Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1[C:6]2[CH:7]=[C:8]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[H-].[Na+].[H][H].BrCC(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:13]1([CH:11]([C:8]2[CH:9]=[CH:10][C:5]3[NH:4][N:3]=[N:2][C:6]=3[CH:7]=2)[OH:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC(c1ccccc1)c1ccc2nnn(O)c2c1
Reactant: [H][H]
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CS(C)=O
Product: OC(c1ccccc1)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a stirred solution of 5.2 parts of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol in 30 parts of dimethyl sulfoxide were added 0.96 parts of a sodium hydride dispersion 50%. The reaction mixture was stirred till no more hydrogen escapted. After the addition of 3.34 parts of ethyl 2-bromoacetate, the whole was stirred for 30 minutes at room temperature. 1.38 Parts of potassium carbonate were added and stirring was continued for 3 hours at 50° C. The dimethyl sulfoxide layer was evaporated and the residue was taken up in water and 20 parts of a hydrochloric acid solution 1N. The product was extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract was dried, filtered and concentrated. The concentrate was crystallized from 32.5 parts of dichloromethane. The product was filtered off and dried, yielding 3.1 parts (68.8%) of α-phenyl-1H-benzotriazole-5-methanol; mp. 143.0° C. (int. 70).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[F:29][C:30]([F:42])([F:41])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:34])[C:32]#[CH:33].CN(C=O)C>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.[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:33]#[C:32][C:31]([OH:34])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([F:29])([F:41])[F:42])[N:5]=2
Reactant: C#CC(O)(c1ccccc1)C(F)(F)F
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(C#CC(O)(c3ccccc3)C(F)(F)F)nc21
Yield: 27.1 %

Procedure:
Same procedure as that described in example 5, stage 5.4, starting from 0.4 g (0.95 mmol) of 2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one, 0.4 g (1.9 mmol) 1,1,1-trifluoro-2-phenyl-but-3-yn-2-ol, 33 mg (0.05 mmol), bis(triphenylphosphine)palladium(II) dichloride, 18 mg (0.1 mmol) copper (I) iodide, 3 ml DMF (degassed), 3 ml triethylamine (degassed). 0.15 g of the title compound is obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Tert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give 3-(aminomethyl)-6-(benzyloxy)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone hydrochloride (0.11 g, 84.6%) as crystals.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31](=[O:43])[NH:32][C@H:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34][OH:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31](=[O:43])[NH:32][C@H:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:34]=[O:35])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(N[C@@H](CO)Cc1ccccc1)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Dess-Martin periodinane (849 mg) was added to a dichloromethane (20 ml) solution containing benzyl((2R)-1-hydroxy-3-phenylpropan-2-yl)carbamate (571 mg), followed by stirring at room temperature for 3 hours and 30 minutes. Insoluble matter was removed by filtration, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 2:1), and a white solid of benzyl((2R)-1-oxo-3-phenylpropan-2-yl)carbamate (501 mg) was thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][N:2]([CH3:24])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1C=Cc2ccccc2C1c1ccc(N(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccccc2C1c1ccc(N(C)C)cc1

Procedure:
A solution of ethyl 1-(4-(dimethylamino)phenyl)isoquinoline-2(1H)-carboxylate (79 mg, 0.24 mmol) in EtOH (4 mL) was stirred with 10% Pd/C (0.062 g, 0.58 mmol) under hydrogen atmosphere at RT for 14 h. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to provide the title compound as a clear oil. MS (ESI pos. ion) m/z: 325 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](/[CH:10]=[C:11](\[C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)/[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(/C=C(/C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Yield: 81.5 %

Procedure:
To 5-[(E)-2-(4-tert-Butyl-phenyl)-2-carboxy-vinyl]-thiophene-2-carboxylic acid methyl ester (600 mg, 1.7 mmol) in 50 ml THF and 10 ml 1 NHCl was added 10% palladium on carbon (1.5 g). The resulting mixture was stirred under 50 psi hydrogen gas for 2 hours. The catalyst was filtered off and the solvent was evaporated. The residue was sonicated in hexane for 30 seconds. The solvent was filtered to afford 5-[2-(4-tert-Butyl-phenyl)-2-carboxy-ethyl]-thiophene-2-carboxylic acid methyl ester as a yellow solid (480 mg, 81%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].N[C@H:11](C(O)=O)[C@@H:12](CC)C>>[CH2:11]([O:4][C:3](=[O:5])[C:2](=[O:1])[C@H:6]([CH3:9])[CH2:7][CH3:8])[CH3:12]
Reactant: CC[C@@H](C)[C@H](N)C(=O)O
Reactant: CC[C@@H](C)[C@H](O)C(=O)O
Product: CCOC(=O)C(=O)[C@H](C)CC
Yield: 93 %

