Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[CH:8]1([CH:2]([C:19]2[CH:18]=[CH:17][C:16]([N+:21]([O-:23])=[O:22])=[C:15]([F:14])[CH:20]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(Cl)C1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])c(F)c1)C1CCCCC1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 48.6 %

Procedure:
8.2 g of potassium tert.butylate were dissolved in 70 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-cyclohexylacetate (36.6 mmol, 7.5 g) and 1-fluoro-2-nitrobenzene (36.6 mmol, 3.9 ml) was carefully added dropwise and stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EtOAc (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EtOAc in cyclohexane) and produced 5.5 g (49%) of product.
Reaction SMILES: [CH:1]([O:3][CH:4]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=O.[CH2:41]([OH:48])[CH2:42][CH:43]([OH:47])[CH2:44]CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:5]([C:4]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:47][CH:43]([CH2:42][CH2:41][OH:48])[CH2:44][CH2:1][O:3]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: OCCC(O)CCO
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCCC(CCO)O1
Temperature: 25 °C
Yield: 116.6 %

Procedure:
A mixture of dilinoleyl ketone (III, 0.80 g, 1.5 mmol), 1,3,5-pentanetriol (II, 0.54 g, 4.5 mmol) and pyridinium p-toluenesulfonate (60 mg, 0.24 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×75 mL), brine (75 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in pale oil (1.1 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 75 mL) with 0-3% methanol gradient in dichloromethane as eluent. This afforded 0.75 g (79%) of pure IV as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:12](=[O:13])[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
The title compound 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) was prepared by the following procedure: To 2-aminobenzothiazole (5.0 g, 30 mmol) was added DCM (36 mL) and the reaction mixture was stirred at 0° C. for 15 minutes. Then, p-nitrophenyl chloroformate (6.64 g, 33 mmol) in DCM (60 mL) was added, followed by pyridine (2.66 mL, 33 mmol) in DCM (36 mL). The reaction mixture was stirred and allowed to warm to rt overnight. The reaction mixture was filtered, washed with DCM, and dried to provide 9.22 g (90%) of the desired product 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19): LC/MS (APCI): m/z 316.0 (M+H).
Reaction SMILES: CS[C:3]([N:7]([CH3:9])[NH2:8])=[N:4][C:5]#[N:6].[NH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1>>[CH3:9][N:7]1[C:3]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH3:23])[CH3:24])[CH:16]=2)=[N:4][C:5]([NH2:6])=[N:8]1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSC(=NC#N)N(C)N
Product: CN(C)Cc1cccc(OCCCNc2nc(N)nn2C)c1
Yield: 58.3 %

Procedure:
A mixture of N-cyano-1-methylhydrazinecarboximidothioic acid methyl ester (200 mg) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (289 mg) was heated at 40° under a reduced pressure of 20 mm of mercury for 4 hours. The reaction mixture was cooled, triturated with ether and the resulting solid recrystallised from ethyl acetate to give the title compound as colourless crystals (246 mg) m.p. 95°-96.5°.
Reaction SMILES: [Na].C(O)C.[CH3:5][O:6][C:7]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]#[N:23].[C:24](=O)([O-:28])[O:25][CH2:26][CH3:27]>C1(C)C=CC=CC=1>[C:22]([CH:21]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:7]=1[O:6][CH3:5])[C:24]([O:25][CH2:26][CH3:27])=[O:28])#[N:23]
Reactant: COc1c(CC#N)cccc1Sc1ccccc1C
Reactant: CCOC(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cccc(Sc2ccccc2C)c1OC
Yield: 96.3 %

Procedure:
Sodium metal (0.7 g), dried ethanol (20 ml), 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (7.7 g), ethyl carbonate (13 g) and toluene (50 ml) were treated in a similar manner to that of Example 22-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolylthio)phenyl]acetate (9.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[CH:21][N:20]=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:25]([C:24]3[C:19]([CH3:18])=[N:20][CH:21]=[N:22][CH:23]=3)=[O:26])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncncc1C(=O)O
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Solvent: O=CO
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cncnc1C
Yield: 80 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-methoxy-9H-beta-carbolin-8-ylamine and 4-methyl-5-pyrimidine carboxylic acid in 80% yield. 1H-NMR (300 MHz, DMSO-d6): δ 2.75 (s, 3H), 3.92 (s, 3H), 8.19 (d, 1H), 8.41 (d, 1H), 8.50 (s, 1H), 8.96 (s, 1H), 9.20 (s, 1H), 9.25 (s, 1H), 10.63 (s, 1H), 11.67 (s,1H). Retention Time (LC, method: formic acid standard): 0.95 min. MS (M+H+): 368.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[CH2:14]([N:16]([CH2:29][CH3:30])[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH3:28])[CH3:15].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:29][CH3:30])[CH2:14][CH3:15])=[C:21]([O:27][CH3:28])[CH:22]=1)=[O:7]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1OC

