Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl.O1CCOCC1>CCOC(C)=O>[CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][NH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CCN[C@H]1c1ncccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To 65F (1.51 g, 3.53 mmol) in EtOAc (15 mL) at rt was added 4.0 N HCl in dioxane (15 mL, 60 mmol). The mixture was stirred at rt for 8.0 h. After removal of the solvent, the crude was diluted in methylene chloride and washed with sat. NaHCO3. The aqueous was extracted with methylene chloride (3×80 mL). The combined organic layer was dried over Na2SO4. After removal of solvent 65G (1.1 g, 95% yield) was obtained as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (t, J=7.03 Hz, 3H) 1.25 (d, J=7.03 Hz, 3H) 1.30 (d, J=7.03 Hz, 3H) 2.11-2.38 (m, 2H) 3.00-3.12 (m, 1H) 3.24-3.29 (m, 1H) 3.36-3.47 (m, 1H) 3.53-3.64 (m, 1H) 4.02-4.14 (m, 2H) 7.58 (dd, J=7.91, 4.83 Hz, 1H) 8.32 (dd, J=8.35, 1.76 Hz, 1H) 8.83-8.93 (m, 1H); LC-MS 327 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[NH:26][C:25](=[O:27])[N:24]([C:28]2[CH:37]=[CH:36][C:31]([C:32](OC)=O)=[C:30]([O:38][CH3:39])[CH:29]=2)[N:23]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[NH:26][C:25](=[O:27])[N:24]([C:28]2[CH:37]=[CH:36][C:31]([C:32]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:7]=3)=[C:30]([O:38][CH3:39])[CH:29]=2)[N:23]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: NC(=NO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.6 %

Procedure:
To a solution of 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.069 g, 0.39 mmol) in dry toluene was added sodium hydride (0.016 g, 0.39 mmol). The reaction mixture was refluxed for 30 minutes followed by addition of methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol). The reaction mixture was refluxed for 5-6 h. The reaction mixture was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford crude product which was further purified by column chromatography to afford 0.015 g of desired product. 1H NMR (DMSO-d6): δ 3.98 (s, 3H), 7.45-7.48 (m, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 3H), 7.83 (d, J=8.1 Hz, 1H), 7.95 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.18 (d, J=8.7 Hz, 1H), 12.90 (br s, 1H). MS [M+H]+: 499.89.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[Cl-].[Ca+2:18].[Cl-].[Ca]>[OH-].[Na+]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[Ca+2:18].[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Agent: [Ca+2]
Agent: [Ca]
Agent: [Cl-]
Product: CC(C)=CCc1ccc(C(C)C(=O)[O-])cc1

Procedure:
4.8 g of 2-(p-prenylphenyl)propionic acid as prepared in Example 1 was dissolved in 5% aqueous sodium hydroxide solution to adjust to pH 9.0. To the solution, 5% aqueous calcium chloride solution was added dropwise until the insoluble calcium salt no longer formed. The aqueous layer was decanted and the residual solid was crystallized from methanol to give 4.2 g of calcium 2-(p-prenylphenyl)propionate, colorless needles, m.p. 64°-65° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCOCC1

Procedure:
Using 1 g of N-(trans-4-methylcyclohexyl)-4-(2-morpholinoethoxy)-3-methoxycinnamamide (Example 144), 0.05 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 0.90 g of N-(trans-4methylcyclohexyl)-3-[4-(2-morpholinoethoxy)-3-methoxyphenyl]propionamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[N:38]=[N:37][CH:36]=[N:35]3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1>ClCCl.CO>[F:2][C:3]1[C:4]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[N:38]=[N:37][CH:36]=[N:35]3)=[CH:32][CH:33]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:23])=[O:24])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-n3ncnn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3ncnn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Hydrochloric acid (4.0 M in 1,4-dioxane, 1.7 mL, 6.63 mmol) was added to a solution of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-tetrazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (500 mg, 0.94 mmol) in dichloromethane:methanol (5:1, 6 mL) at room temperature. The reaction was stirred for 1 h then was concentrated under reduced pressure affording a residue, which was triturated in diethyl ether:pentane (1:1) overnight. The solid was collected via filtration and dried under reduced pressure to afford the title compound as a solid (340 mg, 76%). MS (LCMS) m/z 451.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 3 H) 2.09-2.21 (m, 1 H) 2.42-2.45 (m, 1 H) 3.09 (s, 3 H) 3.78 (m, J=11.80, 11.80, 5.20 Hz, 1 H) 3.97-4.10 (m, 1 H) 6.63 (d, J=7.61 Hz, 1 H) 7.84 (dd, J=8.68, 1.66 Hz, 2 H) 8.00-8.15 (m, 3 H) 10.16 (s, 1 H) 11.08 (br. s., 1 H).
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)/[C:3]([OH:20])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 97.2 %

