Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].C([O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([CH3:18])=[CH2:17])[CH:11]=1)(=O)CC.O1CCOC[CH2:20]1>>[C:16]([C:12]1[CH:11]=[C:10]([CH:9]([CH3:20])[C:8]([OH:7])=[O:1])[CH:15]=[CH:14][CH:13]=1)([CH3:18])=[CH2:17]
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: C=C(C)c1cccc(CCOC(=O)CC)c1
Agent: [Na+]
Product: C=C(C)c1cccc(C(C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1N NaOH (5 ml) was added to a solution of the ester in dioxan (5 ml) and the solution is stirred at r.t. overnight. After evaporation of the organic solvent, the mixture is acidified to pH=2 with 2N HCl until complete precipitation of the product, which is isolated, as a white solid by filtration.
Reaction SMILES: [H-].[Na+].N[C:4]1[C:5]([CH3:12])=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].I[CH3:14].O.[CH3:16][N:17](C=O)C>>[Cl:10][C:9]1[C:4]([CH2:16][NH2:17])=[C:5]([CH3:12])[C:6]([O:11][CH3:14])=[CH:7][CH:8]=1
Reactant: CI
Reactant: CN(C)C=O
Reactant: Cc1c(O)ccc(Cl)c1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cl)c(CN)c1C
Reaction time: 0.5 h

Procedure:
NaH, 60% (0.236 mol) was stirred in DMF (500 ml), at room temperature. 3-amino-4-chloro-2-methylphenol (0.236 mol) was added portionwise (exothermic temperature rise to 32° C.). The reaction mixture was stirred for 30 minutes, allowing the temperature to drop to room temperature. Iodomethane (0.236 mol) was added dropwise. The reaction mixture was stirred for one hour at room temperature. Water was added (at first, slowly). This mixture was extracted with toluene. The separated organic layer was dried, filtered and the solvent evaporated, yielding 40.5 g 6-chloro-3-methoxy-2-methylbenzylamine (interm. 22) (quantitative yield; used in next reaction step, without further purification).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[C:27]([CH3:34])=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[C:27]([CH3:34])=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Cl)cccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1c(Cl)cccc1-n1nccc1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-chloro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=441.0 (M)+
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([N:10]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH:22]2[CH2:25][N:24](C([O-])=O)[CH2:23]2)[CH2:6][CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH:24]1[CH2:25][CH:22]([C:11]2[N:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]3)[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=2)[CH2:23]1
Reactant: N#CC[C@H]1CC[C@H](n2c(C3CN(C(=O)[O-])C3)nc3cnc4ccsc4c32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@H](n2c(C3CNC3)nc3cnc4ccsc4c32)CC1

Procedure:
3-{1-[trans-4-(Cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}azetidine-1-carboxylate (14 mg, 0.031 mmol) was treated with trifluoroacetic acid (1 mL) in methylene chloride (1 mL) at room temperature for 1 h. The mixture was stripped to dryness, diluted with MeOH and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C19H22N5S (M+H)+: m/z=352.2. Found: 352.0.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:18][CH2:19]3)[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 100 °C

Procedure:
To a sealed tube containing 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (Compound B-1) (1.24 g, 2.48 mmol) in 1,4-dioxane (20 mL) was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (1.12 g, 2.61 mmol) and Pd(PPh3)4(0.87 g, 0.75 mmol). The mixture was flushed with N2, and was sealed and heated to 100° C. After 14 h of heating, the mixture was cooled to rt, was diluted with MeOH, and was filtered through a pad of celite to remove any solids. The solution was concentrated under reduced pressure, and was re-dissolved in DMF. The DMF solution was loaded on the prep HPLC for purification. After purification, the title product was isolated as an off-white solid (0.901 g). LCMS: m/e 559.6 (M+H)+, ret time 2.283 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 14.52 (s, 1 H) 12.35 (s, 1 H) 8.26-8.41 (m, 2 H) 7.36-7.76 (m, 6 H) 4.29-4.47 (m, J=6.71 Hz, 2 H) 3.09-3.80 (m, 8 H) 1.36 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[CH3:6][O:7][CH:8]([O:18]C)[CH:9]([CH:13](OC)OC)[C:10]([O-])=O>CN(C)C=O>[CH3:6][O:7][C:8]([C:9]1[CH:10]=[N:4][C:3]([NH2:5])=[N:2][CH:13]=1)=[O:18]
Reactant: COC(OC)C(C(=O)[O-])C(OC)OC
Reactant: N=C(N)N
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N)nc1
Temperature: 140 °C

