Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][C:13]=1[C:28](OCC)=[O:29]>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([NH:3][C:28]([C:13]2[N:14]=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[C:21]([C:12]=2[OH:11])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:29])=[N:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)c2ccccc2c1O
Reactant: Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cn1)c1nc(-c2ccccc2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
A stirred slurry of 2.3 g of sodium hydride in 100 ml of dry tetrahydrofuran was treated with 6.1 g of 2-amino-5-chloropyridine and immersed in an ultrasonic bath for 30 minutes. The stirred slurry was then treated with a solution of 7.0 g of 4-hydroxy-1-phenyl-3-isoquinolinecarboxylic acid, ethyl ester in 70 ml of tetrahydrofuran and refluxed for 16 hours. Thereafter, the solution was cooled to room temperature and quenched with 20 ml of water. The resulting precipitate was solubilized in 500 ml of aqueous methanol and treated with carbon dioxide gas. Recrystallization of the precipitate from 500 ml of warm dimethylformamide afforded 7.5 g (84%) of N-(5-chloro-2-pyridyl)-4-hydroxy-1-phenyl-3-isoquinolinecarboxamide, m.p. 249°-251° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[Br:15]Br.N1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:15][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:12][CH:11]=2
Reactant: FC(F)(F)c1ccc2ncccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2ncc(Br)cc2c1
Reaction time: 1 h

Procedure:
19.7 g of 6-trifluoromethyl-quinoline is introduced into 200 ml of tetrachloromethane. 5.2 ml of bromine is instilled and the solution is refluxed for one hour. Within twenty minutes, 7.9 g of pyridine in 8 ml of tetrachloromethane is instilled in the boiling solution. After one hour, it is allowed to cool, decanted from the precipitated salt and the solution is concentrated by evaporation. After column chromatography, 14.6 g of 3-bromo-6-trifluoromethyl-quinoline of melting point 79° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([NH:47][O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NOCc1ccccc1
Yield: 72.9 %

Procedure:
The title compound was prepared as described in Example 34. B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.365 g, 0.74 mmol), O-benzylhydroxylamine hydrochloride (0.16 g, 1.0 mmol), and 4-(N,N-dimethylamino)pyridine (0.121 g, 1.0 mmol) to provide the title compound (0.323 g, 73% yield): 1H NMR (CDCl3) 8.00 (br, 1H), 7.70 (d, 1H), 7.30-7.42 (m, 12H), 7.01 (d, 2H), 6.92 (m, 2H), 6.66-6.82 (m, 6H), 5.03 (s, 2H), 4.97 (s, 2H), 4.75 (t, 1H), 3.56 (m 1H), 3.47 (m, 1H), 3.17 (dd, 1H), 2.88-3.00 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 599 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([Cl:18])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Li]CCCC.[CH3:24][O:25][C:26]([C:28]1[CH:29]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH:33]([CH2:34][C:35]=1OS(C(F)(F)F)(=O)=O)[CH2:32][N:31]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:30]2)=[O:27].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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.CCOC(C)=O>[CH3:24][O:25][C:26]([C:28]1[CH:29]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])[CH:33]([CH2:34][C:35]=1[C:10]1[S:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]3[C:13]([Cl:18])=[CH:14][C:15]([CH3:17])=[CH:16][C:2]=3[Cl:1])=[N:12][CH:11]=1)[CH2:32][N:31]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:30]2)=[O:27]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)c(OCCOc2nccs2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2cnc(OCCOc3c(Cl)cc(C)cc3Cl)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A cooled (−78° C.) sol. of 2-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]thiazole (3.11 g, 10.2 mmol) in anhydrous THF (90 mL) was treated dropwise with BuLi (1.6 M in hexane; 7.00 mL; 11.2 mmol). After additional stirring at −78° C. for 1 h, ZnCl2 (1M in THF, 12.3 mL, 12.3 mmol) was added dropwise, and the resulting reaction mixture was allowed to warm up to rt for 1.5 h. A sol. of compound Y (4.34 g, 8.18 mmol) and Pd(PPh3)4 (284 mg, 0.246 mmol) in THF (20 mL) was added and the resulting mixture was heated to 50° C. for 1 h. The mixture was cooled to 0° C., and aq. sat. NH4Cl (30 mL) was added. EtOAc (200 mL) was added, and this mixture was successively washed with aq. sat. NH4Cl (150 mL) and brine (150 mL). The org. phase was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc, 3:2) yielded the title compound as a pale yellow solid (5.21 g, 93%). LC-MS: tR=1.19 min, ES+: 684.16.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][NH:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:44][CH2:43][C:40]3([CH2:42][O:41]3)[CH2:39][CH2:38]2)=[CH:31][CH:30]=1)#[N:28]>O.O1CCCC1>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][N:37]2[CH2:44][CH2:43][C:40]([CH2:42][N:13]([CH3:12])[C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:25][CH:26]=3)([OH:41])[CH2:39][CH2:38]2)=[CH:31][CH:30]=1)#[N:28]
Reactant: CNc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 49.7 %