Procedure:
A solution of (E)-3-cyclohexyl 2-(3,4-difluoro-phenyl)-acrylic acid methyl ester (0.55 g, 1.97 mmol) in ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (4 mL). The solution was heated at 40° C. For 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (30 mL) and then acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclohexyl-2-(3,4-difluoro-phenyl)-acrylic acid (0.51 g, 97%) as a white solid: mp 119-121° C.; EI-HRMS m/e calcd for C15H16F2O2 (M+H)+267.1196, found 267.1200.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:19])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)N
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC(C)C)C1(C)C

Procedure:
The product from Example 173 and isopropylamine (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.02-1.05 (m, 6H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.44 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.95-2.08 (m, 1H), 2.60-2.67 (m, 3H), 2.72-2.82 (m, 1H), 3.80-3.92 (m, 1H), 7.39 (d J=7.4 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 436 (M+H)+. Anal. calcd. for C24H41N2O3S: C, 66.16; H, 9.49; N, 9.65. Found: C, 65.80; H, 9.54; N, 9.50.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.FC(F)(F)C(O)=O.[N:32]1([C:41](=[O:50])/[CH:42]=[CH:43]/[C@@H:44]([NH2:49])[CH2:45][CH:46]([CH3:48])[CH3:47])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.[C:51]([O:55][C:56]([NH:58][C:59]1([C:65](O)=[O:66])[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)=[O:57])([CH3:54])([CH3:53])[CH3:52].CCN(CC)CC>C(Cl)Cl>[N:32]1([C:41](=[O:50])/[CH:42]=[CH:43]/[C@@H:44]([NH:49][C:65]([C:59]2([NH:58][C:56](=[O:57])[O:55][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:60][CH2:61][O:62][CH2:63][CH2:64]2)=[O:66])[CH2:45][CH:46]([CH3:48])[CH3:47])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: CC(C)C[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(NC(=O)OC(C)(C)C)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.3 %

