Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH2:13][C@H:12]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24]C)[N:18]=2)=[O:15])=[CH:4][N:3]=1.Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][C@@:11]2([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH2:13][C@H:12]2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([OH:24])[N:18]=2)=[O:15])=[CH:4][N:3]=1
Reactant: COc1nc(NC(=O)[C@@H]2C[C@@]2(COc2cnc(C)nc2C)c2cccc(F)c2)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ncc(OC[C@@]2(c3cccc(F)c3)C[C@H]2C(=O)Nc2ccc(F)c(O)n2)c(C)n1
Temperature: 115 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
A mixture of the compound 325-3 (70 mg) and pyridine hydrochloride (367 mg) was stirred at 115° C. for 2.5 hours. The temperature of the reaction solution was returned to room temperature. Thereafter, water was added to the reaction solution, and the obtained mixture was extracted with ethyl acetate. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate (19:1 to 0:1) to ethyl acetate:methanol (9:1)). The obtained purified product was further repurified by preparative silica gel TLC (ethyl acetate:methanol=19:1), so as to obtain the title compound (30 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[NH:16]2)=[CH:11][CH:10]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O>[C:9]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:19][O:18][C:17](=[O:20])[N:16]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:11][CH:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C1N[C@@H](c2ccc(-c3ccccc3)cc2)CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1OC[C@H](c2ccc(-c3ccccc3)cc2)N1c1ccnc(Cl)n1
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (46.5 mg, 0.312 mmol) and (S)-4-(biphenyl-4-yl)oxazolidin-2-one (74.7 mg, 0.312 mmol) in DMF (700 μL) was added NaH (60% wt., 10.49 mg, 0.437 mmol) in two portions within ˜5 min [Caution: exotherm; gas development] at room temperature (water bath). The reaction mixture was stirred for 1.5 hour. The mixture was diluted with EtOAc (25 mL), stirred for 5 min and then diluted slowly with diluted brine (10 mL; 1:1 brine/water). The mixture was poured into diluted brine (40 mL) and EtOAc (25 mL). The separated organic phase was washed with diluted brine (3×40 ml), dried over Na2SO4, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane] to provide (S)-4-(biphenyl-4-yl)-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (49.5 mg). LCMS m/z 352.2 (M+H)+, Rt 1.06 min.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]=[C:6]([CH2:8][N:9]([C@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C(=O)OC(C)(C)C)[O:5][N:4]=1>CCOCC>[ClH:1].[CH3:2][C:3]1[N:7]=[C:6]([CH2:8][NH:9][C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:5][N:4]=1
Reactant: Cc1noc(CN(C(=O)OC(C)(C)C)[C@H]2C[C@H]2c2ccccc2)n1
Agent: Cl
Solvent: CCOCC
Product: Cc1noc(CN[C@@H]2C[C@H]2c2ccccc2)n1
Yield: 12.8 %

Procedure:
HCl 2N in Et2O was added to tert-butyl (3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcyclopropyl)carbamate (35 mg, 0.106 mmol). The Et2O was decanted and the solid was washed twice with 5 mL of Et2O. The solid was dried by vacuum to get (trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamine hydrochloride (14 mg. Yield 12.8%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32]([CH3:34])[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:32]([CH3:34])=[N:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)c(C)n1
Yield: 64.3 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in 1,2-dimethoxyethane (2.5 mL) was added 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (144 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (28 mg, 0.024 mmol), and 2 M Na2CO3 (361.2 μL, 0.72 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and purified by silica gel chromatography eluting with (0-20% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (70 mg, 61%). ESI-MS m/z calc. 453.44. found 454.3 (M+1)+. Retention time 1.89 minutes.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C1C=CC=CC=1>[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[C:9]([N:3]1[CH2:2][CH:1]2[O:8][CH:5]([CH2:6][CH2:7]2)[CH2:4]1)=[O:19])([OH:14])=[O:13]
Reactant: C1CC2CNCC1O2
Reactant: O=C1OC(=O)c2ccccc21
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1C(=O)N1CC2CCC(C1)O2
Reaction time: 1 h

