Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.C(O)(=O)C.[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14].[Na]>ClCCl.ClCCCl>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)[CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Reactant: O=Cc1ccncc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)Cc3ccncc3)ccc21
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
4-Pyridinecarbaldehyde (1.18 ml, 12.5 mmol) and a catalytic amount of acetic acid were added to a 1,2-dichloroethane solution (40 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (4.44 g, 10.5 mmol), and stirred for 30 minutes. Sodium triacetoxyhydroborate (3.33 g, 15.7 mmol) was added to the resulting mixture, and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride aqueous solution in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.73 g (yield: 88%) of 1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-ylmethylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][N:5]=[C:6]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]CC2C=CC=CC=2)[CH:8]=1)([CH3:3])[CH3:2]>[C].[Pd].C(OCC)(=O)C>[CH:1]([O:4][N:5]=[C:6]([N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)ON=C(c1cccc(OCc2ccccc2)c1)n1cncn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)ON=C(c1cccc(O)c1)n1cncn1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To 150 ml of ethyl acetate were added 5.0 g of 1-(O-isopropyl-3-benzyloxybenzohydroximoyl )-1H-1,2,4-triazole (melting point: 62° C. to 67° C.) And 1 g of 10% palladium carbon at room temperature. In connection with the mixture, the hydrogenolysis reaction was carried out. After 8 hours, the palladium carbon was removed. The filtrate was then concentrated. The residue was purified by column chromatography, thus yielding 3.2 g (yield: 89%) of the desired product having a melting point of 160° C. to 163° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][CH:11]=[C:12]=[CH:13][CH:14]=[CH:15][CH2:16][OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22]O)(C)(C)C>C1C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[C:1]1([C:7]#[C:8][C:9]#[C:10][CH:11]=[C:12]=[CH:13][C@@H:14]2[O:22][C@H:15]2[CH2:16][OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC=CC=C=CC#CC#Cc1ccccc1
Reactant: CC(C)(C)OO
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: c1ccccc1
Product: OC[C@@H]1O[C@H]1C=C=CC#CC#Cc1ccccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 20 mg (0.090 mmole) of 10-phenyl-7,9-decadiyne-2,4,5-trien-1-ol in 4 ml of benzene was added 2 mg of vanadyl acetylacetonate and 50 μl (0.26 mmole) of a 5.43M solution of t-butyl hydroperoxide in benzene. The mixture was stirred for two hours. The mixture was concentrated and the residue was purified via flash chromatography to afford 7 mg of the title compound as an approximately 1:1 mixture of diastereomers.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])=O.[NH4+].C(O)=O>>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of 100 grams (1.0 mole) of hydantoin, 106 grams (1.0 mole) of benzaldehyde, 63 grams (1.0 mole) of ammonium formate, and 230 grams (5.0 moles) of formic acid were held for 3 hours at reflux temperature. After the cooling off, there were obtained 173 grams of 5-benzylidene hydantoin, corresponding to 92% of theory based on hydantoin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25]NCCC)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:32]([NH2:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH:37][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:23][CH:24]=3)=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CCN
Reactant: CCCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1
Product: CC(C)CCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1

Procedure:
Compound 5 was synthesized using the procedure described for Compound 2 except that isoamylamine was used in the final reductive amination step. Compound 5 was obtained as a white solid. MS 462; 1H NMR (CDCl3) δ 4.10 (t, 2H), 3.86 (s, 2H), 3.77 (s, 2H), 3.03 (t, 2H), 2.63 (t, 2H), 0.89 (d, 6H).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:39])=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([O:35]CC)=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1.[OH-].[Na+]>O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:39])=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([OH:35])=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(C)cc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Yield: 88.7 %

Procedure:
To 1 mL of an ethanol solution containing 0.25 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate, 1 mL of 5 mol/L aqueous sodium hydroxide solution was added and stirred under reflux with heating for 5 hours. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 0.21 g of 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:12]2[C:13]([CH:14]=[N:15][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11]2)=[C:16]([CH3:17])[N:18]=1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccco4)n3n2)cc1
Yield: 24.9 %

