Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=O)C.[CH2:16]([CH2:18][NH2:19])[OH:17].CN.Cl>O.C(Cl)Cl>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]([NH:19][CH2:18][CH2:16][OH:17])=[O:12])=[CH:14][CH:15]=1
Reactant: NCCO
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Agent: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccc(O)cc1)NCCO
Temperature: 40 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
43.6 g (194 mmol) of p-acetoxycinnamoyl chloride was added to 200 ml of methylene chloride and heated at 40° C. to make a homogeneous solution. The solution was cooled down to 15°-20° C., into which 35.5 g (582 mmol) of monoethanolamine was dropped. Since the system generated heat during the dropping, it was cooled and the dropping rate was so controlled that the liquid temperature was maintained at 15°-20° C. After completion of the dropping, the system was stirred at room temperature for 1 hour, and was then heated under reflux and stirred for further 1 hour to complete the reaction. After distillation of the methylene chloride under reduced pressure, 50 ml of ethanol was added so as to obtain a substantially homogeneous solution. Thereafter, 30.1 g (388 mmol) of a 40% methylamine aqueous solution was added to the system at one time, followed by heating to 40°-50° C. and stirring for 1 hour. The reaction solution was poured into 800 ml of water, to which a 12% hydrochloric acid aqueous solution was added to a pH of about 3. The resultant crystals were filtered off and recrystallized from acetone to obtain 24.9 g of p-hydroxy-N-(2-hydroxyethyl)cinnamamide as colorless or slightly yellow crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>O>[N:21]([C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+:22]=[N-:23]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(N=[N+]=[N-])cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A mixture of 5.0 g (0.0155 mol) of product of Example 19, 1.0 g (0.0154 mol) of sodium azide and 20 ml of DMF was stirred for 1 hour and poured into 100 ml of water. The organic was extracted into 100 ml of CH2Cl2 which was washed with 50 ml of water and concentrated. The residue (6.0 g) was dissolved in 50 ml of petroleum ether then washed with 50 ml of water twice, dried (MgSO4) and concentrated to give a solid which was recrystallized from petroluem ether at low temperature to give 4.2 g (82%) of product as a light yellow solid; mp 63°-64.5° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.Cl>C(O)C>[ClH:12].[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:11])=[CH:5][CH:6]=3)=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Product: CNC(=O)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
A mixture of 0.1 mole of N-methyl-p-aminobenzamide, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 10 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is stirred at about 25° C. for 30 minutes. A precipitate begins to form, and the mixture is then heated at reflux for 4 hours. The mixture is cooled and filtered to obtain p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].C(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>O>[Cl:13][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2ccccc2c1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1nccc2ccccc12
Reaction time: 3 h
Yield: 44.9 %

Procedure:
69.3 g (448 mmol) of isoquinoline N-oxide (made by Tokyo Kasei) and 225 ml of chloroform were placed and dissolved in a 1 liter-three-necked flask, and under stirring and cooling with ice, 219.6 g (1432 mmol) of phosphorus oxychloride was gradually added dropwise thereto while the internal temperature was held at 15-20° C. Thereafter, the temperature was raised, and reflux under stirring was performed for 3 hours. The reaction product was cooled by standing to room temperature and poured into iced water. After extraction with ethyl acetate, the organic layer washed with water until neutrality, and the solvent was removed under a reduced pressure to provide a dry solid, which was then purified by silica gel column chromatography (eluent: chloroform/hexane=5/1) to obtain 35-5 g (yield: 44.9%) of 1-chloroisoquinoline white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][NH:21][CH3:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([N:21]([CH3:22])[CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with dimethylamine in ethanol gives 4-(3-bromoanilino)-6-dimethylaminopyrido[3,4-d]pyrimidine. 1H NMR (DMSO) δ 9.71 (1H, s), 8.83 (1H, s), 8.43 (1H, s), 8.21 (1H, brs), 7.94 (1H, brd, J=7.5 Hz), 7.42-7.29 (2H, m), 7.26 (1H, s), 3.17 (6H, s).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].N12CCN(CC1)CC2.Cl>C(OCC)(=O)C.O>[CH3:14][O:13][C:9](=[O:12])[C:10](=[CH2:11])[CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccccc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C(=O)OC)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 119 h

Procedure:
A mixture of benzaldehyde (63.67 g; 600 mmol), methyl acrylate (60 ml; 667 mmol) and 1,4-diazabicyclo[2.2.2]octane (13.46 g; 120 mmol) is stirred at ambient temperature for 119 hours. To the reaction solution is added water (60 ml), 37 % hydrochloric acid (60 ml) and ethyl acetate (120 ml), and then, the organic phase is extracted. The resulting organic phase is washed twice with saturated saline (60 ml), dried over anhydrous sodium sulfate and filtered, then concentrated under reduced pressure, to give a crude product of the title compound at a yield of 108.8 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Br:18][C:19]1[CH:31]=[CH:30][C:22]2[NH:23][C:24]([C@@H:26]([NH:29][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][OH:28])=[N:25][C:21]=2[CH:20]=1
Reactant: N[C@@H](CO)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](CO)c2nc3cc(Br)ccc3[nH]2)ccc1N1CCOCC1=O