Procedure:
To a stirred solution of 4.30 g guanidine hydrochloride in 50.00 g dimethyl formamide, 10.00 g 3,3-dimethoxy-2-dimethoxymethyl-propionate were added. The resulting clear solution was heated to 100° C. for 2 hours and to 140° C. for an additional 20 hours. After cooling to 60° C., the solvent was completely removed in vacuo and the resulting light brown residue thoroughly extracted with boiling tetrahydrofurane. After distilling off the majority of the solvent, the crystalline product was isolated by suction filtration and subsequent drying in vacuo. A total of 4.34 g (63% of theory based on 3,3-dimethoxy-2-dimethoxymethyl-propionate) of methyl-2-amino-pyrimidine-5-carboxylate could be isolated in this way. Identification of the product was based on 1H-NMR-, 13C- and IR-spectra.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].[N:20]1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCOC(C)=O>O1CCOCC1>[C:9]([C:8]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=[C:6]([CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:10])[NH2:20]
Reactant: c1ccncc1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(N)=O)cc(C(=O)OCC)c1
Yield: 92.7 %

Procedure:
NH4HCO3 (0.15 g, 1.89 mmol, 1.26 eq) was added to a stirred solution of 3,5-bis(ethoxycarbonyl)benzoic acid (0.42 g, 1.5 mmol, 1 eq), pyridine (0.24 mL, 0.237 g, 3.0 mmol, 2 eq), and (Boc)2O (0.45 mL, 0.43 g, 1.95 mmol, 1.3 eq) in 2 mL anh. dioxane under Ar. The reaction was stirred over the weekend to form a white solid. EtOAc was added, but the solid did not dissolve. The mixture was washed with 0.1 N HCl (×2) and water (×4). The solid stayed suspended in the organic layer, but did dissolve. The solvent was removed in vacuo yielding 0.369 g (1.39 mmol, 93% yield) of diethyl 5-carbamoylisophthalate as an insoluble white solid.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1)[CH:11]=O.[CH2:22]([O:24][C:25](=[O:42])[CH:26](P(OCC)(OCC)=O)[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:23].O.[OH-].[Li+]>C(OCC)(=O)C.O>[CH2:22]([O:24][C:25](=[O:42])/[C:26](=[CH:11]/[C:10]1[CH:13]=[CH:14][C:15]([N:16]2[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]2)=[C:8]([O:7][CH3:6])[CH:9]=1)/[CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:23]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(CCC1OCCO1)P(=O)(OCC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC1OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a THF (20 mL) solution of (1.75 g) of the 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde obtained in Example 1, 2-(diethoxyphosphoryl)-4-[1,3]dioxolan-2-yl-butyric acid ethyl ester (2.50 g) and lithium hydroxide monohydrate (388 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; heptane-ethyl acetate=1:2→ethyl acetate), and 1.05 g of the title compound as an isomer mixture (E:Z=4:1) was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=[C:2]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21](=[O:27])[NH:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[O:15])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH2:49]([N:53]=[C:54]=[O:55])[CH2:50][CH2:51][CH3:52]>ClCCl>[CH2:49]([NH:53][C:54]([N:37]1[CH2:38][CH2:39][N:34]([C:2](=[O:1])[CH2:3][NH:4][C:5]([C:7]2[CH:11]=[C:10]([O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21](=[O:27])[NH:22][CH:23]3[CH2:24][CH2:25][CH2:26]3)=[O:15])[N:9]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:8]=2)=[O:6])[CH2:35][CH2:36]1)=[O:55])[CH2:50][CH2:51][CH3:52]