Procedure:
Applying the Cyclization Procedure 1, using N[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-furancarboxamide (Intermediate 59) (85 mg, 0.25 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.19 mL, 2.04 mmol), to afford 7-(2-furanyl)-5-methyl-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (20 mg) as a yellow solid. MS m/z 322 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:20][CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[CH3:19].C1(C)C=CC=CC=1>C(O)C>[CH2:18]([N:20]([CH2:21][C:22]1([CH3:27])[O:26][CH2:25][CH2:24][O:23]1)[C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CCNCC1(C)OCCO1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC1(C)OCCO1)c1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 54.4 %

Procedure:
4-t-butyl-2,6-dinitro chlorobenzene (2.5 grams; 0.01 mole), 2-(ethylamino)methyl-2-methyl-1,3-dioxolane (2.9 grams; 0.02 mole) and toluene (50 ml) were placed into a glass reaction vessel equipped with a stirrer, oil bath and thermometer and heated to 70° C. with stirrer for 30 hours. Ethanol (50 ml) was added to the cooled mixture and the solid filtered therefrom. The filtrate was evaporated to a volume of approximately 10 ml. It was then chromatographed on silica gel to yield the desired product (2.0 grams). The product was analyzed for C17H25N3O6 :
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOCC>[C:17]([Si:21]([O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(Cl)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
A solution containing 2-chloro-5-methylphenol 79 (3.50 g, 25 mmol), triethylamine (3.8 mL, 27 mmol), and DMAP (0.030 g, 0.25 mmol) in 50 mL of DMF was chilled to 0° C. under N2. A solution of tert-butylchlorodimethylsilane (3.9 g, 26 mmol) in 5 mL of DMF was added to the reaction mixture slowly via syringe over 5 min. The reaction was warmed to room temperature and stirred for 12 h. The mixture was diluted with ether and it was extracted with 2×1 N HCl, water, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 30% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give tert-butyl(2-chloro-5-methylphenoxy)dimethylsilane 80 (6.15 g, 98% yield) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[O:9][CH2:10][CH:11]([OH:13])[CH3:12])=[CH:2]1.S1C=CC(C2C=C(C=CC=2)OCC(=O)C)=C1.S1C=CC(C2C=C(O)C=CC=2)=C1.BrCC(=O)C.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].[H-].[Na+].Br[CH2:61][C:62]([O:64][CH2:65]C)=[O:63]>C(O)C.CN(C)C=O.O.C(OCC)C>[CH3:12][CH:11]([O:13][CH2:61][C:62]([O:64][CH3:65])=[O:63])[CH2:10][O:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(O)COc1cccc(-c2ccsc2)c1
Agent: CC(=O)CBr
Agent: CC(=O)COc1cccc(-c2ccsc2)c1
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(C)COc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.68 g of 1-[3-(3-thienyl)phenoxy]-2-propanol [synthesized by reducing 3-(3-thienyl)phenoxyacetone, prepared by the reaction of 3-(3-thienyl)phenol and monobromoacetone in the presence of potassium carbonate, with sodium borohydride in ethanol] was dissolved in 7 ml of dimethylformamide, and 48 mg of 60% oily sodium hydride was added. After the mixture was stirred at room temperature for 20 minutes, 0.12 ml of ethyl bromoacetate was added. The mixture was stirred at room temperature for 2 hours, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=10/1] to give 0.12 g of methyl [1-methyl-2-[3-(3-thienyl)phenoxy]ethoxy]acetate as a colorless oil.
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O.P(Cl)(Cl)([Cl:30])=O>>[C:6]([C:5]1[CH:11]=[N:12][C:13]2[C:18]([C:4]=1[Cl:30])=[CH:17][C:16]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[CH:15][CH:14]=2)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccc(C2CCCCCC2)cc1)C(=O)OCC
Solvent: O
Product: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1Cl
Reaction time: 2 h

Procedure:
10 g of p-cycloheptyl-anilinomethylene-malonic acid diethyl ester are dissolved in 50 ml of phosphorus oxychloride, 0.2 g of polyphosphoric acid is added and the mixture is boiled for 2 hours under reflux, with exclusion of water. The mixture is then evaporated to dryness in vacuo, the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 3 times 100 ml of 2 N sodium hydroxide solution and the organic solution is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The evaporation residue is treated with active charcoal and a little silica gel and crystallised from petroleum ether to give 3-carboethoxy-4-chloro-6-cycloheptyl-quinoline of melting point 61°-62°C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=O)[CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[CH2:11][CH2:10][C@@:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1
Reactant: CN1C(=O)C[C@]2(c3ccccc3)CCCC[C@@H]2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC[C@]2(c3ccccc3)CCCC[C@@H]2C1
Yield: 94.5 %

