Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].C(C1(CCO[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[O:47]1[CH2:51][CH2:50][O:49][CH:48]1[CH2:52][OH:53]>>[Na:1].[O:47]1[CH2:51][CH2:50][O:49][CH:48]1[CH2:52][O:53][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)=[O:25])[C:18]=1[CH3:35]
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: OCC1OCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCC2OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 17.2 %

Procedure:
The same procedure as in the steps (4f) to (4j) described in Example (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 1,3-dioxolan-2-ylmethanol obtained in the step (66b) above to obtain the title compound (411 mg, total 17.2% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH2:27]1[C@@H:30]([C:31]([OH:33])=[O:32])[NH:29][CH2:28]1>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([N:29]5[CH2:28][CH2:27][C@H:30]5[C:31]([OH:33])=[O:32])[CH:26]=[CH:25][C:5]=43)[CH:9]=2)[N:15]([CH2:20][C:21]([F:22])([F:24])[F:23])[N:16]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(CC(F)(F)F)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(N4CC[C@H]4C(=O)O)cc2OCC3)n(CC(F)(F)F)n1

Procedure:
Following the procedure in Example 551, 8-bromo-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene and (L)-azetidine-2-carboxylic acid were reacted to give (S)-1-{2-[5-Methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-azetidine-2-carboxylic acid. LCMS: RT=2.93 min, [M+H]+=449
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH3:11][N:12]([CH3:39])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:24]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[CH3:39][N:12]([CH3:11])[C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][CH:38]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:35])=[C:23]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:29][CH:28]=2)[CH:24]=1)=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(OCCCN2CCOCC2)cc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
4-(3-Chloropropyl)morpholine (0.1 g) was added to a stirred mixture of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-hydroxybenzamide (0.195 g), potassium carbonate (0.21 g) and DMA (5 ml). The mixture was then heated to 60° C. for 36 hours. The mixture was poured into water (150 ml) and the resultant solid was collected, washed with water and with diethyl ether. The product was dried under vacuum. There was thus obtained the title compound (0.203 g) as a colourless solid; NMR Spectrum: (DMSOd6) 1.88 (m, 2H), 2.18 (s, 3H), 2.36 (t, 4H), 2.41 (t, 2H), 2.96 (s, 6H), 3.58 (t, 4H), 4.08 (d, 2H), 6.9 (m, 1H), 7.01 (d, 2H), 7.19 (m, 3H), 7.26 (t, 1H), 7.58 (d, 1H), 7.78 (s, 1H), 7.98 (d, 2H), 9.72 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+H+517.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][N:10](C=O)[C:9]=2[CH:8]=[C:7]([N+:18]([O-:20])=[O:19])[CH:6]=1)=[O:4].[N+]([NH-])([O-])=O.[OH-].[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:8]=[C:7]([N+:18]([O-:20])=[O:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCCN2C=O
Agent: Cl
Agent: [NH-][N+](=O)[O-]
Agent: [Na+]
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCCN2
Temperature: 100 °C

Procedure:
The previously prepared nitroamide 9-formyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid methyl ester (4.76 grams, 17 mmol) was suspended in 1N HCl and heated to 100° C. for 2 hours. After cooling to room temperature, the pH of the reaction mixture was adjusted to 12 with 1N NaOH. The precipitate formed was extracted with ethyl acetate. The latter was dried over anhydrous magnesium sulfate, filtered and evaporated.
Reaction SMILES: [C:1]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([O:25]CC)=[O:24])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.Br[CH2:34][C:35]1[CH:47]=[CH:46][C:38]([O:39][CH2:40][C:41]([O:43]CC)=[O:42])=[CH:37][CH:36]=1.[Na+].[Cl-]>O.CS(C)=O>[C:41]([CH2:40][O:39][C:38]1[CH:46]=[CH:47][C:35]([CH2:34][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:15]2[C:23]([OH:25])=[O:24])=[CH:36][CH:37]=1)([OH:43])=[O:42]
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Reactant: CCCCCCCCCCCC(=O)c1c(C(=O)OCC)[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCC(=O)c1c(C(=O)O)n(Cc2ccc(OCC(=O)O)cc2)c2ccccc12

