Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:29]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)c(F)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml), washed with 10% aqueous citric acid solution and water successively, dried over anhydrous sodium sulfate and concentrated. To the resulting residue was added hot methanol to crystallize and then cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 18 ml) and stirred at room temperature for an hour. The reacting mixture was neutralized with concentrated aqueous ammonia and the resulting precipitate was collected by filtration, washed with ice-water sufficiently and recrystallized from dichloromethane-methanol (1:1) to give the title compound (0.41 g) as colorless prisms, mp 232°-234° C. (decompd.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[C:8]2Cl)(=[O:3])[CH3:2].C(NC1C=C2C(=CC=1)NC(C)CC2)(=O)C.N1C2C(=CC=CC=2)CCC1.C([O:44][CH:45]=[C:46]([C:52](OCC)=O)[C:47]([O:49]CC)=[O:48])C.NC1C=C2C3N(C=C(C(O)=O)C2=O)C(C)CCC=3C=1.C(OC(=O)C)(=O)C>>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:12]3[N:11]([CH:52]=[C:46]([C:47]([OH:49])=[O:48])[C:45]2=[O:44])[CH:10]([CH3:15])[CH2:9][CH2:8][C:7]=3[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2nc(C)cc(Cl)c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC(=O)Nc1ccc2c(c1)CCC(C)N2
Agent: CC1CCc2cc(N)cc3c(=O)c(C(=O)O)cn1c23
Agent: c1ccc2c(c1)CCCN2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c3c(c1)c(=O)c(C(=O)O)cn3C(C)CC2
Temperature: 140 °C

Procedure:
6-Acetamido-4-chloro-2-methylquinoline is reduced catalytically to the novel compoound 6-acetamido-2-methyl-1,2,3,4-tetrahydroquinoline. The tetrahydroquinoline is condensed with diethyl ethoxymethylenemalonate by heating without a solvent for 1 hour at 140° C. Polyphosphoric acid is added, and the solution is heated at 100° C. for one-half hour. The product, 9-amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid is reacted with acetic anhydride as described in Example 49 to provide 9-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. >310° C. The product is characterized by spectral analysis and elemental analysis, which are found to be consistent with the indicated structure.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]1([CH3:42])[C:40]([OH:41])=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:27]=3[O:41][C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:42])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: Cc1ccccc1O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccc2C)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with o-cresol as in Example 45 to afford 0.038 g (25%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) 71 m/Z exact mass calculated for C31H27O5F3 537.1888, found 537.1893.
Reaction SMILES: [C:1](=[O:53])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:42])[C@@H:12]([NH:20][C:21](=[O:41])[C@@H:22]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:37](=[O:38])[CH:36]=[CH:35][C:34]2=[O:39])[CH:23]([CH3:25])[CH3:24])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1.[N:54]1([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(OCC)C>CS(C)=O>[O:39]=[C:34]1[CH:35]=[CH:36][C:37](=[O:38])[N:33]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:22]([C:21]([NH:20][C@H:12]([C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([N:57]2[CH2:56][CH2:55][N:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:59][CH2:58]2)=[O:53])=[CH:9][CH:8]=1)=[O:42])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:18])[NH2:19])=[O:41])[CH:23]([CH3:24])[CH3:25])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
Step 1 4-((S)-2-((S)-2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-nitrophenyl carbonate 58 (30 mg, 0.041 mmol) was reacted with tert-butyl piperazine-1-carboxylate (5.3 mg, 0.0287 mmol) in anhydrous DMSO under argon atmosphere at room temperature (FIG. 7d). The reaction mixture was stirred for 1 h, until disappearance of the starting material (HPLC-MS analysis). Diethyl ether (80 ml) was then added to the reaction mixture and the precipitate thus obtained was collected by filtration to give N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-L-valyl-N-{4-[({[4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}oxy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide 59 as a yellow solid, 22.0 mg) was isolated and used without further purification in the next step. MS (ESI): 785 [M+H]+. Retention time=4.87 min (method 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C(N1C=CC(=O)C(O)=C1C)(=O)C.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:45]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCCCO
Agent: CC(=O)n1ccc(=O)c(O)c1C
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with 1-amino-5-hydroxypentane under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one as white crystals, m.p. 136°-138° C.; δmax (nujol) 1625, 3350 cm-1 : δ(d6DMSO) 1.3 (m, 6H), 2.40 (s, 3H), 3.25 (t, 2H), 4.20 (t, 2H), 7.20 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [CH:1]([C:4]([CH:6]([CH3:8])[CH3:7])=[O:5])([CH3:3])[CH3:2].[C:9]1([CH3:32])[CH:14]=[CH:13][C:12]([S:15](OCC2C([N+]([O-])=O)=CC=CC=2[N+]([O-])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C1(S(C(S(C2CCCCC2)(=O)=O)=[N+]=[N-])(=O)=O)CCCCC1>>[CH3:2][C:1]([S:15]([C:12]1[CH:13]=[CH:14][C:9]([CH3:32])=[CH:10][CH:11]=1)(=[O:17])=[O:16])([C:4](=[O:5])[CH:6]([CH3:8])[CH3:7])[CH3:3]
Reactant: CC(C)C(=O)C(C)C
Reactant: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Agent: [N-]=[N+]=C(S(=O)(=O)C1CCCCC1)S(=O)(=O)C1CCCCC1
Product: Cc1ccc(S(=O)(=O)C(C)(C)C(=O)C(C)C)cc1

