Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[Cl-].[CH3:3][CH2:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12](Br)[C:13]#[CH:14].S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[OH:11][C:6]([CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][C:4]#[CH:3]
Reactant: C#CCBr
Reactant: CCCCC(=O)CCC
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C#CCC(O)(CCC)CCCC

Procedure:
14 Grams of powdered (50 mesh) magnesium metal is suspended in 80 ml of ether and activated by addition of 200 mg of mercurie chloride. A solution of 38.4 g of 4-octanone and 36.6 g of propargyl bromide in 120 ml of ether and 50 ml of benzene is added dropwise at a rate which produced a gentle reflux. After the addition is complete, the reaction mixture is stirred for several hours and is then poured into 500 ml of cold 5% sulfuric acid. The organic layer is separated, washed with water twice, dried over sodium sulfate and stripped of solvent. The residue is distilled under vacuum to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([NH2:13])[NH:10][N:9]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[NH:16]1[C:17]2[CH:22]=[C:21]([C:23]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:12]=4)[C:25](=[O:26])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[N:14]=[N:15]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: Nc1nc(-c2ccccc2Cl)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3nn[nH]c3c2)[nH]c2nc(-c3ccccc3Cl)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chlorophenyl)-1H-1,2,4-triazol-5-amine (50 mg, 0.26 mmol, 1.00 equiv), ethyl 3-(1H-1,2,3-benzotriazol-5-yl)-3-oxopropanoate (100 mg, 0.43 mmol, 1.67 equiv), butan-1-ol (1 mL), and p-TsOH (5 mg, 0.03 mmol, 0.11 equiv) was stirred for 1 h at 170° C. in an oil bath. After the reaction was completed, the solids were collected by filtration and washed with MeOH (3×1 ml). This resulted in 25.3 mg (27%) of 5-(1H-benzo[d][1,2,3]triazol-6-yl)-2-(2-chlorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-7(4H)-one as a grey solid.
Reaction SMILES: O1CCCC1.C([O:8][C:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:14]=2[CH:15]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[O:20]([C:18]1[CH:17]=[CH:16][C:14]2[CH:15]=[C:11]([CH2:9][OH:8])[O:12][C:13]=2[CH:19]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc2ccc(Oc3ccccc3)cc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccc(Oc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 6-phenoxy-benzofuran-2-carboxylic acid ethyl ester (251 mg, 889 μmol) described in Production Example 49-1-1 was added lithium aluminum hydride (135 mg, 3.56 mmol) at 0° C., which was stirred at room temperature for 2 hours. To the reaction solution were added water (135 μL), 5 N aqueous sodium hydroxide solution (135 μL) and water (405 μL) at 0° C., followed by filtering through celite. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the title compound (177 mg, 83%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].O(C1C=C(C(O)C)C=CC=1)[C:18]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].[CH3:16][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]([CH3:11])[CH3:18])=[O:8])[CH:3]1[C:13]([O-:15])=[O:14]
Reactant: CC(O)c1cccc(Oc2ccccc2)c1
Agent: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C
Solvent: c1ccccc1
Product: CC(C)OC(=O)C=CC1C(C(=O)[O-])C1(C)C

Procedure:
Using the procedure of Example 9, (1R, cis, ΔZ) 2,2-dimethyl-3-(3-isopropoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid and 1-(R) (3-phenoxyphenyl)-ethanol were reacted to obtain 1(R)-(3-phenoxyphenyl)-ethyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-isopropoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+140°±2.5° (c=1% in benzene).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4](S(OCCCCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:19][C:20]([F:32])([F:31])[CH2:21][CH2:22][S:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:32][C:20]([F:19])([F:31])[CH2:21][CH2:22][S:23]([CH:26]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[CH:18])[C:27]([O:29][CH3:30])=[O:28])(=[O:24])=[O:25]
Reactant: C#CCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 21.9 %