Procedure:
A solution of 70 mg (0.290 mmol) of (2,4-dichloro-phenoxy)-acetylchloride in 0.5 mL dichloromethane was added to a solution of 66 mg (0.278 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (intermediate product Z6b) and 96 μL (0.56 mmol) of ethyl-diisopropylamine in 1.5 mL abs. dichloromethane and the mixture was stirred for 15 hours at RT. The reaction mixture was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:13][CH:12]=1.Cl>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:41][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Agent: Cl
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(F)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-(6-(4-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.11 (s, 1H), 7.65–6.84 (m, 12H), 5.21–5.10 (m, 1H), 3.66–3.56 (m, br, 2H), 3.02–2.82 (br, 2H), 2.82–2.56 (m, br, 4H), 2.54 (s, 3H), 2.53–2.32 (m, br, 2H), 2.02–1.70 (m, br, 6H), 1.64–1.48 (m, br, 1H), 1.48–1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 547.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:11].C(N(CC)CC)C>ClCCl>[N:1]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:10]=[O:11]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN=C=O
Temperature: 7.5 °C
Reaction time: 4 h
Yield: 302.6 %

Procedure:
Into a 500-mL 3-necked round-bottom flask was placed tert-butyl 2-aminoacetate (135.1, 5.9 g, 44.98 mmol, 1.00 equiv). Then dichloromethane (180 mL) and ditrichloromethyl carbonate (4.43 g, 14.93 mmol, 0.33 equiv) were added at 0° C. After 30 min triethylamine (13.65 g, 134.89 mmol, 3.00 equiv) was added to the above mixture. The resulting solution was stirred for 4 h at 5-10° C. in a water/ice bath. The solids were filtered out. The filtrate was concentrated under vacuum. The resulting solution was diluted with 50 mL of ethyl ether. The solids were filtered out. The resulting mixture was concentrated under vacuum. Purification afforded 7.1 g (crude) of tert-butyl 2-isocyanatoacetate (135.2) as a yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.034 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, work-up and purification as in Example 32 gave the title compound (15 mg).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1cccc2c1sc1ccccc12
Yield: 78.9 %

Procedure:
The 300 ml round-bottom flask equipped with reflux condenser and magnetic stirrer was charged with 2-bromoaniline (8.00 g, 46.5 mmol), 4-dibenzothiopheneboronic acid (10.5 g, 46.5 mmol), potassium carbonate (20 g, saturated solution in water), tetrakis(triphe-nylphoshine)palladium (0) (500 mg) and 100 ml of toluene. The reaction mixture was refluxed overnight under nitrogen atmosphere, filtered through silica plug and evaporated. Product was purified by column chromatography on silica gel, eluent hexane/ethyl acetate 4/1 mixture, providing 2-(dibenzo[b,d]thiophen-4-yl)aniline (10.1 g) as yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][OH:24])[C@@H:20]([OH:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([CH2:23][O:24][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@@H:20]([O:25][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Sodium hydride (140 mg, 60% oil dispersion, 3.7 mmol) was added portionwise to a stirred solution of benzyl bromide (300 μL, 2.8 mmol) and 1 (200 mg, 0.92 mmol) in DMF (10 mL) at 0° C. On complete addition the resulting suspension was allowed to warm to r.t., diluted with toluene (100 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to afford a syrup. Chromatography afforded 2 (350 mg, 96%) as an oil which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([O:20][N:21]=[C:22](C)[CH3:23])=[C:7](C(=O)C)[N:6]=1)=[O:4]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[C:22]([CH3:23])=[N:21][O:20][C:8]2=[C:9]([F:19])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4]
Reactant: COC(=O)c1nc(C(C)=O)c(ON=C(C)C)c(F)c1Nc1ccccc1F
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2c(C)noc2c(F)c1Nc1ccccc1F
Reaction time: 1 h

