL/50 mL). The layers are separated and the aqueous layer is extracted with tert-butyl methyl ether (2×50 mL). The organic layer and extracts are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (12.1 g, 97% yield) as a colorless oil; 1 H NMR (CDCl3) δ 5.1 (m, 1 H), 4.2 (m, 1 H), 2.99 (s, 3 H), 2.3 (m, 1 H), 2.0 (m, 3 H), 1.8 (m, 2 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21])([CH3:3])[CH3:2].[H-].[Na+].[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].Cl>C1COCC1>[CH2:28]([O:27][C:26](=[O:30])[CH2:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:13]=1)=[O:19])[CH3:29]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
Then, 3-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-3-oxo-propionic acid ethyl ester 45 was prepared as follows. To a solution of compound 44 (11.5 g, 34.0 mmol) in THF (150 mL) was added 60% sodium hydride in mineral oil (1.84 g, 40.8 mmol). The mixture was stirred at room temperature for 10 minutes. Diethyl carbonate (46.5 mL, 340 mmol) was added and the mixture was heated under reflux for 2 hours. 10% HCl aq. (100 mL) was added and the solution was extracted with ethyl acetate (200 mL). The organic layer was separated, washed with brine (5×250 mL), dried over MgSO4 and filtered. The filtrate was concentrated on a rotor-vapor to give a brown oil 45 (10.6 g, 76%); MS (DCI) m/z 411 (M+H)+; 428 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:36]=[C:35]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=5)[CH:40]=[CH:39][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-c2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-biphenyl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]2)[CH:2]=1.[CH3:13][C:14]([CH3:16])=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OC(C)C)(=O)C>[CH:14]([NH:12][C:10]1[CH:9]=[N:8][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:11]=1)([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: Nc1cnn(-c2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cnn(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-pyridin-3-yl-1H-pyrazol-4-ylamine (0.6 g, 3.7 mmol) was dissolved in isopropyl acetate (8.5 ml). To the mixture, acetone (0.261 g, 4.5 mmol), trifluoroacetic acid (0.855 g, 7.5 mmol) and sodium triacetoxyborohydride (0.945 g, 4.5 mmol) were added. The reaction was stirred under nitrogen at room temperature for 4.5 hours and then quenched with 10% sodium hydroxide solution until the pH reached˜9. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated to dryness. The crude material was purified by silica gel chromatography (gradient elution of 5% methanol/dichloromethane) to give the title compound as an off white solid (0.35 g, 46%): mp 105-107° C.; 1H NMR (300 MHz, CDCl3) δ 8.82 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.94-7.77 (m, 1H), 7.38 (dt, J=15.2, 7.6 Hz, 1H), 6.99 (t, 1H), 3.72 (m, 1H), 1.30 (t, J=10.0 Hz, 6H). ESIMS 214 m/z (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-phenylbutanoic acid methyl ester, 138 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-phenylheptanedioic acid dimethyl ester.
Reaction SMILES: C([O:8][CH:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[C:16]2/[C:17](=[O:37])[CH:18]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[CH:19]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:20]/2)[CH2:11][CH2:10]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]2[CH2:20][CH:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:26])[CH3:24])[CH:18]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[C:17]2=[O:37])[CH2:11][CH2:10]1
Reactant: Cc1cc(C)c(C2C(=O)/C(=C/C3CCC(OCc4ccccc4)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C2C(=O)C(CC3CCC(O)CC3)CC2OC(=O)C(C)(C)C)c(C)c1
Yield: 36.7 %

Procedure:
The 2,2-dimethyl-propionic acid 4-[1-(4-benzyloxy-cyclohexyl)-meth-(E)-ylidene]-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (4.5 g, 9.0 mmol) is dissolved in ethyl acetate (40 ml), 1 g of 5% palladium on carbon is added and the reaction mixture is placed under hydrogen pressure (3 bars) for 3 hours. The reaction mixture is filtered and washed with ethyl acetate. The filtrate is absorbed onto silica gel and purified by flash chromatography to give a sticky solid. The solid was crystallised from hexane to give 2,2-dimethyl-propionic acid 4-(4-hydroxy-cyclohexylmethyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopentyl ester (1.37 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12]CC(C1C=C(Cl)C=CC=1Cl)=O>>[Br:12][CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])=[O:11]
Reactant: CC(=O)c1ccc(F)cc1Br
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Product: O=C(CBr)c1ccc(F)cc1Br
Yield: 63 %

