Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: N#CC1CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 119.3 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (300 mg, 1.3 mmol) and azetidine-3-carbonitrile hydrochloride (231 mg, 1.95 mmol). DMF (6 ml) was added followed by N,N-diisopropylethylamine (0.68 ml, 3.9 mmol) and HATU (543 mg, 1.43 mmol). The light yellow solution was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 458 mg of [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:29]2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)c1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2F)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(4-hydroxyphenyl)ethanone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 559.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:12].C([Li])CCC.[CH3:18][C:19]([CH3:21])=[O:20].O>O1CCCC1>[F:12][C:6]1[CH:7]=[C:8]([C:19]([OH:20])([CH3:21])[CH3:18])[CH:9]=[CH:10][C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: COC=Cc1ccc(Br)cc1F
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of compound 2-(4-bromo-2-fluorophenyl)vinyl methyl ether (115.5 g, 0.5 mol) in tetrahydrofuran (666 mL) at −78° C. was added n-butyllithium (240 mL of 2.5M in hexanes, 0.6 mol), and the resulting mixture was stirred at −78° C. for 1 hour. A solution of acetone (37.7 g, 0.65 mol) in tetrahydrofuran (280 mL) was added dropwise to the reaction mixture. Then the reaction solution was slowly warmed to 0° C., stirred for 30 minutes, and then at room temperature for 30 minutes. Water (300 mL) was added to quench the reaction. The biphasic mixture was extracted with ethyl acetate (2×). The combined organics were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13]>>[NH2:13][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: N
Product: Nc1ncc(C(F)(F)F)cc1Cl
Reaction time: 5 h

Procedure:
6.5 g of 2,3-dichloro-5-trifluoromethylpyridine and 20 ml of 28% aqueous ammonia were placed in a 50 ml autoclave, and the mixture was reacted for 24 hours at 100° C., and further for 5 hours at 125° C. (inner pressure: about 2 atms.). After completion of the reaction, the reaction product was allowed to cool to obtain crystals. The thus obtained crystals were then washed with water and dried to obtain 1.5 g of 2-amino-3-chloro-5-trifluoromethylpyridine having a melting point of 90° to 92° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11]1([OH:17])C=CC=C[CH:12]=1>>[CH3:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1)=[O:17]
Reactant: Oc1ccccc1
Reactant: CC(=O)Oc1ccccc1
Product: CC(=O)c1ccc(O)cc1

Procedure:
4-Acetoxyacetanilide is produced by subjecting phenyl acetate to a Fries rearrangement or phenol and an acetylating agent to a Friedel-Crafts acetylation to form 4-hydroxyacetophenone which is then reacted with hydroxylamine or a hydroxylamine salt to form 4-hydroxyacetophenone oxime. The oxime is then subjected to a Beckmann rearrangement and accompanying acetylation with acetic anhydride to form the 4-acetoxyacetanilide.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:23][CH2:24][CH2:25][OH:26])(=[O:22])[CH3:21]>C(OCC)C.B(F)(F)F.CCOCC>[C:20]([O:23][CH2:24][CH2:25][O:26][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:22])[CH3:21]
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCO
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.95 g (31.3 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 20 ml of diethyl ether under N2 and cooled to 0° C., and 5.87 ml (31.3 mmol) of 2-hydroxyethyl acetate (50% strength) and 3 drops of BF3.Et2O were added. After removal of the ice bath, the mixture was stirred at RT for 2 h.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][OH:20].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: OCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 1 g (4.76 mM) of [5-(3-thienyl)tetrazol-1-yl]acetic acid and 590 mg (5.71 mM) of 1,5-pentanediol in 10 ml of N,N-dimethylformamide was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=60/0) for separation and purification, to give 670 mg (yield 47.5%) of [5-(3-thienyl)tetrazol-1-yl]acetic acid 5-hydroxypentyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23](O)=[O:24])([O-:20])=[O:19].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[N+:18]([C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH:15][C:12]1[CH:13]=[N:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[N:10][CH:11]=1)=[O:24])([O-:20])=[O:19]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To 2-(3-(trifluoromethyl)phenyl)pyrimidin-5-amine (750 mg, 3.14 mmol, 1.00 equiv) in dichloromethane (50 mL) was added 2-nitro-5-(piperidin-1-yl)benzoic acid (1.18 g, 4.72 mmol, 1.50 equiv), EDC.HCl (1.2 g, 6.28 mmol, 2.00 equiv) and 4-dimethylaminopyridine (770 mg, 6.31 mmol, 2.00 equiv) and the resulting solution was stirred for 48 h at room temperature. The reaction was diluted with 25 mL of water and then extracted with 2×25 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, concentrated, and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30˜1:5) to give 0.4 g (27%) of product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]2[CH:3]=1.[CH2:21]([N:23]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)[S:24]([CH3:27])(=[O:26])=[O:25])[CH3:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:21]([N:23]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)[S:24]([CH3:27])(=[O:25])=[O:26])[CH3:22]
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(C)C)cn23)n[nH]1
Reactant: CCN(c1cccc(B(O)O)c1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCN(c1cccc(-c2cc3nc(C(C)C)cn3c(Nc3cc(C)[nH]n3)n2)c1)S(C)(=O)=O

