Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:34]=1.[CH:35]([Mg]Cl)([CH3:37])[CH3:36].[C:40]([O:47][CH2:48][CH3:49])(=[O:46])[C:41]([O:43]CC)=O.Cl.C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC=CC=1>[OH:43][C:41]([C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:18])([F:17])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:6]=2[CH:34]=1)([CH:35]([CH3:37])[CH3:36])[C:40]([O:47][CH2:48][CH3:49])=[O:46]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)[Mg]Cl
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (787 mg, 1.28 mmol, intermediate 61) in 2 ml of THF was added a solution of isopropyl magnesium chloride (5.12 ml, 10.24 mmol) in THF (2M) at 0° C. and stirred for 30 min. Then the reaction mixture was added to a solution of diethyl oxalate (4.34 ml, 32 mmol) in 8 mL of toluene and stirred for 30 min. at 0° C. Then the reaction mixture was poured into 3.5 mL of 2 N HCl and 5 mL of ice-water, and the pH was adjusted to pH=7-8 with aqueous NaHCO3. The mixture was extracted with ethyl acetate (3×20 ml) and dried with Na2SO4. The combined organic layers were evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (4/1-3/1) to give title compound 509; Mass Spectrum: m/e=634 (M+1). Further elution of the column afforded the title compound 510; Mass Spectrum: m/e=590 (M+1).
Reaction SMILES: [N:1]1([CH2:7][C:8](=[S:10])[NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.C(=O)(O)[O-].[Na+].S(Cl)(Cl)=O>ClCCCl.O1CCOCC1>[ClH:11].[Cl:11][CH2:12][C:13]1[N:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:10][CH:15]=1
Reactant: NC(=S)CN1CCOCC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Product: Cl
Product: ClCc1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
2-Morpholin-4-ylethanethioamide (0.403 g, 2.52 mmol), 1,3-dichloroacetone (0.353 g, 2.77 mmol) and sodium bicarbonate (0.234 g, 2.77 mmol) was stirred in 1,2-dichloroethane (4 mL) at room temperature for 74 h at which point 1,4-dioxane was added in an attempt to improve solubility and the mixture was stirred for a further 30 h. The reaction mixture was filtered and the filter cake was washed with 1,2-dichloroethane. The filtrate was added dropwise to a cooled (ice bath) solution of thionyl chloride (0.202 mL, 2.77 mmol) in 1,2-dichloroethane (3 mL). The solution was stirred at 70° C. for 0.5 h and then cooled to room temperature. The brown mixture was filtered and washed with 1,2-dichloroethane to afford 4-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}morpholine hydrochloride as a very pale brown solid (0.024 g, 0.091 mmol, 4% yield). 1H NMR (400 MHz; D2O): 3.29-3.39 (m, 4H); 3.78-3.92 (m, 4H); 4.63 (s, 2H); 4.67 (s, 2H); 7.67 (s, 1H); MS (EI) for C9H13ClN2OS: 233 (MH+)
Reaction SMILES: [OH-].[Na+:2].CCO.[C:6](#[N:10])[CH2:7][C:8]#[N:9].[C:11](=[S:13])=[S:12]>>[C:8]([C:7]([C:6]#[N:10])=[C:11]([S-:13])[S-:12])#[N:9].[Na+:2].[Na+:2]
Reactant: N#CCC#N
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#CC(C#N)=C([S-])[S-]
Temperature: 15 °C
Yield: 79 %