Procedure:
A solution of 11.3 grams (0.1 mole) 8-oxa-3-azabicyclo (3.2.1)octane in 20 ml of benzene was added to a suspension of 14.8 grams (0.1 mole) of phthalic anhydride in 50 ml of benzene at 8° C. The reaction mixture was stirred for 1 hour and then left overnight at room temperature. The product, 20.0 grams which separated, was filtered off and recrystallized from benzene ethanol. The product represented by formula (X) had a melting point of 149°-150.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.[OH2:21]>C(O)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: O
Reactant: N#Cc1ccc(CN)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CC(=O)O
Product: N#Cc1ccc(C=O)cc1
Yield: 82 %

Procedure:
39.6 g of p-cyanobenzylamine, 21.1 g of hexamethylenetetramine, 150 ml of water and 150 ml of acetic acid were mixed and reacted at 100° C. for 2 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and 300 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 32.8 g (yield: 82%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]>CCCCCC>[CH2:12]([O:14][C:15](=[O:26])[C:16](=[CH:22][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(F)c([N+](=O)[O-])c1)C(=O)OCC
Reaction time: 2 h
Yield: 89.3 %

Procedure:
50 g of 4-fluoro-3-nitroaniline and 69 g of ethoxymethylene malonic acid-diethyl ester were heated for 3 hours to 120° C. The mixture was added to n-hexane, stirred for 2 hours, and the crystalline material was suctioned off and dried in a vacuum at room temperature. 93 g of N-(4-fluoro-3-nitrophenyl)-aminomethylene malonic acid diethyl ester is obtained. The latter is added in 3 portions of 31 g to respectively 150 ml of a mixture that consists of 26.5% diphenyl and 73.5% diphenyl ether (DOWTHERM A⊕) that is preheated to 260° C., and it is stirred for 30 minutes at this temperature. After cooling, it is diluted with 500 ml of n-hexane, and the precipitate is suctioned off. A total of 64 g of a mixture of 1,4-dihydro-6-fluoro-5-nitro-4-oxo-quinoline-3-carboxylic acid ethyl ester and 1,4-dihydro-6-fluoro-7-nitro-4-oxo-quinoline-3-carboxylic acid-ethyl ester is obtained.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:29][C:28]2[N:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21]1>>[O:18]=[C:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([N:2]3[CH2:7][CH2:6][N:5]([CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:26]4[N:27]=[C:28]5[C:23]([CH2:22][CH2:21][C:20](=[O:19])[NH:29]5)=[CH:24][CH:25]=4)[CH2:4][CH2:3]3)[CH:9]=[CH:10][CH:11]=2)[NH:16]1
Reactant: O=C1CCc2cccc(N3CCNCC3)c2N1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4NC(=O)CC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride (Chem. Pharm. Bull. 1984, 32, 2100–2110) was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 450.2 (Exact Mass: 449.24).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[C:12]([C:22]([O:24]CC)=[O:23])=[N:11]2)=[CH:6][CH:5]=1.[OH-].[K+].C(O)C>O>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(F)c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn(-c2ccc(OC(F)(F)F)cc2)c2cccc(F)c2c1=O
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Ethyl 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-fluorocinnoline-3-carboxylate (2.31 g) and potassium hydoxide (0.67 g) were added to a mixed solvent of ethanol (24 ml) and water (6 ml), and the resultant mixture was stirred at 60° to 70° C. for 7 hours. After being allowed to cool to room temperature, the mixture was diluted with water (100 ml), and washed with diethyl ether (30 ml). The water layer was neutralized with concentrated hydrochloric acid to pH 2 to precipitate crystals. The precipitated crystals was collected by filtration, washed two times with water (20 ml), and dried under reduced pressure to give 2.14 g of desired 1-(4-trifluoromethoxyphenyl)-1,4-dihydro-4-oxo-5-fluorocinnoline-3-carboxylic acid (yield: 99.5%). m.p., 200° C. (decomposed)
Reaction SMILES: [CH2:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])[CH3:2].[CH:10](N)(C)C.C(N)C>>[CH:1]([NH:3][C:4](=[N:7][C:8]#[N:9])[S:5][CH3:6])([CH3:10])[CH3:2]
Reactant: CCNC(=NC#N)SC
Reactant: CC(C)N
Agent: CCN
Product: CSC(=NC#N)NC(C)C

