Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:11]([C:24]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])=[O:25])=[CH:10]2)=[O:5].CN(C)CCCN=C=NCC.Cl.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51]>CN(C)C1C=CN=CC=1.ClCCl>[C:50]([NH:54][C:30]([C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:11]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:36])([CH3:1])[CH3:37])=[CH:15][CH:14]=3)=[O:25])[CH:35]=[CH:34][CH:33]=1)=[O:31])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cccc(C(=O)O)c1)n2Cc1ccccc1F
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cccc(C(=O)NC(C)(C)C)c1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 mg (0.04 mmol) of the compound from Example 64, 11.5 mg (0.06 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl and 2.5 mg (0.02 mmol) of 4-dimethylaminopyridine are initially charged in 1 ml of dichloromethane. 3.5 mg (0.05 mmol) of tert-butylamine are added, and the mixture is stirred at RT overnight. For work-up, the mixture is diluted and extracted with aqueous hydrochloric acid and dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure. Purification is carried out by chromatography on silica gel.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:20](Cl)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1.Cl>COCCOCCOC>[Cl:11][C:12]1[C:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: O=C(O)c1cc(Oc2ccc(Cl)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 10 °C

Procedure:
To 30 ml of dry diglyme under a nitrogen atmosphere was added 0.960 g (0.02 mol) of sodium hydride dispersion in mineral oil (50%). The solution was cooled to 10° C. and 1.28 g (0.01M) 4-chlorophenol in 15 ml of dry diglyme was added dropwise while maintaining the temperature at 10° C. This was followed by the dropwise addition of 2.36 g (0.01 mol) of 4,5-dichloro-2-nitrobenzoic acid in 15 ml of dry diglyme. The reaction mixture was then heated to 153° C. (oil bath) for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The pH was then adjusted to 1.5 with 6N hydrochloric acid. The solution was extracted with ethyl acetate, and the organic layer dried over anhydrous magnesium sulfate. The solvent was removed and the crude solid triturated with hexane, followed by recrystallization from carbon tetrachloride to give the title compound: yield 1.65 g (50%) m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1(C)[O:23]C(=O)C[C:20](=O)[O:19]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:17][C:18]([O:19][CH3:20])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(Benzyloxycarbonylamino)propanoic acid [N-Cbz-β-alanine] (5.0 g, 22.4 mmoles) is suspended in methylene chloride (100 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 22.9 mmoles), triethylamine (8.5 mL, 61.0 mmoles) and diethyl cyanophosphonate (3.7 mL, 22.8 mmoles) are added. All solids dissolve quickly, and the reaction quickly turns yellow. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated to an orange syrup. The syrup is dissolved in anhydrous methanol (200 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product purified on silica gel (150 mL bed volume) eluting with methylene chloride (500 mL) then methylene chloride:methanol (99.5:0.5 [v/v], 500 mL then 99:1 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow oil. The oil is dried well in vacuo. The yield is 4.5 g (68%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:2]=1>[Pd].C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:2]=1
Reactant: OCCC#Cc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: OCCCCc1cnc2ccccc2c1
Yield: 99.9 %

Procedure:
A solution of 4-(3-quinolinyl)-3-butyn-1-ol (17.0 g, 0.086 mol) is hydrogenated over palladium on carbon (1.0 g) in ethanol (400 mL) at room temperature. After the catalyst is filtered, the solvent is removed under reduced pressure to give 17.3 g of a brown oil. The oil is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give 13.5 g of the title compound as a yellow oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CO.[Pd]>[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:24]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=3[N:3]=2)=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCCN4)cc3)nc12
Reaction time: 18 h

Procedure:
A mixture of 2,3-diaminobenzamide dihydrochloride (1 g), 4-pyridin-2-ylbenzaldehyde (0.82 g) and 10% Pd/C (0.3 g) in methanol (30 mL) at reflux was stirred for 18 hours, cooled, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was crystallized from methanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CCc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: c1ccc2nc(COc3ccc(CCc4ccc(-c5nnn[nH]5)cc4)cc3)ccc2c1
Temperature: 110 °C