Procedure:
A solution of 50 wt % ®T3P in EtOAc (1.2 mL, 2.016 mmol) was added dropwise to a solution of [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-(2-methylpropyl)-4-oxo-2-buten-1-yl]amine trifluoroacetate (500 mg, 1.343 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (329 mg, 1.343 mmol), and Et3N (0.93 mL, 6.71 mmol) in CH2Cl2 (5 mL) at 0° C. (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 1 h 20 min, the reaction was washed with saturated aq. NaHCO3 (1×5 mL) and 10% citric acid (1×5 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 204 mg (31%) of the title compound. LC-MS m/z 486 (M+H)+, 1.07 min (ret time).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:17][CH:18]=2)[CH:13]=[CH:14][N:15]=1>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[C:11]2[N:12]([C:16]([CH:19]3[CH2:20][CH:21]([CH2:23][OH:24])[CH2:22]3)=[N:17][C:18]=2[I:8])[CH:13]=[CH:14][N:15]=1
Reactant: OCC1CC(c2ncc3c(Cl)nccn23)C1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCC1CC(c2nc(I)c3c(Cl)nccn23)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Ar was added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.67 g) dissolved in anh DMF (30 mL). The flask containing [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsed with another portion of anh DMF (20 mL) and the rinse was added to the reaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min) and the stirred at this temperature for 3 h. The mixture was then cooled to rt, partitioned between 1M aq Na2S2O3 (60 mL), brine (60 mL) and DCM (160 mL). The aq layer was extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and purified by flash chromatography on SiO2 (0-8% MeOH in DCM) to provide a material, homogenous by UV on both TLC and HPLC, still containing DMF. The material was dissolved in DCM (200 mL) and washed with water (3×40 mL), dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale yellow solid; HPLC (polar5 min) 2.52 min; MS (ES+): m/z (rel. int.) 364.0 (100, M++1); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=4.8 Hz, 1 H), 7.49 (d, J=4.8 Hz, 0.22H, minor isomer), 7.29 (d, J=4.8 Hz, 1 H), 7.28 (d, J=5.2 Hz, 0.23H, minor isomer), 3.83-3.80 (m, 0.7H), 3.72-3.62 (m, 3H), 2.75-2.55 (m, 4H), 2.42-2.32 (m, 1-2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:13]([O:30][CH3:31])[CH:12]=3)[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[C:13]([O:30][CH3:31])[CH:12]=4)[CH:9]=3)[N:4]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:34])=[O:33])[CH:3]=2)[CH:49]=[N:48]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 71.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperidine-1-carboxylate (intermediate 67A) (260 mg, 0.378 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (172 mg, 0.567 mmol) using Pd(dppf)Cl2 (14 mg, 0.018 mol) and sodium carbonate (121 mg, 1.134 mmol) in toluene/ethanol/water (6/2/1 ml) to afford 200 mg (71.9% yield) of the titled compound after column purification using 2% methanol in DCM as eluent. MS: m/z=736.4 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH2:33][C@H:34]2[CH2:39][C@H:38]([N:40]3[CH2:45][CH2:44][CH:43]([CH:46]4[C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=5[CH2:50][CH2:49][N:48]5[C:57]6[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=6[N:59]=[C:47]45)[CH2:42][CH2:41]3)[CH2:37][CH2:36][NH:35]2)[CH:29]=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:35]1[CH2:36][CH2:37][C@@H:38]([N:40]2[CH2:41][CH2:42][CH:43]([CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][N:48]4[C:57]5[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=5[N:59]=[C:47]34)[CH2:44][CH2:45]2)[CH2:39][C@@H:34]1[CH2:33][C:28]1[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc(C[C@H]2C[C@H](N3CCC(C4c5ccccc5CCn5c4nc4ccccc45)CC3)CCN2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@H](N2CCC(C3c4ccccc4CCn4c3nc3ccccc34)CC2)C[C@@H]1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