Reactant: O=C(NCC(=O)N1CCNCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCNC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 100 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide in 5 ml dichloromethane were added at 0° C. 56 l DIPEA and 25 l butyl isocyanate. After stirring for 12 h it was concentrated and the residue obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 55 mg MS (ES+): m/e=637.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]3[CH2:23][CH2:22][CH2:21][C@@H:17]3[C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.[H-].[Na+].[C:30](OC(=O)[C@H]1CCCN1NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:33])([CH3:32])[CH3:31]>COCCOC.CCOC(C)=O>[C:30]([O:19][C:18](=[O:20])[C@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:24][C:25]([NH2:27])=[NH:26])=[CH:11][CH:10]=1)(=[O:15])=[O:14])([CH3:33])([CH3:32])[CH3:31]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline hydrochloride ##STR41## Guanidine hydrochloride (220 mg, 2.3 mmol) was added in one portion to a stirred suspension of NaH (55 mg, 80% dispersion by wt in mineral oil, 1.83 mmol) in DME (8 mL) and the mixture was heated at 60° C. under N2 for 30 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-proline t-butyl ester (250 mg, 0.58 mmol) was added and the mixture heated at reflux for 5 h. The cooled mixture was diluted with EtOAc, washed with water, brine, dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-proline t-butyl ester (200 mg, 0.44 mmol) as a yellow solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[NH2:13][C:14]1[C:26]([Br:27])=[CH:25][C:17]2[C:18]([C:21]([NH:23][CH3:24])=[O:22])=[CH:19][O:20][C:16]=2[CH:15]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:39](=[O:41])[CH3:40]>C1COCC1>[C:39]([C:19]1[O:20][C:16]2[CH:15]=[C:14]([NH2:13])[C:26]([Br:27])=[CH:25][C:17]=2[C:18]=1[C:21]([NH:23][CH3:24])=[O:22])(=[O:41])[CH3:40]
Reactant: CNC(=O)c1coc2cc(N)c(Br)cc12
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1c(C(C)=O)oc2cc(N)c(Br)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of diisopropylamine (3.76 g, 37.1 mmol) in THF (25 mL) was slowly added a solution of n-BuLi (2.5 mol/L in hexane) (16.5 mL, 40.5 mmol) under N2 at −78° C. and the resulting solution was stirred at −78° C. for 30 minutes. A solution of compound 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (2 g, 7.43 mmol) in THF (50 mL) was slowly added to the fresh lithium diisopropylamide at −78° C. and stirred for another one hour. To the resulting mixture was added N-methoxy-N-methylacetamide (3.83 g, 37.16 mmol) at −78° C. and stirred for another one hour. The reaction was quenched with saturated NH4Cl at −78° C. and the mixture was slowly warmed to room temperature. Water was added and the mixture extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (700 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 10.00 (s, 1H), 8.76 (s, 1H), 6.86 (s, 1H), 4.54 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 311/313.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:43])[CH2:9][C@@H:10]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C)=O)[CH2:22]1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][NH2:45].C(O)C>>[Cl:42][C:38]1[CH:37]=[C:36]([C@H:27]([O:28][CH2:29][CH2:30][CH2:31][C:32]([NH:45][CH3:44])=[O:34])[C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:19]([NH:18][C@@H:10]([CH2:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][N:8]([CH3:43])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:20])[CH2:22]2)[CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
methyl 4-((R)—((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoate (70 mg, 0.11 mmol) was dissolved in the CH3NH2/C2H5OH (20 mL), which was stirred at rt overnight. After the reaction was completed, the solvent was removed in vacuo. The product was purified via preparative TLC to afford tert-butyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(4-(methylamino)-4-oxobutoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate (50 mg, 71% yield), which was used immediately in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([OH:20])[CH:14]=2)[N:9]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:20][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[F:21])[N:9]=[C:8]([Cl:7])[C:17]([CH:18]=[O:19])=[CH:16]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc2cc(O)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc2cc(OCc3ccccc3)c(F)cc2nc1Cl
Temperature: 0 °C
Yield: 81.9 %