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-hydroxy-ethylamine, TBTU and NMM in DMF with subsequent purification by preparative HPLC.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH2:13]CC1C=CC=CN=1>>[C:3]([NH2:13])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)C(Cl)(Cl)Cl
Reactant: NCc1ccccn1
Product: NC(=O)c1ccccc1

Procedure:
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-α,α-dichloroacetophenone as an intermediate by chlorinating the α-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60° C. The α,α-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100° C. to yield the α,α,α-trichloroacetophenone. The (α,α,α-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([O:32]C)=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([OH:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of compound 48 (0.514 g, 1.17 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was treated with 4 M NaOH (5 mL). The reaction mixture was refluxed for 1 h, cooled to rt, and concentrated on a rotary evaporator. The residue was dissolved in a small amount of water and made acidic with concentrated hydrochloric acid. The solid precipitate was filtered, washed with water, and dried to afford 49 as a white solid (0.52 g, 100%). ESI-MS m/e 427.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C[C:22]([N:24](C)C)=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.[C-]#N.[Zn+2].[C-]#N>[CH3:9][O:8][C:5]1[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=2[C:2]([C:22]#[N:24])=[CH:7][N:6]=1
Reactant: CC(=O)N(C)C
Reactant: COc1ncc(Br)c2ccn(COCC[Si](C)(C)C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2ccn(COCC[Si](C)(C)C)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (1.80 g) in DMA (20.15 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.58 g) and zinc cyanide (0.88 g) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.51 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH:8]([NH2:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.CN(C)N1C=CC=CC1.[CH2:35]([O:42][C:43]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:44]=1[S:52](Cl)(=[O:54])=[O:53])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[CH2:7][C@H:8]([NH:16][S:52]([C:44]1[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:43]=1[O:42][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:53])=[O:54])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(OCC)C(N)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Agent: CCN1CCOCC1
Agent: CN(C)N1C=CC=CC1
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A mixture of 7.69 g (31 mmol) 3-amino-4,4-diethoxy-butyric acid tert-butyl ester, 4.2 mL (33 mmol) N-ethylmorpholine, 0.37 g (3 mmol) N N-dimethylaminopyridine was stirred in 75 mL dichloromethane and cooled to 0° C. in an ice/water bath. 10.1 g (31 mmol) of % 2-benzyloxy-4-nitro-benzenesulfonyl chloride was added in one portion and the resulting mixture was stirred at room temperature 18 h. TLC analysis indicated complete reaction. The reaction mixture was transferred to a separatory funnel and washed with water and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a pale yellow oil. The oil was purified over silica eluting with 1:1 ethyl acetate:hexanes to give 11.7 g (21.7 mmol, 70%) (S)-3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a pale yellow oil. MS (APCI) m/z 538.1 (M−1).
Reaction SMILES: [F:1]C1C(N)=NC(=O)NC=1.FC1C=CC(B(O)O)=CC=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[C:44]([F:1])=[CH:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: Nc1nc(=O)[nH]cc1F
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Agent: OB(O)c1ccc(F)cc1
Product: O=c1n(-c2ccc(F)cc2)cc(F)c2nc(CCl)cn12

Procedure:
2-Chloromethyl-8-fluoro-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 5-fluorocytosine and 4-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: BrCC1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].Cl.[C:18]([O:22][C:23](=[O:32])[C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:25][CH2:26][CH3:27])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:6]([C:5]1[CH:4]=[C:27]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:26][NH:25][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:32])#[N:7]
Reactant: N#Cc1cc(F)cc(CBr)c1
Reactant: CCN[C@H](CC(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1.O.CN([CH:24]=[O:25])C>>[Cl:6][C:7]1[C:12]([CH:24]=[O:25])=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1
Reactant: CC1CCCCN1c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Phosphoryl chloride (1.62 mL) was added dropwise to DMF (5 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 2-chloro-6-(2-methylpiperidin-1-yl)pyrazine (1.85 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 16 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.18 g, 57%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])[CH3:17].CNC>>[CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]([OH:9])([CH2:17][C:16](=[O:18])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(=O)c2ccccc21
Reactant: CC(=O)c1ccccn1
Agent: CNC
Product: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a clean dry flask equipped with a stir bar was added the N-butyl isatin (0.4 grams, 1.97 mmol, 0.3 M in Methanol). 2-acetyl pyridine (0.44 mL, 3.94 mmol, purchased from Fisher Scientific) was then added to the stirring solution followed by 49 μL of dimethyl amine (40% by weight in water, purchased from Fisher Scientific). The stirring solution was stirred overnight at room temperature. The next day the solution was heated to 60° C. for 5 minutes. The solution was then concentrated and purified on a silica gel column using hexanes/ethyl acetate (2:1) to afford 0.513 grams, 80% yield. 1H-NMR δ 8.69 (d, 1H), 8.14 (d, 1H), 7.92 (t, 1H), 7.56 (m, 1H) 7.30 (m, 2H), 7.06 (t, 1H), 6.87 (d, 2H), 3.81 (d, 1H), 3.69 (m, 2H), 3.52 (d, 1H), 1.71 (m, 2H), 1.43 (m, 2H), 0.97 (t, 3H). Calculated mass for C19H20N2O3, 324.37. Observed 325.0 (M+1), 347.2 (M+Na).
Reaction SMILES: B.CSC.[OH:5][C@H:6]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:7][NH:8][C:9]([C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([I:21])[CH:17]=2)[O:12]1)=O>O1CCCC1>[I:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[O:12][C@@H:11]([CH2:9][NH:8][CH2:7][C@@H:6]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[OH:5])[CH2:20][CH2:19]2
Reactant: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: O[C@@H](CNC[C@H]1CCc2cc(I)ccc2O1)c1cccnc1
Temperature: 0 °C