Procedure:
A mixture of 223 mg (0.6 mmol) of ethyl 3-dodecanoylindole-2-carboxylate, 81 mg (0.72 mmol) of potasisum t-butoxide and 2 ml of absol. DMSO is stirred in an oil bath at 110° C. for 5 min. Then 197 mg (0.72 mmol) of ethyl 2-[4-(bromomethyl)phenoxy]acetate are added, and the mixture is heated at the same temperature for a further 10 min. Cooling and addition of water and NaCl are followed by extraction with ether. The organic phase is dried over Na2SO4, the solvent is distilled off, and the residue is chromato-graphed on silica gel with petroleum ether/ethyl acetate (9+1). The resulting ethyl 3-dodecanoyl-1-{4-[(ethoxycarbonyl)methoxy]benzyl}indole-2-carboxylate is hydrolyzed in analogy to Example 2E. The product is precipitated from ether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:22]([OH:25])[C:23]#[CH:24])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:24]#[C:23][CH:22]([C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[OH:25])=[CH:4][N:3]=1
Reactant: Nc1ncc(I)c(N)n1
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(O)C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 77.8 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (444 mg) as per the general procedure to afford 3-(2,4-Diaminopyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)-prop-2-yn-1-ol as a yellow powder (257 mg, 78%): Rf=0.12 (9:1, CHCl3:MeOH); mp=203-205° C.; 1H NMR (DMSO-d6) δ 7.84 (s, 1H), 6.83 (s, 2H), 6.34 (s, 2H), 6.01 (d, J) 5.6 Hz, 1H), 5.50 (d, J) 5.4 Hz, 1H), 3.78 (s, 6H), 3.65 (s, 3H); 13C NMR (DMSO-d6) δ 163.8, 162.3, 158.2, 152.7, 138.3, 136.7, 109.3, 103.6, 96.3, 79.3, 63.4, 60.0, 55.8; Anal. (C16H18N4O4) C, H, N.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C1CCN2C(=NCCC2)CC1.[C:26](Cl)(=[O:28])[CH3:27].Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:13][C:2]([O:1][C:26](=[O:28])[CH3:27])([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.1 %

Procedure:
To a 0° C. solution of 2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one (150 g, example 1, Step 2), DBU (217 g) and DMAP (7 g) in dichloromethane (850 mL) was added acetyl chloride (112.2 g) dropwise and the mixture was stirred for 6 h. at 25° C. More DBU (32.5 g) was added and the mixture was stirred an additionnal 16 h. The reaction mixture was poured over 2N HCl (800 mL) and the organic layer was separated, washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and the solvent was evaporated under vacuum. The residue was swished in Et2O, then 25% ethyl acetate in hexane, then filtered and dried giving 74 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29]CC)=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([OH:29])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(Br)c3)cc1)n2C1CCCCC1
Yield: 95.1 %

Procedure:
Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (1.0 g) obtained in Example 1 was dissolved in tetrahydrofuran (10 ml) and ethyl alcohol (10 ml), and 4N sodium hydroxide (10 ml) was added. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 6N hydrochloric acid and the precipitated crystals were collected by filtration to give the title compound (0.9 g, yield 96%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][CH:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:16]3)=[CH:10][CH:11]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>C(#N)C>[N:35]1([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[O:19][CH:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]4)=[CH:10][CH:11]=2)=[O:4])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and morpholine (53 mg). The mixture was stirred at room temperature. Water was added to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was dried and evaporated. 2-Morpholin-4-yl-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) δ: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0 Hz), 4.23 (s, 2H), 4.02-3.76 (m, 4H), 3.55-3.20 (m, 4H), 3.00-2.92 (m, 1H), 2.75-2.69 (m, 1H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H).
Reaction SMILES: C(Br)CCC.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.C([N:35]1[C:41]2[C:42]([Cl:49])=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:40]=2[C:39]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])=[N:38][C:37]([CH3:58])([CH3:57])[C:36]1=[O:59])CCC>>[Cl:49][C:42]1[C:41]2[NH:35][C:36](=[O:59])[C:37]([CH3:58])([CH3:57])[N:38]=[C:39]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[F:56])[C:40]=2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=1
Reactant: CCCCN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCCBr
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Cl)c2NC1=O

