Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].Br[C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=[O:15]>>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:2][NH:1][C:13]([CH3:18])([CH3:17])[C:14]([O:16][C:3]([CH3:4])([CH3:10])[CH3:2])=[O:15])#[N:7]
Reactant: N#Cc1cc(F)cc(CN)c1
Reactant: CC(C)(Br)C(=O)[O-]
Product: CC(C)(C)OC(=O)C(C)(C)NCc1cc(F)cc(C#N)c1
Yield: 91 %

Procedure:
The title compound was prepared following the general procedure 11, starting from 3-(aminomethyl)-5-fluorobenzonitrile and 2-bromoisobutyrate, affording the title compound as a light yellow liquid (5 g, 91%). 1H NMR (DMSO-d6, 400 MHz): δ 7.67 (d, J=7 Hz, 2H), 7.57 (d, J=9.5 Hz, 1H), 3.67 (d, 2H), 2.67 (t, 1H), 1.40 (s, 9H), 1.19 (s, 6H). LC/MS (Method A) 293.2 (M+H)+. HPLC (Method A) Rt: 2.29 min (Purity: 99.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([O:22][CH3:23])[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:24][O:12][C:11](=[O:13])[C:10]1[C:14]([O:22][CH3:23])=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC)cc(C(F)(F)F)cc1OCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 380 mg (1.165 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzoic acid in 3.8 ml N,N-dimethylformamide under nitrogen at room temperature, was added 177.1 mg (1.281 mmol) potassium carbonate and 87.2 ul (1.398 mmol) methyliodide. The mixture was stirred under nitrogen for 3 days. The mixture was poured into water. The aqueous layer was extracted once with ethyl acetate. The organic layer was washed once with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude light yellow oil (410 mg) was purified with flash column chromatography on silica (10 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>10% in 15 minutes) to provide 352 mg (y: 88.8%) of the title compound as a colorless oil, which crystallized on standing. MS (m/e): 341.2 (MH+).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>C(O)(=O)C>[CH3:9][N:10]([CH3:14])[C:11]([C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2])=[O:12]
Reactant: Oc1ccc(O)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cc(O)ccc1O
Temperature: 110 °C

