Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:47]=[CH:48][C:49]([CH2:52]O)=[N:50][CH:51]=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:52][C:49]4[CH:48]=[CH:47][C:46]([C:45]([F:54])([F:44])[F:55])=[CH:51][N:50]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1n(Cc2ccc(C(F)(F)F)cn2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.28 mmol), prepared as described in Example 1, Ph3P (220 mg, 0.84 mmol) and (5-trifluoromethyl-pyridin-2-yl)methanol (50 mg, 0.28 mmol) in THF (2.0 mL) was added 40 wt % diethyl azodicarboxylate (DEAD) solution in toluene (0.33 mL, 0.84 mmol) at RT under argon. The reaction was stirred at RT for 30 min. Water (5.0 mL) was then added and the resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) followed by saturated aqueous NaCl (2×5 mL). The combined organic layers were concentrated under reduced pressure to obtain the crude product. This crude product was purified using reverse phase preparative HPLC to give the title compound 7,8-bis(4-chlorophenyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (69.2 mg, 48%) as a yellow solid. MS (M+H)=516; 1H NMR (CDCl3): δ 8.83 (1H, s), 8.20 (1H, s), 7.93 (1H, d, J=8.2 Hz), 7.40 (1H, d, J=10.0 Hz), 7.26-7.34 (6H, m), 7.11 (2H, d, J=10.0 Hz), 5.47 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Cc1cccc(N)c1C
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1cccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1C

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,3-dimethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,3-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (87%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, CDCl3) δ7.98 (s, 1H), 7.69-7.53 (m, 2H), 7.46-7.33 (m, 2H), 7.33-7.11 (m, 6H), 7.11-6.99 (m, 3H), 6.45 (s, 1H), 6.40 (s, 1H), 5.34-5.17 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.52 (t, J=8.7 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 2.32 (s, 3H), 2.22 (s, 3H); MS (ES+) m/z 539.1 (M+23).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[NH2:18][CH2:19][CH2:20][NH:21][CH3:22]>>[C:1]([NH:3][C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CNCCN
Product: CNCCNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 15 h

Procedure:
N-Cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.4 g) and (2-aminoethyl)methylamine (25 ml) were mixed together and left for 15 hours at 20° C. Evaporation to dryness and azeotroping with aceonitrile to remove excess diamine gave a solid residue which was recrystallised from isopropanol to give the title compound (4.8 g), m.p. 146°-148° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:24][C:22]=1[NH2:23]>>[F:18][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)=[CH:27][C:21]=2[O:20][CH3:19])=[N:3][CH:4]=1
Reactant: Cn1cc(-c2nc(Cl)ncc2F)c2ccccc21
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(F)c(-c2cn(C)c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole (INTERMEDIATE 50) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+].CO>O>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 0.19 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.19 g of potassium carbonate and 3 ml of methanol was heated under reflux for 27 hours. To this mixture was added 93 mg of potassium carbonate, and the mixture was further heated under reflux for 2 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.16 g of 3-methoxy-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 9”).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[Br:26]C1C=C(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)C=CC=1>>[Br:26][C:22]1[CH:21]=[C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CSc1ncnc2sc(-c3c(-c4cccc(Br)c4)ncn3C)cc12
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(3-bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 58) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Pale yellow foam (740 mg, 82%);
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:30])[CH2:9][CH3:10])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@@H:8]([C:11]1[C:12]([F:30])=[C:13]([C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:20]=1)[C:27]#[N:28])=[O:29])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(OC)c(C#N)c2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(OC)c(C#N)c2)c1F
Reaction time: 60 h
Yield: 92.3 %

Procedure:
Step 5 To a solution of {(R)-1-[4-Chloro-3-(3-cyano-4-methoxy-benzoyl)-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (59 mg, 0.13 mmol) in DCM (2 mL) was added 4M HCl in dioxane (0.17 mL, 0.66 mmol, 5 eq.) and the reaction mixture was stirred for 60 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL) made basic with 5M NaOH. The aqueous phase was extracted with further DCM (10 mL) and then the combined organics were dried (MgSO4), filtered and concentrated to give 5-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-2-methoxy-benzonitrile (41 mg, 0.12 mmol) as a viscous gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:4]([CH3:24])[N:3]=1.O=S(Cl)[Cl:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:9]([NH:8][C:6]1[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:27])=[CH:16][C:15]=2[O:22][CH3:23])=[C:4]([CH3:24])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Temperature: 25 °C