Procedure:
N-Methyl-4a-phenyl-1,3-diketo-cis-decahydroisoquinoline (1.9 g) in 75 ml of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (2.0 g) and refluxed overnight. The reaction was quenched by the successive addition of 2.0 ml of water, 2.0 ml of 15% sodium hydroxide and finally 6.0 ml of water. The inorganic salts were filtered and washed well with ether. The combined filtrates were evaporated to yield 1.6 g of an oil which was evaporatively distilled, bp 125° (0.05 mm), nD20 1.5514, and identified as N-methyl-4a-phenyl-cis-decahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=1.C1C=CC=CC=1.P(Br)(Br)[Br:33]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][Br:33])=[CH:18][CH:17]=1
Reactant: BrP(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCO)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCBr)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a mixture of 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propan-1-ol (2.6 g) and benzene (50 ml) was added phosphorus tribromide (PBr3) (2.1 g), which was stirred for 2 hours at 70° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off to leave 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl bromide (0.98 g, 32%), which was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.78°-79° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[CH:13]([OH:27])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]O>>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@:14]([F:26])([CH3:25])[CH:13]([O:27][CH3:28])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)C(O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: CO
Product: COC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@]1(C)F
Temperature: 80 °C
Yield: 56.2 %

Procedure:
To a stirred solution of ((2R,3R,4R)-3-benzoyloxy-4-fluoro-5-hydroxy-4-methyl-tetrahydrofuran-2-yl)methyl benzoate (about 60 g, 160 mmol) in methanol (about 300 ml), boron trifluoro etherate (about 60.02 ml, 481 mmol) was added at room temperature then reaction mixture was heated to about 80° C. for about 5 hours. After that the reaction was quenched with saturated sodium bicarbonate solution, methanol was removed under reduced pressure, extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over sodium sulphate. The organic layer was removed under reduced pressure and the residue was purified by silica gel column chromatography using 8% ethyl acetate: hexane as eluent furnished title compound A (17 g), and 15% ethyl acetate eluded title compound B (18 g) as a colorless liquid. Yield: Combined yield: 56.2%; Intermediate A: 1H NMR (300 MHz, CDCl3) compound D: δ 8.01-7.93 (m, 4H), 7.56-7.48 (m, 6H), 5.53 (dd, 1H, J=24.3 Hz, 7.80 Hz), 4.97 (d, 1H, J=9.6 Hz), 4.58-4.53 (m, 2H), 4.41-4.38 (m, 1H), 3.30 (s, 3H), 1.44 (d, 3H, J=22.8); Mass: [M+Na]+: 413 (80%), [M-OCH3]+:357.19 (100%); IR cm−: 3439, 2961, 2939, 1728, 1602, 1452, 1270, 1117, 710.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: ClCCN1CCCCC1
Reactant: O=C(Nc1cc(Cl)cnc1N1CCNCC1)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCN(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 26 %

