Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][NH2:28])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CO>[C:1]1([C:7](=[N:28][O:27][CH2:26][CH2:25][NH:24][C:23](=[O:29])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1c[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)NCCON
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 89 %

Procedure:
tert-Butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (Reference Example 8) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104: Rf 0.42 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) δ1.38-1.39 (9H, s), 3.40-3.44 (2H, m), 3.17-3.20 (1H, t, J=5.7 Hz), 3.26-3.28 (1H, t, J=5.3 Hz), 6.50-6.80 (1H, m), 7.30-7.50 (5H, m), 7.86-8.32 (2H, m), 8.76 (1H, s); ESI MS m/z 381 [C21H24N4O3+H]+; HPLC (Method A) 96.8% (AUC), tR=17.7 min.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO.O>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[C:14]([C:15]#[N:16])[C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCOc2c(C#N)cc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN1CCOc2c(C#N)cc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a stirred solution of Methyl 4-butyl-8-cyano-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (184 mg) in methanol (3 mL) was added potassium hydroxide (7 mL of a 1.0 M solution in water). The mixture was stirred at room temperature overnight then concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 154 mg of the title compound: 1H NMR (300 MHz, CDCl3) (57.62, 7.46, 4.44, 3.41, 3.33, 1.60, 1.41, 0.98.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](OCC)C.[Si](C=[N+]=[N-])(C)(C)C.CC(O)=O>ClCCl.CO>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:9][C:8]=2[C:16]([F:17])([F:18])[F:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCC
Reactant: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
To a stirred solution of 4-cyclohexyl-3-(trifluoromethyl)benzoic acid (Preparation 118B, 0.5 g, 1.836 mmol) in dichloromethane (2 mL) and MeOH (2 mL) was added 2M diethyl ether solution of TMS-diazomethane (1.836 mL, 3.67 mmol) dropwise at 0° C. till no gas evolved. The mixture was stirred at room temperature for 1 hr before AcOH (0.210 mL, 3.67 mmol) was added at 0° C. to quench the reaction. The mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate solution (5 mL) and extracted with dichloromethane (3×3 mL). The combined dichloromethane extracts were dried (sodium sulfate) and concentrated under reduced pressure to give a liquid. Flash chromatography purification (silica gel column, 10→40% dichloromethane in n-heptane) afforded methyl 4-cyclohexyl-3-(trifluoromethyl)benzoate (0.5 g, 1.746 mmol, 95% yield) as a colorless liquid. The compound had an HPLC retention time=4.03 min. (condition C); LC/MS M+1=287.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8]([N:17]3[CH2:18][CH2:19][CH2:20][N:14]([CH3:13])[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Cc1cc2oc(S)nc2cc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc2oc(N3CCCN(C)CC3)nc2cc1Cl

Procedure:
5-Chloro-6-methyl-2-mercaptobenzoxazole (200 mg) was dissolved in chloroform (20 ml), N-methylhomopiperazine (1.24 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 days. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-6-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (183 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[C:15]([O-])(O)=O.[Na+]>CO.Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1cc(F)c(CC(=O)O)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(F)cc(OC)cc1F
Yield: 92 %

Procedure:
A solution of PMW04140 (3.37 g, 16.7 mmol) in MeOH (70 mL) containing conc. HCl (15 drops) was heated at reflux overnight. The mixture was allowed to cool and was neutralised with sat aq. NaHCO3. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with H2O (100 mL), sat. aq, NaHCO3 (100 mL) and brine (100 mL) then dried (MgSO4) and the solvent was removed in vacuo. The title compound (3.30 g, 92%) was obtained as a pale yellow oil; 1H NMR. (270 MHz, DMSO-d6) 3.61 (2H, s, CH2), 3.69 (3H, s, CH3), 3.76 (3H, s, CH3), 6.40-6.49 (2H, m, ArH); 19F NMR (376.4 MHz, DMSO-d6)-114.4 (d); HRMS (ES+) calcd, for C10H11F2O3 (M++H) 217.0657. found 217.0663; LC/MS (ES+) tr=1.69 min, m/z 216.8 (M+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:44](=[O:46])[CH3:45])[CH:42]=1>>[C:44]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]1[CH:42]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:52])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:46])[CH3:45]
Reactant: COCCCN(C(C)=O)c1cc(CCl)ccc1C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN(C(C)=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.147 g of N-(5-chloromethyl-2-methylphenyl)-N-(3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.12 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:8].Cl[CH2:10][C:11](O)=[O:12].C(=O)([O-])[O-].[K+].[K+]>O>[NH:1]1[C@@H:2]2[C@@H:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[NH:8][CH2:10][C:11]1=[O:12]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CN[C@@H]2CCCC[C@@H]2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.4 %