Procedure:
The product from step (iii) (2.2 g) in DCM (100 mL) was cooled to 0° C. and SOCl2 (0.486 ml) was added dropwise. The reaction was allowed to warm up to rt over 1 hr, and poured cautiously into sat. NaHCO3 and the aqueous phase was separated. The organic phase was dried, filtered and the solvent evaporated under reduced pressure to give the subtitle compound as a yellow solid, 2.260 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:21]2[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:28].[CH3:27][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]3[CH2:31][CH2:30][O:29][CH2:34][CH2:33]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C)CC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CN(C)CC1

Procedure:
5,5-Dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-methyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-morpholinobutyric acid hydrochloride and dicyclohexylcarbodiimide are combined in equimolar amounts in methylene chloride and reacted as in Example 1 to give the desired product.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][C:29]([CH3:44])([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)=[O:32])[CH3:30])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19](=[O:21])[NH2:20])[N:17]([S:22]([O-:25])(=[O:24])=[O:23])[C:16]2=[O:26])=[O:13])[N:10]=1)=O.[Na+:45].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:27][O:28][C:29]([CH3:44])([C:31]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=2)=[O:32])[CH3:30])[C:12]([NH:14][C@H:15]2[C@@H:18]([C:19](=[O:21])[NH2:20])[N:17]([S:22]([O-:25])(=[O:24])=[O:23])[C:16]2=[O:26])=[O:13])[N:10]=1.[Na+:45]
Reactant: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CC(C)(ON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1C(N)=O)c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
In 20 ml of water is dissolved 280 mg of sodium cis-3-{2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer) as obtained in Example 131C, and under ice-cooling and stirring, 104 mg of sodium monomethyldithiocarbamate is added. The mixture is stirred at room temperature for 1.5 hours. The reaction mixture is twice washed with ether, and then purified by column chromatography on Amberlite XAD-II (40 g), eluting with water and then 20% ethanol. The fractions including the desired product are combined and lyophilized to give sodium cis-3-{2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido}-4-carbamoyl-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][N:20]2[CH2:23][CH2:24][CH2:25][N:14]([CH2:15][CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:14]12[CH2:25][CH2:24][CH2:23][N:20]([CH2:21][CH2:22][NH:11][CH2:12][CH2:13]1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2
Reactant: O=C(OCc1ccccc1)N1CCN2CCCN(CC1)CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: C1CN2CCNCCN(C1)CCNCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
To a solution of 3 (3.67 g, 7.64 mmol) in ethanol (60 mL) was added 10% Pd/C (1.10 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×10 mL). The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 4 (1.57 g, 97% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2SCC)(=[O:3])[CH3:2]>[Ni]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[CH:7]2)(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(SCC)cc(C(=O)OC)nc12
Agent: [Ni]
Product: CCCc1c(O)c(C(C)=O)cc2ccc(C(=O)OC)nc12
Yield: 72.6 %

Procedure:
Methyl 6-acetyl-4-ethylthio-7-hydroxy-8-propylquinoline-2-carboxylate (1.0 g), was added to Raney Nickel (16 g wet wt; previously washed with ethanol) in dry ethanol (100 mls), and reflux for 11/2 hours. The catalyst was filtered off, and the filtrate evaporated to dryness. The residue was triturated with 40°-60° petroleum ether and the yellow solid collected by filtration to give 0.6 g of the sub-title product. A recrystallisation from ethanol gave 0.2 g, mp 110°-111°.
Reaction SMILES: [C:1]([N:4]([CH3:8])[C:5](Cl)=[O:6])(=[O:3])[CH3:2].[N:9](=[C:11]1[C:16]([CH3:18])([CH3:17])[NH:15][C:14](=[O:19])[CH2:13][S:12]1)[OH:10]>>[C:1]([N:4]([CH3:8])[C:5]([O:10][N:9]=[C:11]1[C:16]([CH3:17])([CH3:18])[NH:15][C:14](=[O:19])[CH2:13][S:12]1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)C(=O)Cl
Reactant: CC1(C)NC(=O)CSC1=NO
Product: CC(=O)N(C)C(=O)ON=C1SCC(=O)NC1(C)C

Procedure:
Utilizing the procedure of Example XII, N-acetyl-N-methylcarbamic acid chloride was reacted with 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one to yield 2-[O-(N-acetyl-N-methylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 218°-220° C. The nmr spectrum supported the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.N#N>O=[Mn]=O.O1CCOCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Agent: O=[Mn]=O
Agent: N#N
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol (550 mg, 1.26 mmol, Intermediate 48: step a), 1,4-dioxane (6.2 mL) and activated MnO2 (551 mg, 6.34 mmol) were combined in a round-bottom flask and the mixture was refluxed under a positive pressure of N2. After 4 hours, the reaction was allowed to cool to ambient temperature, then filtered through Celite® and rinsed with dichloromethane. The filtrate was washed with water, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([S:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=S([O-])c1cccc(Cl)c1
Reactant: O=Cc1cccnc1Cl
Agent: [Na+]
Product: O=Cc1cccnc1S(=O)(=O)c1cccc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 5a using 2-chloropyridine-3-carbaldehyde and 3-chlorobenzenesulfinic acid sodium salt.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2(O)[CH2:19][CH2:18][CH:17]([N:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.Cl>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH3:21])[CH3:22])[CH2:16][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C1CCC(O)(c2ccccc2Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)C1CC=C(c2ccccc2Cc2ccccc2)CC1
Reaction time: 72 h
Yield: 99.7 %