Procedure:
From 10 g (0.028 mol) of 9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and n-butyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 9 days and purification of the product by chromatography on silica gel (elution agent: methylene chloride), 1-butyl-9-chloro-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 125°-127° (hexane/petroleum ether).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18](=[O:27])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:35][CH2:36][CH3:37])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:28]([N:17]([C:18](=[O:27])[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:38])=[O:5])[C:9]([CH2:35][CH2:36][CH3:37])=[N:10][C:11]=2[CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3c(F)cccc3F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3c(F)cccc3F)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(2,6-difluoro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. 1H NMR (d6-DMSO) δ7.28 (m, 8H), 6.93 (m, 2H), 6.79 (m, 1H), 5.09 (s, 2H), 4.58 (s, 2H), 2.61 (t, 2H), 1.69 (m, 2H), 0.92 (t, 3H). MS calculated for C26H23F2N3O3+H: 464, observed: 464.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[C:9]1[C:15]1[CH:27]=[CH:26][C:18]2[NH:19][C:20](=O)[O:21][C:22]([CH3:24])([CH3:23])[C:17]=2[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:15]2[CH:27]=[CH:26][C:18]3[NH:19][C:20](=[S:37])[O:21][C:22]([CH3:24])([CH3:23])[C:17]=3[CH:16]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=S)N2
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To 2-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-cyano-pyrrole-1-carboxylic acid tert-butyl ester (1.3 g, 35 mmol, 1 eq) in toluene (130 mL) was added Lawesson's reagent (1.58 g, 3.9 mmol, 1.1 eq) and the reaction mixture was heated to 80° C. for 2 h. The solvent was removed in vacuo and the residue was dissolved in acetone/dichloromethane and adsorbed onto silica gel. Purification by flash column chromatography (10% ethyl acetate/hexane) gave the product (0.51 g, 38%) as yellow crystals. 1H NMR (DMSO-d6) δ 1.35 (s, 9H), 1.64 (s, 6H), 6.47 (d, 1H, J=3.6 Hz), 7.07 (d, 1H, J=8.1 Hz), 7.32 (d, 1H, J=3.6 Hz), 7.37 (dd, 1H, J=1.8, 8.1 Hz), 7.43 (d, 1H, J=1.8 Hz), 12.28 (s, 1H); MS (ESI) [M−H]−=382; Anal. Calcd. For C20H21N3O3S: C, 62.64; H, 5.52; N, 10.96. Found: C, 62.53; H, 5.6; N, 10.87.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:6]([CH3:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C
Yield: 92.9 %

Procedure:
The product was prepared by procedures which are well known in the art, that is, by the alkylation of 4-nitro-2-methylphenol (2. 508 g, 0. 0164 mol) with ethyl bromoacetate (3.00 g, 0.018 mol) in acetonitrile (50 mL) in the presence of potassium carbonate (2.76 g) to afford ethyl 4-nitro-2-methylphenoxyacetate (4.0 g, 100%); hydrogenation of the latter (4.0 g, 0.0164 mol) in ethanol (250 mL) in the presence of 10% palladium on carbon (1.0 g) to afford ethyl 4-amino-2-methylphenoxyacetate; which was then dissolved in CH2Cl2 (50 mL) and treated with pyridine (4.0 mL), followed by methanesulfonyl chloride (1.88 g) in CH2Cl2 (5.0 mL) to afford 3.27 g (69.4%) of N-[4-(ethoxycarbonylmethoxy)-3-(methyl) phenyl]methanesulfonamide, m.p. 83°-84 ° C., after purification by column chromatography on silica.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][C:3]1=[O:16].Cl.[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)CCO>[CH3:1][N:2]1[C:7]([NH:18][CH2:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[N:4][C:3]1=[O:16]
Reactant: CSc1nc(-c2ccncc2)nc(=O)n1C
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: Cn1c(NCC(=O)c2ccccc2)nc(-c2ccncc2)nc1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.12 g (0.51 mmol) of 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one in 1 mL of 3-methyl-1-butanol was added 0.088 g (0.51 mmol) of 2-Amino-1-phenyl-ethanone hydrochloride (commercially available). To the resulting mixture was added 7.1 mg (0.051 mmol) of potassium carbonate. The resulting mixture was stirred at 120° C. for 1 h. Then, 7.1 mg (0.051 mmol) of potassium carbonate were added each hour during 2 h.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([CH2:17][CH:18]([O:35]C(=O)C)[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1[N:9]([CH2:17][CH:18]([OH:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(OCC(Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(OCC(O)Cn2c(C(=O)OC(C)(C)C)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.213 g (0.408 mmol) tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate is dissolved in 10 ml absolute methanol, mixed with 1.64 ml (0.82 mmol) of a 0.5M sodium methanolate solution and stirred at room temperature for 15 min. Following concentration to half the volume on the rotary evaporator, the batch is diluted with diethyl ether. Washing of the organic phase with semi-saturated and with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellowish oil which is purified on silica gel by means of column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a yellowish oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O.[C:30]([OH:47])(=[O:46])[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][CH3:45].C=O.[C:50]([O-])(=[O:66])CCCCCCCCCCCCCCC.[Li+]>O1CCCC1>[OH:66][CH2:50][CH: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][CH3:45])[C:30]([OH:47])=[O:46]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)[O-]
Agent: C=O
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(CO)C(=O)O
Yield: 69 %

