Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Cl.[N:12]([O-])=O.[Na+].[C:16]([CH:19](C(=O)C)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])[CH3:17]>N1C=CC=CC=1.C(O)C.O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][NH:12][CH:19]([C:16](=[O:18])[CH3:17])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(NNc1ccc2[nH]ncc2c1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-aminoindazole in 50 ml. of ethanol, 100 ml. of water and 8 ml. of 12 M hydrochloric acid was cooled to 0° C. and a previously cooled solution of 3.41 g. (49.5 mmoles) of sodium nitrite in 10 ml. of water was added dropwise. After 30 minutes, the dark red mixture was added to the solution of 9.2 g, (49.5 mmoles) of ethyl 3-acetyl-4-oxopentanoate in 20 ml. of ethanol and 14.2 ml. of pyridine. The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for an additional 30 minutes and finally the solid collected by filtration to give 11.2 g. of solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][N:3]=1.NN>C(Cl)Cl.CCO>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[N:3][N:4]=1
Reactant: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2-[(3-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (2.00 g, 7.40 mmol) in DCM (10.0 mL) and EtOH (10.0 mL) was charged with hydrazine (0.58 mL, 18.5 mmol) and stirred at rt for 8 h, then heated to 45° C. for an additional 16 h. The reaction was charged with an additional 0.5 equiv of hydrazine (0.116 mL, 3.70 mmol) and heated to 45° C. for 4 h. The reaction mixture was allowed to cool to rt then filtered through a fritted funnel and the cake was washed with 2 portions of cold 1:1 EtOH/DCM (75 mL) and the filtrate was concentrated resulting in 622 mg of a pale yellow solid which was taken on to the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 3.72 (s, 2H); MS (ES+): m/z 141.06 [MH+].
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[NH2:58][CH2:59][CH2:60][CH:61]1[CH2:66][CH2:65][CH2:64][N:63]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62]1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([NH:58][CH2:59][CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:6])=[O:7])[CH2:2][CH2:3]1.[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([NH:58][CH2:59][CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][N:63]([C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[CH2:62]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCN)C1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)NCCC3CCCN(C(=O)OC(C)(C)C)C3)co2)C2CC2)c(C)c1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)NCCC3CCCNC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (38 mg, 100 mop, EDCI (23 mg, 120 mop, HOBt monohydrate (18 mg, 120 μmol), DIPEA (69 μL, 400 mol), tert-butyl 3-(2-aminoethyl)piperidine-1-carboxylate (23 mg, 100 μmol) and DMF (750 L). The resulting crude compound was purified by FCC eluting with 100% EtOAc to afford tert-butyl 3-[2-({[2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazol-4-yl]carbonyl}amino)ethyl]piperidine-1-carboxylate. Yield: 38 mg, 64%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=O)C>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:22])[CH2:19][C:13]2[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(Cl)ncc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Cc2cc(Cl)ncc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran; 11.00 mL) is added drop wise to 5-bromo-2-chloro-4-picoline (950 mg) in tetrahydrofuran (15 mL) at −40° C. under an argon atmosphere. The mixture is stirred for 2 h at −35° C. to −45° C. prior to the addition of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.33 g), dissolved in tetrahydrofuran (15 mL). The reaction mixture is allowed to warm to room temperature over a period of 1 h. Ice cold water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40) to give the title compound. LC (method 7): tR=1.43 min; Mass spectrum (ESI+): m/z=417, 419 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:43]=[CH:42][C:15]([CH2:16][C@H:17]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:18][C@@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:14][C:13]=1[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])C1C=CC=CC=1>CO.[Pd].