Procedure:
A solution of 7.0 g of 1-[2-(phenylmethyl)phenyl]-4-dimethylaminocyclohexanol of Example 1 in 30 ml of acetic acid and 3 ml of hydrochloric acid (concentrated) is heated to reflux for 41/2 hours. After the contents are allowed to stand at 5° C. for 3 days, the solvent is evaporated off and the residue is dissolved in 50 ml of water. The solution is filtered and made alkaline with a slight excess of 50% aqueous NaOH. After cooling, the product is collected by suction filtration, and the filter cake is washed with water and dried in vacuo over P2O5 at 40° C. to yield 6.57 g (99.7% yield) of 1-[2-(phenylmethyl)phenyl]-4-dimethylaminocyclohex-1-ene m.p. 44°-45° C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH2:19])[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][S:3][C:1](=[O:4])[CH3:2])[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(O)=S
Reactant: C=C(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)OCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)CC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 23 h
Yield: 79 %

Procedure:
Thioacetic acid (5 mL), which had been cooled to 0° C., was added to a mixture of 3-(2-ethoxycarbonyl-allyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.72 g; 2.54 mmol) and triethyl amine (0.37 mL; 2.67 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 23 hours and then poured onto ice-water (400 mL). The aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with saturated NaHCO3, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/EtOAc: 1/10→68/32) to yield 3-(3-acetylsulfanyl-2-ethoxycarbonyl-propyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.72 g, 79%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>C(N(CC)CC)C>[NH2:10][CH2:7][CH2:8][CH2:9][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Product: NCCCN1CCOCC1
Reaction time: 5 h

Procedure:
One mole of morpholine is reacted with 1.1 moles of acrylonitrile, added at about 28° C. with about 0.05 moles of a basic triamine, such as triethylamine, as a catalyst. The reaction is exothermic. After stirring for about 5 hours, the reaction mixture is distilled free of unreacted acrylonitrile. The resulting acrylonitrile adduct is reduced to the amine at 100° C. -150° C. under 1000 psig hydrogen using a copper catalyst. The resulting product is distilled to purity.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]4[CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(NCc1nccnc1Cl)N1CCn2c(nnc2C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1nnc2n1CCN(c1ncc3c(Cl)nccn13)C2
Temperature: 60 °C
Reaction time: 24 h
Yield: 25.1 %

Procedure:
To N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1.382 mmol, 500 mg) in ethyl acetate (5 ml) at 0° C. was added phosphorus oxychloride (5.53 mmol, 0.515 ml). The reaction mixture was stirred at room temperature for two days and at 60° C. for one day. The reaction mixture was cooled to 0° C., an excess solid sodium hydrogencarbonate was added and the suspension was stirred at 0° C. for 10 minutes and at room temperature for 20 minutes. Then the suspension was again cooled to 0° C., water was added and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane applying a gradient 0 to 10% methanol) to give 7-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (119 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O.C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:18]2[CH2:19][CH2:20][CH2:21][C:22]2=[O:24])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCN
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)CN(Cc2ccccc2)CCC1N1CCCC1=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To an ice cold solution of 1-benzyl-3,3-dimethyl-piperidin-4-one (0.5 g, 2 mmol) (J. Med. Chem. Lett. 2003, 13, 1627) in CH2Cl2 (10 ml) was added methyl 4-aminobutyrate hydrochloride (0.7 g, 5 mmol), acetic acid (0.4 ml, 7 mmol), triethylamine (0.5 ml, 5 mmol) and sodium triacetoxyborohydride (0.5 g, 3 mmol). The mixture was allowed to reach room temperature and was stirred for 16 h after which time it was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. The residue (0.6 g, 2 mmol) was then redissolved in MeOH (10 ml), potassium carbonate (0.3 g, 2 mmol) added and the mixture heated to 70° C. for 2 h. The mixture was then filtered, the methanol evaporated and the residue redissolved in DMF (10 ml) and reacted with EDCl (0.4 g, 2 mmol) at 60° C. for 2 h after which time the DMF was evaporated, the residue taken up in CH2Cl2, washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:n-heptane 2:1) afforded the title compound (0.4 g, 85%) as yellow oil. MS: 287.4 (MH+).