Procedure:
In the solution of 220 g(2 mol) of hydroquinone in 500 ml of acetic acid, 107.5 g(1 mol) of dimethylcarbamyl chloride was drop-added for one hour while agitating the solution at 110° C. The mixture was maintained at 110° C. for two hours, and acetic acid was distilled under vacuum. 1 liter of methylene chloride was added to the reaction mixture, and the unreacted excess hydroquinone was filtered and collected (recoverd amount: 110 g, recycled without any purification process). A desired mono N,N-dimethylcarbamyl hydroquinone was obtained by evaporating the residue under vacuum. (Yield: 178.6 g(98%). mp: 144-146° C., 1H-NMR(200 MHz, CDCl3, ppm) 3.05 (d, 6H), 6.59 (d, 2H), 6.80 (br, 1H) 6.82 (d, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([CH2:21]O)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH3:23])=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:5]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3[CH:15]=[C:20]([Cl:3])[CH:19]=[C:18]([CH3:21])[C:17]=3[N:14]=[C:13]2[CH3:23])=[CH:9][CH:10]=1
Reactant: Cc1nc2ccc(CO)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc2c1nc(C)n2Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2 ml) is added to a chloroform solution (30 ml) of 1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole (3.62 g), and the solution is stirred for one hour at 60° C. A sodium bicarbonate aqueous solution is added and the reaction is halted. The chloroform layer is washed with water and dried. After removing the solvent through evaporation under reduced pressure, ethyl acetate is added and crystallization is performed. After the crystals are separated through filtration and washed with ethyl acetate, they are dried and thus, 1-(biphenyl-4-ylmethyl)-6-chloro-methyl-2-methylbenzimidazole (2.04 g) is obtained. 1H-NMR (CDCl3, δ): 2.67 (3H, s), 4.71 (2H, s), 5.40 (2H. s), 7.12 (2H, d, J=8.2 Hz), 7.31-7.38 (3H, m), 7.43 (3, s), 7.52-7.58 (4H, m), 7.75 (1H, d, J=8.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH:19]([CH3:21])[CH3:20])=[C:16]([C:22]([OH:24])=[O:23])[C:15]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH:19]([CH3:21])[CH3:20])=[C:16]([C:22]([OH:24])=[O:23])[C:15]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: CC(C)c1[nH]c(C=O)c(-c2ccccc2)c1C(=O)O
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)O
Yield: 58.4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (205 mg) using method D to give 210 mg (58%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-methyl 2-(4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.3 g, 0.94 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 6 mL, 34.26 mmol) and the solution stirred at room temperature overnight. The solvent was evaporated and the residue was purified by preparative HPLC (Instrument: Agilent, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) 5-(Trans-2-(4-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (54 mg, 22%) was isolated. 1H NMR (400 MHz, dmso) δ 1.75-2.10 (m, 4H), 2.67-2.77 (m, 1H), 2.80-2.89 (m, 1H), 3.11-3.18 (m, 1H), 3.70 (d, 1H), 5.94 (s, 1H), 7.07-7.15 (m, 2H), 7.36-7.43 (m, 2H). HRMS Calculated for [C14H15FN2O2+H]+: 263.1196. Found: 263.1201
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=O)=[N:33][CH:34]=1)=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:35]([C:32]4[CH:31]=[CH:30][C:29]([C:27]([OH:28])=[O:26])=[CH:34][N:33]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil (1.45 g, 4.33 mmol), from Example 1, part (d) above, in dichloromethane (25 mL) was added the intermediate 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.78 g, 5.52 mmol) and diisopropylethylamine (Aldrich, 0.84 g, 6.5 mmol). This reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was taken up in 1N sodium hydroxide and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with acetic acid and the product precipitated from the reaction mixture to provide 6-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)nicotinic Acid (1.44 g, 56%) as a green solid. 1H-NMR (300 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.10 (d, J=3.1 Hz, 1H), 8.43 (m, 1H), 8.12 (m, 1H), 6.71 (br s, 1H), 4.12-3.60 (br m, 4H), 1.80-1.40 (m, 11H), 1.35-0.91 (m, 11H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15]O)[C:4]=2[CH:3]=[CH:2]1.S(Cl)([Cl:19])=O.CN(C)C=O>C(Cl)Cl>[Cl:19][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]1[C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCOCCc1cccc2sccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCCCOCCc1cccc2sccc12

Procedure:
1.40 g of 3-(2-(1-benzothiophene-4-yl)ethoxy)-1-propanol was dissolved in 7.0 ml of methylene chloride. Thereafter, 1.10 ml of thionyl chloride and 0.05 ml of N,N-dimethylformamide were added to the obtained solution, and the obtained mixture was then heated to reflux for 5 hours. Subsequently, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; hexane:ethyl acetate=20:1), so as to obtain 1.43 g of a yellow oil product, 4-(2-(3-chloropropoxy)ethyl)-1-benzothiophene.
Reaction SMILES: [CH2:1]([P:20](=[O:37])([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[P:2](=[O:19])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C=O.[CH2:40](NCC)C>CO>[C:1]([P:2](=[O:19])([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([P:20](=[O:37])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH2:40]
Reactant: CCNCC
Reactant: CCCCCCCOP(=O)(CP(=O)(OCCCCCCC)OCCCCCCC)OCCCCCCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCCCCC)OCCCCCCC)P(=O)(OCCCCCCC)OCCCCCCC
Yield: 74.4 %