Procedure:
Solid NaOH (187.2 g, 4541 mmol) was added to EtOH (2000.0 mL, 34253 mmol) at rt and stirred until disolved. The solution was cooled to 15° C. and malononitrile (150 g, 2300 mmol) was added in one portion and the resulting suspension was stirred until the malononitrile had dissolved (reaction is slightly endothermic). The reaction mixture was stirred for 1 h and carbon disulfide (136.6 mL, 2271 mmol) was added while keeping the temperature between 10 and 20° C. After about half of the carbon disulfide was added the reaction mixture begins to solidify and becomes very difficult to stir. The addition of carbon disulfide was continued and the reaction was stirred mechanically with a spatula. When the addition was complete the reaction mixture was warmed to 30° C. and then cooled to room temperature. The product was filtered and dried under vacuum at 82° C. for 2 days. The solid material obtained was ground up with a mortor and pestal and then dried under vacuum to give the title compound (335 grams, 79%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.Cl.N1C=CC=CC=1.[OH-].[NH4+]>O>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2cnccc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2cnccc2c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Heat a mixture of 6-methoxy-isoquinoline (2.1 g, 13.2 mmol) and pyridine hydrochloride (30 g) in a heavy walled screw cap sealed tube at 160° C. overnight. Cool to room temperature, add water and concentrated ammonium hydroxide to bring the pH of the mixture to 10-11, extract with ethyl acetate (4 times), wash the combined organic extracts with water (4 times), and concentrate under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-3% of 2N NH3/MeOH in dichloromethane afford the title compound (520 mg, 27%): δH (DMSO-d6, 400 MHz): 7.09 (s, 1H), 7.19 (dd, 1H, J=9, 2Hz),7.56(d, 1H, J=6 Hz),7.94 (d, 1H, J=9 Hz), 8.29 (d, 1H, J=6 Hz), 9.05 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][O:44][CH2:43]2)=[CH:38][C:37]=1[CH3:50].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1>[CH3:50][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:47]=[C:48]([CH3:49])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCC2CCOC2)cc(C)c1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCOC6)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (170 mg) and 3-((4-bromo-3,5-dimethylphenoxy)methyl)tetrahydrofuran (170 mg) and K3PO4 (290 mg) are suspended in tetrahydrofuran (10 mL). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium (27 mg) is added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the mixture is diluted with diethylether and washed with saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→50:50) to give the title compound. Yield: 47 mg; LC (method 1): tR=1.48 min; Mass spectrum (ESI+): m/z=569 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: O=C1CCCc2cc(-c3ccc(F)c(Cl)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chloro-4-fluorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 275.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13](Cl)(=[O:15])=[O:14].N1C=CC=CC=1>C1COCC1.Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 92.2 %

Procedure:
A mixture of 4-chloro-3-nitroaniline (5.0 g, 29 mmol), methanesulfonyl chloride (2.37 mL, 30.4 mmol) and pyridine (5.9 mL, 72.4 mmol) in THF (100 mL) was stirred for 24 h. Poured in 1M HCl (500 mL). The resulting precipitate was filtered and air-dried to provide the title compound as a solid (6.7 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14].[C:15](=[O:18])([O-])[O-].[K+].[K+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[C:11]([O:12][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:10]([O:13][CH2:4][C:3]2[CH:8]=[CH:9][C:10]([O:18][CH3:15])=[CH:11][CH:2]=2)[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:14]
Reactant: O=C1NCCc2c1cc(O)c(O)c2Cl
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc3c(c(Cl)c2OCc2ccc(OC)cc2)CCNC3=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154.6 %