Procedure:
A hexane solution of n-butyllithium (1.57M; 2.68 mL) was added dropwise to an anhydrous tetrahydrofuran solution (4.22 mL) of the compound (874 mg) obtained in Step 1 at the internal temperature of below 5° C. and the mixture was stirred under cooling with ice-water for one hour. To the mixture was added dropwise an anhydrous tetrahydrofuran solution (4.22 mL) of the compound (1.02 g) obtained in Step 3 of Example 1 at the internal temperature of below 5° C. over thirty minutes, stirred at the same temperature for one hour and further at room temperature for fifty two hours. To the solution added water (40 mL) under cooling with ice-water and the residue was extracted with ethyl acetate. After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex NH™)(eluent; hexane:ethyl acetate=7:3 to 1:1) to obtain the titled compound (940 mg) as powder.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[N:13]1[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]1.[CH3:20][C:21]1[CH:26]=[C:25]([N:27]2[C:31]([CH3:32])=[C:30]([CH3:33])[C:29]([CH3:34])=[N:28]2)[CH:24]=[CH:23][C:22]=1[OH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][CH:10]([F:12])[O:9][C:8]1[C:3]([CH2:2][O:35][C:22]2[CH:23]=[CH:24][C:25]([N:27]3[C:31]([CH3:32])=[C:30]([CH3:33])[C:29]([CH3:34])=[N:28]3)=[CH:26][C:21]=2[CH3:20])=[C:4]([N:13]2[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[N:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Reactant: Cn1nnn(-c2cccc(OC(F)F)c2CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(OC(F)F)cccc1-n1nnn(C)c1=O
Temperature: 25 °C

Procedure:
A mixture of 1-(2-bromomethyl-3-difluoromethoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 1) 0.30 g, methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol (described in Reference Preparation example 20) 0.26 g, potassium carbonate 0.21 g and acetonitrile 10 ml was stirred with heating under reflux for six hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was then concentrated. The resulting residue was subjected to a silica gel column chromatography to give 1-{3-difluoromethoxy-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 1”) 0.31 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)=[C:3]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:4]=1[O:12][CH3:13]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(S(C)(=O)=O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCc1ccc(S(C)(=O)=O)cc1
Temperature: 85 °C
Yield: 22.4 %

Procedure:
To a stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-(4-(methylsulfonyl)benzyloxy)benzene (200 mg, 0.457 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (445 mg, 1.371 mmol), tetrakis(triphenylphosphine) palladium(0) (26 mg, 0.022 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (142 mg, 0.548 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (50 mg, 22%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:2]1([O:1][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:18][C@@H:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][OH:21])=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccccc1COc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1COc1ccccc1
Yield: 84 %

Procedure:
2 g (8.8 mmol) of 2-phenoxymethylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 2.7 g (84%) of the product were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:24][CH:25]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Cc1ccc(CCl)nc1
Product: Cc1ccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)nc1
Yield: 32.5 %

Procedure:
4-(5-(2-Amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1 and the 2-chloromethyl-5-methyl-pyridine (32 mg, 0.23 mmol) described in Manufacturing Example 42-1-2 were used to obtain the title compound (23 mg, 33%) according to the methods similar to those of Example 10.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C)C=O.O>[C:4]([C:3]1[C:2]2[O:1][CH2:20][CH2:19][O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: BrCCBr
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cccc2c1OCCO2
Temperature: 65 °C

Procedure:
A mixture of 10.8 g (70 mmol) of 2,3-dihydroxybenzoic acid, 38.6 g (280 mmol) of dry potassium carbonate and 24 ml (278 mmol) of 1,2-dibromoethane in 40 ml of N,N-dimethylformamide is heated at 65° C. for 24 hours under an inert atmosphere. After cooling, the reaction mixture is diluted with water and then extracted with ether. The aqueous phase is then acidified with a 3N hydrochloric acid solution and subsequently extracted with dichloromethane. After removal of the solvent by evaporation in vacuo, the residue obtained is recrystallised from toluene to yield the title acid in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[OH-].[K+]>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Reaction time: 3.5 h

Procedure:
A solution of ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.013 mol) (example 3) in dioxane is treated with potassium hydroxide (0.13 mol in 30 ml water) solution. The reaction mixture is stirred for about 3-4 hrs and concentrated under reduced pressure. It is acidified with hydrochloric acid to pH of about 3-4, extracted with ethyl acetate, washed with brine and dried under vacuo
Reaction SMILES: [I-].[Na+].[CH3:3][O:4][CH:5]([O:12][CH3:13])[C:6](=[O:11])/[CH:7]=[CH:8]\[CH2:9][CH3:10]>C(O)(=O)C>[CH3:13][O:12][CH:5]([O:4][CH3:3])[C:6](=[O:11])/[CH:7]=[CH:8]/[CH2:9][CH3:10]
Reactant: CC/C=C\C(=O)C(OC)OC
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC/C=C/C(=O)C(OC)OC

