Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>CO>[C:23]([NH:27][CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC2CO2)cc1
Reactant: CC(C)(C)N
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC(O)CNC(C)(C)C)cc1

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-4,4',6-trimethylbenzophenone (10 g.), t-butylamine (10 ml.) and dry methanol (50 ml.) was heated at reflux overnight. The mixture was evaporated in vacuo, and the residue was recrystallized from cyclohexane to give DL-1-t-butylamino-3-(3,5-dimethyl-2-p-toluoylphenoxy)-2-hydroxypropane (7 g.), m.p. 116°-118° C.
Reaction SMILES: [NH2:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:23][CH2:24][CH2:25][O:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:36]>[Cu](Cl)Cl.C(O)C>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:20]([O:21][CH3:22])[CH:19]=[CH:18][CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:33]=[C:34]([CH3:35])[C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2cccc(OC)c2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3c(OC)cccc3c2=O)cc1
Temperature: 100 °C

Procedure:
To a 100-mL round bottom flask were added 2-amino-N-(4-sec-butyl-phenyl)-3-methoxy-benzamide (0.533 g, 1.79 mmol), 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.382 g, 1.96 mmol), anhydrous copper (II) chloride (0.722 g, 5.37 mmol), and anhydrous ethanol (40 mL). The mixture was refluxed at 100° C. under N2 for 5 hours. The mixture was concentrated to dryness. Water (approximately 20 mL) was added and extracted with EtOAc (3×50 mL). The EtOAc solutions were combined and dried over Na2SO4. The crude product was purified by column chromatography on silica gel using hexane/EtOAc (1:1 to 1:2) as eluent. The product fractions were concentrated to dryness then re-crystallized in ether to afford the title compound as white solid. Yield: 0.460 g (54%). MP 158-159° C. 1H-NMR (400 MHz, CDCl3): δ 7.93 (d, 1H), 7.46 (t, 1H), 7.24 (d, 1H), 7.12 (d, 2H), 7.05 (d, 2H), 7.00 (s, 2H), 4.03 (s, 3H), 3.89 (m, 2H), 3.75 (m, 2H), 2.56 (m, 1H), 2.11 (s, 6H), 1.52 (m, 2H), 1.19 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.27 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1ccc(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a mixture of 0.5 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.80 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-y]nitrobenzene and 5 ml of N,N-dimethylformamide was added 0.35 g of potassium carbonate, and the mixture was stirred for 1.5 hours at 50° C. The solution was cooled to room temperature, poured into a mixture of water, hydrochloric acid and saline, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[N:9][CH:8]=[CH:7][N:6]2[C:21]=1[C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH3:2].[CH2:27]([Mg]Br)[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])=[N:9][CH:8]=[CH:7][N:6]2[C:21]=1[C:22]([OH:26])([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])[CH3:2]
Reactant: CCC[Mg]Br
Reactant: CCCC(=O)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The resulting 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (220 mg, 0.63 mmol) was dissolved in tetrahydrofuran (2 mL), then a 0.90M propylmagnesium bromide solution in tetrahydrofuran (3.6 mL, 3.2 mmol) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 2 hours. An aqueous saturated ammonium chloride solution was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:5) to give the title compound (150 mg) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.O([Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])[CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CNc1nccc(-c2cc[nH]c2-c2ccc(F)cc2)n1
Product: CNc1nccc(-c2ccn([Si](C(C)C)(C(C)C)C(C)C)c2-c2ccc(F)cc2)n1
Yield: 82 %

Procedure:
In a similar manner to that described in Example 7(ii) above, 2-(4-fluorophenyl)-3-(2-methylaminopyrimidin-4-yl)-1H-pyrrole [prepared as described in step 1(iii) above] was reacted with triisopropylsilyl triflate, to afford the title compound (yield 82%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: O=C1CCc2cc(NCC(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-quinolin-2-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 206. Melting Point: 197-200° C. (ethyl alcohol)
Reaction SMILES: C([N:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])C.[Cl:16][CH2:17][C:18](=O)[CH2:19][C:20](OCC)=[O:21].OS(O)(=O)=O>>[C:4]([NH:3][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH2:17][Cl:16])=[CH:19][C:20](=[O:21])[O:15]2)=[CH:13][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)N(CC)c1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1ccc2c(CCl)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A suspension of ethyl 3-hydroxyphenylurethane (1.81 g, 0.01 mmole), ethyl 4-chloroacetoacetate (1.81 mL, 0.011 mole) and 70% H2SO4 (50 mL) is stirred for 4 hours at room temperature. The clear solution is poured into 400 mL of ice-water, with constant stirring, to yield a yellowish precipitate. The solid is filtered, washed with water and dried. The product is recrystallized from methanol to give colorless needles (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH:10]2[CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CO)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (735 mg) in THF (10 ml) were added triethylamine (0.41 mL) and methanesulfonyl chloride (0.21 mL) under ice-cooling, and the mixture was stirred for 1 hr. Triethylamine (0.14 ml) and methanesulfonyl chloride (0.076 ml) were added, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with 1 N hydrochloric acid, distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (863 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH2:8][C:7]([CH2:10][CH3:11])([CH3:9])[NH:6][C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)N=1)[CH3:2].[Br-].[NH4+].[OH2:19]>CO>[CH2:10]([C:7]1([CH3:9])[CH2:8][C:3](=[O:19])[CH:1]([CH3:2])[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:6]1)[CH3:11]
Reactant: O
Reactant: CCC1=NC2(CCCCC2)NC(C)(CC)C1
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: CCC1(C)CC(=O)C(C)C2(CCCCC2)N1

