Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3]/[C:4](/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:5](\[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][CH:18]=1)/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][NH:15][CH3:16])=[CH:8][CH:7]=1>C(O)C.C(OC(=O)C)C>[Cl:1][CH2:2][CH2:3]/[C:4](/[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[C:5](\[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)/[C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][NH:15][CH3:16])=[CH:10][CH:11]=1
Reactant: CNCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccc(O)cc2)cc1

Procedure:
5.99 g of Z-4-chloro-1-(4-benzyloxyphenyl)-2-phenyl-1-[4-[2-(N-methylamino)ethoxy]phenyl]-1-butene is hydrogenated in ethanol-ethylacetate (1:1) using 10% Pd--C as a catalyst. The catalyst is filtered off and the solvents are evaporated. The residue is recrystallized from ethanol-water (1:1). The yield is 3.21 g (66%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH:10][CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>C1COCC1>[CH2:6]([N:10]([CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]1=2)[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCNC1CS(=O)(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN(C1CS(=O)(=O)c2ccccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
6.63 g (57 mmol) of methanesulfonyl chloride were added dropwise to a solution of 11.7 g (41 mmol) of butyl-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-amine and 15.5 g (153 mmol) of triethylamine in 120 ml of THF, and the reaction mixture was stirred at RT overnight. Most of the THF was distilled off, the residue was diluted with 250 ml of water and the precipitate was filtered off with suction. Drying under reduced pressure gave 13.8 g of N-butyl-N-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)methanesulfonamide; m.p. 171-173° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([O:20]C)=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])[O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1
Reactant: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)OC)cc23)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(=O)O)cc23)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 93.7 %

Procedure:
After adding methanol (14 ml) and 2N sodium hydroxide aqueous solution (7 ml) to methyl 4-(3-chloro-4-(((ethylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxylate (1.50 g, 3.49 mmol), the mixture was stirred at 60° C. for 90 minutes. The reaction solution was allowed to cool to room temperature, and after neutralization by addition of 2N hydrochloric acid, the methanol was distilled off and the precipitated white crystals were filtered out, thoroughly washed with water and dried at 60° C. to obtain the title compound (1.36 g, 3.27 mmol, 94%).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH:14](=O)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([NH:7][C:3]1[CH:2]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(-c2ccccc2)c1
Yield: 90.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, biphenyl-3-amine (500 mg, 2.95 mmol) and butyraldehyde (265 μL, 2.95 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 7.65-7.57 (m, 2H), 7.55-7.41 (m, 2H), 7.40-7.32 (m, 1H), 7.31-7.23 (m, 1H), 6.99-6.90 (m, 1H), 6.85 (t, J=2.0 Hz, 1H), 6.64 (ddd, J=8.0, 2.4, 0.9 Hz, 1H), 3.78 (br s, 1H), 3.21 (t, J=7.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.54-1.44 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 226.1 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:18][C:17]1=[NH:25])[CH2:13][C:14]#[CH:15].[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:19]1[S:18]/[C:17](=[N:25]\[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[N:16]([CH2:12][CH2:13][C:14]#[CH:15])[CH:20]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: C#CCCn1cc(C(C)(C)C)sc1=N
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.9 %

Procedure:
A mixture of 3-(but-3-ynyl)-5-tert-butylthiazol-2(3H)-imine p-toluenesulfonate (prepared as described in US20080242654) (2.6 g, 6.83 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (1.55 g, 6.83 mmol) in anhydrous CH2Cl2 (30 mL) was treated dropwise at 0° C. with triethylamine (1.91 mL, 1.38 mmol). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with hexane-EtOAc (2:1) to afford 2.5 g of the title compound. MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[C:27]([CH3:32])=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.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>[CH3:31][N:29]1[CH:30]=[C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:14]3[C:13]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:24][CH2:23]2)[C:27]([CH3:32])=[N:28]1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)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: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccc(Cl)c(F)c2)CC1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
Add 4-chloro-3-fluorobenzeneboronic acid (125 mg, 0.72 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL) and deoxygenated water (2 mL). Add potassium carbonate (215 mg, 1.72 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 6 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.036 g, 14%). MS (ES): m/z=401 [M+H]+
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH2:25])=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH:15]=2)[CH:5]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:25][C:13]1[N:12]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])=[CH:15][C:14]=1[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cccc(C(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 50 °C

