Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4])(=[O:30])[CH3:29]
Reactant: N#Cc1ccc(CNC(=O)C(N)c2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (RS)-2-amino-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.1 g) in dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (58 μl) and acetyl chloride (28 μl). The reaction mixture was stirred at rt for 1 hr, then diluted with dichloromethane, washed with 1N HCl and brine. The organic layer was dried over MgSO4, filtered and concentrated. The product was isolated by chromatography (silica gel, gradient dichloromethane=>dichloromethane/MeOH 9:1) to give (RS)-2-acetylamino-N-(4-cyano-benzyl)-2-phenyl-acetamide (98 mg). Off-white solid. MS 308.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:47])(=[O:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]>CN1C(=O)CCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:47])(=[O:46])[CH2:41][CH2:42][C:43]([O-:45])=[O:44]
Reactant: O=C(O)CCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN1CCCC1=O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Nilotinib base (0.5 g, 0.94 mmol) and succinic acid (0.144 g, 0.94 mmol) were mixed with NMP (1.5 mL, 3.0V). The mixture was stirred and heated to 80° C. to dissolution. The stirring was continued at the same temperature for 5 h, after which the mixture was allowed to cool to room temperature resulting in precipitation. The precipitate was separated by filtration to give Nilotinib succinate form III. The filter cake was then washed with EtOH (27 mL, 95%) and dried in a vacuum oven (30 mbar) at 40° C. for 16 h to give Nilotinib succinate form III (0.17 g) as an off-white solid.
Reaction SMILES: B(F)(F)F.CSC.[Br:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[C:10]=1[C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]>C(Cl)Cl.CCOC(C)=O>[Br:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:10]=1[C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]
Reactant: COc1ccc(-n2c(-c3c(C)noc3C)c(Br)c3ccccc32)cc1
Agent: FB(F)F
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1c(Br)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
At 0° C., 10 eq of boron trifluoride-dimethyl sulfide was added to 4-[3-bromo-1-(4-methoxyphenyl)-1H-indol-2-yl]-3,5-dimethylisoxazole (the intermediate product of step (b) from the synthesis of Example 22), dissolved in DCM and stirred at ambient temperature over night. The mixture was diluted with EtOAc and washed with brine, the organic phase was concentrated and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by ES/MS m/z: 385.1 (M+H), 383.09 (M−H) and 1H NMR (acetone-d6, 500 MHz): 7.60 (m, 1H), 7.31-7.23 (m, 3H), 7.17 (m, 2H), 6.95 (m, 2H), 2.28 (s, 3H) and 1.99 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[C:30]1([C@H:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:43])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:43][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C@@H:36]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: O[C@H]1CCCCC[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Yield: 28.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 350 mg, 0.786 mmol), (1S*,2R*)-2-phenylcycloheptanol (150 mg, 0.788 mmol), sodium hydride (63%; 60 mg, 1.58 mol) and DMSO (4.0 mL), to yield the title compound (140 mg, 29%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:19]=2)=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8]C(C)C)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:19]=2)=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)cc(-c2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of isopropyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methylphenyl]methylamino]phenoxy]acetate (127 mg, 0.29 mmol, 1.0 eq) in THF (3 mL) was added NaOH (2M aqueous solution, 0.57 mL, 1.15 mmol, 4.0 eq) at room temperature. The reaction was stirred at room temperature for 1 h and then the THF removed in vacuo and the aqueous residue adjusted to pH 4 by addition of 1M HCl. The precipitate was collected by filtration, dried in vacuo and crystallized from CH2Cl2 and petroleum ether to give the title compound (I(d)) as a white solid (50 mg, 44%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C)C1C=CN=CC=1.O1CCOCC1>[O:17]=[C:16]1[C:15]2[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](=[O:18])[N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(CCCO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1C(CCCO)c1ccccc1
Temperature: 155 °C