Procedure:
11.1 g of the 2,4-diethyl-4-methyl-1,5-diazaspiro[5.5]undec-1-ene thus obtained and 2.5 g of ammonium bromide were dissolved in 70 ml of methanol. 45 ml of water were added to the solution, with stirring. The mixture was then stirred at room temperature for 8 hours. Methanol was removed by evaporation under reduced pressure and the residue was then distilled under reduced pressure, giving 7.4 g of the title product, bp 119°-122° C./1.5 mmHg.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1)[CH3:22]
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 60 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (900 mg, 3.0 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), iPr2NEt (1.05 mL, 6.0 mmol), Pd2dba3 (69 mg, 0.08 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed with N2 for 10 minutes. The reaction was heated to 60° C. for 1.5 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 5w.
Reaction SMILES: C([O:5][C:6](=[O:47])[C@@H:7]([NH:39]C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:26][CH:25]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:7]([CH2:8][CH2:9][C:10](=[O:38])[NH:11][C:12]1[C:17]([C:18]2[O:22][N:21]=[C:20]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:26][CH:25]=3)[CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]([OH:47])=[O:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-4-(3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylcarbamoyl)-butyric acid tert-butyl ester (980 mg, 1.5 mmol) described in Manufacturing Example 1-1 and dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 0° C., which was stirred overnight at room temperature. The solvent was evaporated under a reduced pressure, and the residue was washed with diethyl ether, so as to obtain the titled compound (850 mg) as the trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cc(Cl)ccn2)C[C@H](C)O1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
cis-2,6-Dimethylmorpholine (2.029 g, 17.62 mmol) was added to a suspension of 2,4-dichloropyridine (2.37 g, 16.01 mmol) and potassium carbonate (6.64 g, 48.0 mmol) in anhydrous acetonitrile (120 mL). After addition, the reaction mixture was stirred at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LC/MS showed starting material and desired product so cis-2,6-dimethylmorpholine (0.500 equivalents) was added to the reaction mixture and then stirred and heated at 100° C. overnight. Crude LCMS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[OH-].[CH2:13]([N+](C)(C)C)[C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1>O.ClCCl>[CH2:19]([C:14]([CH3:13])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]#[CH:16])[CH3:18]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C#CC(C)(CC)Oc1ccc(C#N)cc1
Reaction time: 96 h

Procedure:
17.47 g of 2-chloro-2-methylpent-1-yne were added to a mixture of 11.9 g of 4-cyanophenol, 6.0 g of sodium hydroxide, 15 ml of a 40% methanolic solution of benzyltrimethylammonium hydroxide in 85 ml of water and 85 ml of dichloromethane and stirred for 4 days. The organic phase was separated, washed with 2M sodium hydroxide solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:9) for the elution to give 10.1 g of 4-(1-ethyl-1-methyl-2-propynyloxy)benzonitrile.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][N:8]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:10]([CH2:9][N:8]([CH2:7][C:3]1[N:2]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][N:4]=1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:28])[NH2:26])=[CH:21][CH:20]=1)([OH:12])=[O:11]
Reactant: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CCN(CC(=O)O)Cc2nccn2CC(=O)O)cc1