Procedure:
56.81 g (44.0 mmol) of tetra-n-heptyl methylenebisphosphonate, 6.61 g (220.0 mmol) of paraformaldehyde and 3.22 g (64.0 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 48 hours. After the methanol is eliminated as described above in Example I, about 19 g of tetra-n-heptyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][N:14]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH2:15]2)[CH2:11]1)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[NH2:7][CH2:8][CH2:9][N:10]1[CH2:11][CH:12]2[O:18][CH:16]([CH2:15][N:14]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[CH2:13]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(CCCOc3ccc(C#N)cc3)CC(C1)O2
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCN2CC3CN(CCN)CC(C2)O3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-{7-[3-(4-Cyanophenoxy)propyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}-ethyl)carbamic acid tert-butyl ester (4.5 g, 0.0104 mol; see step (i) above) was added to a solution of HCl in dioxane. The reaction was stirred at room temperature for 2 h, after which the reaction mixture was filtered and the resultant solid washed with dioxane, then diethyl ether and dried to give the title compound (3.89 g) as a white solid.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:30])[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:14]([OH:13])[CH:23]([OH:30])[CH2:24][N:25]([CH2:26][CH3:27])[CH2:28][CH3:29]
Reactant: CCN(CC)CC(O)C1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CC(O)C(O)[C@@H](N)CC1CCCCC1
Yield: 109.9 %

Procedure:
44 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-(diethylamino)ethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. The mixture was treated in the same manner as in Example 17 to obtain 29.5 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-diethylamino-2,3-pentanediol as colorless oily substance.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])=[N:15][N:16]=2)=[CH:8][CH:7]=1.S(=O)(=O)(O)O>CC(C)=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[O:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)=[N:16][N:15]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccccc1-c1nnc(-c2ccc(C3OCCO3)cc2)o1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=Cc1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Yield: 90 %

Procedure:
A mixture of 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-(2-nitrophenyl)-1,3,4-oxadiazole (1.75 g), 0.5 M sulfuric acid (15 ml) and acetone (50 ml) was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, volume ratio) to give 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzaldehyde (1.37 g, yield 89%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 189–190° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([Cl:12])=[N:4][N:3]=2)[CH2:22][C:21]1=[O:26])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CNCCN1Cc1ccccc1
Reactant: Clc1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1CN(c2nnc(Cl)c3ccccc23)CCN1Cc1ccccc1

