Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](OC)(=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O.[OH-].[Na+]>C(OCC)C>[CH2:7]([OH:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\CCCCCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCC/C=C\CCCCCCCO
Temperature: 0 °C
Reaction time: 5 h

Procedure:
0.95 g lithium aluminium hydride was suspended in 150 ml diethyl ether under blanketing gas and 10 g methyl (Z)-8-tetradecenoate (4) was added dropwise at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and for 5 h at room temperature. 1 ml water and 1 ml NaOH solution (15%) were added and the mixture was filtered through silica gel. The silica gel was washed with ether, the organic phase was dried over sodium sulphate and the solvent was distilled off. (Z)-8-tetradecen-1-ol (5) was obtained.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:36]([CH2:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:44](=[O:45])[CH2:43][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) in dry dimethylformamide (3 ml) containing dry pyridine (0.06 my was added a solution of 2-phenoxyacetyl chloride (0.12 g) in dry dimethylformamide (1 ml) at 0° C., and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 30 minutes. Additional pyridine (0.02 ml) and a solution of 2-phenoxyacetyl chloride (0.025 g) in dry dimethylformamide (0.3 ml) were added to the reaction mixture. After being stirred for 30 minutes, the mixture was poured into water (43 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a silica gel column chromatography. Elution with toluene-ethyl acetate afforded (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-phenoxyacetyl)piperazine (0.34 g) as a white powder.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]1[O:22][CH:11]1[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC=CCOCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OCC1OC1COCc1ccccc1
Yield: 99.1 %

Procedure:
7.13 g (0.04 mol) of 4-benzyloxy-2-buten-1-ol was dissolved in 250 ml of dichloromethane and 8.6 g (0.04 mol) of m-chloroperbenzoic acid (purity: 80%) was added thereto in four portions under ice-cooling and stirring. After stirring the mixture at the same temperature for additional 1 hour, the precipitate thus formed was filtered off. The filtrate was poured into a 10% aqueous solution of sodium hydrosulfite, extracted with dichloromethane, washed with water, and dried. After distilling off the solvent, the obtained liquid residue was purified by column chromatography (silica gel, hexane/ether) to thereby give 7.7 g of 4-benzyloxy-2,3-epoxybutan-1-ol as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[NH2:15][CH2:16][CH:17]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][NH:15][CH2:16][CH:17]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]1=[O:14]
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c(CNCC(c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc2ccccc21
Reaction time: 16 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (0.590 g, 3.15 mmol), tert-butyl 4-(2-amino-1-phenylethyl)piperidine-1-carboxylate (1.2 g crude, 3.94 mmol), and acetic acid (0.677 ml, 11.83 mmol) were combined in CH2Cl2 (20 ml). Sodium triacetoxyborohydride (2.506 g, 11.83 mmol) was added and the reaction stirred for 16 hours. The mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The product was carried on without further purification.
Reaction SMILES: O[CH:2]([CH3:27])[CH2:3][CH2:4][C:5](=[O:26])[CH2:6][PH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:28][B-:29]([F:32])([F:31])[F:30].C([O+](CC)CC)C>C(Cl)Cl.C(=O)=O.CC(C)=O>[F:28][B-:29]([F:32])([F:31])[F:30].[C:8]1([P+:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[C:5]2[CH2:4][CH2:3][CH:2]([CH3:27])[O:26]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(O)CCC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC1CCC(=C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 g of (5-hydroxy-2-oxohexyl)triphenylphosphorane was dissolved in 20 ml of methylene chloride under a nitrogen atmosphere, cooled in dry ice/acetone bath and 15 ml of triethyloxonium tetrafluoroborate as a 1 M solution in methylene chloride was added. The reaction mixture was stirred at about -78 C. for 0.5 hour and allowed to warm to room temperature over about 2 hours, decanted into ice water and stirred vigorously with the addition of an additional 30 ml of methylene chloride. The extraction was repeated twice, the extracts combined, and solvent removed to afford the desired product, m.p. 118.5°-122° C. and having the formula ##STR8##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12](C=O)C>C(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])cn1
Reaction time: 0.33 h