Procedure:
Heat a solution of δ-aminobenzenebutanol (7.32 g), phthalic anhydride (6.57 g) and 4-(dimethylamino)pyridine (0.050 g) in dioxane (100 ml) under a nitrogen atmosphere at reflux for one hour. Evaporate the solvent at atmospheric pressure and heat the residue at 155° C. under a nitrogen atmosphere for 21/2 hours. After cooling, dissolve the residue in EtOAc (400 ml). Wash the solution with 10% aqueous citric acid (50 ml) followed by saturated aqueous NaHCO3 (50 ml) and brine (50 ml). Dry the organic layer over Na2SO4, filter and vacuum evaporate the solvent to obtain the title compound.
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([Zn+])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[O:26])=[CH:19][CH:18]=1>CN(C)C(=O)C.[Cu]I.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].ClCCl>[CH3:33][C:29]1[CH:28]=[C:27]([C:25](=[O:26])[CH2:24][C@H:23]([C:20]2[CH:21]=[CH:22][C:17]([CH:12]3[CH2:13][CH2:14][N:9]([C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:8])[CH2:10][CH2:11]3)=[CH:18][CH:19]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])[CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])CC1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Temperature: 85 °C
Yield: 57 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl) zinc(II) iodide solution (0.5 M in N,N-dimethylacetamide, 2.0 mL, 1.0 mmol; preparation according to J. Org. Chem. 2004, 69, 5120) was added at room temperature under argon to a mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 200 mg, 507 μmol), copper(I) iodide (9.7 mg, 51 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (18.6 mg, 25.4 μmol) in N,N-dimethylacetamide (3 mL). The reaction mixture was heated at 85° C., then after 4 h partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (144 mg, 57%). Off-white foam, MS (ESI+): m/z=499.3 ([M+H]+).
Reaction SMILES: CC([O-])(C)C.[K+:6].[CH3:7][C:8]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])=[O:9].[C:20]([O:25][CH2:26][CH3:27])(=[O:24])[C:21]([O-])=[O:22]>C(O)C>[K+:6].[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[C:8]([O-:9])=[CH:7][C:21](=[O:22])[C:20]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: COc1cccc(OC)c1C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 1 h

Procedure:
A solution of 13.4 g of 95% potassium tert-butylate in 72 ml of ethanol is added over 6 minutes to a solution, stirred and heated to 50° C., of 18 g of 2,6-dimethoxyacetophenone in 54 ml of ethanol. The mixture is heated to reflux, 16.3 ml of ethyl oxalate are added over 9 minutes and refluxing is continued for 1 hour. 40 ml of ethanol are then distilled off and the mixture is allowed to cool with stirring for two and a half hours. The mixture is filtered, and the precipitate is washed with 40 ml of ethanol and dried under vacuum at 60° C. for 17 hours to obtain 31 g of expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4](I)[C:3]=1[F:23].[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH:24]=[CH2:25])[C:3]=1[F:23]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C(C)Oc1c(C2(C)OCCO2)cc(Cl)c(F)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1c(F)c(Cl)cc(C2(C)OCCO2)c1OC(C)C(=O)OCC
Temperature: 80 °C
Yield: 157.2 %