Procedure:
Borane-dimethylsulfide complex (2.0 M in tetrahydrofuran, 46 mL, 92 mmol) was added dropwise (20 minutes) to a cooled (0° C.) and stirred solution of (2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide (Example 35, Method A, 7.75 g, 18.3 mmol) in tetrahydrofuran (300 mL). The solution was warmed to reflux for 1 hour and then cooled to room temperature. The reaction was quenched with addition of methanol (12 mL) and 2 M hydrochloric acid (95 mL), and then the resulting solution was heated at reflux for 1 hour. The reaction was cooled to room temperature and then the solution was adjusted to pH 9 using 1 M aqueous sodium hydroxide. The mixture was diluted with brine (500 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 30-50% ethyl acetate/hexane afforded product (6.32 g, 84%) as a waxy yellow solid: 1H NMR (acetone-d6, δ): 8.59 (d, J=1.9 Hz, 1 H), 8.44 (dd, J=5.0, 1.5 Hz, 1 H), 7.77 (ddd, J=8.0, 1.8, 1.8 Hz, 1 H), 7.25-7.39 (m, 3 H), 6.56 (d, J=8.4 Hz, 1 H), 4.80 (dd, J=8.4, 4.0 Hz, 1 H), 4.08-4.18 (m, 1 H), 2.67-3.00 (m, 10 H), 1.67-1.82 (m, 1 H); mass spectroscopy gave m/z=410.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[N:3]=1.Cl[CH2:13][CH:14]=O>C(O)C.O>[Br:1][C:2]1[N:3]=[C:4]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: NC(=S)Nc1cccc(Br)n1
Solvent: CCO
Solvent: O
Product: Brc1cccc(Nc2nccs2)n1
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
A suspension of 2-bromo-6-thioureidopyridine (3 g, 12.92 mmol) and chloroacetaldehyde (3.28 mL, 25.85 mmol) in ethanol (27 mL) and water (7 mL) was heated at reflux for 4.75 h. The solution was concentrated in vacuo and the residue was diluted with 1 N aqueous NaOH solution at 0° C., stirred for 10 min, and the pH was then adjusted to 8.5 by addition of 6 N aqueous HCl solution. The precipitate was collected by filtration, washed several times with water and dried in vacuo over P2O5 to obtain the titled compound (3.17 g, 96%) as a light yellow solid.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:8]([C:10]2[CH:11]=[C:12]([Cl:32])[C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:20]([O:22]C)=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1>O.C1COCC1>[N:4]1([C:8]([C:10]2[CH:11]=[C:12]([Cl:32])[C:13]([O:16][C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:31])[CH2:29][OH:30])[CH:26]=3)[C:20]([OH:22])=[O:21])=[N:14][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(O[C@@H](C)CO)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Lithium hydroxide monohydrate (529 mg, 12.59 mmol) in water (25 mL) was added to a solution of methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoate (5.3 g, 12.6 mmol) in THF (50 mL) and stirred at RT for 3 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL), and the organics washed with brine, dried (MgSO4), and concentrated in vacuo to give the desired compound as a white foam (3.74 g).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C:5](=[O:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>P([O-])([O-])([O-])=O>[Cl:1][CH2:2][C@@H:3]([OH:15])[CH2:4][C@@H:5]([OH:14])[CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Large-sized test tubes were charged with 7 mL of said medium B and, after sterilization, inoculated with the bacteria shown in Table 2, respectively. Then, aerobic shake culture was carried out at 30° C. for 1 day. From the resulting culture broth, the cells were harvested by centrifugation and suspended in 0.5 mL of 50 mM phosphate buffer (pH 6.5) containing 0.5% of tert-butyl (5S)-6-chloro-5-hydroxy-3-oxohexanoate and 1.5% of glucose. The suspension was placed in a 10 mL test tube equipped with a stopper and the reaction was carried out under shaking at 30° C. for 20 hours. After completion of the reaction, the reaction mixture was extracted with 0.5 mL of ethyl acetate and the ethyl acetate phase was analyzed by high performance liquid chromatography (column: Nakalai-Tesque's Cosmocil 5CN-R (4.6 mm×250 mm), eluent: 1 mM phosphoric acid/H2O:acetonitrile=5:1, flow rate: 0.7 mL/min., detection: at 210 nm, column temperature: 30° C.) for reaction rate and for the diastereomer ratio of the product tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate. The results are shown in Table 2.