Procedure:
cis-1,2-Diaminocyclohexane (4.1 g, 36 mmol) is dissolved in 150 ml of H2O. Chloroacetic acid (3.4 g, 36 mmol) in 50 ml of H2O is added dropwise at 10° C. in 5 minutes, then potassium carbonate (7.9 g, 57 mmol) in 30 ml of H2O is added dropwise at 10 C. The reaction mixture is allowed to warm slowly to room temperature and stirred 24 hours. The solution is heated at 90° C. for 2 hours, concentrated. The resulting solid is taken-up in boiling toluene (100 ml), filtered while hot, concentrated to give (+/−)-cis-decahydroquinoxalin-2-one (0.8 g, 14% yield) as a white solid.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)(=[O:11])[C:8]([Cl:10])=[O:9].O>ClC(Cl)C>[ClH:10].[C:2]([C:1]1[O:5][C:7](=[O:11])[C:8](=[O:9])[N:6]=1)([CH3:4])=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: CC(Cl)Cl
Solvent: O
Product: C=C(C)C1=NC(=O)C(=O)O1
Product: Cl

Procedure:
A warm solution of methacrylamide (21.25 g) in dichloroethane (90 ml) was dropwise added in 1 hour to oxalyl chloride (34.5 g) kept at room temperature (20° C.) while stirring. The resultant mixture was cooled with water to room temperature. The produced 2-isopropenyloxazoline-4,5-dione hydrochloride (37 g) was collected by filtration under suction, washed with hexane and dried under reduced pressure. Decomposition temperature, 102° to 103° C.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17]CC)=O)[CH2:4][NH:3][CH2:2]1.Cl.[CH3:21][NH2:22].CN>C1COCC1>[CH3:21][NH:22][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][NH:3][CH2:4]1)=[O:17]
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)C1CNCCc2c1[nH]c1ccccc21
Temperature: 80 °C
Yield: 65.8 %

Procedure:
Ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (1.29 g, 5 mmol; European Patent No. EP 064 317 B1) and methylamine hydrochloride (0.67 g, 10 mmol) were added to a solution of methylamine in THF (2 M, 15 mL) and the suspension was heated to 80° C. in a sealed tube under nitrogen stirring for 72 hours. Solvent was evaporated to give a crude product, which was purified by chromatography on silica gel eluting with MeOH-DCM (1:9 to 1:4) to give the title compound (0.8 g); 1H-NMR (CDCl3): δ 8.46 (1H, br s), 8.24 (1H, s), 7.48 (1H, d)), 7.30 (1H, d), 7.16 (1H, m), 7.10 (1H, m), 3.70 (1H, d), 3.66 (1H, dd), 3.46 (1H, dd), 3.08 (2H, m), 2.87 (2H, m), 2.73 (3H, d), 1.9 (1H, br s); MS (ES): 244 (MH+).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][C@@:13]12[C:22]3[CH:23]=[CH:24][C:25]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:21]=3[CH2:20][CH2:19][C@H:18]1[NH:17][C:16](=[O:34])[CH2:15][CH2:14]2.CI>C(OCC)(=O)C>[CH3:1][N:17]1[C@H:18]2[C@@:13]([CH3:12])([C:22]3[CH:23]=[CH:24][C:25]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:21]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:34]
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3ccccc3)ccc12
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccccc4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 471.2 %

Procedure:
Potassium t-butoxide (0.22 g, 1.9 mmol) was added to 5 mL of t-butanol in a 25 mL round bottom flask. The (4aR)-(10bR)-10b-methyl-8-phenylthio-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one, (0.183 g, 0.566 mmol) was added followed by methyl iodide while cooling briefly in an ice bath. The mixture was allowed to stir at room temperature for 18 h before diluting with ethyl acetate and filtering to remove inorganics. Filtrate was concentrated in vacuo to give a oil which was triturated in hexane/diethyl ether to facilitate crystallization. Recrystallization from ethyl acetate/hexane gave 0.90 g of white crystals: mp 109°-112°; FD MS 337 M+; Calcd for C21H23N1O1S1.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=1>ClC1C=CC=CC=1Cl>[Cl-:4].[NH2:16][C:14]1[S:15][C:9]2[CH:8]=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=2[NH+:13]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: NC(=S)Nc1ccc(Br)cc1
Solvent: Clc1ccccc1Cl
Product: Nc1[nH+]c2ccc(Br)cc2s1
Product: [Cl-]
Temperature: 20 °C