Procedure:
Using diisopropylketone, the reaction was carried out in the same manner as described in Synthesis Example 9, (2) and (3). The crude solid was recrystallized from n-hexane/benzene to afford 2,4-dimethyl-2-(p-toluenesulfonyl)pentan-3-one as white leaflets.
Reaction SMILES: [O:1]1CCOC[CH2:2]1.[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20](Br)[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8].C[Zn]C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCCCCCC.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20]([O:1][CH3:2])[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8]
Reactant: COCc1cc(OC)c(-c2c(Br)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Zn]C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2c(OC)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 60 °C

Procedure:
To a dioxane (15 mL) solution of tert-butyl{2-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl}carbamate (323 mg, 0.612 mmol) were added 2M dimethyl zinc (0.612 mL, 1.22 mmol) and bis(tri-tert-butylphosphine)palladium(0) (15.6 mg, 0.031 mmol), and the mixture was heated at 60° C. for one hour. After the reaction was completed, the solvent was directly distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/1) to obtain the title compound (205 mg, 0.442 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+].C(OCCOCCO)C>O>[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:2][CH2:3][N:4]([CH2:13][CH3:14])[C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1)=[O:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCN(CCCl)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCCOCCO
Product: CCN(CCOc1ccc(C=O)cc1)c1ccc(C=O)cc1

Procedure:
A mixture of 4-[[2-Chloroethyl]ethylamino]benzaldehyde 10.6 g (0.05 m), p-hydroxybenzaldehyde (6.1 g, 0.05 m), 50% NaOH (4.4 g), water (50 mL), and 2-(2-ethoxyethoxy)ethanol was heated at reflux for 6 hours and then allowed to cool. A semi-solid product was obtained which was washed with water by decantation and recrystallized from methanol. After being collected by filtration, washed with methanol, and dried in air the product weighed 6.5 g and the structure was confirmed by mass spectral analysis to be as follows: ##STR14##
Reaction SMILES: [C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13](I)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1)#[CH:23]>>[C:1]([C:5]1[N:10]2[N:11]=[CH:12][C:13]([C:23]#[C:22][C:24]3[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=3)=[C:9]2[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Product: CC(C)(C)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 7-tert.-butyl-5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidine (70 mg, 0.17 mmol) and 5-ethynyl-thiophene-2-sulfonamide (example D.3) (32 mg, 0.17 mmol) according to general procedure II. Obtained as a yellow solid (28 mg, 28%). MS (ISP) 471.1 [(M+H)+]; mp 253-255° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][CH:13]([O:38][CH3:39])[C:14]1[N:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[C:24](OC2C=CC=CC=2)=[O:25])=[CH:16][C:15]=1[N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.[NH2:40][C:41]1[CH:48]=[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])[C:44]([C:45]#[N:46])=[CH:43][N:42]=1>C1COCC1>[C:45]([C:44]1[C:47]([NH:49][CH2:50][CH2:51][O:52][CH3:53])=[CH:48][C:41]([NH:40][C:24]([N:21]2[C:22]3[C:17](=[CH:16][C:15]([N:33]4[CH:37]=[CH:36][N:35]=[CH:34]4)=[C:14]([CH:13]([O:12][CH3:11])[O:38][CH3:39])[N:23]=3)[CH2:18][CH2:19][CH2:20]2)=[O:25])=[N:42][CH:43]=1)#[N:46]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1-n1ccnc1)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-n4ccnc4)c(C(OC)OC)nc32)ncc1C#N
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
A solution of LHMDS (1M in THF, 260 μL, 0.260 mmol) was added to suspension of phenyl 7-(dimethoxymethyl)-6-(1H-imidazol-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 320, 49.7 mg, 0.126 mmol) and 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 25 mg, 0.130 mmol) in THF (1 ml) at −70° C. and the reaction mixture was stirred at −65° C. for 90 min. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with ethyl acetate and water. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (2-3%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.79 min; ESI-MS 493.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([NH:18][CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([N:18]([CH3:23])[CH3:19])[N:14]([CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1nc2c(OCc3ccccc3)cccc2n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc2c(OCc3ccccc3)cccc2n1C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
To a solution of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (200 mg) in dimethylformamide (2 ml) was added sodium hydride (32.9 mg) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added methyl iodide (127 mg), and the mixture was stirred for 15 minutes under ice-cooling and then for 2 hours at ambient temperature. Water was added to the reaction mixture, and extracted with chloroform. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (chloroform:methanol=50:1, v/v) to give 4-benzyloxy-1-methyl-2-dimethylamino-1H-benzimidazole (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C:20]1([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C1(N)CC1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.3 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH2:37][CH2:38][CH2:39]Cl)[CH3:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>CN(C)C=O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][N:35]([CH2:37][CH2:38][CH2:39][O:16][C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:15][N:14]=2)[CH3:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 100 °C
Yield: 64 %

