Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[C:23]([CH2:24][CH:25]=O)=[C:22](Cl)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:17][C:18]1[C:23]2[CH:24]=[CH:25][N:1]([C@H:2]3[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8][OH:9])[CH2:3]3)[C:22]=2[N:21]=[CH:20][N:19]=1
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: N[C@@H]1C[C@@H](CO)[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OC[C@@H]1C[C@@H](n2ccc3c(Cl)ncnc32)C[C@@H]1O
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of (1S,2S,4R)-4-amino-2-(hydroxymethyl)cyclopentanol (250 mg, 1.90 mmol) and triethylamine (380 mg, 3.80 mmol) in 2-propanol (30 mL) was treated with 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (330 mg, 1.71 mmol) at 80° C. The reaction was monitored by HPLC and all aldehyde was found to have been consumed after 19 h. The reaction mixture was cooled to ambient temperature. Approximately 80% of the solvent was removed under reduced pressure and the resulting brown solution was added with stirring to water (30 mL). The resulting clear solution was cooled in an ice-water bath resulting in product crystallization. The resulting slurry was stirred at less than 5° C. for thirty minutes and filtered. The filter cake was washed with cold water (10 mL) and dried in a vacuum oven at 40° C. for 14 h to obtain the title compound as a brown solid (311 mg, 68% yield). 1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.68 (d, J=3.7 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 5.54 (m, 1H), 4.52 (m, 1H), 3.82 (dd, J=10.7, 7.2 Hz, 1H), 3.68 (dd, J=10.8, 6.5 Hz, 1H), 2.64 (m, 1H), 2.32 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH4+].[OH-].CS(O)(=O)=[O:5].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:22]([NH:24][C@H:25]([CH3:42])[C@:26]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:22]([NH:24][C@H:25]([CH3:42])[C@:26]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[F:41])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[O:23])=[C:19]([CH3:21])[N:20]=2)=[CH:12][CH:11]=1)(=[O:5])[NH2:9]
Reactant: CS(=O)(=O)O
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(N)=O)cc2)sc1C(=O)N[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
To a solution of NH4OH in a H2O--THF mixture was added (1R,2R)-2-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-methyl thiazole-5-carboxamide methanesulfonate (0.5 g, 0.84 mmol, obtained in example 31). The mixture was refluxed for 2 days, then was concentrated and the aqueous residue was extracted with CHCl3. The organic layer was separated, dried over Na2SO4, filtered and the filtrate was concentrated to a solid (0.53 g). This was purified by flash chromatography to give the title compound as a white solid: 133°-135° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 7.98 (d, J=8.3, 2H, arom), 7.87 (d, J=8.3, 2H, arom), 7.81 (s, 1H, triazole), 7.71 (s, 1H, triazole), 7.40 (dt, Jd =6.5, Jt =8.8, 1H, arom), 6.8-6.6 (m, 2H, ) arom), 6.57 (br d, J=9.5, 1H, NH), 6.27 (br s, 2H, NH2), 5.63 (s, 1H, OH), 5.05 (d, J=14.5, 1H, TrCH(H)), 4.98 (br quint, J=7, 1H, CHMe), 4.57 (d, J=14.5, 1H, TrCH(H)), 2.81 (s, 3H, Me-thiazole), 1.05 (d, J=6.8, 3H, MeCH); MS 288 and 289 (ethylaminoacyl group, C14H15N3O2S), 245 (acyl group, C12H9N2O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-74.5° (c 1, MeOH). Analysis calculated for C24H22F2N6O3S: C 56.24; H 4.33; N 16.40; S 6.26. Found: C 55.90; H 4.64; N 15.29; S 5.62.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([CH2:23][CH2:24][O:25][CH3:26])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:4][CH2:3]1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[O:27]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][CH2:23][CH2:24][O:25][CH3:26])[CH2:6][CH2:7]1