Procedure:
190 Parts of sulfuryl chloride were added homogeneously within 4 hours at a temperature of 45°-50° C. with stirring to 231 parts of 4-bromophenylthiourea suspended in 1,200 parts of o-dichlorobenzene. After the gas development had ceased, the batch was cooled to about 20° C., the curde 2-amino-6-bromobenzothiazolium chloride precipitated was suction-filtered and washed with o-dichlorobenzene. The filter cake moist with the solvent was suspended in 1,000 parts of water, the adhering o-dichlorobenzene was distilled off by blowing in steam, and the solution of 2-amino-6-bromobenzothiazolium chloride obtained was filtered off from the greasy undissolved matter after having added 10 parts of active charcoal at 95° C. The clear filtrate was adjusted to pH 8 with 25% sodium hydroxide solution, which caused the free 2-amino-6-bromobenzothiazole to precipitate as yellowish, slightly tacky matter. After cooling, the solids having become vitreous were isolated and dried in vacuo at 40°-50° C. 167 Parts of 2-amino-6-bromobenzothiazole having a purity degree of 88% were obtained (=147.1 parts of 100% compound, 64.2% of th.). By repeated redissolution in dilute hydrochloric acid with addition of active charcoal, 2-amino-6-bromobenzothiazole having a purity degree of >95% was obtained. However, this purification was very expensive and caused great losses, so that at best 82 parts of the intended compound were obtained (35.8% of th., relative to 4-bromophenylthiourea used).
Reaction SMILES: ClC1[CH:3]=[CH:4][C:5]([NH:16][CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:18][N:19]=[C:20]=[O:21].[CH2:22]([Cl:24])Cl>>[Cl:24][C:22]1[CH:15]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH3:17])[C:20](=[O:21])[N:19]([CH3:18])[C:7]2([OH:8])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCCl
Reactant: CN=C=O
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CN1C(=O)N(C)C(O)(c2ccccc2)c2cc(Cl)ccc21
Yield: 47 %

Procedure:
A solution of 12.3 g (0.05 mole) of 5-chloro-2-methylaminobenzophenone and 6 ml (0.1 mole) of methyl isocyanate in 50 ml of methylene chloride was refluxed for 3 days, and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 7.05 g (47%) of 6-chloro-3,4-dihydro-4-hydroxy-1,3-dimethyl-4-phenyl-2(1H)-quinazolinone as light yellow crystals; mp 174°-176°; 1H nmr (DMSO-d6) δ 2.67 ppm (s, 3H), 3.38 ppm (s, 3H), 6.8-7.7 ppm (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][C:28](=[O:31])[CH2:29][CH3:30])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: CCC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (0.51 g) and triethylamine (0.27 mL) in dichloromethane (40 mL) at 0° C. was added propionyl chloride (0.17 mL) in dichloromethane (10 mL) dropwise over 25 minutes. The resulting mixture was stirred for an additional 1 hour at 0° C., followed by 14 hours at room temperature. The reaction mixture was then stirred with an aqueous 5% citric acid solution (40 mL) for 10 minutes. The layers were separated, and the aqueous layer was further extracted with dichloromethane (50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then decanted from the desiccating agent and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography using a dichloromethane/methanol gradient to afford N-[7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]propionamide (0.49 g) as an off white solid, ms m/z 347 (MH+).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:34]5[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=5)[CH:25]=[CH:24][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)[O:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a degassed solution of 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (764 mg, 2.470 mmol), and potassium carbonate (683 mg, 4.94 mmol) in dioxane (12 mL) and water (4 mL) was added Pd(Ph3P)4 (114 mg, 0.099 mmol). The mixture was stirred at 100° C. under argon overnight. The mixture was cooled to rt, diluted with water (40 mL), and extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol, 28% yield) as a yellow foam. LCMS (m/z)=526 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14][Br:15]>CN(C)C=O.C(OCC)(=O)C>[BrH:15].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH2:14][N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: NC(=O)c1cccnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: N=c1c(C(N)=O)cccn1Cc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 14 h
Yield: 38.2 %