Procedure:
Anhydrous tetrahydofuran (THF) (825 ml) and 49.5 g (0.49 mole) of diisopropylamine were added to a dry three neck flask purged with nitrogen and maintained under a nitrogen atmosphere. After cooling the mixture to -20°, 300 ml of n-butyllithium in hexane (1.6 M) (0.49 mole) was added slowly to prevent the temperature from exceeding 0° and then 79.3 ml of anhydrous hexamethylphosphoramide (HMPA) (0.44 mole) was added. A solution of 51.28 g of palmitic acid (0.198 mole) in 400 ml of THF was added dropwise with stirring while maintaining the reaction temperature below 0°. A milky white suspension resulted after the addition of palmitic acid. The reaction mixture was brought to about 40° by using a warm water bath. The suspension changed to a clear solution as the temperature gradually reached 40°. This system was then connected to a formaldehyde generating system. Paraformaldehyde (40 g) was heated in a three neck flask at 180°-200° to generate formaldehyde and the formaldehyde vapors were carried by a stream of nitrogen over the surface of the stirred solution of α-lithiated lithium palmitate prepared previously. The reaction was terminated after complete depolymerization of paraformaldehyde (2 to 21/2 hrs.). The reaction solution was cooled in an ice bath and neutralized with hydrochloric acid until acidic. The organic layer was separated and was concentrated under reduced pressure on a rotavac to remove most of the THF solvent. The resulting oily residue was dissolved in 2 liters of ether and was washed three times with 10% hydrochloric acid solution and then twice with water. The ether layer was dried over Na2SO4 and the solvents were removed under reduced pressure to give 43.3 g (75%) of crude product, α-hydroxymethylpalmitic acid, which was recrystallized once from acetone to give 39.0 g (69% yield) of the product with m.p. 67°-71°, which was used without further purification in the next synthetic step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.C(O[Cl:15])(C)(C)C.O>C(Cl)(Cl)Cl>[Cl:15][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1]
Reactant: CC(C)(C)OCl
Reactant: Cc1cc(Cl)c(F)cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ncc(F)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.87 g (6 mmol) of 4-chloro-5-fluoro-2-picoline, the product of Example 66, in 20 mL of chloroform cooled to -45° C., is added 0.75 mL of t-butylhypochlorite. The reaction mixture is stirred at -45° C. for 2 hours and at 0° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture is extracted with methylene chloride. The organic solution is dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and distilled to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[S:11][C:10]=1[C:18]([O:20]C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[S:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(S(C)(=O)=O)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(OCc2ccccc2)c(C(=O)O)s1
Temperature: 25 °C
Yield: 91 %

Procedure:
A mixture of methyl 3-benzyloxy-5-(methylsulfonyl)-2-thiophenecarboxylate (16.7 g, 51.2 mmol), 50 ml 2N NaOH and 50 ml of tetrahydrofuran is heated at reflux temperatures for 1 hour, cooled to room temperature and concentrated in vacuo to an aqueous residue. The residue is diluted with water, acidified to pH 1-2 with 6N HCl and filtered. The filtercake is washed with water and dried to give the title product as a white solid, 14.55 g (91% yield). A small sample was recrystallized from aqueous ethanol to give white needles, mp 188-189° C., identified by 1HNMR, 13CNMR, IR and mass spectral analyses.