Procedure:
To a solution of 3.0 g of 6-heptynyl p-toluenesulfonate and 2.6 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 1.6 g of potassium carbonate was added at room temperature. The mixture was heated to 90° C. and stirred at the same temperature for 6 hours. The reaction mixture was allowed to stand near room temperature, and 10% hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.80 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-8-nonynoate (hereinafter referred to as the present compound (14)).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[OH:18])/[C:8]([O:10]CCS(C)(=O)=O)=[O:9])[N:6]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[O:18][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
In 200 ml of acetone was suspended 10 g (0.0341 mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 3. After a serial addition of 9.98 g (0.0512 mole) of t-butyl bromoacetate, 0.6 ml of water and 18.85 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for 2 hours followed by addition of 200 ml of water. The mixture was stirred at 30°-35° C. for about an hour, whereby the methylsulfonylethyl group was hydrolytically eliminated. Then, the ethyl acetate was added to the hydrolysis reaction mixture. The organic layer was extracted with water and the aqueous layers were combined and adjusted to pH 2 with 2N HCl. The resulting white crystalline precipitate was collected by filtration and dried to give 9.0 g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic acid. (Yiled, 87.6%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)[CH:3]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[C:18]([Cl:26])[CH:17]=2)[CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNc1ccc(Cl)cc1Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product from step (ii) (0.5 g), methanol (5 ml), water (4 ml) and 2M NaOH (2 ml) were stirred at room temperature for 4 h then partitioned between ethylacetate/2 M HCl. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with diethylether/isohexane and filtered, yield 0.1 g.
Reaction SMILES: [C:1]([C:4]1([OH:28])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH:12]=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(N(CCC)CCC)CC>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:12][CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][C:4]3([O:28][C:37](=[O:38])[N:36]([C:33]4[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=4)[C:1]3=[CH2:2])[CH2:9][CH2:8]2)=[CH:19][CH:18]=1
Reactant: CC(=O)C1(O)CCN(CCC=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CCCN(CCC)CCC
Product: C=C1N(c2ccc(Cl)cc2)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution containing 5.8 g of 4-acetyl-1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-hydroxypiperidine and 7.0 g of 4-chlorophenyl isocyanate in 30 ml of tripropylamine is gently refluxed under argon while stirring for 3 hours, then the solvent is distilled off under reduced pressure. After adding benzene to the residue and filtering off the insoluble part, the benzene filtrate is filtered through a silica gel bed and evaporated under reduced pressure. The solid evaporation residue is recrystallized from ethanol under clarifying by activated carbon to obtain the title compound in 52% yield, m.p.: 186°-188° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:17])OC1C=CC([N+]([O-])=O)=CC=1.C(N(CC)CC)C.Cl.[NH:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:19][Si:2]([CH3:1])([CH3:18])[CH2:3][CH2:4][O:5][C:6]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:17]
Reactant: O=C1CCNCC1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)N1CCC(=O)CC1
Yield: 88.3 %

Procedure:
Carbonic acid 4-nitro-phenyl ester-2-trimethylsilanyl-ethyl ester (8.33 g, 29.3 mmol), triethylamine (12.3 g, 122 mmol) and DMAP (3.6 g, 29.5 mmol) were added to a room temperature solution of 4-piperidone hydrochloride (4.52 g, 33.4 mmol) in 100 mL of acetonitrile. The resulting mixture was heated at reflux for 2 h, then cooled and the volatiles were removed in vacuo. The residue was dissolved in dichloromethane, washed with water and 1M NaOH solution, and concentrated in vacuo to leave 6.3 g of product.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH:1]1([C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1CCc2ccccc21
Product: CN(C(=O)C1CCc2ccccc21)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from indane-1-carboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 403.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=4[C:24]=3[C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Na+].C(S)C>C(O)C>[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=4[C:24]=3[C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: CCO
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 75 °C