Procedure:
7-chloro-2-isopropyl-N-(5-methyl-1H-pyrazol-3-yl)imidazo[1,2-c]pyrimidin-5-amine (0.17 mmol, 0.05 g), 3-(N-ethylmethylsulfonamido)phenylboronic acid (0.35 mmol) and (Ph3)4Pd (O) (0.086 mmol, 0.1 g) were stirred in dioxane (3 mL) and sat. K2CO3 (1.5 mL) The reaction mixture was heated to 150° C. using a microwave reactor for 20 minutes. The mixture was then concentrated and purified by LC-MS to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.07 Hz, 3H) 1.35 (d, J=6.82 Hz, 6H) 2.29 (s, 3H) 3.04 (s, 3H) 3.76 (q, J=7.07 Hz, 2H) 6.70 (s, 1H) 7.57 (s, 1H) 7.59-7.67 (m, 2H) 8.11 (d, J=7.58 Hz, 1H) 8.17 (s, 1H) 8.45 (s, 1H) 10.80 (s, 1H) 12.35 (s, 1H); ESI-MS: m/z calc'd for C22H27N7O2S 453.56; found 454.4 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:54]1[C:59](=[O:60])[CH2:58][CH2:57][C:55]1=[O:56])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[O:56]=[C:55]1[CH2:57][CH2:58][C:59](=[O:60])[N:54]1[O:11][C:10](=[O:12])[C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:13]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:40]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
5-(15-tert-Butoxycarbonyl-pentadecanoylamino)-isophthalic acid mono-tert-butyl ester (140 mg, 0.25 mmol) was dissolved in dry THF (3.5 ml). TSTU (95 mg, 0.30 mmol) and DIPEA (70 ul, 0.30 mmol) were added. The mixture was stirred at RT under nitrogen over the week-end. The reaction mixture was almost dry. EtOAc was added and the precipitate was removed by filtration. The filtrate was extracted with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give the title compound as a syrup containing a trace of an impurity in a quantitative yield (0.165 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>ClCCl>[CH3:31][N:32]([CH3:36])[C:33]([NH:23][CH2:22][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)=[O:34]
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.63 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (9 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (69 μL, 0.754 mmol) in anhydrous dichloromethane (1 mL). After stirring for 3 h at 0° C., the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5 to 90:10) to give the title compound (80 mg, 32%). 1H NMR (400 MHz, CDCl3) δ7.13 (d, 2H), 6.86 (d, 2H), 3.98 (t, 2H), 3.84 (t, 1H), 3.74 (m, 2H), 3.52 (m, 2H), 3.36 (d, 2H), 2.69 (s, 6H), 2.65 (m, 2H), 2.57 (m, 4H), 2.02-1.95 (m, 4H), 1.84-1.78 (m, 6H).
Reaction SMILES: [OH:1][C@:2]1([CH3:25])[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:23])[CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br.O>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:24])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:23])[CH2:16]2)[C@:19]2([CH3:22])[C@H:4]([CH2:3][C@@:2]([OH:1])([CH3:25])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C1