Procedure:
A mixture of ethyl 2-[4-chloro-3-fluoro-2-iodo-6-(2-methyl-1,3-dioxolan-2-yl)phenoxy]propanoate (1.83 g, 3.99 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.880 mL, 5.19 mmol), and potassium carbonate (1.65 g, 12.0 mmol) in 1,4-dioxane (15.6 mL) and water (7.8 mL) was degassed with nitrogen for 10 min. The reaction mixture was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (163 mg, 0.199 mmol), degassed with nitrogen for another 10 min, and heated at 80° C. for 2 h. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was poured into water. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated give a crude residue. Purification by flash column chromatography (100% hexanes to 15% EtOAc/hexanes) gave the desired product (2.25 g, 57%) as a mixture of enantiomers. LCMS calculated for C17H21ClFO5 (M+H)+: m/z=359.1; found: 359.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[O:12]1[CH:18]2[CH:13]1[C:14]([CH3:31])([CH3:30])[O:15][C:16]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:17]=12>CS(C)=O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C@@H:18]2[C:17]3[CH:19]=[C:20]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][C:14]([CH3:30])([CH3:31])[C@H:13]2[OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Reactant: COc1ccc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccn([C@@H]2c3cc(S(=O)(=O)C(F)(F)F)ccc3OC(C)(C)[C@H]2O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
98 mg of 3-methoxy-2(1H)-pyridone were added to a suspension of 38 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 3 ml of dimethyl sulfoxide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 200 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) in 1.5 ml of dimethyl sulfoxide was added at the same temperature and under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 4 days, after which it was worked up in a similar manner to that described in Example 2. The product was then purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 16 mg of the title compound, melting at 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH2:6][C:7]1[C:14]([F:15])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:16])[CH:8]=1.C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH2:6][C:7]1[C:14]([F:15])=[CH:13][C:10]([C:11]([NH2:12])=[O:22])=[C:9]([F:16])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a stirred solution of 4-((3,4-dichlorophenoxy)methyl)-2,5-difluorobenzonitrile (Preparation 23, 153 mg, 0.481 mmol) in DMSO (5 mL) was added potassium carbonate (133 mg, 0.962 mmol), followed by dropwise addition of 30% aqueous hydrogen peroxide solution (0.29 mL, 2.90 mmol). After 3 hours, the reaction was quenched with saturated aqueous potassium bisulphate solution (10 mL), and extracted with DCM (3×10 mL). The combined organics were washed with brine (2×10 mL), dried over magnesium sulphate, and concentrated in vacuo to afford the title compound as a white solid (60 mg, 38%).
Reaction SMILES: [CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].O1CCCC1.Cl>C(O)C.O>[CH2:1]([C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCCCc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Yield: 82.7 %

Procedure:
8 g of this ester were dissolved in 50 ml of ethanol and treated with a solution of 10 g of potassium hydroxide in 10 ml of water and 20 ml of ethanol. After the addition of 50 ml of tetrahydrofuran the mixture was heated to 40° C. for 4 hours. The clear, yellow reaction solution was poured into a mixture of ice and 6N hydrochloric acid, extracted with ethyl acetate, the organic phase was washed with water, dried and evaporated. After recrystallization of the crystalline residue from hexane/ethyl acetate there were obtained 6.2 g of p-[(E)-2-(3-hexyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)vinyl]benzoic acid in the form of white crystals, melting point 134-136° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1>CO.[OH-].[NH4+].[Ni]>[F:18][C:2]([F:1])([F:17])[C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][NH2:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: N#CC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCC1CCN(c2ccnc(C(F)(F)F)n2)CC1
Yield: 100.5 %

Procedure:
A solution of VII (19.0 g, 74.2 mmol) in methanol (150 mL) and ammonium hydroxide (50 mL of a 30% solution) was hydrogenated over a Raney nickel catalyst (ca 5 g) at 60 psi for 30 hr. The mixture was filtered and concentrated in vacuo to give the product as a light green oil (19.40 g, 100%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19](O)[C:20]([CH3:22])=[CH2:21])=[C:16]([O:24][CH3:25])[C:15]([CH3:26])=[C:14]2[C:10]=1[C:11](=[O:27])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC)(OC)(OC)CC.C(O)(=O)CC>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:22])/[CH2:21][CH:10]([CH3:9])[C:11]([O:12][CH3:13])=[O:27])=[C:16]([O:24][CH3:25])[C:15]([CH3:26])=[C:14]2[C:10]=1[C:11](=[O:27])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCC(OC)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)C(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2

Procedure:
A solution of 4-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy -7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene (0.91 g) in trimethyl orthopropionate (25 ml) and propionic acid (0.08 ml) was heated to 110° C. for 2.5 hours. The solvents were evaporated under vacuum to afford methyl (E)-6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate as an oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[Cl-].C([Al+]CC)C.[C:21](Cl)(=[O:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:21](=[O:23])[CH3:22]
Reactant: FC(F)(F)Oc1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: CC[Al+]CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ccc(OC(F)(F)F)cc12
Reaction time: 0.5 h