Procedure:
The crude product produced in Example II is dissolved in 6 ml of acetic acid with 0.1 g of sodium iodide. By GLC analysis on Carbowax(polyethylene glycol) it is clear that the 1,1-dimethoxy-cis-3-hexene-2-one is converted to a new material of later retention time. After one-half hour less than 5 percent of "cis" material remains.
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:25])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OO
Reactant: CCCCCCC/C=C/CO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC(C)CC(C)(C)C
Solvent: ClCCl
Product: CCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2.00 g of 4A powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 273 mg (1.00 mmole) of Ti(OiPr)4 and 314 mg (1.34 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butylhydroperoxide in isooctane (3.8M, 7.57 ml, 28.8 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 3.00 g (19.2 mmole) of E-2-decen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 min before being added to the mixture slowly, with stirring, at -20° C. The solution was then placed in the freezer (-30 ° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 5.00 g of FeSO4 in 15 ml H2O. The organic layer was separated and the aqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers are combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O: petroleum ether afforded 2.43 g of white solid, mp 50°-1° C. 1H NMR δ3.92 (ddd, 1, J=2, 6, 12 Hz), 3.63 (ddd, 1, J=4, 8, 12 Hz), 2.94 (m, 2), 1.73 (dd, 1, J=6, 7 Hz), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M-31(-CH2O H)(0.5)148.1, M(100)69.1.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16]([O-:19])(O)=[O:17].[Na+]>N1C=CC=CC=1.CCCCCC>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][C:16]([O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:17])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC(=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of triethylsilyloxy keto diol 6 (883 mg, 2.31 mmol) in 35 mL of pyridine under nitrogen at 0° C. was added dropwise 0.485 mL (2.771 mmol) of TBSOTf. The solution was then warmed to room temperature. After 2 h at room temperature, the solution was diluted with 100 mL of hexane and poured into 150 mL of a saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with two 100 mL portions of hexane. The organic layers were combined, and washed with 50 mL of a 10% aqueous CuSO4 solution followed by 20 mL of H2O, and dried over anhydrous Na2SO4. Removal of the solvent followed by flash chromatography purification (2.5% EtOAc/hexane) to give 1.122 g of t-butyldimethylsilyloxy ketone 7 (98% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([F:32])[C:18]=1[CH:33]([F:35])[CH3:34].[F-].[K+].CC#N>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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([CH:33]([F:35])[CH3:34])[C:19]=2[F:32])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(C(C)F)c2F)c(F)c(N)c1OC
Yield: 81 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), 2-(4-chloro-2-fluoro-3-(1-fluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared as described in WO2009029735 A1 20090305; 0.671 g, 2.216 mmol), PdCl2(PPh3)2 (0.120 g, 0.170 mmol), and KF (0.258 g, 4.43 mmol) were combined in a 1:1 mixture of CH3CN (2.84 mL) and H2O (2.84 mL). The reaction mixture was irradiated in a Biotage microwave at 115° C. in a sealed vial for 20 min. The cooled reaction mixture was partitioned between EtOAc and H2O. The organic phase was dried and concentrated. The product was purified by flash chromatography (SiO2, 5-40% EtOAc in hexane gradient) to provide the title compound as a sticky brown-orange solid (0.545 g, 81%): 1H NMR (400 MHz, CDCl3) δ 7.53-7.46 (m, 1H), 7.29 (dt, J=8.4, 1.1 Hz, 1H), 6.39-6.03 (m, 1H), 4.61 (s, 2H), 3.97 (d, J=2.1 Hz, 6H), 1.85-1.68 (m, 3H); 19F NMR (376 MHz, CDCl3) δ −113.81, −113.87, −113.90, −113.95, −137.05, −137.14, −175.47, −175.52; ESIMS m/z 375 ([M+H]+), 373 ([M−H]−).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]>[Ni]>[NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Agent: [Ni]
Product: NC(C(=O)O)C1CCC(O)CC1

Procedure:
Bicyclic diamines of general formula (32), wherein P2 is a nitrogen protecting group, can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460). Amino(4-hydroxyphenyl)acetic acid, purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid. Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide (benzoylamino)(4-oxocyclohexyl)acetic acid. (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxylamine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid. (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCl and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid. 2-Amino-3-(2-aminoethyl)hexanedioic acid can be distilled at 180-200° C./0.1 torr to provide octahydro[1,7]naphthyridine-2,8-dione. Octahydro[1,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23].O1CCOCC1>C(O)(C)(C)C>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])=[CH:4]2
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: COc1cccc(F)c1CCC#N
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1cccc(F)c1Cc1cc2cc(Cl)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-chlorobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile. Instead of dioxane, tert-butanol was used from [sic; as] the solvent. Reaction time: 5 minutes at 120° C.