Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:28]([O:14][C@@H:12]([CH3:13])[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])[C:15]([NH:16][CH2:17][CH2:18][CH:19]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])=[O:26])(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCOC(CCNC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](C)O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)O[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a solution of [(1S,2S)-1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-propyl]carbamic acid benzyl ester (300 mg, 0.785 mmol, obtained from Reference Example 17) in methylene chloride (5 ml) was added myristic acid (163 mg, 0.714 mmol), dicyclohexylcarbodiimide (162 mg, 0.785 mmol) and dimethylaminopyridine (9 mg, 0.074 mmol). The resulting mixture was stirred under nitrogen at room temperature for 18 hours. The mixture was filtered, the filtrate was washed with 2% hydrochloric acid, aqueous sodium bicarbonate and saturated sodium chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 30% ethyl acetate in hexane) to provide (1S,2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(3,3-diethoxypropyl)amino]-1-methyl-3-oxopropyl myristate (352 mg, 83%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.0430 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0500 g, 63%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.70 (1H, m), 7.04-7.09 (1H, m), 7.26-7.28 (2H, m), 8.11-8.15 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.54 (1H, s), 8.60 (1H, s), 9.16 (1H, s). m/z=516.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25](C(OCC(Cl)(Cl)Cl)=O)[CH:24]=2)[C:9]1=[O:40])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O>CN(C=O)C.C(O)(=O)C.[Cl-].[Cd+2].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:9]1=[O:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2cn(C(=O)OCC(Cl)(Cl)Cl)c3ccccc23)c2ccccc21
Agent: [Cd+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The product of step d) (0.21 g, 0.34 mmol), zink powder (0.23 g, 3.44 mmol) and cadmium(II) chloride (0.020 g, 0.086 mmol) was suspended in DMF (4 ml) and acetic acid (4 ml). The suspension was stirred for 1 hour at room temperature, ethyl acetate (10 ml) and water (20 ml) were added and the phases separated. The organic phase was washed with water (3×5 ml), dried over Na2SO4. Solvent removal followed by chromatographic purification on silica, eluting with ethyl acetate, gave the sub-title product (0.12 g, 81%) as a colourless solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37].[BrH:40].N([O-])=O.[Na+].S(=O)(O)[O-].[Na+]>C(#N)C.O.[Cu]Br.CCOC(C)=O.CCCCCC.CCOC(C)=O>[Br:40][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(S(C)(=O)=O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
To a solution of 6-(N-(4-amino-3-(methylsulfonyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.4 g, 0.700 mmol) in acetonitrile (3 mL) was added 8M HBr (0.437 mL, 3.50 mmol). The resulting solution was cooled in an ice water bath for 15 minutes and the mixture was treated with a solution of sodium nitrite (0.072 g, 1.050 mmol) in water (2 mL) over 5 min. The resulting yellow suspension was stirred in an ice bath for 1.5 hours and then treated with copper(I) bromide (0.201 g, 1.399 mmol) in small portions over 5 minutes. This dark brown solution that was warmed to 60° C. and stirring continued for additional 2 h. The mixture was cooled to RT and poured into a mixture of 5% aqueous sodium bisulfite (6 mL) and EtOAc (80 mL). The phases were separated and the aqueous solution extracted with two additional 15 mL portions of EtOAc. The combined EtOAc solutions were washed with 5% aqueous sodium bisulfite, saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate and concentrated to dryness at reduced pressure to give a yellow foam. This material was subjected to flash chromatography (silica gel, gradient from 9:1 hexane/EtOAc to EtOAc) to afford the title compound (0.3 g, 68%). LCMS (m/z, ES+)=635, 637 (M+H+).