[H][H]>[C:24]([O:23][C:21]([NH:20][C@H:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18][C@H:17]([CH2:16][C:15]1[CH:42]=[CH:43][C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH:14]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOCc2ccccc2)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCO)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 340 mg (0.506 mmol) di-tert-butyl (4S)-4-{4-[2-(benzyloxy)ethoxy]-3-tert-butoxybenzyl}-N-(tert-butoxycarbonyl)-L-glutamate in 5 ml methanol was added a little amount of palladium on carbon. The solution is stirred in hydrogen atmosphere for 4 hours. The reaction mixture is filtrated. The filtrate is concentrated. The crude product is concentrated in vacuo. The crude product (310 mg) was used in the following reaction without further purification.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C1C2N[C:17]3[C:12](=CC=C[CH:16]=3)SC=2C=CC=1.C(N(CC)CC)C.CC(=O)C[C:30](=[O:32])C>[Hf].[Cl-].[Cl-].[Cl-].[Cl-].[Hf+4].CO>[C:30]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:32])[C:17]([CH3:16])=[CH2:12]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)CC(C)=O
Reactant: CCCCO
Agent: [Hf+4]
Agent: [Hf]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCC
Reaction time: 2 h

Procedure:
An example utilizing an in-situ hafnium catalyst was performed by adding 20.0 g (274 mmol) n-butanol, 135 g (1.35 mole) MMA, 20 mg phenothiazine to a 300 ml round bottom flask equipped with an agitator, thermometer, and Vigreux fractional distillation column. The solution was dehydrated by refluxing the mixture at atmospheric pressure and removing water via a MMA/water azetrope. The mixture was then cooled to 0° C. (ice bath) where 1.63 g (16.1 mmol) triethylamine, 1.0 g (10.0 mmol) 2,4-pentanedione, and 870 mg (2.72 mmol) hafnium tetrachloride were added to the solution. The catalyzed mixture was heated to reflux at 1 atm. pressure while azetropic mixture of MMA and MeOH was removed from the upper part of the fractionating column. The reaction was continued in this manner for approximately 2 hours while the temperature at the top of the column was 65°-67° C. and the temperature in the pot was 97°-112° C. Analysis of the reaction mixture by gas-liquid chromatographic analysis showed greater than 99% conversion of the n-butanol to n-butyl methacrylate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](=[O:16])([O-])[O-:14].[Na+].[Na+].C(=O)([O-])ON1C(=O)CC([CH2:27][CH:28]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)C1=O>COCCOC>[CH:30]1[C:29]2[CH:28]([CH2:27][O:14][C:13](=[O:16])[NH:1][CH2:2][CH:3]([OH:4])[CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])ON1C(=O)CC(CC2c3ccccc3-c3ccccc32)C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(NCC(O)C(O)C(O)C(O)CO)OCC1c2ccccc2-c2ccccc21

Procedure:
D-glucamine (Compound 34: 9.0 g, 49.7 mmol) was mixed with 200 ml of a 10% aqueous solution of sodium carbonate, and this was followed by stirring under ice cooling. 9-Fluorenylmethylsuccinimidyl carbonate (16.7 g, 49.7 mmol) was dissolved in 200 ml of DME (1,2-dimethoxyethane) and added to the reaction system, and this was followed by stirring under ice cooling for 30 minutes. The precipitating crystal was collected by filtration and washed with H2O×3 and MeOH×3. The crystal was dried under reduced pressure to yield the desired compound (2,3,4,5,6-pentahydroxy-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (Compound 35: 20 g) quantitatively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=2)[CH:5]=[CH:4][N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]2[O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnc(N)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc([C@H]2CCCC[C@@H]2Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)ccn1
Yield: 57.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(2-aminopyridin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (42.7 mg, 0.0698 mmol) prepared in Example 35c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (18.6 mg, 58%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: Cc1nc2c(Br)cc(Cl)cc2[nH]1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(Br)cc(Cl)cc2n1C1CCCCO1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methyl-1H-benzo[d]imidazole (3.5 g, 14.26 mmol), p-TsOH.H2O (272 mg, 1.43 mmol), and 3,4-dihydro-2H-pyran (5.9 g, 71.30 mmol) in THF (20 mL) was stirred at 75° C. for 4 h. The reaction mixture was concentrated in vacuo and water was added. The mixture was extracted with EtOAc and the combined extracts dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM:MeOH gradient (0 to 9% MeOH) to afford 4-bromo-6-chloro-2-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole as a white solid (3.2 g, 69.6%). MS (ESI): m/z=329.0 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[O:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2o1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1Cl