3,5-di(trifluoromethyl)benzoyl chloride (0.003 mol) and then triethylamine (0.0045 mol) were added dropwise to a mixture of (±)-trans-6-[1-[2-[(3,4-dichlorophenyl)-methyl]-4-piperidinyl]-4-piperidinyl]-11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepine (0.003 mol) in CH2Cl2 (25ml). The mixture was stirred at RT overnight, washed with water and separated into its layers. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 98/2 to 96/4). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.23 g (51%) of (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-1-piperidinyl]piperidine (comp. 63).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[Cl:8][C:9]([Cl:13])([Cl:12])[CH2:10]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:7][CH2:10][C:9]([Cl:13])([Cl:12])[Cl:8])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(O)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of finely powdered malonic acid (10.4 g, 0.1 mol), 2,2,2-trichloroethanol (9.6 mL, 0.1 mol) and p-toluenesulfonic acid monohydrate (570 mg, 3% in benzene (30 mL) was stirred under azeotropic reflux for 26 hours, then cooled at room temperature. The unreacted malonic acid (4.6 g) was filtered and washed with benzene (2×10 mL). Water (50 mL) was added to the filtrate followed by portionwise addition of sodium bicarbonate until a basic pH was reached. The aqueous phase was decanted, washed with ether (3×50 mL), then acidified with concentrated aqueous HCl and extracted with methylene chloride (4×50 mL). The combined extracts were washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to give 2,2,2-trichloroethyl hydrogen malonate (4.34 g, 18.4 mmol, 18%) that slowly crystallized; m.p. 42°-43°; NMR (CDCl3): δ11.0 (S, CO2H), 4.83 (S, --OCH2CCl3 ), 3.61 (S, --O2C--CH2CO2 --).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)Nc2ccc(OCCCN(C)C)c(-c3ccnn3C)c2)cc1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.9 mg, 0.167 mmol) in CH2Cl2 (2 mL) was added 4-methylphenyl isocyanate (0.24 μL, 0.191 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 130 as a colorless solid (61.8 mg, 91%). LCMS m/z (%)=408 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (bs, 1H), 8.52 (bs, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.43 (dd, J=8.91, 2.73 Hz, 1H), 7.36 (d, J=2.70 Hz, 1H), 7.31 (d, J=8.43 Hz, 2H), 7.08 (d, J=8.92 Hz, 1H), 7.06 (d, J=8.32 Hz, 2H), 6.23 (d, J=1.82 Hz, 1H), 3.96 (t, J=6.36 Hz, 2H), 3.65 (s, 3H), 2.23 (s, 3H), 2.19 (t, J=7.05 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15].[NH:19]1[CH2:22][CH:21]([C:23]2[C:24]([O:43][CH3:44])=[C:25]([CH:31]([NH:33][C:34]3[N:42]=[CH:41][N:40]=[C:39]4[C:35]=3[N:36]=[CH:37][NH:38]4)[CH3:32])[CH:26]=[C:27]([Cl:30])[C:28]=2[CH3:29])[CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:5][C:6]([F:11])([F:10])[C:7]([OH:9])=[O:8].[Cl:30][C:27]1[C:28]([CH3:29])=[C:23]([CH:21]2[CH2:22][N:19]([C:3]([NH:2][CH3:1])=[O:4])[CH2:20]2)[C:24]([O:43][CH3:44])=[C:25]([CH:31]([NH:33][C:34]2[N:42]=[CH:41][N:40]=[C:39]3[C:35]=2[N:36]=[CH:37][NH:38]3)[CH3:32])[CH:26]=1.[C:14]([OH:16])([C:13]([F:18])([F:17])[F:12])=[O:15]
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CC(c2c(C)c(Cl)cc(C(C)Nc3ncnc4[nH]cnc34)c2OC)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl isocyanate (1.3 μL, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H25ClN7O2 (M+H)+: m/z=430.2. found: 430.2. 1H NMR (300 MHz, DMSO-d6) δ 8.32 (1H, br s), 8.18 (2H, m), 7.44 (1H, s), 6.31 (1H, m), 5.68 (1H, m), 4.20 (3H, m), 3.96 (1H, m), 3.82 (1H, m), 3.75 (3H, s), 2.52 (3H, s), 2.15 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5].[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1.O>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: CN(C)CC1CC2(CCC1(O)c1cccc(F)c1)OCCO2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CC(=O)CCC1(O)c1cccc(F)c1
Reaction time: 16 h
Yield: 47.1 %

Procedure:
11.4 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-(3-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (10.83 g, 31.3 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The mixture was adjusted to pH 11 with 32% sodium hydroxide solution, and extraction was carried out with ether. After evaporation of the solvent in vacuo, the residue was taken up in diisopropyl ether and EE, and the corresponding salt was precipitated by addition of methanesulfonic acid (1.88 ml, 28.9 mmol). 4.92 g (53%) of the product were obtained in the form of a colorless solid.
Reaction SMILES: [Br:1]Br.[C:3]12[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8][C:7](=[O:14])[O:6][C:4]2=[O:5]>O>[Br:1][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:14])[O:6][C:4](=[O:5])[C:3]=2[CH:13]=1
Reactant: BrBr
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: O
Product: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
Bromine (35 mL, 660 mmol) was added dropwise to a suspension of isatoic anhydride (100 g, 610 mmol) in 1.6 L water at 50° C. This temperature was maintained for an additional 2 hours. After cooling the solution to room temperature, the solid was filtered and washed twice with water and twice with acetone, yielding 125.6 g (85%) 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione as a pink solid.