Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:14])=O>>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][C:5](=[O:9])[C:6]([Cl:14])=[O:7]
Reactant: CC(C)CCC(=O)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)CCC(=O)C(=O)Cl

Procedure:
reacting 5-methyl-2-oxohexanoic acid with at least a 10% excess of the stoichiometric amount of oxalyl chloride under anhydrous conditions at a temperature of 25° to 60° C. for from 40 to 60 hours to form 5-methyl-2-oxohexanoyl chloride;
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:43]([N:45]=[C:46]=[S:47])=[O:44])[CH:40]=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1cccc(C(=O)Cl)c1
Agent: COc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 90%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:43])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:25]=[N:26][N:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)[CH:28]=2)[CH2:5]1>O1CCOCC1.C(Cl)Cl.CO>[CH3:2][N:3]([CH3:43])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[N:25]=[N:26][N:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)[CH:28]=2)[CH2:5]1
Reactant: CN(C)C1CCN(c2ccc3c(c2)c(-c2cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn2)nn3C2CCCCO2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)C1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Hydrogen chloride (0.72 mL of a 4 N solution in dioxane) was added to a solution of N,N-dimethyl-1-[3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]pyrrolidin-3-amine (110 mg; 0.19 mmol; 1.0 eq.) in DCM (1.1 mL) and MeOH (0.55 mL). The reaction mixture was stirred at RT O/N. Solvents were then removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a yellow powder (65 mg, 69%). 1H NMR (300 MHz, MeOD): 8.98 (s, 1H), 8.14 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.1 Hz, 2.0 Hz, 1H), 3.80-3.68 (m, 9H), 3.63-3.43 (m, 4H), 2.84 (s, 6H), 2.61-2.51 (m, 1H), 2.30-2.21 (m, 1H). HPLC (max plot) 96.0%; Rt %2.12 min. UPLC/MS: (MS+) 487.4, (MS−) 485.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[C:24](Cl)[N:23]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[N:8]([C:24]3[CH:25]=[C:26]([N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[N:27]=[C:22]([NH2:21])[N:23]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2ccc(Br)cc2CN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(N3Cc4cc(Br)ccc4CC3CO[Si](C)(C)C(C)(C)C)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 49, Step 5 and 6 starting from 7-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline, 2-amino-4,6-dichloropyrimidine and 1-methylpiperazine. LCMS (M+H)+: m/z=547.2.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([OH:11])[C@H:9]([CH3:12])[O:8][C:7](=[O:13])[C@@H:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][O:4][CH2:3]1.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:24][CH:23]([CH3:25])[C:22]([O:1][C@@H:2]1[C@@H:10]([O:11][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:9]([CH3:12])[O:8][C:7](=[O:13])[C@@H:6]([NH:14][C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:5][O:4][CH2:3]1)=[O:26]
Reactant: CC(C)C(=O)Cl
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@@H]1OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7,8-dihydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (115.0 mg, 0.245 mmol) in pyridine (1.75 mL) was added DMAP (6.40 mg, 0.0520 mmol) followed by isobutyryl chloride (0.10 mL, 0.956 mmol) at 0° C. and the reaction was slowly warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with H2O and the reaction was stirred at room temperature for 30 min and then extracted with Et2O. The phases were separated and the aqueous phase was further extracted with Et2O. The combined organic phases were washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless, thick oil (115 mg, 94%): IR (neat) 3353, 2976, 1742, 1519, 1368, 1251, 1155 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.41 (d, J=8.2 Hz, 1H), 5.21-5.12 (m, 1H), 5.12-5.04 (m, 1H), 4.92-4.83 (m, 1H), 4.74 (dd, J=13.4, 6.9 Hz, 1H), 3.95 (dd, J=11.7, 7.0 Hz, 1H), 3.80-3.65 (m, 3H), 2.64-2.41 (m, 2H), 1.44 (s, 9H), 1.32 (d, J=6.2 Hz, 3H), 1.20 (d, J=7.0 Hz, 3H), 1.16 (d, J=7.0 Hz, 3H), 1.14 (d, J=7.0 Hz, 3H), 1.10 (d, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 175.57, 175.47, 171.37, 155.18, 80.34, 74.52, 74.30, 74.15, 73.35, 71.34, 34.01, 33.91, 28.30, 19.01, 18.88, 18.74, 18.71, 18.03; HRMS-ESI (m/z) [M]+ calcd for C21H35NO9, 445.2312; found, 445.2322.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:22][CH3:23])[N:11]2[CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:7]([NH2:24])[N:6]=1.C(N(CC)CC)C.[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>CN(C)C=O>[CH3:23][O:22][C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:24])[N:6]=[C:5]([NH:4][CH2:3][CH:2]1[CH2:25][O:26][C:34](=[O:35])[O:1]1)[N:13]=2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1nc2c(N)nc(NCC(O)CO)nc2n1Cc1ccc(C)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(NCC3COC(=O)O3)nc2n1Cc1ccc(C)nc1
Reaction time: 14 h
Yield: 26.6 %