Temperature: 0 °C
Yield: 75.6 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 19, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.8 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (206 mg, 76%) as a light orange foam: [α]23589=−24.4° (c=0,119,chloroform); EI-HRMS m/e calcd for C22H23ClN2O4S (M+) 446.1067, found 446.1083.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14]C)=O)[C:6](OCC)=O)(=O)[CH3:2].[Na].Cl.[N:18]1[CH:23]=[CH:22][C:21](CCl)=[CH:20][CH:19]=1.C([OH:28])C>>[CH2:1]([N:4]1[CH:5]([CH2:6][C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[CH2:11][O:13][C:14]1=[O:28])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCO
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na]
Product: CCN1C(=O)OCC1Cc1ccncc1
Temperature: 25 °C

Procedure:
Diethyl acetamidomalonate (20.0 g, 0.921 mol) is dissolved in 200 mL of absolute ethanol. Sodium metal (4.2 g, 0.1827 mol) is added and the mixture is stirred at room temperature until all of the metal is dissolved. The solution is cooled to 0-5° C. and 13.3 g (0.0811 mol) of 4-picolyl chloride hydrochloride in 100 mL of absolute ethanol is added rapidly. After stirring at room temperature overnight, the mixture is filtered through celite and the filtrate concentrated to a dark oily solid. The residue is dissolved in 200 mL of concentrated hydrochloric acid and refluxed for 4 hours and concentrated in vacuo to a dark oily solid. The residue is dissolved in 200 mL methanol and 2 mL of concentrated hydrochloric acid and refluxed overnight. The solution is concentrated to 16.7 g of orange solid. The hydrochloride salt is purified by trituration with ethanol and ethyl acetate to yield the title compound of a pale yellow solid; mp 180-182° C.
Reaction SMILES: [OH:1][C:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:20]1[CH:24]=[CH:23]SC=1)[C:3]([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[S:38]([C:35]1[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=1)([OH:41])(=[O:40])=[O:39].[CH:20]1([C:2]([OH:1])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:3]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[O:4])[CH2:37][CH2:32][CH2:33][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)C(O)(c2ccccc2)c2ccsc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: O=C(OCC1CCNCC1)C(O)(c1ccccc1)C1CCCCC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 159.7 %

Procedure:
To a stirred solution of tert-butyl 4-((2-hydroxy-2-phenyl-2-(thiophen-3-yl)acetyloxy)methyl)piperidine-1-carboxylate (0.84 g, 1.94 mmol) in acetonitrile (10 mL), p-toluenesulfonic acid monohydrate (0.55 g, 2.91 mmol) was added. The reaction was stirred at 30° C. overnight and then concentrated under reduced pressure to afford the title compound (1.17 g, >100%) that was used without further purification in the next step.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:29])=[N:19][C:20]([N:23]2[CH:27]=[C:26](I)[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][PH:31]([O-])([O-:35])[O:32][CH2:33][CH3:34].CCN(CC)CC>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:29])=[N:19][C:20]([N:23]2[CH:27]=[C:26]([P:31]([CH3:30])(=[O:35])[O:32][CH2:33][CH3:34])[CH:25]=[N:24]2)=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: O=C(NC(c1ccccc1)c1ccccc1)c1cnc(-n2cc(I)cn2)nc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(C)(=O)c1cnn(-c2ncc(C(=O)NC(c3ccccc3)c3ccccc3)c(O)n2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a mixture of product of step C, compound 1-1-c, (1.2 g, 2.4 mmol), ethyl methyl-phosphite (522 mg, 4.8 mmol) and Et3N (610 mg, 6 mmol) in DMF (20 mL) was added PdCl2(dppf) (176 mg). The mixture was allowed to stir overnight at 80° C. The mixture was cooled to room temperature and diluted with water. The resulting mixture was then filtered and the filtrate was extracted with dichloromethane/methanol (5/1). The organic layer was dried over sodium sulfate and concentrated under vacuum. And the residue was purified over silica gel (dichloromethane:methanol=3/1) to provide the product, 1-1-d, (500 mg, 44%).