Procedure:
To 50 ml. of dry DMF were added 1.2 g. (2.6 mmole) of the product from Example 16. Sodium hydride (625 mg.; 26 mmole) was added to the mixture under a nitrogen atmosphere. To the resulting mixture then were slowly added by syringe 620 mg. (10 mmole) of ethyl mercaptan. A vigorous effervescence occurred. When the effervescence had ceased, the reaction mixture was heated at 75° C. in an oil bath for 12 hours. Ethanol (5 ml.) then was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with 50 ml. of aqueous sodium chloride solution, and then repeatedly with 15 ml. portions of 1N hydrochloric acid. The hydrochloric acid extracts were combined, washed with ether, and rendered alkaline by addition of cold 1N sodium hydroxide. The alkaline mixture then was extracted with ethyl acetate, and the ethyl acetate extract, after drying over magnesium sulfate, was evaporated to obtain 0.54 g. of a yellow oil. The yellow oil was chromatographed to obtain 400 mg. of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:11]=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:11]=[O:12]
Reactant: O=Cc1c(Cl)[nH]c2ncccc12
Reactant: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (70 mg, 0.39 mmol) cupric acetate (140 mg, 0.77 mmol), phenylboronic acid (93 mg, 0.76 mmol), 4A molecular sieve (200 mg), triethylamine (106 μl), pyridine (61 μL) and dichloromethane (5.5 mL) is vigorously stirred at room temperature for 48 hr. The solids are removed by filtration through a pad of Hi-Flo and the filtrate is concentrated. The residue is purified by chromatography eluting with dichloromethane-2% methanol. Product containing fractions are combined and concentrated to give 2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (25 mg, 25% yield) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+].ClCCl>C1(C)C=CC=CC=1.CCOC(C)=O.O.O1CCOCC1>[Cl:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1Cl
Temperature: 25 °C
Yield: 58.9 %

Procedure:
To a solution of methyl 4-bromo-2-chlorobenzoate (0.40 g, 1.6 mmol) and 4-nitrophenylboronic acid (0.67 g, 4.0 mmol) in toluene (8 mL) was added Na2CO3 (1.02 g, 9.62 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride complex with dichloromethane (0.03 g, 0.03 mmol), 1,4-dioxane (4 mL), and water (4 mL). The mixture was heated at reflux for 3 h and then allowed to cool to rt. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 0.275 g (59%) of the title compound. 1H NMR (400 MHz, CD2Cl2) δ 3.98 (s, 3H), 7.58 (d, 2H), 7.68-7.82 (m, 3H), 7.97 (d, 1H), 8.33 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[O-]CC.[Na+].CS(C)=O.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:1]([C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: Cc1ccc2c(c1)=NC(=O)N=2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CCCCCc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methylbenzimidazol-2-one (50 mg, 3.378×10−4 mol) in dry ethanol (5 ml), the freshly made sodium ethoxide in ethanol (1M, 1.01×10−3 mol equivalents) was added dropwise under a nitrogen atmosphere. At room temperature the mixture was stirred for 3 hrs under an atmosphere of nitrogen and the ethanol was then removed under reduced pressure. To this a solution of dry DMSO (3 ml) and 1-bromobutane (54 μl, 5.1×10−4 mol) was added and stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was then quenched with ice and neutralised using 1M hydrochloric acid solution, forming a white solid product. The solid was collected by filtration and purified using preparative thin liquid chromatography with 10% MeOH/CHCl3.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:15][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium methoxide (4M, 1.0 mL, 4.0 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (1.2 g, 3.5 mmol) in THF (30 mL). Stir at room temperature overnight, add water (25 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the residue by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH3:12])=[C:5]([O:13][CH3:14])[N:4]=1.C(N(CC)CC)C>CCO.[Pd]>[CH3:14][O:13][C:5]1[N:4]=[C:3]([CH3:2])[C:8]([NH2:9])=[CH:7][C:6]=1[CH3:12]
Reactant: COc1nc(C(Br)Br)c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1nc(C)c(N)cc1C
Yield: 72.6 %