Procedure:
17 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one were dissolved in 200 ml of dimethylformamide. 11 g of potassium carbonate were added to the solution and the reaction mixture was heated at 100° C. under a nitrogen atmosphere for 0.5 hours. A solution of 21 g of 3-[N-(2-(3,4-di-methoxyphenyl)-ethyl)-N-methylamino]-propylchloride in 150 ml of dimethylformamide was then added dropwise. After 2 hours the salts which formed were filtered out, the filtrate was evaporated to dryness, and the residue was dissolved in ethyl acetate. The solution was subsequently washed with 7% strength aqueous sodium hydroxide solution in order to remove unreacted 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one, dried with sodium sulfate and evaporated to dryness. The residue which remained was 35 g of oily crude product. This product was purified by chromatography over finely particulate silica gel under slightly elevated pressure (flash chromatography) using tert-butyl methyl ether/methanol 10:1 as eluent. 22.3 g of the title compound were obtained as an oil. IR spectrum of the base (as film): 1513 cm-1, 1260 cm-1, 1236 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:7](=[O:17])[CH2:6][CH2:5]2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.CCOCC>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:17]
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.045 g, 0.182 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.103 g, 0.361 mmol) at room temperature and the resulting mixture was stirred over night (18 h). The reaction was diluted with ether (45 mL) and the precipitate collected by vacuum filtration. The precipitate was washed from the filter with methanol and the solvent was evaporated. The residue was diluted with 1N sodium hydroxide solution (5 mL) and product was extracted into ethyl acetate (3×10 mL). The combined ethyl acetate layer was washed with brine and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 1:19). Product was dried under high vacuum. Yield: 40 mg of yellow oil 4 (58%) 1H NMR (CDCl3) δ 7.44 (dd, J=1, 5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.1, 8.4 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 4.87 (br s, 2H), 3.98 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.25 (s, 6H), 1.89-1.79 (m, 2H). MS (ESI): 357.2 (M+1). ESI-HRMS calculated for C19H25N4SO (MH+): 357.1743, Observed: 357.1752.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 0.20 g (0.573 mmol) of the product of Example 321 in 2.5 mL of DMF was added 0.099 g (0.602 mmol) of 3-picolyl chloride hydrochloride and 0.249 g (1.805 mmol) of potassium carbonate. The reaction was stined for 18 h at room temperature and then the reaction was then diluted with water and extracted with ether. The combined organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with ether to give 0.158 g (63%) of the product as tan crystals. Electrospray Mass Spec: 440.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=[C:4]([NH2:13])[N:3]=1.[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCOCC1>[NH2:13][C:4]1[N:3]=[C:2]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]([CH2:8][CH2:9][O:10][CH3:11])=[C:6]([CH3:12])[N:5]=1
Reactant: CCCCCN
Reactant: COCCc1c(C)nc(N)nc1Cl
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1CCOC
Reaction time: 7 h
Yield: 57.5 %

Procedure:
A mixture of 4-chloro-5-(2-methoxyethyl)-6-methylpyrimidine-2-ylamine (150 mg, 0.74 mmol), amylamine (0.86 ml) and dioxane (1.5 ml) was kept at 90° C. for 7 hours. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform and a saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (4%MeOH: CHCl3) to give the object compound (108 mg, 57.5%).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]([NH:9][CH:10]1[C:20]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=2[C:18]2[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:28][CH3:29])[C:17]=2[O:26][CH3:27])[CH2:12][CH2:11]1)=[O:8].O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[S:2]([OH:5])([O:25][C:22]1[CH:23]=[CH:24][C:19]2[C:18]3[C:17]([O:26][CH3:27])=[C:16]([O:28][CH3:29])[C:15]([O:30][CH3:31])=[CH:14][C:13]=3[CH2:12][CH2:11][C@H:10]([NH:9][C:7](=[O:8])[CH3:6])[C:20]=2[CH:21]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OS(=O)(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Chlorosulphonic acid (1 ml) was added at 0° C. in portions to a solution of pyridine (10 ml). After 15 minutes at 0° C., a solution of N-acetyl-colchicinol (1 g, 2.8 mmol) in pyridine (10 ml) was added. The solution was stirred overnight at ambient temperature. Water (30 ml) was added and the mixture was adjusted to pH8 by addition of sodium hydrogen carbonate. The aqueous layer was extracted with ether (3×20 ml) and purified on HP20SS resin, eluted with a 0–40% gradient of methanol/water. The volatiles were removed by evaporation to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl hydrogen sulphate as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[N:17][N:16]=[CH:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]=[N:16][N:17]=[C:18]2[C:19](=[O:21])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(CN2CCC(n3cnnc3)CC2)cc1
Product: CC(=O)c1nncn1C1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 1-benzyl-4-(4H-1,2,4-triazol-4-yl)piperidine (200 mg) in acetic anhydride (20 ml) was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure to a thick oil. Flash chromatography eluting with dischloromethane then 5% methanol in dichloromethane gave 1-[4-(1-benzylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl]ethanone as a colourless oil (60 mg).