Procedure:
A mixture of 0.35 g (0.96 mmol) of 4-(4-(2-quinolinylmethyloxy)phenethyl)benzonitrile, 0.31 g (4.8 mmol, 5 equiv.) of sodium azide, and 0.55 g (4.8 mmol, 5 equiv.) of pyridine hydrochloride in 15 ml of DMF are heated at 110° C. for 48 hours. The mixture is poured into ice water and the precipitate that forms filtered off and recrystallized from methanol-water to obtain 5-(4-(4-(2-quinolinylmethyloxy)phenethyl)phenyl)tetrazole. (M.P. 203° C.-206° C.)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:32][C:33]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:34][N:35]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:32][C:33]([C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:34][N:35]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(c1cnc(Br)s1)N1CCCC1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ncc(C(=O)N3CCCC3)s2)cc1
Yield: 14 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (199 mg, 0.5 mmol) and (2-bromo-thiazol-5-yl)-pyrrolidin-1-yl-methanone (120 mg, 0.46 mmol) to give 30 mg (14% yield). MS (ES+) 453.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].N#N.[ClH:14]>CO.[OH-].[OH-].[Pd+2]>[ClH:14].[NH2:11][CH2:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Agent: [Pd+2]
Agent: Cl
Agent: N#N
Solvent: CO
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 26 h
Yield: 90 %

Procedure:
To a solution of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (10.0 g, 67.5 mmol) in MeOH (1.50 L) and conc. HCl (30 mL) was added 10% Pd(OH)2 (19 g) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 26 hours at RT under hydrogen atmosphere. The H2 gas was displaced by N2 gas. The mixture was filtered through Celite, washed with MeOH and concentrated. The residue was triturated with EtOH, collected with Buchner funnel, and dried under vacuum pressure to give the titled compound as a white solid (11.5 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.86 (brs, 1H), 5.98 (s, 1H), 3.78 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[C:18]([C:20]2[O:24][CH:23]=[N:22][CH:21]=2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:25][C:23]1[O:24][C:20]([C:18]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([F:11])[CH:19]=2)=[CH:21][N:22]=1
Reactant: N#Cc1ccc(-c2cnco2)cc1F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cnc(Cl)o2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
LiHMDS (1.06 M in THF, 1.32 mL, 1.40 mmol) was added to a solution of 2-fluoro-4-(oxazol-5-yl)benzonitrile 38 (0.22 g, 1.17 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (0.415 g, 1.75 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide 4-(2-chlorooxazol-5-yl)-2-fluorobenzonitrile 39 (0.18 g, 70% yield) as white solid. MS (ES) m/z 223 (M+H+).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=2[C@H:14]2[CH:18]=[CH:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:4][CH:1]2[CH2:2][CH2:3]2)=[C:6]([C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@@H]1c1cc([N+](=O)[O-])ccc1SC1CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(N)ccc1SC1CC1
Yield: 97.8 %

