Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([O:12][CH3:13])[C:8]([O:10]C)=[O:9].O>C1COCC1.CO>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([O:12][CH3:13])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)(OC)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(CCCCl)(C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81.5 %

Procedure:
A 4 N sodium hydroxide solution (0.2 mL) was added to a mixed solution of methyl 5-chloro-2-(4-fluorophenyl)-2-methoxyvalerate (141 mg) in THF (1 mL) and methanol (0.5 mL), and the reaction solution was stirred at room temperature for 3.5 hours. Methanol (0.5 mL) and a 4 N sodium hydroxide solution (0.1 mL) were added to the reaction solution, and the reaction solution was further stirred at room temperature for 1.5 hours. Water was added to the reaction solution which was then washed with diethyl ether. 1 N hydrochloric acid (1.4 mL) and ethyl acetate were added to the resulting aqueous layer, and the organic layer was separated. The resulting ethyl acetate layer was washed with brine and dried over anhydrous magnesium sulfate. The resulting ethyl acetate layer was concentrated under reduced pressure to obtain 109 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]=[C:6]2[NH:16][N:17]=[C:18]([I:19])[C:5]=12.Cl[CH2:21][C:22]([N:24]1[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]1)=[O:23].[Li+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[C:6]2[N:16]([CH2:21][C:22]([N:24]3[CH2:28][CH2:27][C@@H:26]([F:29])[CH2:25]3)=[O:23])[N:17]=[C:18]([I:19])[C:5]=12
Reactant: O=C(CCl)N1CC[C@@H](F)C1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(I)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.1 %

Procedure:
Sodium hydride (60% in mineral oil, 240 mg, 6 mmol) was added to a solution of 4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (1.06 g, 3 mmol) and 2-chloro-1-[(3R)-3-fluoropyrrolidin-1-yl]ethanone (740 mg, 4.5 mmol) in dry DMF (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. 4% LiCl aq. solution and ethyl acetate was added. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica gel, isohexane/ethyl acetate 1:0 to 3:7). The resulting solid was dissolved in minimum CH2Cl2 and diethyl ether was added until a solid precipitated. The solid was collected by filtration to provide Compound It as a solid (846 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S:16][CH3:17])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=O)C=1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH3:14])[CH:5]=[C:4]([CH2:15][S@@:16]([CH3:17])=[O:26])[N:3]=1
Reactant: CSCc1cc(N2CCOC[C@H]2C)nc(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1cc(C[S@@](C)=O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
(R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), to this was added mCPBA (7.96 g, 46.13 mmol) in one portion and the reaction mixture was stirred for 10 minutes at 25° C. An additional portion of mCPBA (0.180 g) was added. The reaction mixture was quenched with saturated Na2CO3 solution (50 ml) and extracted with DCM (3×50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was dissolved in DCM (80 ml) in a 150 ml conical flask which was placed into a beaker containing Et2O (200 ml) and the system covered with laboratory film and then left for 3 days. The obtained crystals were filtered, crushed and sonicated with Et2O. The crystallisation procedure was repeated to afford (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine as white needles (3.87 g, 29%); 1H NMR (400 MHz, CDCl3) 1.33 (3H, d), 2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H, s).
Reaction SMILES: [CH:1]1([N:4]([CH3:26])[C:5]2[N:25]=[C:8]3[CH:9]=[C:10]([NH:13][C:14]([C:16]4[N:20]([CH3:21])[N:19]=[CH:18][C:17]=4[C:22]([OH:24])=O)=[O:15])[CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:3][CH2:2]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:1]1([N:4]([CH3:26])[C:5]2[N:25]=[C:8]3[CH:9]=[C:10]([NH:13][C:14]([C:16]4[N:20]([CH3:21])[N:19]=[CH:18][C:17]=4[C:22]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:24])=[O:15])[CH:11]=[CH:12][N:7]3[N:6]=2)[CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: CN(c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1)C1CC1
Product: CN(c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1)C1CC1
Yield: 83.7 %