Procedure:
To a solution of 2-(dibromomethyl)-6-methoxy-5-methyl-3-nitropyridine (110 g, 0.323 mol) from Part J, in EtOH (1.1 L) in a Parr bottle was added triethylamine (135 mL, 0.970 mol) followed by 10% Pd/C (11.0 g). The mixture placed on a Parr shaker under an H2 atm at 45 psi for 18 h. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was partitioned between water and EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10%→20%→35%→50% ethyl acetate in hexanes) to give 6-methoxy-2,5-dimethylpyridin-3-amine (35.7 g, 73% yield) as a light-brown solid: mp 39.8-41° C.; 1H NMR (400 mHz, DMSO-d6) δ 6.82 (s, 1H), 4.37 (s, 2H), 3.73 (s, 3H), 2.16 (s, 3H), 2.00 (s, 3H); 13C NMR (100 mHz, DMSO-d6) δ 152.7, 135.8, 134.8, 126.3, 116.1, 52.1, 19.2, 14.7; LRMS, (ESI) m/e 153.2 [(M+H)+, calcd for C8H13N2O, 153.1].
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25])=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]=[O:25])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
Pyridinium chlorochromate (3.26 g, 15.2 mmol) was added to a solution of (2S)-N-(tert-butoxycarbonyl)-2-(hydroxymethyl)pyrrolidine (2.77 g, 13.8 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 12 h. The solvent was removed on a rotary evaporator to give a dark brown gum, which was chromatographed, using ethyl acetate:hexane (1:1, v/v) as eluant. Selected fractions containing the product were combined and concentrated on a rotary evaporator to give 1.45 g (52.9% yield) of a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22]Br)=[CH:19][CH:18]=1.[OH-].[Na+]>CO>[F:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: Fc1ccc(CCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(CCc3ccc(F)cc3)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 4-fluorophenethyl bromide according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 3.09 (2H, t, J=7.1 Hz), 4.27 (2H, t, J=7.2 Hz), 7.11 (2H, t, J=8.8 Hz), 7.24 (2H, t, J=7.1 Hz), 7.57 (1H, d, J=3.8 Hz), 7.63 (1H, s), 7.82 (1H, s), 8.26 (1H, s), 8.63 (1H, d, J=5.0 Hz). [M+H] Calc'd for C17H14FN3O2, 312. Found, 312.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:24])([F:12])[F:25])[CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2cccc(C(F)(F)F)c2)c(C)[nH]1
Yield: 16 %

Procedure:
5-Methyl-4-[2-(3-trifluoromethyl-phenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (120) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/−40° C. Purification: prep/HPLC. Yield: 16%. 1H (CDCl3, 400 MHz): δ 10.7 (NH, broad s), 7.48 (4H, m), 7.34 (1H, s), 4.37 (2H, q), 4.15 (2H, s), 2.59 (3H, s), 1.39 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.3, 161.6, 141.2, 136.0, 133.2, 131.2, 128.8, 128.2, 126.4, 123.6, 121.4, 120.6, 116.9, 61.0, 46.3, 14.3, 13.9 ppm. LC/MS: 100%.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1([F:17])[CH2:16][CH2:15][CH2:14]1.[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([CH2:21][O:22][C:4]2[N:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=2[C:13]2([F:17])[CH2:16][CH2:15][CH2:14]2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(C2(F)CCC2)c(Cl)n1
Reactant: OCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C2(F)CCC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.3 %

Procedure:
Powdered potassium hydroxide (240 mg, 4.28 mmol) was added to a solution of 6-chloro-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (Example 130 e, 393 mg, 1.71 mmol) in DMSO (7.86 mL). The mixture was stirred at ambient temperature for 15 minutes. Cyclopropylmethanol (136 mg, 153 μL, 1.88 mmol) was added and stirring was continued for 5 h at 60° C. Additional cyclopropylmethanol (68 mg, 76 μL, 94 mmol) was added, the mixture was stirred for 14 h at ambient temperature, poured onto ice/brine (100 mL) and extracted with TBME (2×100 mL). The aqueous layer was acidified with 1 N HCl and extracted with EtOAc (2×150 mL). The combined organic layers were washed with ice/brine (50 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash-chromatography (20 g SiO2, dichloromethane/MeOH 0-3% in 75 min) to give the title compound (65 mg, 31%) as colorless oil, MS (ESI) m/e=264.5 [M−H−].