Procedure:
Potassium carbonate (9.2 g, 66 mmol) is added to a solution of 2-chloro-7-fluoro-6-hydoxy-3-quinolinecarbaldehyde (obtained according to 1.c, 13 g, 58 mmol) in anhydrous N,N-dimethylformamide (120 ml) and the mixture, placed under an argon atmosphere, is cooled down to 0° C. Benzyl bromide (7.9 ml, 66 mmol) is added dropwise and the reaction medium is maintained under agitation at ambient temperature for 16 hours. The reaction medium is then poured into ice cold water (200 ml) and the resulting yellow solid is filtered, then taken up in ethanol (200 ml) and concentrated under reduced pressure. The residue is taken up in ethyl ether (200 ml) and the resulting yellow solid is filtered then dried under reduced pressure in order to produce 15 g (82%) of a yellow solid, m.p. 228° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[NH2:37][C@@H:38]1[CH2:41][C@H:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])[C:39]1([CH3:50])[CH3:49]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:37][C@@H:38]4[CH2:41][C@H:40]([C:42]([N:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[C:39]4([CH3:50])[CH3:49])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCC1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)N4CCCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.336 g, 0.674 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in DCM (1 ml) Oxolyl chloride (0.58 ml, 6.746 mmol) in DCM (3.15 ml) was added at 0° C. and stirred at room temperature for about 3 hours and completion of the reaction monitored by TLC then the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to the above stirred solution of ((1S,3R)-3-amino-2,2-dimethylcyclobutyl)(pyrrolidin-1-yl)methanone (step 2, 0.264 g, 1.349 mmol) at 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with aqueous 1N HCl, then washed with water and brine, and dried over Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 15% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.350 g: Yield: 76.7%; 1H NMR (300 MHz, CDCl3): δ 6.28 (d, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.51-4.06 (m, 2H), 3.56-3.27 (m, 8H), 3.18-3.08 (m, 1H), 2.91-2.74 (m, 2H), 2.60-2.46 (m, 2H), 2.37-2.20 (m, 3H), 2.08 (s, 3H), 1.99-1.11 (m, 26H), 1.00-0.75 (s, 18H); Mass: [M+Na]+ 699 (100%); IR (KBr, cm−1): 3268, 3077, 2955, 2873, 1734, 1716, 1618, 1549, 1455, 1452, 1371, 1344, 1242, 1180, 1150, 1033, 980, 869; M.R: 94.9° C.-101.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.[H-].[Na+].IC.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2
Reactant: O=C([O-])O
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccncc1-c1cc2cc(C#N)ccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 178 mg, 0.649 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (78 mg, 1.95 mmol) and the suspension is stirred for 30 min. Iodomethane (138 mg, 0.97 mmol) is then added to the reaction mixture which is stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added to quench the reaction and the mixture is filtered and purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 2-(4-methoxy-pyridin-3-yl)-1-methyl-1H-indole-5-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (s, 3H), 3.89 (s, 3H), 6.67 (s, 1H), 7.27 (d, J=5.8 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.60 (d, J=5.8 Hz, 1H). HRMS (ESI) m/z 264.1138 [(M+H)+ calcd for C16H14N3O: 264.1137].
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25](=[O:45])[C:26]1[CH:31]=[C:30]([CH:32]([OH:36])[CH2:33][CH2:34][CH3:35])[C:29]([C:37]([F:40])([F:39])[F:38])=[CH:28][C:27]=1[NH:41][C:42](=[O:44])[CH3:43].O.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:23][O:24][C:25](=[O:45])[C:26]1[CH:31]=[C:30]([C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[C:29]([C:37]([F:38])([F:40])[F:39])=[CH:28][C:27]=1[NH:41][C:42](=[O:44])[CH3:43]
Reactant: CCCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC(=O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of Dess-Martin periodinane (514 mg, 1.18 mmol) in DCM (2.5 mL) at r.t. was added 2-acetylamino-5-(1-hydroxy-butyl)-4-trifluoromethyl-benzoic acid methyl ester (245 mg, 0.735 mmol). The reaction was stirred at r.t. for 1 h then diluted with EtOAc and poured onto 1:1 mixture water/sat. aq Na2SO3. The organic phase was washed twice with aq KHCO3, brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give the title compound (237 mg, 97% yield) as a beige product. ESI-MS: m/z 332 [M+H]+, m/z 330 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:3]=1[CH2:4]N1C2C(=CC=C(C(F)(F)F)C=2)C2(C(=O)NC(=O)N2)C1=O.ClC1C=C([Br:53])C=CC=1C[N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[C:36](=[O:47])[C:35]1=[O:48]>>[Cl:1][C:2]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:3]=1[CH2:4][Br:53].[F:46][C:43]([F:44])([F:45])[C:40]1[CH:41]=[C:42]2[C:37]([C:36](=[O:47])[C:35](=[O:48])[NH:34]2)=[CH:38][CH:39]=1
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2Cl)c2cc(C(F)(F)F)ccc21
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1Cl)c1cc(C(F)(F)F)ccc12
Product: Clc1cc(Br)ccc1CBr
Product: O=C1Nc2cc(C(F)(F)F)ccc2C1=O

Procedure:
(Example 5): 1'-(2-chloro-4-bromobenzyl)-6'-trifluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione, as a solid, m.p. 299°-301° C., starting from 1-(2-chloro-4-bromobenzyl)-6-trifluoromethylindoline-2,3-dione (itself obtained as a solid, m.p. 132°-134° C., by reaction of 2-chloro-4-bromobenzyl bromide with 6-trifluoromethylindoline-2,3-dione in an analogous manner to that described for the starting material in Example 1).