Procedure:
The synthesis was carried out in three steps, according to the following scheme: ##STR8## 2.1. Synthesis of (+)-(2S, 3R)-2-hydroxy-3-methylpentanoic acid [6]This compound was synthesised from (+)-L-allo isoleucine [5] ([α]D20 =+37° (5% in 6M HCl)) as described in 1.1. (yield: 93%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][OH:31])=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:37])=[CH:34][CH:35]=[N:36][C:19]2=3)[CH2:17][CH2:16]1.O[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=[CH:41][CH:40]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][O:31][C:39]4[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:42]=[CH:41][CH:40]=4)=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:37])=[CH:34][CH:35]=[N:36][C:19]2=3)[CH2:17][CH2:16]1
Reactant: Oc1ccnc2ccccc12
Reactant: Cc1ccnc2c1NC(=O)c1cc(CCO)cnc1N2C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccnc2c1NC(=O)c1cc(CCOc3ccnc4ccccc34)cnc1N2C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
Diisopropyl azodicarboxylate (DIAD) (167 μL, 0.85 mmol) was added drop-wise to a solution of 11-(cyclopropyl)-5,11-dihydro-8-(2-hydroxyethyl)-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (175 mg, 0.57 mmol), 4-hydroxyquinoline (123 mg, 0.85 mmol) and Ph3P (223 mg, 0.85 mmol) in THF (2.8 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and the solution was successively washed with 3 N aqueous NaOH (3×20 mL), aqueous saturated NH4Cl (20 mL) and brine (20 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH; 95:5) to give the title compound (74 mg, 30% yield) as a white solid: MS (ESI) m/z 438 (MH)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=O)[S:8][C:9]=1[N+:10]([O-:12])=[O:11].N1C=CC=CC=1>CCO>[Br:4][C:5]1[CH:6]=[C:7]([CH:13]=[N:2][OH:3])[S:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: NO
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=[N+]([O-])c1sc(C=NO)cc1Br
Temperature: 25 °C
Yield: 88 %

Procedure:
Hydroxylamine hydrochloride (85 g, 1.2 mol) was added to a solution of 4-bromo-5-nitro-thiophene-2-carbaldehyde (234 mg, 0.529 mmol, Example 286: step a) in EtOH (7.5 mL, 200 proof—anhydrous):pyridine (100 mL, anhydrous) at rt over 5 min. The reaction mixture was heated to reflux overnight, then cooled to rt. The solvents were removed in vacuo resulting in a solid residue that was washed with water and filtered. The solid was dried overnight under high vacuum to afford the title compound as a yellow solid (225 g, 88%). The solid was used for the next step without further characterization.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]1[C:17]([F:27])=[C:18]([CH:24]=[CH:25][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20].CC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[F:27][C:17]1[C:16]([CH2:15][O:13][C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:8][CH:9]=2)=[CH:26][CH:25]=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1cnc(N2CCOCC2)nc1
Reactant: CCOC(=O)c1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1cccc(COc2cnc(N3CCOCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-(Morpholin-4-yl)pyrimidin-5-ol (300 mg) and ethyl 3-(bromomethyl)-2-fluorobenzoate (850 mg) were mixed with MeCN (5 ml), THF (2 ml) and DMF (1 ml), and potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (378 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[O:29]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[C:39]3[CH:40]=[CH:41][C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:37][CH:38]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(cccc3-c3ccc(Oc4ccccc4)cc3)C2=O)cc1
Yield: 42 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-phenoxyphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (42%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2cccc(C(F)(F)F)c2)C1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 53.7 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]methanone (29 mg, 0.074 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 15 mg of the title compound.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:5]=1[CH:14]([CH3:16])[CH3:15].C([O-])(=O)C.[K+]>C(O)(=O)C.O.[O-]S([O-])=O.[Na+].[Na+]>[Br:1][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([F:3])[C:5]=1[CH:14]([CH3:16])[CH3:15]
Reactant: COc1ccc(C(C)C)c(F)c1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(C(C)C)c(F)c1OC
Reaction time: 8 h