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[C:5]([C:7]1[CH:8]=[N:9]C=C[CH:12]=1)#[N:6]>>[C:8]([C:7]1[CH:5]=[N:6][C:1]([OH:4])=[CH:2][CH:12]=1)#[N:9]
Reactant: N#Cc1cccnc1
Reactant: CC(=O)[O-]
Product: N#Cc1ccc(O)nc1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
To an Erlenmeyer flask equipped with navels was filled a nutrient solution containing 1 g of yeast extract, 1 g of glucose, 0.3 g of K2HPO4, 0.1 g of KH2PO4, 1 mg of FeSO4, 50 mg of MgSO4, 1 mg of MnSO4 and 100 ml of water, and the resultant mixture was sterilized at 120° C. for 20 minutes. After cooling to 30° C., the mixture was added with separately sterilized 1 mg of CuSO4 and 0.2 g of 3-cyanopyridine as an inducer. One of the microorganisms listed in Table 1 which was incubated on nutrient agar medium for 24 hours was inoculated into the above mixture with a platinum loop, and the mixture was incubated at 30° C. for 24 hours using a rotary shaker of 160 rpm. After 24 hours, the broth was recovered and centrifuged. The cells separated were suspended in and washed with 0.02 mol of an acetate buffer (pH 5.5) and centrifuged to give a resting cell. To a 100 ml reactor was added 20 ml of 1.0% 3-cyanopyridine (pH 5.5), and the mixture was heated at 30° C., and mixed with the resting cell obtained above. The resultant mixture was stirred sufficiently for 24 hours to give 3-cyano-6-hydroxypyridine. The product was identified by means of HPLC, IR and 1H-NMR. Table 1 shows the results.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C:16](OC)=[O:17])[O:14][CH2:13][CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:27]([Mg]Br)=[CH2:28].[CH2:31]1COC[CH2:32]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:15]([C:16]([OH:17])([CH:27]=[CH2:28])[CH:31]=[CH2:32])[O:14][CH2:13][CH2:12][N:11]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Reactant: C=C[Mg]Br
Solvent: O
Product: C=CC(O)(C=C)[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-tert-butyl 7-methyl (6R,7R)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4,7-dicarboxylate (2.86 g) in THF (30 mL) was added 1.0 M vinylmagnesium bromide/THF solution (15.6 ml) under ice-cooling. The mixture was stirred at 0° C. for 20 min under nitrogen purging, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (2.31 g) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CN(C)C=O>O.CO>[C:1]1([CH:7]2[CH2:8][C:9](=[O:14])[CH:10]=[C:11]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=3)[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (1.51 g, 8.04 mmol), 3-(trifluoromethyl)-aniline (1.00 mL, 1.29 g, 8.04 mmol), Ytterbium(III) trifluormethanesulfonate (25 mg, 40 μmol, 0.5 mol %) and N,N-dimethylformamide (2.5 mL) is stirred at room temperature over night. Methanol and water are added and the mixture is filtered. The precipitate is dissolved in a mixture of N,N-dimethylformamide, methanol and some drops of aqueous ammonia. Water is added and the precipitate is filtered. Yield: 1.51 g; ESI mass spectrum [M+H]+=332, Retention time HPLC: 1.09 min (Z003—001).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:3]2[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)C1CCNCC1
Reactant: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 160 °C
Yield: 27 %

Procedure:
To a mixture of 2-[4-(3-chloro-pyrazin-2-yloxy)-piperidin-1-yl]-quinoline (see PREPARATION P2.1; 0.34 g, 1.0 mmol) and methyl piperidine-4-carboxylate (0.14 g, 1.0 mmol) and K2CO3 (0.27 g, 2.0 mmol) was added i-PrOH (2 mL) and water (0.5 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (0.12 g, 0.27 mmol, 27% yield) as white solid. ESI-MS (M+1): 448 calc. for C25H29N5O3 447.