Procedure:
1-Isopropyl-2-methyl-3-cyanoisothiourea was prepared following the same procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250) except isopropylamine was used in lieu of ethylamine. 1H NMR (CDCl3) δ 1.25 (d, 6H, J=6 Hz), 2.49 (br s, 3H), 3.84 (br s, 1H), 6.22 (br s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:6]([C:10]1[CH:15]=[C:14]([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CC(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.42 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)acrylamide was prepared by adding a solution of 10 grams of acryloyl chloride in 50 milliliters of benzene to a mixture of 22.1 grams of 2,6-di tert.butyl-4-aminophenol, 6 grams of sodium carbonate, and 100 milliliters of benzene. The addition was accomplished in 25 minutes at 19° C. to 38° C. The mixture was stirred for 21/2 hours and the precipitate which had formed was filtered off, washed thoroughly with water, and dried. The yield was 12.5 grams and the product melted at 204° C. to 206° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[C:5](/[C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:8]=1)[C:17](=[O:18])[CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)/C(=C\c1cccc(C(F)(F)F)c1)C(=O)C1CCC(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc(C(F)(F)F)c1)C(=O)C1CCC(c2ccccc2)CC1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A mixture of (Z)-2-(4-phenylcyclohexanecarbonyl)-3-(3-trifluoromethylphenyl)-acrylic acid ethyl ester (10) (12.3 g, 28.6 mmol) and 100/Pd on carbon (2.5 g, 20% by weight) in denatured ethanol (250 mL) was stirred under a hydrogen atmosphere for 2 hr. The solids were removed by filtration through celite and washed with ethanol. The filtrate was evaporated under vacuum to yield a clear oil. The residue was purified by column chromatography on silica gel (gradient: 0 to 10% tert-butyl methyl ether in cyclohexane) to afford 8.6 g (70%) of 3-oxo-3-(4-phenylcyclohexyl)-2-(3-trifluoromethylbenzyl)-propionic acid ethyl ester (22). 1H NMR (400 MHz, 192227). LCMS (method A), Rt=4.76 min, (M+H)+=433.2 (94%); R=5.22 min, (M+H)+=262.9 (6.5%).
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:11]([CH3:36])[C:10]=1[CH3:37].[Na].[F:39]/[C:40](=[CH:49]\[CH:50]=[C:51](/[CH3:54])\[CH:52]=O)/[C:41](/[CH3:48])=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12](/[CH:13]=[CH:54]/[C:51](/[CH3:52])=[CH:50]/[CH:49]=[C:40](\[F:39])/[C:41](/[CH3:48])=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]([CH3:36])[C:10]=1[CH3:37]
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Temperature: -30 °C

Procedure:
A solution of 6.06 ml. (14.4 mmol) of n-butyllithium (2.3 M in hexane) was added dropwise under argon, at -72° C., to a stirred suspension of 4.61 g. (10 mmol) of 4-methoxy-2,3,6-trimethylbenzyl triphenylphosphonium chloride in 25 ml. of dry tetrahydrofuran. After addition of reagent was complete the mixture was stirred at -30° C. until an orange solution was formed. The resulting solution was first cooled to -72° C. and then treated dropwise with a sodium of 2.03 g. (9.0 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 10 ml. of dry tetrahydrofuran. The reaction mixture was gradually allowed to come to 25° C. and further stirred at this temperature under argon for 2.0 hours. It was poured onto 100 ml. of cold water and extracted with methylene chloride (4×100 ml.). The combined organic extracts were washed with water (2×100 ml.) dried over anhydrous magnesium sulfate and concentrated to give 6.4 g. of oily crude product. This material was filtered through 300 g. of florisil and eluted with methylene chloride to yield 2.97 g. of yellow crystalline substance, which on crystallization from ether-petroleum ether (~1:9) afforded ethyl (E,Z,E,E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp 92°-96° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2].[C:24]([O:28][C:29]([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:34]3[CH2:35][CH2:36][CH:32]([NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:33]3)=[CH:12][CH:13]=2)[N:8]([C:18]2[S:19][CH:20]=[C:21]([F:23])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(Cl)ccc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nc(F)cs2)c2nc(N3CCC(NC(=O)OC(C)(C)C)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A mixture composed of 7-chloro-1-(4-fluoro-2-thiazoly)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (30 mg) obtained in Example A-2, 3-(t-butoxycarbonylamino)pyrrolidine (19 mg), triethylamine (26 mg) and acetonitrile (10 ml) was stirred at room temperature for 30 minutes. Solvent was distilled off under reduced pressure, and water was added, and then, the resulting mixture was extracted with chloroform. The obtained extract was dried over anhydrous sodium sulfate, and solvent was distilled off under reduced pressure. The resulting residue was subjected to recrystallization with use of ethyl acetate, and thus, there was obtained 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-(4-fluoro-2-thiazolyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (40 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9]CC1C=CC=CC=1)[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCC(OCC)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(O)OCC