Procedure:
Bromine (80.6 mg, 26 μL, 0.504 mmol) was added to a solution of 2-fluoro-1-isopropyl-3,4-dimethoxybenzene (50.0 mg, 0.252 mmol) and potassium acetate (49.5 mg, 0.504 mmol) in acetic acid (1 mL) at room temperature and the reaction was stirred overnight. The reaction was diluted with water (10 mL) and saturated Na2SO3 (10 mL), then extracted with EtOAc (3×20 mL). The combined extracts were washed with saturated NaHCO3 (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford 1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene. 1H NMR (600 MHz, CDCl3) δ 6.86 (d, J=2.0 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.43-3.34 (m, 1H), 1.31-1.29 (dd, J=7.1, 1.4 Hz, 6H).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[C:16]([CH3:27])=[N+:17]([O-])[CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:14][C:15]1[C:16]([CH2:27][OH:4])=[N:17][CH:18]=[C:19]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:20]=1
Reactant: Cc1c(Cl)cc(C2OCCO2)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1ncc(C2OCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
Trifluoroacetic anhydride (231 μl, 1.635 mmol) was added to a solution of 3-chloro-5-(1,3-dioxolan-2-yl)-2-methylpyridine 1-oxide (225 mg, 1.043 mmol) in DCM (4 ml) at 0° C. and the mixture was stirred at room temperature for 48 h. Full conversion was observed by HPLC. MeOH (0.5 ml, 12.36 mmol) was added and, after stirring for 10 min, DCM and 10% Na2CO3 solution were added. Extraction, drying (MgSO4), and filtration afforded 223.2 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded [3-chloro-5-(1,3-dioxolan-2-yl)-2-pyridinyl]methanol (142.7 mg, 63%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1.C(Cl)Cl>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]5[C:35]([CH3:39])=[N:36][N:37]([CH3:38])[C:33]=5[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (2.0 g, 4.77 mmol) in pyridine (30 mL) under argon at 25° C. was treated with 5-chloro-1,3-dimethyl-pyrazole-4-sulfonyl chloride (1.31 g, 5.72 mmol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then diluted with methylene chloride (500 mL) and washed with a 1.0N aqueous hydrochloric acid solution (3×100 mL). The combined water layers were extracted with methylene chloride (1×250 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was stirred in acetonitrile (25 mL) for 20 min and then placed in the freezer for 1 h. The solids were collected by filtration, washed with cold acetonitrile, and dried in vacuo to afford 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (2.53 g, 87%) as a yellow solid; FAB-HRMS m/e calculated for C28H27ClFN7O4S (M+H)+ 612.1596, found 612.1585.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]2[C:20](=[O:26])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:30]CC1.Cl.[Li+].[OH-]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH:22]([OH:21])[CH2:24][CH2:25][CH:19]2[C:20]([OH:30])=[O:26])(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCC(O)CN1S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a mixture of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (0.10 g, 0.26 mmol) and 2 mL of THF was added 0.2 mL of 1M aqueous HCl. After stirring for 10 min, 0.15 mL of 12M aqueous HCL was added. After stirring for 30 min, TLC indicated no detectable reaction. The mixture was then treated with 2 mL of saturated aqueous LiOH and 2 mL of methanol. After stirring for 20 min at room temperature, the mixture was acidified with 1M HCl, extracted 3× into ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, affording 1-(4-benzyloxy-benzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid (0.10 g) as a colorless syrup:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCOCCCl
Reactant: C1=COCCC1
Solvent: ClC(Cl)Cl
Product: ClCCOCCOC1CCCCO1
Temperature: 40 °C
Reaction time: 0.03 h
Yield: 101.2 %

Procedure:
In a drybox, 2-(2-chloroethoxy)ethanol (50.0 g, 0.401 moles) and 135 mL chloroform were added to a 500 mL 3-necked flask equipped with a stir bar, addition funnel and septum. 3,4-Dihydro-2H-pyran (39.7 g, 0.472 moles) in 35 mL chloroform was added dropwise over 30 min using an addition funnel. At the end of the addition, the flask was warm. The addition funnel was removed from the flask and replaced with a stopper, and the flask was transferred to the hood and placed under an atmosphere of nitrogen. Twelve drops of concentrated HCl were added dropwise via syringe. The septum was then replaced with a water condenser. The reaction was heated at 40° C. for 1 hr, and then allowed to cool to room temperature. The flask was opened to the air, 9 g of K2CO3 were added to the reaction mixture, and the mixture was stirred for two min before filtering. The solvent was removed via rotary evaporation, and the product was dried under vacuum for 8 hr at room temperature to give 84 g (0.406 moles) of 2[2-(2-chloroethoxy)ethoxyl]-tetrahydropyran.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]([O:9][CH2:10][Cl:11])=[O:8].N1C=CC=CC=1>C(OCC)C>[C:7](=[O:8])([O:9][CH2:10][Cl:11])[O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)OCCl
Reactant: CCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)OCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
A solution of butyl alcohol (50 mmol) and chloromethyl chloroformate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO4, filtered, and concentrated on a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+:31]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.N[C@H](C(O)=O)C.CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[OH-].[Na+]>>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH2:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: C[C@H](N)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)OC(=O)N1CCCCC1N

Procedure:
To a flask containing 0.6 g of a substrate N-Boc-3-piperidinone, 0.82 g of D-glucose, 4 mg of NAD+, 1.62 g of L-alanine, and 4.0 mg of pyridoxal phosphate, a culture fluid of the recombinant E. coli HB101 (pNTPSPAG), obtained in Example 10, which expresses TPS, PALDH, and GDH was added so that total volume was 30 ml. The resultant product was stirred at 30° C. for 20 hours while being adjusted to a pH of 6.8 by drippage of 5 N aqueous solution of sodium hydroxide. The amount of N-Boc-aminopiperidine produced and the optical purity thereof were measured according to the method described in Example 19. In the result, the amount produced was 0.54 g. The absolute configuration of N-Boc-aminopiperidine was (S), and the optical purity was 99.4% e.e.