Procedure:
A stirred solution of 3α-hydroxy-3β-methyl-5α-pregnane-11,20-dione (5.0 g., 15.0 mmole) in methanol (300 ml.) was treated with a solution of bromine (1.0 ml.) in methanol (30 ml.) at 0° and at such a rate that the yellow colour of the solution disappeared before further addition of the bromine solution took place. The mixture was then poured into water, the precipitated title compound (2.8 g.) was collected by filtration and dried over P2O5 in vacuo.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1.Cl.O>C(O)C>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1
Reactant: COCOCc1ccc(-c2nccs2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: OCc1ccc(-c2nccs2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis (triphenylphosphine) palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:11]([N:6]1[CH2:7][CH:8]([N:23]([CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([Br:18])[CH:20]=2)[CH3:24])[CH2:9][CH:5]1[C:3]([OH:2])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: CNCc1cccc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(Cc1cccc(Br)c1)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a solution of 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (1 mmol), (3-bromo-benzyl)-methyl-amine (1 mmol) in 2 mL of CH2Cl2 were added NaBH(OAc)3 (2 mmol) and 5 drops of AcOH, and the resulting mixture was stirred for 3 h. The mixture was treated with aq. NaHCO3, extracted by CH2Cl2 (3×5 mL), and the combined extracts were washed by brine (10 mL), dried over Na2SO4, and concentrated to give 261.3 mg of crude product in 65% yield.
Reaction SMILES: [CH3:1]O.CO.C[O-].[Na+].[OH:8][C@H:9]([C@H:24]1[CH2:28][O:27]C(=O)[O:25]1)[C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1>C1(C)C=CC=CC=1>[OH:25][C@H:24]([CH2:28][OH:27])[C@H:9]([C@H:10]1[C@H:15]2[N:16]=[C:17]([CH3:19])[O:18][C@@H:14]2[CH:13]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[O:11]1)[O:8][CH3:1]
Reactant: CO
Reactant: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](O)[C@H]2COC(=O)O2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1=C[C@H]2OC(C)=N[C@@H]2[C@H]([C@H](OC)[C@H](O)CO)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanol (460 ml) and a 25.4% sodium methoxide methanol solution (14.36 g) were added to a toluene solution (approximately 675 ml) of a compound, which was obtained by subjecting methyl (3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate (46.00 g) to Step A-5 of Example 1, at room temperature, and the mixture was stirred for 30 minutes at the same temperature. The solvent of the reaction solution was distilled off under reduced pressure until the amount of solution became approximately 138 ml, methanol (460 ml) was added, and the reaction solution was stirred for 30 minutes at room temperature. After acetic acid (4.41 g) was added to the reaction solution and the solvent was distilled off under reduced pressure until the amount of solution became approximately 138 ml, toluene (230 ml) was added to the reaction solution and then the solvent was distilled off again under reduced pressure until the amount of solution became 138 ml to give a toluene suspension of the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14](Cl)=[CH:15][CH:16]=1.Cl>CS(C)=O.O>[CH2:3]([S:9][C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14]([S:9][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: CCCCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCSc1ccc(SCCCCCC)c(C(=O)O)n1
Temperature: 135 °C
Yield: 75.4 %

Procedure:
To 300 ml of DMSO was added 84.5 g of powdered NaOH with vigorous stirring followed by the addition of 150 g of n-hexyl mercaptan. The anion of the mercaptan was allowed to form and then 111 g of 3,6-dichloro-2-pyridinecarboxylic acid in 110 ml of DMSO was added through a dropping funnel. The temperature was increased during addition to 135° C. and maintained at that temperature for 21/2 hours. Upon cooling the brown solution was poured into three volumes of water. The resulting solution was acidified with HCl and extracted with 1,1,1-trichloroethane. The organic layer was dried over MgSO4 and the solvent removed on a rotary evaporator. The reaction yielded 155 g (68% yield) of 3,6-bis(n-hexylthio)-2-pyridinecarboxylic acid as a dark oil which solidified on standing; m.p. 40°-42° C.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:45]([S:52][CH:53]([CH:56]([O:59][CH3:60])[O:57][CH3:58])[CH2:54][NH2:55])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([S:52][CH:53]([CH:56]([O:57][CH3:58])[O:59][CH3:60])[CH2:54][NH:55][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
To a solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.662 g) in N,N-dimethylformamide (20 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.414 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.292 g) and 2-(benzylthio)-3,3-dimethoxypropan-1-amine (0.500 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-60:40) to give the title compound (0.776 g, yield 70%) as a colorless amorphous solid.