Procedure:
To a solution of acetone oxime (2.20 equivalents) at room temperature is added t-BuOK (2.20 equivalents, 1.0 M solution in THF). After stirring for 30 minutes room temperature, the reaction mixture is cooled to 0° C. A solution 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) in THF is added. After stirring for 1 hour at 0-5° C., the reaction mixture is quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic layer is washed with brine, dried over MgSO4, concentrated in vacuo to give 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester that is used directly. A mixture of 6-acetyl-4-fluoro-3-(2-fluorophenylamino)-5-isopropylideneaminooxy-pyridine-2-carboxylic acid methyl ester in 5% aqueous MeOH is refluxed with stirring for 1 hour. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:14])(=[O:24])=[O:23]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
First step: To a stirred solution of commercially available (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.38 g, 12 mmol) in CH2Cl2 (25 mL) at 0° C. were added pyridine (1.91 mL, 24 mmol) and methanesulfonyl chloride (0.92 mL, 12 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (20 mL) and TFA (4 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 0.83 g (39%) of (s)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[N:10]=1)=[O:5])[CH3:2].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH:11][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:17][CH:18]=2)=[O:24])[N:10]=1)=[O:5])[CH3:2]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1nc(N)cn1C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.22 g (3.61 mmol) of 4-amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (synthesis analogous to Example 1A, Stage 3, or else according to Tetrahedron Lett. 2003, 44, 1607 and literature cited there) is mixed in 50 ml of THF under argon with 1.46 g (7.21 mmol) of 4-(trifluoromethoxy)phenylisocyanate and stirred overnight at room temperature. The reaction mixture is filtered, the filtrate is concentrated by evaporation in a vacuum, and it is purified chromatographically.
Reaction SMILES: [Na].Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[C:10]#[N:11])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccncc1
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=Cc1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
After sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL), 4-pyridyl acetonitrile hydrochloride (33 g, 121 mmol) was added thereto and stirred at room temperature. After 10 minutes, 3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto and stirred as such for 30 minutes. The resulting precipitates were collected by filtration and washed with a small amount of water, to give the title compound (8.2 g, 56%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH2:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.N>O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]2[N:1]=[C:2]([NH2:4])[S:3][CH:7]=2)[CH:11]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: N
Solvent: O
Product: Nc1nc(-c2cccnc2)cs1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A solution of thiourea (70,4 g) in water (265 ml) was added dropwise to a stirred solution of 3-bromoacetylpyridine hydrobromide (251,6 g) in water (1 1) over 15 minutes. The solution, which turned yellow and became quite hot, was allowed to stand for one hour, and was then basified by addition of aqueous ammonia. The resulting solid was filtered off, washed with water, and dried in vacuo at 65° C. to give 4-(pyridin-3-yl)-thiazol-2-amine, (155 g) Mp 200° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][OH:23]>O1CCCC1>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][O:23][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzonitrile (8.0 g, 42.3 mmol, Aldrich) in tetrahydrofuran (50 mL) were added sodium hydride (1.9 g, 46.5 mmol) and (S)-(1-methylpyrrolidin-2-yl)methanol (5.5 mL, 46.5 mmol, Aldrich). After stirring at room temperature for 3 h, the reaction mixture was quenched with saturated NaHCO3 (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 12.0 g (100%) of the title compound. LCMS (APCI+) m/z 285 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=1[CH3:8].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:21]([C:22]1[CH:30]=[CH:29][C:27]([O:28][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=3)[C:14]([O:16][CH3:17])=[O:15])[O:6][C:7]=2[CH3:8])=[C:24]([O:25][CH3:26])[CH:23]=1)=[O:20]
Reactant: COC(=O)c1cc(-c2nc(CCl)c(C)o2)ccc1C
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)ccc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of methyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-methylbenzoate (1.21 g), vanillin (0.65 g), anhydrous potassium carbonate (0.59 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methylbenzoate as colorless crystals (1.45 g, yield 85%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[C:43]([N:47]1[CH2:52][CH2:51][N:50]([C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1)([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:59][C:56]2[CH:55]=[CH:54][C:53]([N:50]3[CH2:49][CH2:48][N:47]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:52][CH2:51]3)=[CH:58][CH:57]=2)=[N:35][CH:34]=1
Reactant: CC(C)(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ncnc12
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2)CC1
Yield: 92.4 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.308 g, 1.107 mmol), 4-(4-tert-butyl-piperazin-1-yl)-phenylamine (0.310 g, 1.33 mmol) and N-ethyldiisopropyl-amine (0.289 mL, 1.66 mmol) in 2-propanol (5 mL). The reaction mixture is partitioned between DCM and 1N NaOH, the organic layer is separated and washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum. Trituration of the residue with diethyl ether and petroleum ether affords the title compound (440 mg, 92%) as a cream solid. LCMS: Rt 2.25 min (96%).