Procedure:
2-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine (230 mg, 0.64 mmol) obtained by Reference example 18, 4-dimethylaminopyridine (5 mg, 0.04 mmol) and triethylamine (0.02 ml, 0.14 mmol) were dissolved in dimethylformamide (2 ml). Thereto was added di-t-butyl dicarbonate (410 mg, 1.9 mmol) in the oil bath kept at 50° C. and the mixture was stirred for 14 hours. The reaction mixture was concentrated and the residue was purified by preparative thin layer chromatography to give the captioned compound (64 mg, 0.17 mmol, yield 26%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13](Br)[CH:14]=1.[CH3:17][O-:18].[Na+]>CO>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N+:11]([O-:16])[CH:12]=[C:13]([O:18][CH3:17])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cc(Br)c[n+]([O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC[C@@H]2CCCN2C)c[n+]([O-])c1

Procedure:
A sample of the compound from step 98a above is reacted with sodium methoxide in methanol according to standard procedures. The reaction is quenched with water, the product is extracted, then purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH2:11])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:13]([CH:14]([NH:11][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)[CH2:15][CH3:16])[CH3:12]
Reactant: CCC(=O)CC
Reactant: Cc1nn2ccccc2c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a suspension of 2-methyl-3-amino-pyrazolo[1,5-a]pyridine (0.158 g, 1.07 mmol) and 3-pentanone (0.11 g, 0.14 mL, 1.29 mmol) in methanol (5.0 mL) was added NaCNBH3 (0.095 g, 1.5 mmol) and a drop of acetic acid. The mixture was stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined and dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (15% ethyl acetate/hexane) to give 0.196 g (85%) of a yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=7.0 Hz, 1H), 7.37 (d, J=8.9 Hz, 1H), 6.99–6.95 (m, 1H), 6.59 (t, J=6.8 Hz, 1H), 2.87 (quintet, J=5.9 Hz, 1H), 2.44 (s, 3H), 1.57–1.47 (m, 4H), 1.01 (t, J=7.4 Hz, 6H); HRMS (FAB) calcd for C13H19N3+H 218.1657. found 218.1647.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][S:5][C@H:4]2[CH2:17][CH2:18][CH2:19][C@@H:20]([CH:21]=[CH2:22])[N:3]12.[H][H]>CO.[Pd]>[CH2:21]([C@H:20]1[N:3]2[C@@H:4]([S:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]2=[O:1])[CH2:17][CH2:18][CH2:19]1)[CH3:22]
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N12
Yield: 80 %