Procedure:
A solution of 90 g (0.4 mol) of pentanediol benzyl ethyl ether and 5.7 g of palladium hydroxide on carbon in 500 ml of ethanol was hydrogenated at under the pressure. After removing off the catalyst by filtration, the reaction mixture was concentrated. The oily residue was purified by distillation under the reduced pressure, to obtain pentanediol monoethyl ether. Boiling point; 55-58° C. (0.3 mmHg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH2:8][CH:9]([C:13](=[O:15])[CH3:14])[C:10](=[O:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:18]=1[OH:19])[CH2:8][CH:9]([CH:13]([OH:15])[CH3:14])[CH:10]([OH:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)O
Yield: 33.2 %

Procedure:
Using the procedure of Example 1, 119 grams of 3-(3,5-ditertiarybutyl-4-hydroxybenzyl)-2,4-pentanedione was reduced with 28.2 grams of lithium aluminum hydride. There was obtained 40 grams of 3-(3,5-ditertiarybutyl-4-hydroxybenzyl)-2,4-pentanediol which melted at 102° to 105° C.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:11]([C:14]3[N:15]([CH3:21])[N:16]=[C:17]([CH3:20])[C:18]=3[F:19])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35]([C:2]2[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]3[CH:10]([C:22]4[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=4)[N:11]([C:14]4[N:15]([CH3:21])[N:16]=[C:17]([CH3:20])[C:18]=4[F:19])[C:12](=[O:13])[C:4]=3[CH:3]=2)=[CH:34][N:33]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nn(C)c(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(C#N)cc2)c1F
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2c(F)c(C)nn2C)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(4-fluoro-2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate BJ) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.00 min, [M+H]+ 516 (LC-MS 1).
Reaction SMILES: [OH-].[Na+].CO.[OH:5][C:6]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[C:15]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40]C)=[O:39])=[C:33]([CH3:42])[CH:32]=3)=[CH:27][CH:26]=2)[C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl>O1CCCC1>[C:11]([O:10][C:8]([C:7]1[C:6]([OH:5])=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:16][C:15]=1[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[C:33]([CH3:42])[CH:32]=2)=[CH:27][CH:26]=1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
A 1N aqueous sodium hydroxide solution (3.0 ml, 3.0 mmol) and methanol (0.5 ml) were added to a solution of tert-butyl 2-hydroxy-6-[({4′-[(methoxycarbonyl)methyl]-3′-methyl-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate (667 mg, 1.26 mmol) obtained in Example (17-3) in tetrahydrofuran (8.5 ml), and the mixture was stirred at room temperature for 6 hours. After the reaction mixture was poured into 0.5N hydrochloric acid and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was crystallized from a mixture solvent of ethanol-ethyl acetate to give the title compound as a colorless powder (552 mg, yield: 84%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[NH:3]1.N.C(O)CO>>[CH3:16][N:13]1[CH2:14][CH2:15][CH:10]([C:8]([C:4]2[N:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: CN1CCC(C(=O)C2CCCC(Br)N2)CC1
Agent: N
Solvent: OCCO
Product: CN1CCC(C(=O)c2ccccn2)CC1
Temperature: 85 °C
Yield: 128.2 %

Procedure:
Load 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-piperidine (20 g, 70.67 mmol, 1 eq) in 73.6 ml of 7M NH3/ethylene glycol (530 mmol, 7.5 eq) into a 130 ml pressure autoclave, and add Cu2O (101 mg, 0.706 mmol, 0.01 eq) as a catalyst. Seal the autoclave and heat the reaction mixture to 85° C. at about 50 psi (345 kPa) for 20 hrs. Cool the reaction mixture to room temperature, transfer the organic layer to a 250 ml flask, and place the flask under reduce pressure to remove ammonia. Add water (70 mL) and of 30% NaOH (38 mL) and then extract the mixture with methyl 1-butyl ether (MTBE) (5×100 ml). Combine the organic fractions and then dry with MgSO4, filter, and concentrate under reduce pressure to obtain crude 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (18.5 g).