Procedure:
To a solution tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (40 mg, 0.079 mmol) in DCM (2.0 mL) and TFA (2.0 mL) was stirred at room temperature for 3 hrs. Solvent was removed under reduced pressure to give 2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid. A solution of 2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid and [NEt4]2[ReBr3(CO)3] (70 mg, 0.09 mmol) in MeOH (2.0 mL) and H2O (2.0 mL) was adjusted pH=9 using 2 N NaOH. The mixture was stirred at 95° C. for overnight at a pressure tube. The reaction mixture was purified by HPLC to give [Re(CO)3][2-(2-(((carboxymethyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetic acid] (20 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.76 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=1.6 Hz, 1H), 7.26 (s, 2H), 7.16 (d, J=1.6 Hz, 1H), 5.05 (d, J=16.4 Hz, 1H), 4.98 (d, J=16.4 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (d, J=16.0 Hz, 1H), 4.00 (d, J=16.8 Hz, 1H), 3.60-3.51 (m, 3H), 3.10-3.05 (m, 2H); MS (ESI), 667.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH2:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][CH2:16][NH:17][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4]
Reactant: OC(CBr)c1cccs1
Reactant: COc1ccc(CCN)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCNCC(O)c2cccs2)cc1OC
Temperature: 25 °C

Procedure:
A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (11.4 g, 0.055 mole), described in Example 4, and the primary amine, 3,4-dimethoxyphenethylamine (15 g, 0.083 mole), in 200 ml toluene is heated at reflux for 12 hr. The mixture is cooled to 25° C, shaken with 10% NaOH and the layers separated. The aqueous layer is extracted with chloroform and the combined organic phases washed with water and brine, dried (K2CO3) and concentrated. The resulting dark brown oil is purified by chromatography on silica gel to give the title compound as an oil; nmr (CDCI3) 2.9 (m, 6H), 3.45 (2H), 3.85 (s, 6H), 5.05 (m, 1H), 6.7 - 7.3 (m, 6H).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25]>CN(C=O)C>[CH2:24]([CH:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:31]1)[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCC1CCN(Cc2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CCC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-ethylpiperidinomethyl)-aniline in DMF.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[NH:19][C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:5]1([CH2:15][N:16]2[C:25](=[O:26])[C:24]3[N:23]([CH2:27][C:28]#[C:29][CH3:30])[C:22]([N:31]4[CH2:36][CH2:35][CH2:34][CH:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]4)=[N:21][C:20]=3[N:19]([CH2:2][C:3]#[N:4])[C:17]2=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2[nH]c(=O)n(Cc3cccc4ccccc34)c(=O)c21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1cccc3ccccc13)c(=O)n2CC#N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
30 μl of bromoacetonitrile are added to a mixture of 0.20 g 1-(naphth-1-ylmethyl)-7-(but-2-ynyl)-8-(3-tert-butoxycarbonylamino-piperidin-1-yl)-xanthine and 0.10 g potassium carbonate in 3 ml of dimethylformamide. The reaction mixture is stirred for 3 h at 60° C. and then cooled to ambient temperature. Water is added and the precipitate is separated off and dried at 60° C.
Reaction SMILES: [O:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCCl.O=[Mn]=O>[O:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1csc(Oc2ccccc2)n1
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: O=Cc1csc(Oc2ccccc2)n1
Temperature: 25 °C

Procedure:
A solution of (2-phenoxythiazol-4-yl)methanol (251 mg; 1.21 mmol) in anh. DCE (12 ml) was treated with MnO2 (843 mg; 9.69 mmol), and the resulting mixture was stirred at reflux, under nitrogen, for 1 h. After cooling to rt, the mixture was filtered over a pad of celite, and the separated solids were washed with DCM. The filtrate was then concentrated to dryness under reduced pressure affording 2-phenoxythiazole-4-carbaldehyde as a pale yellow oil. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 206.04 g/mol.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:5].C(O)(=O)C.[N:16]1([CH2:23][C:24]2[S:25][C:26]([C:29]([NH:31][NH2:32])=O)=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CO>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[NH:32][N:31]=[C:29]([C:26]2[S:25][C:24]([CH2:23][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:28][CH:27]=2)[N:5]=1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: N#Cc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2nc(-c3ccc(CN4CCCCCC4)s3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.7 %

Procedure:
81 mg (1.5 mmol) of sodium methoxide was added to 13.5 ml of methanol solution containing 1.56 g (15.0 mmol) of 2-cyanopyridine and stirred at room temperature for 3.5 hours. The reaction mixture was ice-cooled, 0.085 ml (1.5 mmol) of acetic acid and 1.52 g (6.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide were added with ice-cooling, and then the mixture was stirred at room temperature for 24 hours. The thus precipitated crystals were collected by filtration to give 1.97 g of the crystals. A 894 mg (2.5 mmol) portion of them was dissolved in 13 ml of acetic acid and heated under reflux for 6.5 hours. The solvent was evaporated, 28% aqueous ammonia and chloroform were added, and then the thus separated organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 715 mg of the title compound.