Procedure:
A solution of tert-butyl (4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (66 mg, 0.20 mmol) in MeOH (2 mL) was purged with argon for 2 min. Then, 10% Pd/C (80 mg, 0.75 mmol) was added. The reaction mixture was stirred for under a hydrogen balloon for 3 days. The reaction mixture was filtered. The filtrate was concentrated and dried under the high vacuum to give tert-butyl (4S,7R,10 aS)-7-ethyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (52 mg, 0.16 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.02 (d, J=5.5 Hz, 1H), 5.39-5.15 (m, 1H), 4.92-4.66 (m, 1H), 4.53-4.30 (m, 1H), 3.38-3.14 (m, 1H), 2.97-2.66 (m, 1H), 2.46-2.20 (m, 1H), 2.15-1.62 (m, 8H), 1.62-1.35 (m, 10H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:15]([OH:17])=[O:16])[CH2:4][C:5]1[C:6]([I:14])=[CH:7][C:8]([I:13])=[C:9]([NH2:12])[C:10]=1[I:11].S(Cl)(Cl)=O.O1CC[CH2:24][CH2:23]1.C(O)(=O)C(C)(C)C>C(O)C.C(Cl)Cl>[CH3:1][CH2:2][CH:3]([C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH2:4][C:5]1[C:6]([I:14])=[CH:7][C:8]([I:13])=[C:9]([NH2:12])[C:10]=1[I:11]
Reactant: C1CCOC1
Reactant: CCC(Cc1c(I)cc(I)c(N)c1I)C(=O)O
Agent: CC(C)(C)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(CC)Cc1c(I)cc(I)c(N)c1I
Temperature: 150 °C

Procedure:
2 g (3.5 mmol) of iopanoic acid was dissolved in 50 ml absolute ethanol, and 0.4 ml (5,25 mmol) thionyl chloride was added. The reaction was refluxed for 3 hours. After cooling, the reaction mixture was evaporated and reconstituted in 100 ml methylene chloride. The organic mixture was washed twice with 25 ml 5% NaOH and twice with 25 ml water. The methylene chloride layer was dried over MgSO4 and evaporated to dryness, yielding 1.73 g of ethyliopanoate (82.4%). The structure was provided by 1H nuclear magnetic resonance and mass spectrometry (M+ 599). The radioisotope exchange reaction was carried out using a known procedure with some modification (Zupon, et al., 1983; Kroschwitz, 1989). Briefly, 10 mg of the ester and 0.3 ml of tetrahydrofuran were placed in a vial and treated with 1.6 mCi of [131I]sodium iodide (in 100 μl of 0.1M sodium borate buffer). Pivalic acid (25 mg) was then added. The reaction vial was sealed and heated at 150° C. for 1.5 hours. The vial was cooled and the ethyliopanoate reconstituted in methylene chloride (0.1 ml) and chromatographed on a silica gel column with methylene chloride/methanol (9:1) as the eluent. This yielded 0.54 mCi ethyliopanoate (34%). Radiochemical purity was determined by co-chromatography on a silica gel plate eluted with methylene chloride methanol (9:1); unlabeled ester served as the standard, with a retardation factor of 0.80.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH3:2].Cl.[NH2:16][OH:17]>>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)[CH3:2]
Reactant: NO
Reactant: CCOCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCOCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Ethoxybutyl)-4-piperidone oxime is prepared from 1-(4-ethoxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[N:22][C:23]([CH:26]([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[N:22][C:23]([CH:26]([F:28])[F:27])=[CH:24][CH:25]=1)[CH2:16][CH:13]1[CH2:14][CH2:15]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: COc1cccc(C(=O)NCC(CC2CC2)c2ccc(C(F)F)nc2)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-3-methoxybenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=395.1, tR (minutes, Method F)=2.96. [α]D20=+28.21 (c=2.80 mg/mL,CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]1(=[O:38])[N:23]([CH2:24][CH2:25][O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[C:22](=[O:33])[C:21]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:20]12>C(O)C>[CH3:7][C:5]1[NH:31][C:29]([CH3:30])=[C:28]([C:27]([O:26][CH2:25][CH2:24][N:23]2[C:22](=[O:33])[C:21]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:20]3[C:19]2=[O:38])=[O:32])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 83.3 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 14.95 g (60 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid methyl ester and 16.46 g (60 mmol) of 3-amino-crotonic acid-(2-phthalimidoethyl)ester in ethanol. 25.25 g (83%) of yellow crystals melting at 181°-182° C. are obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[ClH:14]>O>[Cl-:14].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]#[N:1])=[CH:9][CH:8]=1
Reactant: Cl
Reactant: COc1ccc(N)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+]#N)cc1
Product: [Cl-]
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of 4-methoxy-phenyl-diazonium chloride was prepared by adding dropwise at 0° C. a solution of 1.8 g of sodium nitrite dissolved in 2.5 ml of water to a solution of 3.075 g of p-anisidine dissolved in 25 ml of water and 8.1 ml of concentrated hydrochloric acid. The reaction mixture was allowed to stand for 2 hours.
Reaction SMILES: Cl.[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4].[C:20]([N:28]1[CH2:33][CH2:32][CH2:31][C:30]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)([CH2:34][CH2:35][CH2:36]OS(C)(=O)=O)[CH2:29]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[ClH:48].[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH2:36][CH2:35][CH2:34][C:30]2([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=3)[CH2:31][CH2:32][CH2:33][N:28]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29]2)[CH2:12][CH2:13]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4]
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)CCCN(C(=O)c2ccccc2)C1
Reactant: C=CC(=O)N(C)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 80 °C
Yield: 63.8 %