Procedure:
A mixture of 0.035 g (0.10 mmol) of 3-chloro-N-(5-chloro-2-piperazin-1-yl-pyridin-3-yl)-benzamide and 0.055 g (0.30 mmol) of 1-(2-chloroethyl)piperidine in acetonitrile (2 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to give 0.012 g (26%) of the title compound (107) as a brown oil. [M+H]+=464.2.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[F:29])=[C:6](\[C:10]1[C:19]([O:20][CH2:21][CH3:22])=[C:18]([Br:23])[C:17]2[C:16]([CH3:25])([CH3:24])[CH2:15][CH:14]=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12]=2[CH:11]=1)/[CH:7]([CH3:9])[CH3:8])C.[H-].C([Al+]CC(C)C)C(C)C>>[Br:23][C:18]1[C:17]2[C:16]([CH3:25])([CH3:24])[CH2:15][CH:14]=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12]=2[CH:11]=[C:10](/[C:6](/[CH:7]([CH3:9])[CH3:8])=[C:5](/[F:29])\[CH2:4][OH:3])[C:19]=1[O:20][CH2:21][CH3:22]
Reactant: CCOC(=O)/C(F)=C(\c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CCOc1c(/C(=C(/F)CO)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure G-1, (2E)-3-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-4-methyl-pent-2-enoic acid ethyl ester (Compound A-127, 196 mg, 0.40 mmol) and diisobutylaluminum hydride (1 M in methylene chloride, 1.0 mL, 1.0 mmol) were reacted to give the title compound as a yellow syrup after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:30]=[C:29]([C:31]2S[C:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:34]=3[N:35]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3].[OH-:40].[Li+]>C1COCC1.O.CO>[CH2:1]([O:4][C:5]1[CH:30]=[C:29]([C:31]2[O:40][C:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:34]=3[N:35]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3]
Reactant: [OH-]
Reactant: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCOc1cc(-c2nc3c(o2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[2-propoxy-4-(4,5,6,7-tetrahydro-1,3-benzthiazol-2-yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 166, 88.0 mg, 0.160 mmol) in THF/Water/Methanol (1:2:1) was added solid lithium hydroxide (38.4 mg, 1.60 mmol). The solution was stirred at rt for 3 h, and the solvent was then removed under reduced pressure. The residue was diluted with water and acidified using HCl (2 N aqueous solution) upon which a white precipitate formed. The solid was isolated by filtration to provide the title compound (43.5 mg, 52%) that did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, 1H), 7.32 (dd, 1H), 7.07 (d, 1H), 7.04 (d, 1H), 6.78 (s, 1H), 6.69 (dd, 1H), 4.15 (t, 2H), 4.11 (t, 2H), 3.96 (t, 2H), 3.33 (m, 1H), 2.61-2.85 (m, 7H), 2.2-2.30 (m, 3H), 2.11-2.19 (m, 2H), 1.58-1.84 (m, 7H), 0.98 (t, 3H); LC-MS: RT 3.80 min, (M+H)+ 22.3.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6][N:5]1[C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([C:18]([NH2:20])=[O:19])[CH:12]=1)(=[O:3])[NH2:2].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[C:1]([CH:4]1[CH2:9][N:8]([CH3:10])[CH2:7][CH2:6][N:5]1[C:11]1[N:16]=[C:15]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:38][CH:37]=3)=[CH:33][CH:34]=2)[N:14]=[C:13]([C:18]([NH2:20])=[O:19])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)OC1(C)C
Reactant: CN1CCN(c2cc(C(N)=O)nc(Cl)n2)C(C(N)=O)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(C(N)=O)nc(-c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)n2)C(C(N)=O)C1
Temperature: 100 °C

Procedure:
To a mixture of 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-chloropyrimidine-4-carboxamide (0.300 g, 1.00 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,2-dioxaborolane (0.404 g, 1.11 mmol), 2M aqueous Na2CO3 (1.0 mL, 2.0 mmol) and PdCl2(dppf) (0.046 g, 0.056 mmol). The reaction vessel was flushed with argon, sealed and heated at 100° C. overnight. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 0-20% MeOH in acetone. The product fractions were evaporated in vacuo and the residue triturated with 1:1 acetonitrile/MeOH (5 mL). The solid was filtered, washed with MeOH (1×1 mL), and acetonitrile (1×1 mL). An additional batch of material was obtained by evaporation of the filtrates, trituration of the residue with 1:1 acetonitrile/MeOH (2 mL) and washing the solid with MeOH (1×0.5 mL) then acetonitrile (1×0.5 mL). The combined solids were dried under vacuum at 40° C. to give 6-(2-carbamoyl-4-methylpiperazin-1-yl)-2-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide as a very pale tan powder (0.271 g, 0.541 mmol, 54% yield). 1H NMR (400 MHz, CD3OD): 8.57 (2H, d, J=9.0 Hz), 7.71 (2H, d, J=8.6 Hz), 7.39 (1H, s), 7.21 (2H, d, J=8.6 Hz), 7.16 (2H, d, J=9.0 Hz), 5.68-5.23 (1H, br), 4.49-3.93 (1H, br), 3.65-3.54 (1H, m), 3.51-3.43 (1H, m), 3.00-2.93 (1H, m), 2.40 (1H, dd, J=12.1 Hz, 4.6 Hz), 2.34 (3H, s), 2.21 (1H, dt, J=11.8 Hz, 3.5 Hz). LC/MS: m/z=501.1 [M+H]+.