Procedure:
A mixture comprising 2-bromo-5-nitropyridine (5.6 g, 27.7 mmol), cuprous cyanide (2.5 g, 27.4 mmol) and DMF (5 mL) was heated at 105° C. for 2.5 hours, cooled and diluted with methylene chloride (200 mL). The mixture was stirred 20 minutes, filtered and concentrated under reduced pressure. The residue was dissolved in methylene chloride and the solution was washed sequentially with 2N sodium hydroxide (150 mL), 7M ammonium hydroxide (150 mL) and water (150 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide 5-nitropyridine-2-carbonitrile (3.14 g, 21 mmol) as a yellow oil. 1H-NMR (300 Mhz, DMSO-d6): 8.4 (d, 1H), 8.8 (d, 1H), 9.5 (s, 1H); MS (EI); Calculated for C6H3N3O2, 149.1, Found (MH+): 149.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1nc2ccccc2s1
Reactant: S=C=NCCC1=CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (3.3 g, 20 mmol) and 2-aminobenzothiazole (3.0 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 17.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized from ethyl acetate to provide 2.57 g (40%) of the title product:
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]([Cl:37])([Cl:36])[CH2:31][O:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:4][CH2:3]1)=[O:34]
Reactant: CN1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
To a mixture of 430 mg (1.55 mmol) of 1-methyl-4-(9H-xanthene-9-ylidene)piperidine [Tetrahedron Letters, 29, 5701 (1988)] and 649 μL (4.65 mmol) of triethylamine in 20 mL of dry toluene at 85° C. under an atmosphere of argon was added over 10 min 1.06 mL (7.7 mmol) of 2,2,2-trichloroethyloxycarbonyl chloride. After 30 min the mixture was cooled to room temperature, poured into a solution of 25% aqueous sodium hydroxide, and was extracted with ethyl acetate (3×). The combined organic portions were dried over sodium sulfate, filtered, and concentrated with vacuo to afford the title compound as a crude oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>[OH-].[Na+].O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:11])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)N[C@H](C(=O)O)C(C)C

Procedure:
The title compound is prepared, in analogy with Example 30a), from L-valine in 2N NaOH and dioxane using ethyl chloroformate (Fluka, Buchs, Switzerland), and subjected to further processing without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][CH2:21][OH:25])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: C#CCCO
Reactant: N#Cc1c(O)c2c(-c3ccc(Br)cc3)csc2[nH]c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCO)cc3)csc2[nH]c1=O
Temperature: 120 °C

Procedure:
To an ambient slurry of 3-(4-bromophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.050 g, 0.14 mmol), but-3-yn-1-ol (0.030 g, 0.42 mmol), copper(I) iodide (0.005 g), triphenylphosphine (0.009 g, 0.03 mmol) and diethyl amine (0.15 mL, 1.4 mmol) in DMF (1.5 mL) was added dichlorobis(triphenylphosphine)palladium(II) (0.002 g, 0.003 mmol) in a single portion. The reaction was heated at 120° C. for 20 min in a microwave, cooled to room temperature, filtered, concentrated and purified by RP-HPLC to afford the title compound. MS (ESI) m/e 334.9 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ ppm 12.02 (br s, 1H), 7.39 (d, J=9, 2H), 7.35 (d, J=9, 2H), 6.94 (s, 1H), 3.59 (t, J=9, 2H), 2.57 (t, J=9, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([OH:22])=O)=[N:10]2)=[CH:5][CH:4]=1.[N:23]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[N+:24]=[N-:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]3[CH2:27][CH2:26][N:23]=[N+:24]=[N-:25])=[O:22])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=NCCC1CCCCN1
Reactant: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C(=O)N3CCCCC3CCN=[N+]=[N-])cc2-c2ccccc2)cn1
Reaction time: 14 h

Procedure:
1-(6-Methoxy-3-pyridyl)-5-phenylpyrazole-3-carboxylic acid (191 mg) obtained from Referential Example 41, 2-(2-azidoethyl)piperidine (100 mg) obtained from Referential Example 80, 1-hydroxybenzotriazole (88 mg), and triethylamine (316 μL) were dissolved in methylene chloride (10 mL). To the resultant mixture, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (186 mg) was added at room temperature, followed by stirring for 14 hours. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was partitioned between water and ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by filtration. The residue obtained by removal through evaporation of the solvent under reduced pressure was purified through silica gel thin-layer chromatography (hexane-ethyl acetate), to thereby give the title compound as an oily product (227 mg, 81%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](CNC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
5′-Amino-2′,5′-dideoxyuridine (0.200 g, 0.88 mmol) was taken in dry pyridine (5 mL) and the mixture was sonicated for a few minutes. Trityl chloride (0.278 g, 1.00 mmol) was added and the reaction mixture was stirred at 50° C. overnight. The reaction was then quenched with water (20 mL). The crude mixture was extracted with DCM (3×10 mL). The organic layers were combined, washed with water (10 mL), dried over MgSO4 and concentrated on the rotary evaporator. The resultant brown oil was further purified by silica gel column chromatography (Isolute Si column) using a gradient elution of 0→10% CH3OH in CHCl3. The fractions with Rf=0.28 (10% CH3OH/CHCl3) were pooled and evaporated to dryness to yield the title compound as a white solid (0.202 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)N.[I-:14].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([I:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: [I-]
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Agent: [K+]
Product: COc1cc(I)cc(C(F)(F)F)c1