Procedure:
A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1 and 0.3 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.2 g of the expected product, m.p.=128° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[O:22][C:23]([CH:26]=O)=[CH:24][CH:25]=2)=[N:17][C:16]([Cl:28])=[CH:15][N:14]=1)(=[O:11])=[O:10].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[O:22][C:23]([CH2:26][NH:32][CH:29]3[CH2:31][CH2:30]3)=[CH:24][CH:25]=2)=[N:17][C:16]([Cl:28])=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: O=Cc1ccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1
Reactant: NC1CC1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1ccc(CNC2CC2)o1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 107b using 2,3-dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 209) (0.3 g) and cyclopropylamine (0.1 g). Yield 0.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[C:24]([C:31](O)=[O:32])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.5 %

Procedure:
To solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2b, 0.093 g, 0.301 mmol) and 3-chloro-5-cyano-2-pyridinecarboxylic acid (Bionet Research, 0.056 g, 0.307 mmol) in THF (1 mL) and MeOH (0.25 mL) at 0° C. was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (Aldrich, 0.084 g, 0.304 mmol). The reaction mixture was warmed to room temperature, stirred for 17 h and concentrated. Purification by flash column chromatography on silica gel (24 g, 10% to 60% EtOAc (10% 2M NH3 in MeOH) in hexanes) afforded the title compound (0.069 g, 0.146 mmol, 48.4% yield) as a pale yellow solid. MS m/z=474.0 (M+H); Calculated mass for C19H13ClF5N5O2: 473.1
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:23])[CH3:22]
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)ON1C(=O)C2C3C=CC(C3)C2C1=O

Procedure:
N-Hydroxy-norborn-5-ene-2,3-dicarboximide (17.92 g, 0.1 mole) is largely dissolved in 100 mL chloroform and 21 mL (0.15 moles) triethylamine, followed by adding 19 mL (0.2 moles) acetic anhydride at 0° C. with stirring. After stirring for 2 hours at room temperature, the solvent is largely removed, the residue is mixed with water and the precipitate is filtered off.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13][CH3:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>C1COCC1>[CH2:13]([N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:11][CH2:10][CH2:9][OH:8])[CH3:14]
Reactant: CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CCCO)C(=O)OCc1ccccc1
Yield: 69.7 %

Procedure:
N-Ethyl 3-benzyloxycarbonylamino-1-propanol t-butyldimethylsilyl ether (8.5 g) was dissolved in THF (120 ml), and to the resulting solution was added under ice-cooling a solution of 1N tetra-butylammonium fluoride in THF (48 ml). The resultant mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so sepasated was washed with water and then dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (4.0 g; 71%)
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:24](=[O:25])[C:23]5=[C:29]([Cl:32])[CH:30]=[CH:31][C:21]([Cl:20])=[C:22]5[C:27]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: ClCCl
Product: O=C1c2c(Cl)ccc(Cl)c2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.44 gm, 9.24 mmoles) and 3,6-dichlorophthalic anhydride (2.01 gm; 9.27 mmoles) in dichloromethane (DCM, 50 ml) was stirred at room temperature for 1 hr. White precipitates formed and the TLC of the reaction mixture showed that there was no starting amine remaining. The solvent was stripped down and the white solids which were poorly soluble in DCM were loaded onto a flash chromatography column, (SiO2; 30 gm) and the column was eluted with a solution of 1% CH3OH in DCM. The desired product thus obtained weighed 2.29 gm (54%). Recrystallization from hot ethanol yielded 2.15 gm of white crystals, m.p.=163°-164° C.