Procedure:
85F (1.52 g, 4.19 mmol) and 10% Pd/C (560 mg) in MeOH (100 mL) was hydrogenated under 45 psi for 3.5 h. TLC and LC-MS indicate a clean conversion to the product. Pd/C was removed by filtration through a pad of Celite®. The filtrate was concentrated to give 85G (1.37 g, 97% yield) as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.52-0.64 (m, 2H) 0.85-0.95 (m, 2H) 1.16-1.24 (s, 7H) 1.45 (s, 2H) 1.71 (m, 1H) 1.82-1.94 (m, 2H) 2.09-2.19 (m, 1H) 2.32 (m, 1H) 3.47-3.57 (m, 1H) 3.59-3.69 (m, 1H) 5.18-5.25 (m, 1H) 6.48 (d, J=2.20 Hz, 1H) 6.58 (dd, J=8.13, 2.42 Hz, 1H) 7.30 (t, J=8.35 Hz, 1H), LC-MS 235 (M-Boc).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=1>CN(C)C=O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:6][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([Cl:26])[N:18]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
L-Alanine methyl ester hydrochloride (8.4 g, 0.06 mol) was dissolved in 100 ml of anhydrous N,N-dimethylformamide, and 16.6 ml (0.12 mol) of triethylamine were added. Subsequently, while stirring vigorously, 10.7 g (0.05 mol) of 2,6-dichloro-3-nitropyridine in 20 ml of anhydrous N,N-dimethylformamide were slowly added dropwise, during which the reaction temperature rose above 40° C. After a further 3 h at room temperature, the reaction mixture was poured into about 400 ml of ice-water, extracted three times with ethyl acetate, dried (sodium sulfate) and concentrated. After chromatography on silica gel (ethyl acetate/heptane=1:5 then 1:2), 9.0 g (69%) of compound A were isolated as a yellow oil,
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:49])(=[O:48])[C@@H:41]([C@H:43]([C:45]([OH:47])=[O:46])[OH:44])[OH:42]>CN(C)C=O>[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:45]([C@@H:43]([C@H:41]([C:40]([O-:49])=[O:48])[OH:42])[OH:44])([O-:47])=[O:46]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN(C)C=O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base Form A (4.00 g, 7.55 mmol) was mixed with dimethylformamide (“DMF”) (40 mL, 10V) to obtain a suspension. The suspension was heated to 80° C. and stirred at the same temperature for 30 min to produce a clear yellow solution. To the solution was added a solution of L-tartaric acid (1.25 g, 8.31 mmol, 1.1 mol eq) in DMF (4 mL, 1V) in one portion. The solution was stirred at 80° C. for 1 hour. Then the heating source was removed and the mixture was allowed to cool to room temperature. The stirring was continued at ambient temperature over a period of 6 h after which time the mixture was transferred to the refrigerator for 16 h. MTBE (400 mL) was added portion-wise to the mixture at room temperature until a light yellow precipitate was formed. The resulting suspension was stirred at room temperature for 6 h and then filtered to give Nilotinib L-tartrate form V as a light-yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.[Cl-].[Na+].Cl>O1CCCC1>[F:23][C:8]([F:7])([F:24])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
178 mg (4.70 mmol) lithium aluminium hydride were given to 5 ml tetrahydrofuran (THF) and stirred at room temperature (r.t.) for 20 min. A solution of 590 mg (2.35 mmol) 5-(4-trifluoromethyl-phenyl)-pyridine-2-carbaldehyde in 5 ml THF was added drop by drop within 15 min., and the mixture stirred for 3 h. 9 ml conc. sodium chloride solution was added slowly at 0° C. and stirring continued for 60 min. The mixture was adjusted to pH=5 by addition of conc. HCl. A formed salt precipitate was isolated by filtration and washed with THF. The combined THF-solutions were evaporated, the residue extracted twice with ethyl acetate, the organic phase dried (sodium sulphate), evaporated, and the obtained material (270 mg, 45%) used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]#[N:12])=[CH:9][C:4]=2[O:3]C1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11]#[N:12])[CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: N#CCc1ccc2c(c1)OCO2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of benzo[1,3]dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol) in CH2Cl2 (15 mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at −78° C. under N2. The mixture was slowly warmed to room temperature and stirred overnight. H2O (10 mL) was added to quench the reaction and the CH2Cl2 layer was separated. The aqueous phase was extracted with CH2Cl2 (2×7 mL). The combined organics were washed with brine, dried over Na2SO4 and purified by column chromatography on silica gel (petroleum ether/ethyl acetate 5:1) to give (3,4-dihydroxy-phenyl)-acetonitrile (0.25 g, 54%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 8.95 (s, 1H), 6.68-6.70 (m, 2H), 6.55 (dd, J=8.0, 2.0 Hz, 1H), 3.32 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.O.[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH3:16][N:8]([C:5]([CH3:7])([CH2:4][CH2:3][CH:2]=[O:1])[CH3:6])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C(=O)OC(C)(C)C)C(C)(C)CCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C(C)(C)CCC=O
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 250 mg of 12d and 500 mg of sodium bicarbonate in 3 ml of THF was added 550 mg of Dess-Martin periodinane reagent. After stirring for 1 h the reaction mixture was diluted with water. A few drops of sat. aq. Na2S2O3 solution were added and stirring was prolonged for 5 min. The product was extracted into diethyl ether. The reaction mixture was filtered over decalite, washed once with 1N NaOH, once with water, dried and concentrated. The residue was purified by chromatography over silica gel, using a gradient of CH2Cl2-diethyl ether as eluent, to provide 160 mg of 12e as colorless oil;
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:20][CH3:21])[CH2:3]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:26]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:13][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:12][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][C:4]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:20][CH3:21])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2ccc(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CC)CN(c2ccccc2)c2ccc(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 97.6 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin (WO9616051; 0.40 g, 1.07 mmol), ethyl bromoacetate (0.23 g, 1.38 mmol), sodium carbonate (0.50 g, 4.7 mmol) and tetrabutylammonium bromide (30 mg, 0.093 mmol) were added to MeCN (10 ml). The mixture was refluxed for 18 hours and then evaporated under reduced pressure. The residue was extracted with DCM/water. The DCM layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography. The product was eluted with DCM/EtOAc (90:10). 0.480 g (97%) of the title compound was obtained. NMR (300 MHz) 0.7–0.85 (m, 6H), 1.0–1.7 (m, 11H), 3.1–3.3 (m, 2H), 3.6–3.8 (m, 2H), 4.3 (q, 2H), 4.6 (s, 2H), 6.9–7.3 (m, 7H), 7.5 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:5]2[C:6]([CH:8]=[CH:9][C@H:3]1[CH2:4]2)=[O:7].[CH3:11][C:12]([C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[C:24]([CH:26]=1)[OH:25])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[OH:25][C:24]1[C:23]2[C@@H:9]3[CH2:8][C:6](=[O:7])[CH2:5][CH2:4][C@H:3]3[C:2]([CH3:1])([CH3:10])[O:27][C:22]=2[CH:21]=[C:20]([C:12]([CH3:11])([CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:26]=1
Reactant: CC1(C)[C@H]2C=CC(=O)[C@@H]1C2
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@@H]21