Reactant: COCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-N-(2-methoxyethyl)-2-nitrobenzenesulfonamide (0.470 g, 1.12 mmol) and thiophenol (0.369 g, 3.35 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.616 g, 4.46 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave the title compound as a yellow solid (0.222 g, 84% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 237 (M+H+), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.15 (br. s., 1H) 2.66-2.71 (m, 2H) 2.71-2.77 (m, 2H) 2.82 (t, J=5.04 Hz, 2H) 2.97-3.05 (m, 4H) 3.05-3.10 (m, 4H) 3.37 (s, 3H) 3.51 (t, J=5.04 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5]2.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[C:26]([CH3:28])=[CH2:27]>C1COCC1>[CH3:28][C:26](=[CH2:27])[C:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:5]2)=[O:29]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2cc(O)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc2cc(/C=C/C(=O)OC)ccc2c1
Temperature: 0 °C

Procedure:
0.89 g (3.9 mmol) of methyl (E)-3-(6-hydroxy-naphthalen-2-yl)-acrylate, a spatula tip of BHT and 0.66 ml of triethylamine were dissolved in 10 ml of THF. After cooling to 0° C. a solution of 0.39 ml (4.07 mmol) of methacryloyl chloride in 4 ml of THF was added dropwise within 30 minutes. The white suspension was stirred at 0° C. for a further hour and then partitioned in ether and water. The organic phase was back-washed twice with water and the aqueous phases were back-washed twice with diethyl ether. The combined organic phases were dried over magnesium sulphate, filtered over Celite and evaporated completely in a vacuum. The crude product was recrystallized from a mixture of 5 ml of hexane and 20 ml of toluene. This gave 0.92 g of white (E)-2-(2-methoxycarbonyl-vinyl)-naphthalen-6-yl 2-methyl-acrylate.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>[OH-].[Na+]>[C:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:2][CH2:3]1)(=[O:28])[CH3:27]
Reactant: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2cc3c(c(C)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
To a solution of 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (40 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride (0.1 ml) at room temperature. After the mixture is made acidic with dilute hydrochloric acid, the resultant is extracted with dichloromethane and the extract is dried over magnesium sulfate. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (29 mg), as white powder, m.p. 261°-263° C.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.Cl.[NH2:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[N:7]=[C:3]([NH:21][C@H:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([NH2:25])=[O:24])[S:4]/[C:5]/1=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@H](NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1ccccc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-amino-2-phenyl-acetamide hydrochloride and DIEA to give (R)-2-{4-oxo-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-4,5-dihydro-thiazol-2-ylamino}-2-phenyl-acetamide. LC-MS m/e 389 (MH+).
Reaction SMILES: [C:1]([CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:29])[C:20]2[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[S:23][CH:24]=3)[O:29][CH:31]2[C:30]([O:34][CH3:35])=[O:33])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C=O
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with methyl glyoxylate followed by purification of the base on a silica gel column using chloroform/petroleum ether/ethyl acetate=5:4.5:0.5 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].C(O)(=O)C>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([CH2:24][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:22][CH2:23]2)=[O:17])=[CH:26][CH:27]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CN2CCOCC2)CC1
Reaction time: 13 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (52 mg, 0.143 mmol) was dissolved in EtOH (5 mL) and morpholine (0.025 mL, 0.285 mmol), sodium cyanoborohydride (18 mg, 0.285 mmol), and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 13 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 100% EtOAc.) The title compound was obtained as an oil. (Yield: 15 mg, 0.034 mmol, 24%) 1H NMR (400 MHz, CDCl3) 7.63, 7.37, 7.27-7.24, 7.14, 7.11-7.04, 6.91, 6.59, 5.47, 4.62, 4.09, 3.67, 2.74, 2.36, 2.08, 1.63, 0.96, 0.61