Procedure:
To the solution of 5-chloro-6,7-dihydroxy-3,4-dihydroisoquinolin-1(2H)-one (0.619 g, 2.9 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added potassium carbonate (1.202 g, 8.70 mmol) followed by 1-(chloromethyl)-4-methoxybenzene (0.767 mL, 5.66 mmol). Stirred at room temperature for 4 hours. The mixture was extracted with ethyl acetate, washed with water, sodium chloride, and dried over magnesium sulfate. The crude mixture was chromotagraphed on silica ISCO column to give 5-chloro-6,7-bis((4-methoxybenzyl)oxy)-3,4-dihydroisoquinolin-1(2H)-one (1.017 g, 2.241 mmol, 77% yield). LCMS (M+H)+: 454.4
Reaction SMILES: C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C.[CH3:15][C:16]1([CH3:40])[O:20][CH:19]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][C:30]([OH:35])=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:36][O:37][CH2:38][CH3:39])[CH2:18][O:17]1.O[CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:15][C:16]1([CH3:40])[O:20][CH:19]([CH2:21][N:22]2[C:34]3[C:33]4[CH:32]=[CH:31][C:30]([O:35][CH:42]5[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:36][O:37][CH2:38][CH3:39])[CH2:18][O:17]1
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC1COC(C)(C)O1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of diisopropyldiazodicarboxylate (0.710 g, 3.50 mmol) in tetrahydrofuran (6 mL) was added dropwise to a mixture of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described in Parts A-D of Example 372, 1.00 g, 2.80 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (0.70 g, 3.50 mmol), and triphenylphosphine (0.920 g, 3.50 mmol) in tetrahydrofuran (35 mL) at 0° C. The resulting solution was allowed to warm to room temperature over 16 hours. The solution was concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, gradient elution with 0-50% CMA in chloroform) to provide 1.16 g of tert-butyl 4-{[1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[N:17]=[C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[N:15]=[C:14]([Cl:29])[CH:13]=1)[CH3:11]>CN(C)C=O>[ClH:29].[CH2:10]([C:12]1[N:17]=[C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])[N:15]=[C:14]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[CH:13]=1)[CH3:11]
Reactant: CCc1cc(Cl)nc(N2CCc3ccccc3C2C)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: CCc1cc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2C)n1
Product: Cl
Yield: 38.1 %

Procedure:
After 2-methyl-4-fluoroaniline(1.1 ml, 10.2 mmol) was added to a mixture solution of 6-ethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(2.0 g, 7.0 mmol) and dimethylformamide(10 ml), 1.1 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9](Cl)(Cl)=S.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]1[NH:22][C:23]2[CH:29]=[C:28]([C:30]([NH:32][NH2:33])=[O:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O.CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9]2[O:31][C:30]([C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([C:15]5[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=5[Cl:13])[NH:22][C:23]=4[CH:29]=3)=[N:32][N:33]=2)=[N:3][CH:4]=1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2-amino-5-chloro-pyridine (130 mg, 1.01 mmol) in a biphasic solution of CHCl3 (25 mL) and saturated NaHCO3 (25 mL). Add thiophosgene (46 uL, 0.606 mmol) to the organic phase and stir the reaction vigorously for 2 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol) and stir overnight. Filter the reaction. Extract the aqueous phase with CHCl3 (25 mL). Concentrate the combined organics and combine with the solid. Evaporate the solvent to yield a yellow solid. Add DMF (3 mL) and EDCI (307 mg, 1.60 mmol) and heat the reaction to 80° C. for 1.5 hr. Allow the reaction to cool to room temp. Dilute with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Take the concentrate up in DMSO (2 mL) and dilute with water (50 mL). Cool the mixture to 4° C. and collect the precipitate. Recrystallize from toluene/ACN/MeOH to afford the title compound as a cream colored solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.68 (m, 1H) 7.70 (s, 1H) 7.72 (d, J=2.02 Hz, 1H) 7.75-7.85 (m, 1H) 7.85-7.93 (m, 1H) 7.97-8.03 (m, 2H) 8.06 (tautomer, s, 1H) 8.19 (tautomer, s, 1H) 8.39 (dd, J=2.21, 0.95 Hz, 1H) 11.50 (br. s., 1H) 13.30 (br. s., 1H); MS m/z=456.9 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:14])[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:12][C:10]1[CH2:11][C:6]([CH3:14])([CH3:5])[CH2:7][C:8](=[O:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC1=CC(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.4 %

Procedure:
Acetyl chloride (1.1 ml, 15.65 mmol) was added to a stirred solution of 5,5-dimethyl-cyclohexane-1,3-dione (2.1 g, 14.23 mmol) and pyridine (1.14 ml), in chloroform (50 ml). The mixture was stirred at room temperature for about 1.5 hours, then washed with water, 0.1N HCl, saturated aqueous sodium hydrogen carbonate and water. The organic phase was dried over sodium sulfate and evaporated to dryness to give 2.5 g (96%) of the title compound as a colourless oil, which was used as such without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](B(O)O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:36][N:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:30]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:36]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:20][CH2:19]3)[N:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(OCc1ccccc1)N1CCc2cc(B(O)O)ccc2C1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 40 h
Yield: 48.4 %

