Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH2:27])=[N:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([CH2:21][N:22]2[CH:26]=[N:25][C:24]([NH:27][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:23]2)=[CH:19][CH:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(Cc2ccc(Cl)cc2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4ccc(Cl)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a colorless solid (Yield=49%). MS ISP (m/e): 390.2 & 392.0 (100 & 48) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)[C@H:13]([OH:25])[CH2:12]2)[C:7]1=[O:26].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C@H:13]([OH:25])[CH2:12]2)[C:7]1=[O:26]
Reactant: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](O)C3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (300 mg, 0.73 mmol) in DCM (20 mL) under nitrogen at −10° C. was added boron tribromide (0.17 mL, 1.8 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with 200 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (290 mg, 0.36 mmol, 50% yield, mixture of 4 diastereoisomers); LCMS (Method F) RT 1.854 min m/z 399.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>COCCOC.O.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>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:10]3[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=3[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=2)=[CH:29][CH:28]=1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)CC(=O)c2c(-c3ccc(Cl)cc3)cn(-c3ccccn3)c2C1
Temperature: 100 °C
Yield: 10.7 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (50 mg, 0.16 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) in ethylene glycol dimethyl ether (2 mL) at 45° C. was degassed with nitrogen for 30 min. A degassed solution of Cs2CO3 (104 mg, 0.16 mmol) in water (1 mL) was added followed by 4-chlorophenylboronic acid (25 mg, 0. 16 mmol). The solution was heated at 100° C. for 18 h then filtered through celite. The filtrate was partitioned between DCM and water. The organic phase was separated, dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with isohexane: EtOAc (3:1) to give the title compound (6 mg, 11%) as a colourless solid. 1H NMR (360 MHz, d6-DMSO) δ 1.05 (6H,s), 2.37 (2H,s), 3.01 (2H,s), 7.38 (2H,d, J=8.5 Hz), 7.46-7.50 (1H,m), 7.56 (1H,s), 7.68-7.74 (3H,m), 8.05-8.09 (1H,m), 8.59-8.63 (1H,m). MS (ES+) 351/353 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[CH2:5][CH2:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(N)C(=O)N(Cc2ccc(OC)cc2OC)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1N
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of ethyl 5-amino-1-(2,4-dimethoxybenzyl)-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (890 mg) in toluene (20 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (785 mg) at room temperature, and the mixture was heated under reflux for 30 min, allowed to be cooled to room temperature, and diluted with ethyl acetate. The insoluble material was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (535 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:30][C:31]1([CH3:48])[CH2:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]([CH3:47])([CH3:46])[NH:32]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=[C:2]([C:35]2[CH2:34][C:33]([CH3:47])([CH3:46])[NH:32][C:31]([CH3:48])([CH3:30])[CH:36]=2)[CH:3]=1)=[O:18]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCOCC2)c(=O)[nH]1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCOCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (14%). LCMS: 519.30 (M+1)+; HPLC: 98.464% (@ 254 nm) (Rt; 4.823); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H); 8.87 (s, 1H); 8.30 (s, 1H); 7.82 (s, 1H); 6.81 (s, 1H); 5.90 (s, 1H); 5.06 (m, 1H); 4.38 (s, 2H); 3.01 (d, J=11.2, 2H); 3.59 (t, J=12.0 Hz, 2H); 2.23 (s, 3H); 2.23-2.19 (m, 2H); 2.12 (s, 3H); 1.90 (d, J=12.0 Hz, 2H); 1.27-1.23 (m, 14H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH:4]1[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=12)[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[Br:30][C:11]1[C:12]([NH2:14])=[CH:13][C:8]2[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:15][C:16]4([CH2:21][CH2:22][C:3]3([CH2:1][CH3:2])[C:9]=2[CH:10]=1)[O:17][CH2:18][CH2:19][O:20]4
Reactant: CCC12CCC3(CC1CCCc1cc(N)ccc12)OCCO3
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC12CCC3(CC1CCCc1cc(N)c(Br)cc12)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
rac-(4aR,11bS)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (22, R2=Ethyl) (0.345 g, 1.145 mmol) in THF (8 mL) was cooled to about 0° C. then NBS (0.204 g, 1.145 mmol) was added. After about 10 min, sat. aq. NaHCO3 (20 mL) and EtOAc (25 mL) were added. The mixture was warmed to rt and the layers were separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-10-bromo-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-amine (23, R2=Ethyl) (0.255 g, 59%); LC/MS, method 3, Rt=2.85 min, MS m/z 380, 382 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.03 (s, 1H), 6.55 (s, 1H), 5.04 (s, 2H), 3.89-3.73 (m, 4H), 2.80-2.73 (m, 1H), 2.58-2.46 (m, 1H), 2.26-2.19 (m, 1H), 2.14-2.05 (m, 1H), 2.02-1.88 (m, 2H), 1.72-1.45 (m, 4H), 1.43-1.18 (m, 5H), 0.60 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH3:37]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Cc1cc(F)ccc1CBr
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(F)cc2C)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-4-fluoro-2-methylbenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.65 (d, J=7.0 Hz, 1 H), 7.41 (d, J=7.0 Hz, 1 H), 7.37-7.30 (m, 2 H), 7.03 (dd, J=6.0, 8.3 Hz, 1 H), 6.96-6.83 (m, 3 H), 6.22 (d, J=3.5 Hz, 1 H), 5.58-5.49 (m, 2 H), 5.44-5.37 (m, 1 H), 2.76 (s, 3 H), 2.47 (s, 3 H), 2.32 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=475 (M+1).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>CCCCCC>[C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([Cl:19])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C2CC2C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A mixture of 2-(5-t-butylthiophen-2-yl)-cyclopropanecarboxylic acid (3.38 g, 0.015 mol) and oxalyl chloride (2.65 g, 0.021 mol) in hexane (35 ml) was stirred at room temperature for 2 hours and then warmed at 60° C. for 3 hours. The hexane and excess oxalyl chloride were removed in vacuo to give 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (3.59 g, 99%) as a pale yellow liquid which was used in the next stage without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[OH:12])(=[O:3])[CH3:2].C([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1)(=O)C.P(Cl)(Cl)(Cl)=O.CC(C)([O-])C.[K+]>ClCCl.C1COCC1.O.N1C=CC=CC=1>[OH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:12][C:5]3[C:4]([C:1](=[O:3])[CH:2]=2)=[CH:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=3)=[CH:19][CH:18]=1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1cc(C#N)ccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2oc(-c3ccc(O)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.5 %