Reaction SMILES: C[O:2][C:3]1C(OC)=C(OC)[C:6]([CH2:13]/[CH:14]=[C:15](\[CH3:57])/[CH2:16][CH2:17]/[CH:18]=[C:19](\[CH3:56])/[CH2:20][CH2:21]/[CH:22]=[C:23](\[CH3:55])/[CH2:24][CH2:25]/[CH:26]=[C:27](\[CH3:54])/[CH2:28][CH2:29]/[CH:30]=[C:31](\[CH3:53])/[CH2:32][CH2:33]/[CH:34]=[C:35](\[CH3:52])/[CH2:36][CH2:37]/[CH:38]=[C:39](\[CH3:51])/[CH2:40][CH2:41]/[CH:42]=[C:43](\[CH3:50])/[CH2:44]CC=C(C)C)=[C:5]([CH3:58])[C:4]=1O>O>[CH3:44][C:43]([CH3:50])=[CH:42][CH2:41][CH2:40]/[C:39](/[CH3:51])=[CH:38]/[CH2:37][CH2:36]/[C:35](/[CH3:52])=[CH:34]/[CH2:33][CH2:32]/[C:31](/[CH3:53])=[CH:30]/[CH2:29][CH2:28]/[C:27](/[CH3:54])=[CH:26]/[CH2:25][CH2:24]/[C:23](/[CH3:55])=[CH:22]/[CH2:21][CH2:20]/[C:19](/[CH3:56])=[CH:18]/[CH2:17][CH2:16]/[C:15](/[CH3:57])=[CH:14]/[CH2:13][CH2:6]/[C:5](/[CH3:58])=[CH:4]/[CH2:3][OH:2]
Reactant: COc1c(O)c(C)c(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)c(OC)c1OC
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO

Procedure:
Oxidation of the crude phenol to the corresponding 1,4-quinone (CoQ9) was performed by using FeCl36 H2O similar to the published procedure of S. Kijima et al.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]C)=[O:13])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)c2[nH]c(=O)[nH]c2c1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
Methyl 7-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (238 mg, 0.878 mmol) and 2 N aqueous sodium hydroxide (1.50 mL, 3.0 mmol) were combined in methanol (5 mL) and heated to 50° C. for 90 minutes. The reaction solution was concentrated to remove the methanol. To the reaction residue was added ethyl acetate (5 mL). The resultant solution was acidified with 1N aqueous hydrochloric acid (1.5 mL) to give a final pH of 4. A precipitate formed which was filtered and dried under vacuum to give the title compound (226 mg, 100%) as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J=1.37 Hz, 1H) 7.65 (d, J=1.37 Hz, 1H).
Reaction SMILES: Cl.C1(NN)C=CC=CC=1.FC1C=CC=C[C:12]=1[C:13](C(CC)C(O)=O)=[O:14].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH:40]([CH2:41][CH2:42][C:43]([OH:45])=O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33]1>>[C:13]([N:33]1[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43](=[O:45])[CH2:42][CH2:41][CH:40]([C:39]=23)[CH:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[F:25])(=[O:14])[CH3:12]
Reactant: O=C(O)CCC1c2ccccc2NC1c1ccccc1F
Reactant: CCC(C(=O)O)C(=O)c1ccccc1F
Agent: Cl
Solvent: NNc1ccccc1
Product: CC(=O)N1c2cccc3c2C(CCC3=O)C1c1ccccc1F
Yield: 22 %

Procedure:
The procedure of Example 1, steps 1 and 2 was repeated using phenylhydrazine hydrochloride (17.9 g) and (2-fluorobenzoyl)butyric acid (15.1 g) to synthesize 2-(2-fluorophenyl)-2,3-dihydroindole-3-propionic acid, which was reacted according the procedures of Example 2, step 1 and Example 3, step 2 to yield 4.8 g (total yield: 22%) of the titled compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>CS(C)=O.O>[CH2:28]([O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1

Procedure:
1.5 gm (5 millimols) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid, m.p. 164° - 165° C, were stirred with 1.05 gm of potassium carbonate and 0.9 ml of n-butyl bromide in 15 ml of dimethyl sulfoxide for 60 hours. The mixture was subsequently diluted with water, and the reaction product was extracted with toluene. After washing, drying and evaporating the extract, the residue (1.7 gm) was recrystallized from cyclohexane. Yield: 1.2 gm (67% of theory); m.p.: 72° - 74° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:43][O:42][C:24]1[CH:23]=[C:22]([CH:41]=[CH:40][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:21][O:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (700 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (930 mg), potassium carbonate (750 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (1.35 g, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nc(CCl)cs2)cc1OC
Reactant: CN1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN3CCN(C)CC3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.1 %

Procedure:
In 10 ml of dimethylformamide were dissolved 860 mg of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole and 320 mg of N-methylpiperazine. Thereto was added 130 mg of sodium hydride. The mixture was stirred at room temperature for 14 hours. The solvent was removed by distillation. The residue was extracted with chloroform. The extract was water-washed, dried and subjected to distillation to remove the solvent, The residue was dissolved in ethanol. To the solution was added ethanol saturated with hydrogen chloride gas, and the mixture was allowed to stand. The resulting crystals were collected by filtration washed with a small amount of ethanol, dried and recrystallized from ethanol to obtain 820 mg of 2-(3,4-dimethoxyphenyl)-4-(4-methylpiperazinylmethyl)thiazole.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:12]1[C:21]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[C:22]([O:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:8][C:9]([N:18]1[CH2:19][CH2:20][C:21]2[N:12]=[C:13]([C:22]([O:24][CH3:25])=[O:23])[CH:14]=[CH:15][C:16]=2[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a vial containing benzyl isocyanate (0.0166 g, 0.125 mmol), was added methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0220 g, 0.0962 mmol), DIPEA (0.0586 mL, 0.337 mmol) and DMF (2 mL). The resulting solution was then shaken at rt for 13 h and then concentrated to give methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:17])[CH2:15][CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[C:14](=[O:17])[CH2:15][CH2:16][C@H:10]12
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)CCN12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CC[C@@H]2CNCCN12
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of (R)-(+)-2-benzylhexahydropyrrolo[1,2-a]pyrazin-6(7H)-one (2 g, 8.69 mmol), ammonium formate (3.83 g, 60.8 mmol) and 10% Pd/C (550 mg) in MeOH (90 ml) was refluxed for 3 hours. After cooling to room temperature, the catalyst was filtered off and the solvent evaporated under vacuum. The residue was purified by flash chromatography (DCM/MeOH/32% NH4OH, 70/30/3 respectively) to afford the title compound as a colourless oil (1.1 g, 90% yield).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:66][C:67]1[CH:74]=[C:73]([O:75][CH3:76])[CH:72]=[CH:71][C:68]=1[CH:69]=[O:70].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:76][O:75][C:73]1[CH:72]=[CH:71][C:68]([CH:69]=[O:70])=[C:67]([O:66][CH2:23][C:22]2[CH:21]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH:25]=2)[CH:74]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(COc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
3,4,5-Tri(octadecyloxy)benzylchloride (93.6 g, wet, <90.8 mmol), 2-hydroxy-4-methoxybenzaldehyde (15.2 g, 0.10 mol) and potassium carbonate (31.4 g, 0.23 mol) were suspended in DMF (830 ml), and the suspension was stirred at 80° C. overnight. The reaction mixture was dissolved in chloroform (1600 ml), and the mixture was washed 3 times with 1N hydrochloric acid (800 ml), once with 5% aqueous sodium hydrogen carbonate solution (800 ml), and once with 20% brine (800 ml). The solvent was evaporated, and the residue was precipitated with methanol (800 ml) and washed with acetonitrile (800 ml) to give 4-methoxy-2-[3′,4′,5′-tris(octadecyloxy)benzyloxy]benzaldehyde (93.5 g, 89.2 mmol, 98%).
Reaction SMILES: [S:1]([NH:5][C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[C:11]#[N:12])(=[O:4])(=[O:3])[NH2:2].[OH-].[Na+].Cl>CCO>[NH:5]1[C:6]2[CH2:10][CH2:9][CH2:8][C:7]=2[C:11]([NH2:12])=[N:2][S:1]1(=[O:4])=[O:3]
Reactant: N#CC1=C(NS(N)(=O)=O)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1=NS(=O)(=O)NC2=C1CCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-sulfamoylaminocyclopent-1-enecarbonitrile (Example 107a) (108 mg, 0.57 mmol) in EtOH was treated with NaOH (2.0 N, 0.5 mL), and the resultant solution was heated to 100° C. and stirred at that temperature for 4 h. After it was cooled down to room temperature, the reaction solution was carefully neutralized with 2N HCl while it was vigorously stirred at 0° C. The reaction solution was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.69-1.63 (m, 2H), 2.2 (t, J=7.6 Hz, 2H), 2.3 (t, J=6.8 Hz, 2H), 5.12 (s, 2H). MS 188 (MH+).