Procedure:
To a stirring suspension of 2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.640 g, 2.06 mmol, 1.00 eq) and 4 ÅMS (0.64 g) in CH2Cl2 (20 ml) was added pyridine (0.168 ml, 2.06 mmol, 1.00 eq) followed by ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (0.404 g, 2.06 mmol, 1.00 eq) and Cu(OAc)2 (0.374 g, 2.06 mmol, 1.00 eq). The resulting blue-green mixture was stirred at 25° C. After 40 h, the mixture was diluted with H2O and decanted away from the molecular sieves. The layers were separated and the organic phase was washed with H2O (2×). The combined aqueous phases were extracted with CH2Cl2 (1×). The combined organic phases were dried (MgSO4), concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes) to afford benzyl 6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.46 g, 48% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.28 (m, 5H), 7.24-7.20 (m, 3H), 6.96 (s, 1H), 5.15 (s, 2H), 4.67 (brm, 2H), 4.17 (q, 2H, J=7.2 Hz), 3.66 (brs, 2H), 2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H), 1.18 (t, 3H, J=7.2 Hz); MS (ESI) m/z: 462.3 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([O:20][CH2:21][CH3:22])[CH:9]=1)([O-:7])=[O:6].[CH3:23]O>>[CH3:23][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][C:10]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCOc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1C(=O)OC
Reaction time: 16 h

Procedure:
Thionyl chloride (315 μl, 4.30 mmol) was slowly added to a mixture of 4,5-dinitro-2-ethoxy-benzoic acid (1.00 g, 3.91 mmol) in methanol (10 mL) at r.t. The mixture was stirred for 16 h, then reduced in vacuo azeotroping with toluene. The residue was then purified by column chromatography using P.E.-EtOAc (1:0-1:1) to give the title compound (606 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.00 (s, 1H), 4.35 (q, 2H), 3.85 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:23].Cl.N>O1CCOCC1.CO>[NH3:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]12[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2)=[O:23]
Reactant: CN(CCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CNCCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 112 %

Procedure:
[3-[[4-Chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methoxy]propyl]methyl-carbamic acid, 1,1-dimethylethyl ester (0.236 g, Example 23b), 4M hydrogen chloride in 1,4-dioxane (5 ml) and methanol (5 ml) were stirred together under nitrogen for 3 h, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica gel, eluting with 19:1:0.1/dichloromethane:methanol:ammonia to afford the title compound as an oil (0.106 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(I)c4c3)o2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: -25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a solution of 5-(3-iodo-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.5 g, 1.12 mmol) in DMF (5 mL) at −25° C. was added NaH (0.059 g, 50% in mineral oil, 1.23 mmol) portion wise. The mixture was stirred for 5 min at −25° C. then a solution of 4-methyl benzene sulfonyl chloride (0.235 g, 1.23 mmol) in DMF (1 mL) was added at same temperature dropwise. The reaction was stirred at −25° C. for 10 min. The mixture was poured into ice cold water and a white solid precipitated out which was collected by filtration and recrystallized by triturating it with 1:3 volume of EtOH (2 mL) and CHCl3 (6 mL) to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.450 g, 0.75 mmol, 66.96%). MS (ESI, pos. ion) m/z: 601.1 (M+1); 1H-NMR (DMSO-d6) δ8.312 (s, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.9-7.90 (m, 3H), 7.68 (s, 1H), 7.44 (d, J=9 Hz, 2H), 7.33 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 4.38 (d, J=6 Hz, 2H), 3.73 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([NH2:26])=[O:25])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: NC(=O)c1ccccc1N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccccc1C(N)=O)C(F)(F)F
Yield: 61 %

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (500 mg) and 2-aminobenzamide (1.17 g) in dimethylformamide (2.5 mL) was heated at 140° C. for 19.5 hours. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 15 to 30% ethyl acetate-hexanes) to give 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentylamino]benzamide as a white foam (447 mg).