Procedure:
2-Acetyl-4-cyanophenol (0.78 g, 4.84 mmol), 4-acetoxybenzoic acid (0.872 g, 4.84 mmol) and phosphorus oxychloride (0.5 mL) and pyridine (2.0 mL) were mixed in anhydrous dichloromethane (10 mL). The reaction mixture was stirred overnight at rt and then poured into cold water and extracted with dichloromethane (150 mL). The organic layer was washed with sodium bicarbonate, brine and dried over sodium sulfate followed by concentration. The crude compound (1.40 g, 89.5%) was obtained after evaporation of the solvent. The crude compound (1.4 g, 4.33 mmol) was dissolved into dry THF (20 mL) and potassium tert-butoxide (0.51 g, 4.55 mmol) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed, followed by addition of water (50 mL) and EtOAc (150 mL) was used to extract out the compound. The organic layer was washed with brine and dried over sodium sulfate. The crude product (1.20 g) and 4 drops of sulfuric acid were added to AcOH (15 mL). The reaction mixture was heated to 110° C. for 1 h. AcOH was removed and sodium bicarbonate solution was added followed by extraction with EtOAc. The organic layer was washed with brine and dried over sodium sulfate and concentrated. The crude and potassium carbonate (1.1 g) was added to MeOH (20 mL). The reaction mixture was stirred for 2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue was purified by preparative HPLC to give 70 mg of 2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile. MS (ES) m/z: 264.91 (M+1), 263.90 (M); Mp. 296-298° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCCCCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1ccc(Cl)c(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCCCCC
Product: COC(=O)c1ccc(Cl)c(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 182.3 %

Procedure:
In the same manner as described in Example 9, 0.5 g (1.35 mmol) of the product of Example 96 provided 0.566 g (80%) of the desired product as a white solid after trituration with hexane. Electrospray Mass Spec 460.2(M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[O:13]=O.[Bi]>[Pd]>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([C:2]([OH:13])=[O:1])=[O:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=O
Agent: [Pd]
Agent: [Bi]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 85 %

Procedure:
A palladium-bismuth catalyst is disclosed in the specification of Japanese Patent Laid-Open No. 163340/1982 which relates to a process for producing 2-keto-L-gulonic acid. In this process, a hydroxyl group of L-sorbose (ketose) is oxidized with oxygen in the presence of a catalyst containing palladium and bismuth to obtain 2-keto-L-gulonic acid in a yield of 85%. The process of the present invention is characterized in that not the hydroxyl group but an aldehydo group of glucose (aldose) is oxidized to obtain gluconic acid. The process of the present invention is different from the above-mentioned process in the functional group to be oxidized and the intended product. It has been unknown in the prior art that the palladium-bismuth catalyst selectively oxidizes only the aldehydo group of glucose as an aldose, leaving the hydroxyl group non-oxidized.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=S(=O)(c1cccs1)N1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
Thiophene-2-sulfonyl chloride (10 g, 54 mmol) was dissolved in dichloromethane (15 mL) and added dropwise to a round-bottom flask containing a solution of piperidine (10.6 mL, 108 mmol) and diisopropylethyilamine (18.8 mL, 108 mmol) in dichloromethane at 0° C. The reaction was stirred at 0° C. for 15 min and then allowed to warm up to room temperature. After 2 h, the reaction was washed successively with a saturated solution of sodium bicarbonate, water, 1 N HCl and a saturated solution of sodium chloride. The organic layer was dried with sodium sulfate, concentrated and placed on a vacuum line to give an off-white solid (11.98 g). MS (M+H)+ 232.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#N)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:24]>[Zn]>[C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]([CH2:18][OH:24])[CH:20]=[CH:21][CH:22]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: N#Cc1cccc(-c2csc(C3(c4ccccc4)CC3)n2)c1
Agent: [Zn]
Product: OCc1cccc(-c2csc(C3(c4ccccc4)CC3)n2)c1