Procedure:
Using conventional procedures 3-methoxy-5-trifluoromethylaniline (J. Chem. Soc., 1951, 2013) was diazotised and reacted with potassium iodide to give 3-methoxy-5-trifluoromethyliodobenzene, as an oil. The product so obtained was reacted with boro tribromide using the conditions described in Note b. above to give 3-hydroxy-5-trifluoromethyliodobenzene in 95% yield, as an oil. The product so obtained was reacted with 2-bromomethylnaphthalene using the conditions described in Example 1 to give 3-(naphth-2-ylmethoxy)-5-trifluoromethyliodobenzene in 62% yield, m.p. 65°-66° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([C:31]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[C:33]([F:39])[CH:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:30])[C:31]4[CH:32]=[C:33]([F:39])[C:34]([F:38])=[C:35]([F:37])[CH:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2cc(F)c(F)c(F)c2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 6 h
Yield: 50.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(3,4,5-trifluorophenyl)ethanol (Preparation 46)(77 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (30 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (71 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:10]([CH3:22])[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:25][CH3:26])[C:13]2[C:8](=[CH:9][C:10]([CH3:22])=[C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OCC)[nH]c2cc1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1cc2c(OCC)cc(C(=O)OCC)nc2cc1C
Reaction time: 8 h

Procedure:
16.3 g of 6-Butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid ethyl ester are dissolved in 330 ml of dimethylformamide, and 2.6 g of a 50% strength sodium hydride dispersion in mineral oil are added. Stirring is carried out overnight at room temperature and then 8.7 ml of ethyl iodide are added dropwise, and the mixture is stirred for 2 hours at room temperature, concentrated under reduced pressure at 60°, poured onto ice, acidified and filtered with suction. 4-Ethoxy-6-butyryl-7-methylquinoline-2-carboxylic acid ethyl ester having a melting point of 123°-124° is obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2].[CH2:14]([OH:17])[CH:15]=[CH2:16].[Na]>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:17][CH2:14][CH:15]=[CH2:16])=[C:5]([CH2:12][CH3:13])[N:4]=1)#[N:2]
Reactant: CCc1nc(C#N)c(C#N)nc1Cl
Reactant: C=CCO
Agent: [Na]
Solvent: CC(C)=O
Product: C=CCOc1nc(C#N)c(C#N)nc1CC
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2,3-Dicyano-5-chloro-6-ethylpyrazine (1.35 g; 0.007 mole) was dissolved in 30 ml of acetone, and while the solution was cooled to -5° C., a solution prepared from 20 ml of allylalcohol and 0.16 g (0.007 mole) of sodium was added dropwise. Then, the mixture was stirred for 30 minutes. The reaction mixture was poured into 200 ml of ice water, and the separated oily product was extracted with toluene. The toluene layer was concentrated under reduced pressure to afford a crude product. The resulting crude product was chromatographed on a column containing silica gel using toluene as an eluent to afford 1.00 g (yield 67%) of 2,3-dicyano-5-allyloxy-6-ethylpyrazine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:28]=[CH:27][C:14]3[C:15](=[O:26])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][O:18][C:13]=3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[Cl-].[NH4+].CCCCCC>CO.CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:28]=[CH:27][C:14]3[C:15]([OH:26])=[C:16]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:17][O:18][C:13]=3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc(-c2ccc3c(=O)c(Cc4ccccc4)coc3c2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc(-c2ccc3c(c2)OCC(Cc2ccccc2)=C3O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the compound of step G (6.50 g, 17.5 mmole) in 35 mL of methanol at room temperature was added sodium borohydride (940 mg, 26.0 mmole) in one portion. The dark mixture was stirred at room temperature for 2 hours then poured into saturated aqueous ammonium chloride solution (75 mL) and extracted with 3×75 mL of diethyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an off-yellow oil. Chromatography on silica gel eluting with 4:1 hexane: ether afforded first 3.26 g of the cis ring isomer of the title compound, and then 1.98 g of the trans isomer of the title compound as viscous oils, total yield 81%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[Cl:42][C:43]1[CH:47]=[CH:46][NH:45][N:44]=1>>[C:1]([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:40])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:45]3[CH:46]=[CH:47][C:43]([Cl:42])=[N:44]3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:22])[F:23])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc[nH]n1
Reactant: Cc1c(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-n3ccc(Cl)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 18a using {8-chloro-2-difluoromethoxy-4-methyl-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]quinolin-5-yloxy}acetic acid tert-butyl ester and 3-chloro-1H-pyrazole.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH2:14].N1C=CC=CC=1.[Cl:22][CH:23]([CH3:27])[C:24](Cl)=[O:25]>ClCCl>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][NH:14][C:24](=[O:25])[CH:23]([Cl:22])[CH3:27]
Reactant: CC(Cl)C(=O)Cl
Reactant: COC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCNC(=O)C(C)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Triethylamine (1.63 g) was added to a suspension of β-alanine methyl ester hydrochloride (2.25 g) in dichloromethane (10 mL) and the reaction mixture was stirred for 30 minutes. After addition of pyridine (1.27 g) the reaction mixture was cooled to 0° C. A solution of 2-chloropropionyl chloride (2.04 g) in dichloromethane (10 mL) was added dropwise for 20 minutes. The reaction mixture was stirred for 2 hours, washed sequentially with water, 1 N hydrochloric acid and saturated sodium bicarbonate, dried with magnesium sulfate, filtered, and concentrated to give yellow oil (2.9 g, yield 93%).