Procedure:
This compound was prepared from 1-(2-bromo-4-fluoro-phenyl)-ethanone (2.5 g, 11.52 mmol) in the manner described for 2-bromo-1-(2,5-dichlorophenyl)-ethanone (Method I-2), affording 2.14 g (63%) of 2-bromo-1-(2-bromo-4-fluoro-phenyl)-ethanone as a clear oil. 1H-NMR (CD2Cl2) δ 7.57 (dd, J=9, 6 Hz, 1H), 7.44 (dd, J=8, 2 Hz, 1H), 7.21 ((m, 7.21–7.14, 1H), 4.51 (s, 2H); TLC Rf=0.38, 15% ethyl acetate-hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43].[Na+].[I-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCCl
Reactant: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)CCOc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol (0.062 g, 0.12 mmol) in THF at 0° C., was added NaH (0.018 g, 0.73 mmol). The mixture was stirred at 0° C. for 30 minutes. 1-Chloro-2-(methylsulfonyl)ethane (0.035 g, 0.24 mmol) and trace amount of NaI were added. The mixture was stirred and warmed to RT for 15 h. The reaction was quenched with sat. NH4Cl, and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% (90:10:1 DCM/MeOH/NH4OH-DCM) to afford 4-(4-chlorophenyl)-N-(4-(6-(2-(methylsulfonyl)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: m/z=[M+H]+. 614.0 Calc'd for C32H25ClN4O3S2: 613.1.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25](F)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]>C1COCC1>[Br:21][C:22]1[C:23]([F:33])=[C:24]([F:32])[C:25]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[Cl:13])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of i-Pr2NH (25.0 mL, 178 mmol) in THF (200 mL) at 0° C. was added n-BuLi (71.0 mL, 178 mmol, 2.5 M solution in hexanes). After stirring for 15 minutes, this solution was cooled to −78° C. 2-Chloroaniline (12.7 mL, 118 mmol) was added. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluorobenzoic acid (14.95 g, 58.63 mmol) in THF (30 mL) was added. The dry-ice bath was removed, and the reaction mixture was stirred for 2 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (120 mL), extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give the crude solid which was triturated with boiling CH2Cl2 (125 mL). The yellow solids were filtered, and dried in vacuo to give the desired product (17.4 g, 82%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]5[CH2:54][CH2:53][CH2:52][C@@H:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:23][CH2:24][OH:25])[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([C:10]1[CH:11]=[C:12]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([N:50]5[CH2:54][CH2:53][CH2:52][C@@H:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH:16]=2)[O:22][CH2:23][CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methanesulfonyl chloride (5.80 μL, 0.074 mmol) was added to a solution of Intermediate 78d (40 mg, 0.057 mmol) and DIPEA (30 μL, 0.17 mmol) in DCM (1 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (2 mL) and washed with water (2×2 mL). The organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound (44 mg, 100%). LCMS (Method 3): Rt: 3.68 min, m/z 777/779 [MH+].
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(O)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][NH:29][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]=2[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(CCN)cc1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CCO
Product: COc1ccc(-c2c(NCCc3ccc(C(C)(C)C)cc3)c(=O)c2=O)cc1
Yield: 81.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and 4-tert-butyl-phenethylamine (0.216 g, 1.22 mmol) in ethanol (2 mL) were converted to the title compound (0.180 g, 81%) m.p.: 258.1-260.2° C.; 1H NMR (DMSO-d6) δ9.07(br t,1H), 7.97(ABq,2H), 7.29(ABq,2H), 7.14(d,2H), 7.09(d,2H), 3.87(m,2H), 3.83(s,3H), 2.84(t,2H), 1.23(s,9H); IR(KBr) 3160, 2950, 1775, 1720, 1580, 1425, 1350, 1300, 1250, 1180, 1020, 840 cm−1; MS (m/z) 364 [M+H+].
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16])=[C:8]([O:14][CH3:15])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1C(=O)NC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CBr)ccc1C(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
An amount of 160 mg (0.72 mmol) of the compound from Example 22A was heated under reflux with 129 mg (0.72 mmol) of N-bromosuccinimide and also 12 mg (0.07 mmol) of 2,2′-azobis-2-methylpropanenitrile in 5 ml of carbon tetrachloride for 16 h. After cooling to RT, the mixture was diluted with 10 ml of dichloromethane and washed with 10 ml of water. It was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was subsequently purified by chromatography [Method 8]. This gave 103 mg (47% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:19]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([CH:19]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCCCC(CC)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCCC(CC)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.11 g of compound 18 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.18 g of ethyl 4-(2-aminophenoxy)butyrate and 1.47 g of 3-[1-(1-ethylpentyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH3:29][C:30]1[C:31]([CH:36]=O)=[N:32][CH:33]=[CH:34][CH:35]=1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cccnc1C=O
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Cc1cccnc1CNCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 3-methylpyridine-2-carboxaldehyde (24.2 mg) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (59.3 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[N:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:34]#CBr.O>CS(C)=O>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[N:9]=[C:8]2[N:5]1[CH2:4][CH2:3][N:2]([C:1]#[N:34])[CH2:7][CH2:6]1
Reactant: N#CBr
Reactant: COc1ccc2c(c1)c(N1CCN(C)CC1)nn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)c(N1CCN(C#N)CC1)nn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.3 %

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-5-methoxy-1-phenylsulfonyl-1H-indazole (55.0 g, 0.14 mol) of Example 5d, potassium carbonate (22.0 g, 0.16 mol) and dimethylsulfoxide (DMSO) [500 ml] under N2 was added dropwise, cyanogen bromide (16.0 g, 0.15 mol) dissolved in DMSO (125 ml). The reaction was stirred at room temperature for 4 hours and was then poured into H2O (2.5 l). The solid which formed was collected and washed well with H2O. The solid was dried and weighed to yield 41.0 g. A 5.0 sample was recrystallized twice from ethanol (utilizing decolorizing carbon) to afford 3.5 g (50%) of 4-(5-methoxy-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile. m.p. 171°-173° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4].Cl.[N:31]1([C:36](N)=[NH:37])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH:1]([CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=[O:27])=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4])[C:36]([NH2:37])=[NH:31]
Reactant: N=C(N)n1cccn1
Reactant: NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1

Procedure:
170 mg (0.05 mmol) 131 was treated overnight with 73.5 mg (0.5 mmol) pyrazole-1-carboxamidine hydrochloride and 172 μL diisopropylethylamine dissolved in 2 mL DMF. Next day the resin was drained, washed five times with DMF to give 132 which was treated immediately to cleave the compound off, as described below in Example 121.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 334 (M+H).