Procedure:
To a solution of 2-aminonicotinamide (0.2 g) in N,N-dimethylformamide (5 ml) was added 2,5-dichlorobenzylbromide (0.39 g) (Table 2, bromide 122), and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (0.21 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16][CH3:17])[CH:9]=2)=[CH:6][C:5](=O)[N:4]([CH3:19])[C:3]1=[O:20].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>N1C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([S:16][CH3:17])[CH:9]=2)=[CH:6][C:5](=[S:22])[N:4]([CH3:19])[C:3]1=[O:20]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1SC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc(=S)n(C)c(=O)n2C)cc1SC
Yield: 159.3 %

Procedure:
To a suspension of 1,3-dimethyl-6-(4-methoxy-3-methylthiophenyl)-1,2,3,4-tetrahydropyrimidine-2,4dione (6.5 g) in pyridine (60 ml) was added phosphorus pentasulfide (4.95 g), and refluxed for 8 hours. After cooled, the mixture was poured into water (600 ml). The precipitates were collected, dried in the air, and refluxed with ethanol (150 ml) for 2 hours. After cooled, resulting precipitates were filtered, and washed with ethanol and diisopropyl ether, to give 1,3-dimethyl-6-(4-methoxy-3-methylthiophenyl)-1,2,3,4-tetrahydro-4-thioxopyrimidin-2-one (5.47 g). mp 174°-176° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([NH2:11])=[N:9][N:10]=1)(=[O:5])=[O:4].[CH:12]1([NH:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1C[O:29][CH2:28]C1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C>[CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([NH:11][C:28]([N:18]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C@H:19]2[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]2)=[O:29])=[N:9][N:10]=1)(=[O:5])=[O:4]
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: C1CCOC1
Reactant: CNS(=O)(=O)c1nnc(N)s1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CNS(=O)(=O)c1nnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Temperature: 40 °C

Procedure:
An mixture of 1,1-carbonyldiimidazole (2 equiv), 5-amino-1,3,4-thiadiazole-2-sulfonic acid methylamide, cyclohexyl-(trans-4-methyl-cyclohexyl)-amine (1 equivalent) and DMAP (5 mol %) in THF-toluene (1:1) was heated for 16 h at 40° C. and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the crude product was dissolved in MeCN and purified (HPLC method 1) to give the title compound.
Reaction SMILES: [I-].[F:2][C:3]([F:41])([F:40])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[CH2:33][CH2:32][C:31](=[O:34])[C:30]=3[CH2:35][N+](C)(C)C)[CH2:18]2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C-:42]#[N:43].[Na+]>C(O)C>[F:2][C:3]([F:40])([F:41])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[CH2:33][CH2:32][C:31](=[O:34])[C:30]=3[CH2:35][C:42]#[N:43])[CH2:18]2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: C[C@@H](O[C@H]1CN(C2=C(C[N+](C)(C)C)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](O[C@H]1CN(C2=C(CC#N)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 32 mg (0.0394 mmol) {2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-en-1-yl}-N,N,N-trimethylmethanaminium iodide (step B) and 41.7 mg (0.8505 mmol) sodium cyanide in 95% ethanol (5 mL) was refluxed for 6 hr. The reaction mixture was cooled to RT and the solvent removed under vacuum. The residue was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band (Rf˜0.4) was isolated to afford the title compound as a glassy yellow solid. 1H-NMR (CD3OD): δ: 1.45 (d, 3H, 6.5 Hz), 2.43 (br. s, 2H), 2.79 (br. s, 2H), 3.4-4.55 (m, 8H), 4.79 (q, 1H, 6.5 Hz), 6.99 (t, 2H, 8.5 Hz), 7.20 (m, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 541.0 (MH+) observed.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH3:23])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=1)[CH:8]=[C:7]2[OH:21].[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]([O:22][CH3:23])[CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)[CH:8]=[C:7]3[OH:21])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Br)c2nc(-c3ccc(OC)c(F)c3)cc(O)c2c1
Product: COc1cc(-c2ccc(C#N)cc2)c2nc(-c3ccc(OC)c(F)c3)cc(O)c2c1
Yield: 56 %

Procedure:
This compound was prepared from 41b using 4-cyanophenylboronic acid according to method P. Orange solid; Yield: 56%; mp 248–250° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.89 (s, 3H), 3.94 (s, 3H), 7.28 (t, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.44 (d, J=2.9 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.75–7.79 (m, 2H), 7.97 (br s, 4H), 11.50 (s, 1H); MS (ESI) m/z 401 ([M+H]+). Anal. Calcd for C24H17FN2O3: C: 71.99, H: 4.28, N: 7.00. Found: C: 71.55, H: 4.47, N: 6.60.