Procedure:
The product was prepared in the same manner as described in example 70f using 5-(2-(cyclopropyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 197 μmol) and azetidine (52.9 μl, 788 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(cyclopropyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (65 mg, 83.7%) as off-white solid. mp: 229.6, MS: m/z=395.0 (M+H+).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:39])[NH:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:26][C@H:25]2[CH3:38])=[O:23])=CC=1)([O-])=O.Cl.[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46].C(N(CC)CC)C>CO>[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH:46][C:11]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:26][C@H:25]1[CH3:38])=[O:23])=[O:39]
Reactant: COC(=O)CCN
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCNC(=O)Nc1cc(Cl)ccc1OCC(=O)N1CCN(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamic acid 4-nitro-phenyl ester (0.10 g, 0.18 mmol) in methanol was added β-alanine methyl ester hydrochloride (0.038 g, 0.27 mmol) and triethylamine (0.038 mL, 0.27 mmol). The reaction was stirred at ambient temperature overnight. The reaction was concentrated and purified via chromatography on silica gel to give the title compound (0.075 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[C:18]([CH3:24])[N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.C[Si](C)(C)N[Si](C)(C)C.C[N:35]([CH:37]=[O:38])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>[CH3:24][C:18]1[N:17]=[C:16]([C:10]2[N:11]=[C:12]3[N:8]([CH:9]=2)[CH2:7][CH2:6][O:5][C:4]2[C:13]3=[CH:14][CH:15]=[C:2]([C:37]([NH2:35])=[O:38])[CH:3]=2)[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(N)=O)cc2OCC3)n(C(C)C)n1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 12-bromo-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.0 g, 2.6 mmol), hexamethyldisilazane (3.0 mL, 14 mmol), and Pd(PPh3)2Cl2 (0.09 g, 0.13 mmol) in dry DMF (10 mL) was heated under CO atmosphere at 80° C. overnight. Most of the solvent was removed and water (20 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (1.3 g, 95% yield) as a gray solid. LCMS (ESI) m/z: 353.3 [M+H+].
Reaction SMILES: [CH2:1]([C:3]([C:7]1[C:8]2[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)=[CH:4][CH2:5][CH3:6])[CH3:2].C(C(C1C2C(C)=C(C)N(C3C(C)=CC(C)=CC=3C)C=2N=C(C)N=1)=CC)CC>C(OCC)(=O)C.[Pd]>[CH2:1]([CH:3]([C:7]1[C:8]2[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)[CH2:4][CH2:5][CH3:6])[CH3:2]
Reactant: CCC=C(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Agent: [Pd]
Agent: CC=C(CCC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Solvent: CCOC(C)=O
Product: CCCC(CC)c1nc(C)nc2c1c(C)c(C)n2-c1c(C)cc(C)cc1C
Reaction time: 15 h

Procedure:
A mixture of two isomers, 4-(1-ethyl-butenyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine and 4-(1-n-propyl-propenyl)-2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (67 mg, 0.185 mmol) in ethyl acetate (18 ml) and 10% Pd/C (38 mg) was hydrogenated at 50 psi for 15 hours. The mixture was filtered through Celite, a trademark for a commercially available diatomaceous earth filtering material. The filtrate was washed with brine, dried and concentrated to give 119 mg of oil. The oil was purified through silica gel column chromatography using 7% ethyl acetate in hexane as eluent to give 31 mg (46%) of the title compound as off-white crystals, mp 100-102° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+].OO>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]([NH2:15])=[O:30])=[C:12]([NH:19][C@H:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH2:21][OH:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 65 °C
Yield: 78.4 %

Procedure:
(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile (Example 6; 0.07 g, 0.2 mmol), was placed in MeOH (5 ml) at 25° C. A 25% aqueous solution (0.2 ml) of KOH (50 mg) was then added, followed by the addition of 0.05 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.065 g, 90%). 1H NMR (400 MHz, CD3OD) δ 7.69 (d, J=12.1 Hz, 1H), 7.39-7.36 (m, 2H), 7.04-7.00 (m, 2H), 5.94 (s, 1H), 5.22-5.16 (m, 1H), 3.87-3.75 (m, 2H), 1.91-1.84 (m, 1H), 0.98-0.96 (m, 2H), 0.74-0.69 (m, 2H). MS: Calcd.: 414. Found: [M+H]+ 415.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22]C)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCn2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (221 mg, 0.701 mmol) in MeOH (5 mL) was added 1N aqueous NaOH (2 mL, 2 mmol). The reaction was stirred for several hours at room temperature and treated with 1N aqueous HCl (2 mL, 2 mmol). The solvents were removed in vacuo to afford the title product. 1H NMR (400 MHz, CD3OD) δ 7.51-7.49 (m, 2H), 7.54-7.26 (m, 3H), 5.26 (s, 2H), 4.39-4.36 (t, 2H), 3.82-3.72 (t, 2H), 3.12 (s, 3H); ES MS (M+1)=302.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][O:12][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C=C/c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccccc1OCc1cccc(Oc2ccccc2)c1
Reaction time: 6 h