Procedure:
The process according to claim 7 wherein (+)-apoverbenone is reacted with about an equimolar quantity of 5-(1,1-dimethylheptyl)resorcinol in dichloromethane in the presence of about an equimolar quantity of aluminum chloride at a temperature of from about -10° C. to about 30° C. for a period of time of from about 48 to about 96 hours to form (-)-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]-pyran-9-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[H-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][O:9][CH2:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1CO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1COCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
0.8 g of 5-bromo-2-methoxyphenyl methanol was dissolved in 30 ml tetrahydrofuran. 2.6 g of 4-(trifluoromethyl)benzyl bromide and 0.22 g of sodium hydride (60% oily) were added thereto, followed by stirring at room temperature for 16 hours. Water was added to the reaction solution, followed by extracting with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 1.4 g of 4-bromo-1-methoxy-2-({[4-(trifluoromethyl)benzyl]oxy}methyl)benzene from fractions eluted with hexane-ethyl acetate (9:1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:37])[C:19]([OH:36])([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=4[CH:35]=3)[C:20]([F:23])([F:22])[F:21])=[C:14]([Cl:38])[CH:13]=2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].O.Cl>O1CCCC1>[Cl:38][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[CH:18]([CH3:37])[C:19]([OH:36])([C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH3:34])[C:28]=2[CH:35]=1)[C:20]([F:21])([F:22])[F:23])[O:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Oc2cnc(C(=O)O)cn2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenoxy}-pyrazine-2-carboxylic acid methyl ester (Example 227, 70 mg, 0.13 mmol) in tetrahydrofuran (0.5 ml) was added 1M aqueous NaOH solution (0.25 ml). The mixture was stirred 2 h at r.t. Water was added and the mixture was acidified using 1M aqueous HCl solution. The aqueous phase was extracted twice with AcOEt, dried (MgSO4) and concentrated. The solid residue was dried under high vacuum leading to the title compound (76 mg) as a white solid. MS (m/e, ISP neg. ion)=536.1 [M−H+].