Procedure:
1,4-dichlorophthalazine (500 mg, 2.51 mmol), 1-benzylpiperazin-2-one (526 mg, 2.76 mmol), potassium carbonate (521 mg, 3.01 mmol), and N-methylpyrrolidinone (3 mL) were heated at 110° for 8 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes/0-40% ethyl acetate gave an off-white solid. MS (M+H)+=353.9.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH:4]([C:14](OC)=[O:15])[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH:4]([CH2:14][OH:15])[NH:3]1
Reactant: COC(=O)C1Cc2ccc(OC)cc2C(C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C)NC(CO)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-methyl-3-methoxycarbonyl-7-methoxyisoquinoline (0.67 g, 2.87 mmol) (described in example 73) in anhydrous tetrahydrofuran (5 mnL) was added dropwise I M solution of lithium aluminium hydride (5.7 nunol) in anhydrous tetrahydrofuran (5.7 mL). The mixture was stirred at rt for 3 hr. The reaction mixture was quenched by a careful addition of 5N NaOH (2 mL). The mixture was stirred at room temperature for 10 min and then filtered and the solid was washed twice with diethylether. The organic filtrates were combined, dried (MgSO4) and concentrated in vacuo to give the desired product as solid foam (0.486 g, 82%): 1H-NMR (CDCl3, δ) 1.48 (d,J=6.31Hz, 3H), 2.46-2.67 (m, 2H), 3.04-3.12 (m, 1H), 3.72 (dd, J=8.4, 11.1 Hz, 1H), 3.72-3.81 (m, 1H), 3.79 (s, 3H), 4.08 (q. J=6.3 Hz, 1H), 6.71-6.75 (m, 2H), 7.02 (d, J =7.8 Hz, 1H): MS showed (M+H) +@ 208.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45][NH2:46])=[CH:43][CH:42]=1>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:9]([CH2:13][O:14][CH:15]([F:16])[F:17])[C:10]([NH:46][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([F:40])=[CH:42][CH:43]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)C(COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
To a solution of 2-(dibenzylamino)-3-(difluoromethoxy)propanoic acid (335.4 mg, 1 mmol) and triethylamine (404.8 mg, 4 mmol) in THF (5 mL) at −5° C., isobutyl chloroformate (143.5 mg, 1.05 mmol) was added dropwise. After 20 minutes, 4-fluorobenzylamine (137.5 mg, 1.1 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture then was diluted with ethyl acetate and washed with water, 0.5 N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated with silica gel and purified by column chromatography, eluting with 10˜20% ethyl acetate in hexanes, to give 2-dibenzylamino-3-difluoromethoxy-N-(4-fluorobenzyl)propionamide (395 mg, 89.2%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.56 (t, 1H), 6.98-7.32 (m, 14H), 6.35 (wt, 1H), 4.61 (dd, 1H), 4.41 (m, 3H), 3.86 (d, 2H), 3.70 (d, 2H) and 3.68 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH:26][C:27]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(NC(=O)C3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cc2ncc(NC(=O)C3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of {6-(2,4-dichloro-phenyl)-3-[(tetrahydro-pyran-4-carbonyl)-amino]-imidazo[1,2-a]pyridin-7-ylmethyl}-carbamic acid tert-butyl ester (79.5 mg, 0.153 mmol) in dioxane (3 mL) was added a 4M HCl solution in dioxane (2 mL) and the mixture was stirred at RT for 15 min. The formed precipitate was filtered and dried under vacuum to yield the title compound (2HCl salt, 58 mg, 0.118 mmol, 48%) as a brownish solid. MS: 419 [M+1]+; HPLC: AtRet=0.83.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O1CCOCC1.[F:26][CH:27](Cl)[F:28]>O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH:27]([F:28])[F:26])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: FC(F)Cl
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSC(F)F)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
4-chloro-4'-mercaptomethylbenzophenone (14.7 g) and potassium hydroxide (15 g) was added to a solvent comprising dioxane (100 ml) and water (100 ml). Difluoromethyl chloride was blown into this solution at 60° C. until the starting material 4-chloro-4'-mercaptomethylbenzophenone disappeared. The reaction product was cooled to room temperature and then subjected to filtration. The organic layer as the filtrate was dried over anhydrous magnesium sulfate add concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the desired product (6.4 g, melting point: 34° to 35° C., yield: 36%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][N:15]([CH2:24][C:25]3[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[CH:16][N:15]([CH2:24][C:25]3[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by cleaving the pivaloyl protecting group of N-[4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-trimethylsilanylethynyl-7H-pyrrolo[2,3-d]pyrimidin -2-yl]-2,2-dimethyl-propionamide with ZnCl2 according to the General Procedure B. tR=6.56 min. 1H NMR (CDCl3) δ 8.22 (s, 1H), 7.11 (s, 1H), 5.30 (s, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H), 0.24 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([O:23]CC)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:4]1[C:32]([OH:33])=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:34][CH3:35])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)OCC)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1c(OCCCOc2cc(O)c(C(C)=O)cc2CC)ccc2c1OC(C(=O)O)CC2
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of ethyl 7-[3-(4-acetyl-2-ethyl-5-hydroxyphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate in dioxane (3.5M solution) was treated with 2N NaOH (3.0 eqv) and stirred at room temperature. After stirring for 4 hours, the dioxane was removed from the reaction, and the remaining solution was diluted with water and acidified with 5N HC1. The resulting milky solution was extracted with EtOAc. The ethyl acetate extract was dried over MgSO4 and filtered. Solvent removal gave a white solid. The solid was purified by flash chromatography on silica gel eluting with 50% EtOAc/Hexane, and the resulting solid was crystallized from EtOAc and hexane. The desired acid was obtained in 47% yield.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([NH2:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:11][C@H:12]([C:23]([NH2:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Yield: 96.8 %

Procedure:
To methanol (300 mL) solution of the compound obtained in Example 125 (3.6 g) was added 5% palladium/carbon (0.36 g) in an argon atmosphere, and the mixture was stirred for 16 hours at room temperature in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was distilled off under a reduced pressure, to give the captioned compound (2.1 g, 95%) as an oily product.