Procedure:
To a solution of 3-phenoxybenzylalcohol (545 mg; 2.72 mmol) in DMF (5 ml) was added NaH (92 mg; 3.1 mmol; 80% dispersion in oil) and ethyl(E)-3-(2-(bromomethyl)phenyl)-2-propenoate (810 mg; 3.0 mmol). After 6 h at r.t., 20 mg extra NaH was added. The final mixture was stirred at r.t. for 10 h then quenched using 0.3 ml of AcOH. The mixture was diluted with Et2O (25 ml), washed with water (3×20 ml) and brine, dried over MgSO4 and concentrated. Flash chromatography with EtOAc:toluene 5:95 afforded the desired material.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:15]([NH:14][CH2:12][CH3:13])=[O:16])=[N:7][C:6]=2[CH:11]=1
Reactant: Nc1nc2cc(Br)ccc2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)ccc2s1
Temperature: 79 °C
Yield: 50 %

Procedure:
To a suspension of 5-bromo-benzothiazol-2-ylamine IV (0.23 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added ethylisocyanate (0.36 g, 0.38 mL, 5.02 mmol). The reaction mixture was heated up to 78-80° C. overnight. After completion of reaction (TLC monitoring), 1,4-dioxane was distilled off and co evaporated with hexane. The resulting solid was treated with water to 60-70° C. for 3-5 h. The resulting solid was filtered off and again washed with hot water, dried under high vacuum to obtain the desired product as off-white solid (0.15 g, 50%). 1H NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.18 (m, 2H), 6.70 (br s, 1H), 7.36 (dd, J=1.60 and 8.0 Hz, 1H), 7.79 (d, J=1.60 Hz, 1H), 7.84 (d, J=8.40 Hz, 1H) and 10.85 (br s, 1H). MS: 300.07 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1.CN(C)C1C=CC=CC=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].Cl>O1CCCC1>[C:29]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: O=C(O)C=Cc1ccc(OCCCCCCO)cc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCCCCCOc1ccc(C=CC(=O)O)cc1
Reaction time: 4 h
Yield: 53.3 %

Procedure:
The resulting 4-(6-hydroxyhexyloxy)cinnamic acid (6 g, 0.023 mole) and N,N-dimethylaniline (6.6 g, 0.054 mole) were dissolved in tetrahydrofuran (50 mL), and to this mixture was further added dropwise a solution prepared by dissolving acryloyl chloride (4.4 g, 0.049 mole) in tetrahydrofuran (20 mL). After this addition, the mixture was stirred for 4 hours. Then, the reaction solution was poured into 10% hydrochloric acid, and deposited crystal was filtrated off. The resulting coarse crystal was dissolved in ethyl acetate (100 mL), and an organic layer was washed with saturated saline solution and dried over magnesium sulfate. The organic solvent was distilled off under reduced pressure, and then the coarse crystal was re-crystallized (n-hexane-ethyl acetate) to obtain 4-(6-acryloyloxyhexyloxy)cinnamic acid (3.9 g, 54%) in the form of a colorless crystalline powder.
Reaction SMILES: [CH:1]([C:3]1[N:10]2[C:6]([S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:5][C:4]=1[CH2:15][CH3:16])=[O:2].[BH4-].[Na+]>CO>[CH2:15]([C:4]1[N:5]=[C:6]2[N:10]([C:3]=1[CH2:1][OH:2])[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7]2)[CH3:16]
Reactant: CCc1nc2sc3ccccc3n2c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1nc2sc3ccccc3n2c1CO
Yield: 63.4 %