Procedure:
To a solution of 5-(trifluoromethoxy)-1H-indole [262593-63-5] (1.00 g, 4.97 mmol) in CH2Cl2 (20 mL), cooled to 0° C., was added dropwise diethylaluminum chloride (1M solution in hexane; 7.46 mL, 7.46 mmol), and stirring was continued for 30 min. A solution of acetyl chloride (0.532 mL, 7.46 mmol) in CH2Cl2 (20 mL) was subsequently added, and the reaction mixture was stirred at 0° C. for 1 h. A 5% aqueous citric acid solution (100 mL) was then added at 0° C., and the mixture was stirred for 15 min at RT. The mixture (two phases) was filtered, and the precipitate was dried at 50° C. in vacuo for 1 h to afford the title compound. Beige solid. MS: 244.0 [M+H]+; tR (HPLC conditions c): 4.60 min. The material thus obtained was used directly in the next step without further purification
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)=[O:7].[OH-].[Na+].Cl.CO>O>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:6]([NH:5][CH2:4][C:3]([OH:18])=[O:2])=[O:7]
Reactant: COC(=O)CNC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1ccc2ccccc2c1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
[(Naphthalene-2-carbonyl)amino]acetic acid methyl ester (10.03 g, 41 mmol, 1.0 eq., see step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 120 mL, 123 mmol, 3.0 eq.). The mixture was heated to 55° C. using an oil bath for 2 hours. The mixture was cooled to 5° C. using an ice/water bath. Concentrated hydrochloric acid (50 mL) was added very slowly to the cooled solution, ensuring that the temperature did not rise above 10° C. A dense yellow precipitate was formed. The mixture was stirred for 10 minutes and was then filtered. The yellow solid was air lo dried for 15 minutes and then dried in vacuo at 40° C. for 16 hours (8.73 g, 93%). Methanol (50 mL, 10 vols) and water (100 ml, 20 vols) were added to a portion of the sub-title compound (5.0 g, 22 mmol). The mixture was heated to 70° C. using an oil bath whilst being stirred. The solution was held at this temperature for 10 minutes, and then was allowed to cool further to 5° C. using an ice/water bath. Crystallisation began at approximately 30° C. The precipitate was collected by filtration, air dried for 15 minutes, then dried in vacuo at 40° C. for 2 hours (3.2 g, 64%). The isolated sub-title compound (3.2 g, 0.014 mol, 64%) was added to water (100 mL, 20 vols) and methanol (50 mL, 10 vols). The mixture was heated to 70° C. to dissolve the solid. The solution was allowed to cool to room temperature, crystallisation occurred on cooling. The mixture was cooled further to 2° C., and then was filtered using a sinter funnel. The solid was air dried for 10 minutes, then dried in vacuo at 40° C. for 16 hours (2.21 g, 44%).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:17]=1[Cl:23]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:7]([S:8][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[C:17]=1[Cl:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Clc1c(Br)cccc1SCc1ccccc1
Reaction time: 8 h

Procedure:
To stirred phenyl-methanethiol (14.8 g, 119.36 mmol) in 175 ml DMF was added Cs2CO3 (38.89 g, 119.36 mmol) under argon. After 10 min 1-bromo-2-chloro-3-fluoro-benzene (25 g, 119.36 mmol) in 25 ml DMF was added and stirring was continued overnight at RT and then 3 h at 80° C. After cooling the mixture was diluted with ethyl acetate/water and washed subsequently with 1 N HCl and brine. The organic layer was dried with MgSO4, filtered and evaporated. Purification by chromatography on silica gel yielded 22 g (59%) as an amorphous, colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.O.C(OC([N:19]1[CH2:24][CH2:23][C:22]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)([CH2:25][NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH2:21][CH2:20]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH:32]1([C:22]2([CH2:25][NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nccs2)(C2CCCCC2)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1csc(NCC2(C3CCCCC3)CCNCC2)n1
Yield: 96 %

Procedure:
A ready-to-use solution of trifluoroacetic acid:methylene chloride:water (1:1:0.1, 7 mL) is added to 4-cyclohexyl-4-(thiazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tert-butyl ester, 12, (312 mg, 0.82 mmol), and the reaction mixture is stirred for 0.5–1.0 hour. The mixture is then concentrated under reduced pressure and partitioned between aqueous sodium bicarbonate and ethyl acetate. The organics are separated and the solvent removed under reduced pressure. The crude product is purified by preparative HPLC to afford 220 mg (96% yield) of the desired compound as the trifluoroacetic acid salt.