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[C:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29])#[N:20]>>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:25][C:24]1[CH:26]=[CH:27][C:21]([C:19]#[N:20])=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:23]=1)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Product: CC(C)(CC(O)(C=Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F)c1ccccc1

Procedure:
Analogously to Example 13, 120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal and 78 mg of 4-cyano-3-(trifluoromethyl)aniline are converted into 71 mg of product.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][CH:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC)cc2)CCN3CC(C)C)cc1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-ethylimidazol-5-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (365 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-ethylimidazol-5-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (516 mg) (Compound 380) as yellow amorphous.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C:5]1[CH:12]=[C:11]([Br:13])[C:10]([O:14][CH3:15])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(C=O)c(OC(C)=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=O)c(O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 200 mL round-bottomed flask containing 6.90 g (25.3 mmol) 2 acetoxy-4-bromo-5-methoxybenzaldehyde (2) in 100 mL of 1% aqueous methanol at room temperature was added 5 g K2CO3, and the mixture was allowed to stir at room temperature for 1 h, at which time TLC analysis indicated complete consumption of starting material and the presence of a slightly more polar compound as the only detectable product. The reaction mixture was then neutralized to pH 5 with the addition of 1N HCl, and the solvent was subsequently removed under diminished pressure. The residue was then dissolved in ethyl acetate (200 mL), washed successively with 1N HCl (1×50 mL), saturated aqueous NaHCO3 (1×50 mL), and brine (1×50 mL), dried over NA2SO4, and concentrated under diminished pressure to give 4.97 g (85%) of the bromophenol as a brownish-red oily solid. A portion of this crude material was recrystallized from 2:1 hexanes/ethyl acetate to give white needles. 1H NMR (400 MHz, CDCl3) δ3.89 (s, 3H, OCH3), 6.97 and 7.27 (2s, 2×1H, Ar--H), 9.83 (s, 1H, OH), 10.71 ppm (s, 1H, CHO). The remainder of the material was carded on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([O:31]C(OC)=O)=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.[OH-].[Na+].O.[ClH:39]>CO>[ClH:39].[F:1][C:2]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCc4ccncc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A suspension of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline (300 mg, 0.63 mmol) and 2M aqueous sodium hydroxide (0.38 ml, 0.76 mmol) in methanol (6 ml) was stirred at ambient temperature for 2 hours. Water was added and the mixture adjusted to pH7 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in methylene chloride/methanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was diluted with isopropanol, and the methylene chloride and methanol solvents were removed by evaporation. The resulting precipitate was collected by filtration, washed with methylene chloride and dried under vacuum to give 4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxy-7-(2-(4-pyridyl)ethoxy)quinazoline hydrochloride (270 mg, 94%).
Reaction SMILES: C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3N(C=2C(O)=O)C=CS3)CC1.[CH:27]1([O:32][C:33]2[C:40]([O:41][CH:42]([F:44])[F:43])=[CH:39][CH:38]=[CH:37][C:34]=2[CH:35]=O)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Br-].[CH2:46]([O:48][C:49]([C:51]1[N:58]2[C:54]([S:55][CH:56]=[CH:57]2)=[N:53][C:52]=1[CH2:59][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:50])[CH3:47].[H-].[Na+]>CS(C)=O>[CH:27]1([O:32][C:33]2[C:40]([O:41][CH:42]([F:44])[F:43])=[CH:39][CH:38]=[CH:37][C:34]=2/[CH:35]=[CH:59]/[C:52]2[N:53]=[C:54]3[N:58]([C:51]=2[C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH:57]=[CH:56][S:55]3)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Reactant: O=Cc1cccc(OC(F)F)c1OC1CCCC1
Agent: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Yield: 80.7 %

Procedure:
This compound was prepared as described in Intermediate 1, step-4, by the reaction of 2-(cyclopentyloxy)-3-(difluoromethoxy)benzaldehyde (3.26 g, 12.766 mmol) with 5-ethyloxy carbonylimidazo[2,1-b][1,3]thiazol-6-yl-methyl(triphenyl)phosphonium bromide (6.40 g, 11.605 mmol) in the presence of sodium hydride (510 mg, 12.766 mmol) in anhydrous DMSO (20 mL) to give 4.20 g the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.9 Hz, 3H), 1.54-1.60 (m, 2H), 1.65-1.72 (m, 2H), 1.80-1.86 (m, 4H), 4.35-4.44 (m, 2H), 4.70-4.78 (m, 1H), 7.10-7.16 (m, 2H), 7.18 (t, J=73.2 Hz, 1H), 7.40-7.46 (m, 1H), 7.54-7.60 (m, 1H), 7.74 (d, J=15.9 Hz, 1H), 7.85 (d, J=16.2 Hz, 1H), 8.10-8.16 (m, 1H); ESI-MS (m/z) 449.10 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([NH:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:25]1[C:24]2[C:28](=[CH:29][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:22][CH:23]=2)[NH:27][C:26]1=[O:30])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-acetamido-2-oxindole to give 0.3 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide as a yellow-orange solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH:43]([O:46][C:47](Cl)=[O:48])([CH3:45])[CH3:44]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:47]([O:46][CH:43]([CH3:45])[CH3:44])=[O:48])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(C)OC(=O)Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: CC(C)NC(C)C
Product: CC(C)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, isopropylchloroformate (9.37 mL, 1.0 mol in toluene, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 2% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was recrystallized from isopropanol to remove aliphatic impurities. The product was not sufficiently pure so was purified by column chromatography eluting with 0 to 10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane and filtered to afford Compound-75 (0.593 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[Br:60][C:61]1[CH:66]=[C:65]([C:67]2([NH2:70])[CH2:69][CH2:68]2)[CH:64]=[CH:63][N:62]=1>CN(C=O)C>[Br:60][C:61]1[CH:66]=[C:65]([C:67]2([NH:70][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:68][CH2:69]2)[CH:64]=[CH:63][N:62]=1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NC1(c2ccnc(Br)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2ccnc(Br)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.120 g, 0.467 mmol) in DMF (2 mL) is added HATU (186 mg, 0.490 mmol). After 30 minutes, N,N-diisopropylethylamine (325 μL, 1.87 mmol) and 1-(2-bromo-pyridin-4-yl)-cyclopropylamine-trifluoroacetic acid salt (223 mg, 0.507 mmol) are added, and the reaction mixture became homogeneous. After 18 hours, the mixture is concentrated in vacuo, reconstituted in ethyl acetate (50 mL) and washed with 1N sodium hydroxide (3×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue is twice purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([CH2:24][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:22][CH2:23]2)=[O:17])=[CH:26][CH:27]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CN2CCOCC2)CC1
Reaction time: 13 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (52 mg, 0.143 mmol) was dissolved in EtOH (5 mL) and morpholine (0.025 mL, 0.285 mmol), sodium cyanoborohydride (18 mg, 0.285 mmol), and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 13 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 100% EtOAc.) The title compound was obtained as an oil. (Yield: 15 mg, 0.034 mmol, 24%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37, 7.27-7.24, 7.14, 7.11-7.04, 6.91, 6.59, 5.47, 4.62, 4.09, 3.67, 2.74, 2.36, 2.08, 1.63, 0.96, 0.61
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was added and the reaction was cooled to 0° C. Acetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow solid (3.01 g,).GC/MS (EI, M+) m/z=249.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>O1CCOCC1.C(OCC)(=O)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: OCCc1ccc(I)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 59.4 %

Procedure:
A mixture of 1.14 g (4.60 mmol) of 2-(4-iodophenyl)ethanol, 0.88 g (6.89 mmol) of 4-chlorophenol, 2.99 g (9.20 mmol) of cesium carbonate, 0.14 g (1.38 mmol) of N,N-dimethylglycine and 0.087 g (0.46 mmol) of cuprous iodide in 4 ml of dioxane is heated at 90° C. for 24 hours with thorough stirring under an argon atmosphere. It is cooled to ambient temperature and taken up in 150 ml of ethyl acetate and 50 ml of water. After the phases have settled and been separated, the organic phase is washed with 25 ml of water and 25 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with an 85/15 then 75/25 mixture of cyclohexane and ethyl acetate, to give 0.68 g of product in the form of an oil.