Procedure:
Furthermore, 3.88 g of 3-formyl-2-ethylimidazo[2,1-b]benzothiazole was suspended in 30 ml of methanol and 1.0 g of sodium borohydride was added to the suspension followed by refluxing for one hour. After completion of the reaction, the reaction solution was evaporated to dryness and the residue was washed with water. The crystals obtained were recrystallized from ethanol to give 2.48 g of the title compound.
Reaction SMILES: C(OC(N1CC(F)C[C@H]1C=C([C:16]1[CH2:22][C@H:21]2N([C:19](=O)[C@@H:20]2[C@H:23]([OH:25])C)[C:17]=1[C:27](OCC=C)=O)C)=O)C=C.N1CC[O:36]CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:20]([C:23]([OH:36])=[O:25])=[CH:21][CH2:22][CH2:16][CH2:17][CH3:27]
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2CC(F)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C1COCCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC=C(C)C(=O)O

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S)-1-allyloxycarbonyl-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.7 g), morpholine (694 μl), and triphenylphosphine (199 mg) in tetrahydrofuran (30 ml) and ethanol (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (263 mg) at room temperature. After stirring for an hour, the precipitate was filtered, washed in turn with dichloromethane (3 times) and acetone (twice), and dried under reduced pressure to give (5R,6S)-3-[2-{(2S)-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1hydroxyethyl]-7-oxo-1-azabicyclo 3.2.0]hept-2-ene-2carboxylic acid (248 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[OH:52][C:45]1[C:44]([CH2:43][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:12])=[C:2]([CH3:1])[CH:3]=2)=[C:49]([CH3:50])[CH:48]=[C:47]([CH3:51])[N:46]=1
Reactant: Cc1cc(C(=O)O)ccc1C(C)Oc1ccccc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(C)c2)c(O)n1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 3-methyl-4-(1-phenoxyethyl)benzoic acid (95 mg, 0.4 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 1 mmol), N-hydroxybenzotriazole (135 mg, 1 mmol), triethylamine (0.2 mL) and dichloromethane (5 mL) were stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methyl-4-(1-phenoxyethyl)benzamide as a white solid (100 mg, 51%). LRMS (M+H+) m/z: calcd. 390.19. found 390. 1H NMR (300 MHz, d6-DMSO): δ 11.47 (s, 1H), 8.23 (t, J=4.8 Hz, 1H), 7.65-7.58 (m, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.18 (t, J=8.1 Hz, 2H), 6.86-6.73 (m, 3H), 5.84 (s, 1H), 5.60 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.41 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.51 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]1[S:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].C(N(CC)CC)C.C[C@H](N)[C@H](O)C1C=CC=CC=1>CO.O>[CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19]
Reactant: CC1SC(C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: C[C@H](N)[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 500 mL of methanol-water (volume ratio 1:1) was suspended 50.6 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 98.8%; trans compound 90.2%, cis compound 9.6%). To the suspension was added 25 mL of triethylamine, which was made into a solution by heating (50° C.). To the solution was added 13.6 g (0.5 equivalent) of (1R,2S)-norephedrine. The mixture was once made into a solution, which was crystallized in about 10 minutes, followed by cooling to 30° C. over about 60 minutes, and then to 5° C. The crystals were aged for 60 minutes at the same temperature. The resulting crystals were collected by filtration, washed with 200 mL of cold methanol-water (volume ratio 1:1) and dried at 35° C. under reduced pressure to afford 29.9 g of substantially pure (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid.(1R,2S)-norephedrine salt as colorless crystals [HPLC area percentage: (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0.86%:0.46%:0.50%:97.9%].
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][CH:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][CH:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]
Reactant: COc1ccc(CSC2CCNC2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C1NCCC1S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 ml of trifluoroacetic acid and 0.41 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 949 mg of 3-(4-methoxybenzylthio)pyrrolidin-2-one in 4 ml of anisole, and then the mixture was stirred at room temperature for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure to leave a residue, which was purified by column chromatography through silica gel, eluted with a 10:1 by volume mixture of ethyl acetate and methanol, to give 728 mg of the title compound as an oil.