Procedure:
3-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]benzonitrile (1-10, 0.10 g, 0.33 mmol) in MeOH (20 mL) was treated with NiCl2-6H2O (0.24 g, 1.0 mmol) and Zn metal (0.17 g, 2.6 mmol) and the resulting mixture was stirred vigorously at reflux for 72 h. The reaction was filtered through celite, concentrated, and partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was concentrated and the crude residue was purified by reverse phase HPLC (C-8, 5-95% MeOH—H2O w/0.1% TFA) to provide pure {3-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]phenyl}methanol (5-1): 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.52 (dt, J=6.8, 1.3 Hz, 2H), 7.40-7.30 (m, 5H), 7.32 (s, 1H), 4.76 (s, 2H), 1.87 (dd, J=6.8, 3.9 Hz, 2H), 1.44 (dd, J=6.8, 3.9 Hz, 2H); MS 307.9 found 309.4 (M+H+) required.
Reaction SMILES: [CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].C=O.[C:14](=O)([O-])[O-].[Na+].[Na+]>CO.O.[Pd]>[CH2:1]([C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C(=O)O)CCCCN1
Agent: [Pd]
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1(C(=O)O)CCCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-ethylpiperidine-2-carboxylic acid (320 mg, 1.65 mmol) in MeOH (4.0 mL) and water (4.0 mL) was added paraformaldehyde (372 mg, 4.13 mmol) and Pd/C (10%) (88 mg, 0.83 mmol). One equivalent of sodium carbonate (175 mg, 1.65 mmol) was added and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for overnight. LC/MS indicated complete conversion of starting material. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with MeOH (2×30 mL). The filtrate was concentrated in vacuo to give the crude product. The crude solid was suspended in methanol (50 mL) and the resulting suspension was filtered and the filtrate was concentrated to give 2-ethyl-1-methylpiperidine-2-carboxylic acid (202 mg, 71.4%) as a solid. LC/MS: 172 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 3.58 (td, J=12.80, 3.51 Hz, 1 H), 3.09-3.20 (m, 1H), 2.81 (s, 3H), 2.17-2.29 (m, 1H), 1.54-1.84 (m, 7H), 0.98 (t, J=7.40 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18]/[C:17](=[N:21]\C(=O)C4C=CC=CC=4)/[NH:16]3)[C:14]3[CH:13]=[C:12]([Cl:30])[N:11]=[C:10]([F:31])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.N.CO>C1COCC1>[Cl:30][C:12]1[N:11]=[C:10]([F:31])[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=3
Reactant: Nc1ccc2c(c1)[C@@]1(CCO/C(=N\C(=O)c3ccccc3)N1)c1cc(Cl)nc(F)c1O2
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Temperature: 50 °C
Yield: 17 %

Procedure:
(S,Z)—N-(7-amino-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazinan]-2′-ylidene)benzamide was dissolved in THF (5 mL) followed by the addition of ammonia, 2.0 m solution in methanol (49.7 ml, 99 mmol) and heated in a sealed tube at 50° C. for 17 h. The mixture was concentrated and chromatographed on silica gel using 0-5% MeOH/DCM to afford a yellow oil as (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.23 g, 0.687 mmol, 17% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Li]CCCC.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24](N2CCC(=O)CC2)=[O:25])[N:23]=1>C1COCC1.CCCCCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[C:21]([CH2:33][CH3:34])=[C:22]([C:24]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:25])[N:23]=1
Reactant: CCc1c(C(=O)N2CCC(=O)CC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Reactant: Brc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1c(C(=O)c2cccs2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 2-bromothiophene (0.22 g, 1.36 mmol) in 2 mL THF was added 0.84 mL of a 1.6 M solution of BuLi in hexane under argon at −78° C. with stirring. The stirring was continued for 1 h. To this was added a solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl]carbonyl}-4-piperidinone in 2 mL THF. The resultant mixture was stirred and gradually allowed to warm up to rt overnight. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the crude product was purified by HPLC to yield [2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazol-4-yl](2-thienyl)-methanone as a solid (60 mg, 31%): Rf=0.13 (1:5 ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)cc(C)c2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone (Example 387) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 438.