Procedure:
To a solution of 3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester (0.980 g, 2.7 mmol) in dioxane/H2O (5:1, 30 mL) was added K2CO3 (1.5 g, 11 mmol), and the mixture was heated at 50° C. for 16 h. Evaporation of the solvents and neutralization with acetic acid gave a precipitate that was filtered off and dried in vacuo to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ=7.51-7.66 (m, 3H), 7.95-8.00 (m, 2H), 8.14-8.18 (m, 4H), 8.24 (d, J=8.4 Hz, 2H), 8.29 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H). MS(ES+): m/z=348.06 (100) [MH+]. HPLC: tR=3.42 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:18][C:17]3[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=3)[C:13]#[N:14])[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Oc1nccc2cnc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2ccc3cnc(Br)cc3c2=O)c1

Procedure:
The alkylation of 7-bromo-1-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 3-cyanobenzyl bromide (1.31 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 3-[1-oxo-7-(3-Phenyl-prop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzonitrile
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[CH2:11]([O:18][C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:22]2[CH2:23][C@H:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)Cn1cncn1
Yield: 30 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 252, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (36 mg, 30%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.14 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.58 (d, 2H), 7.41-7.28 (m, 5H), 7.19 (t, 2H), 7.06-6.92 (m, 4H), 5.27 (q, 2H), 4.58 (d, 2H), 4.49 (t, 1H), 4.40-4.34 (m, 1H), 3.90-3.75 (m, 2H) 2.42-2.22 (m, 1H), 2.11-2.01 (ml H). MS (EI) for C28H26FN5O4. found 516.0 (MH+).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14]([NH2:16])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>O>[Cl:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Cl:17])[C:13]=1[C:14](=[S:19])[NH2:16]
Reactant: NC(=O)c1c(Cl)cncc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1c(Cl)cncc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Into a 3000-mL three-necked round bottom flask equipped with a condenser, mechanical stirrer under an atmosphere of nitrogen was added pyridine (1500 mL), then 3,5-dichloro-4-pyridine-carboxamide (92.9 g., 0.486 mole) (which dissolved), and tetraphosphorus decasulfide (237 g., 0.535 moles)(which had almost dissolved then a bright yellow precipitate formed and an exotherm heated the mixture to 60° C.). The slurry was allowed to stir for 1 hr (temperature had dropped to 45° C.) and then the temperature was then raised and when it reached 100° C. all of the solids had dissolved and continued heating to 118° C. and was maintained at 115° C. for 4 hr. The mixture was poured into water (3750 mL) carefully as gas began to evolve and the temperature of the aqueous solution rose to approximately 45° C. and was allowed to sit at room temperature over two nights. To the resulting mixture was added water (6000 mL) and was extracted with methylene chloride (3×2000 mL), washed with water (3×1000 mL) and the solvent removed in vacuo to give a brownish yellow liquid, with much pyridine present. The vacuum pump was connected to the rotary evaporator to remove the residual pyridine. The residue (brown solid) was triturated with diethyl ether (3×1500 mL), treated with decolorizing carbon and the solvent removed in vacuo to give a solid which contained pyridine. The yellow solid was slurried in water (2×200 mL) and dried in vacuo at 60° C. to give 63.2 g of a light yellow solid (62.8% yield): mp 186-187° C.; TLC[50/50 ethyl acetate/hexanes] showed amide at Rf=0.31 and thioamide Rf=0.53; 1H NMR (DMSO-d6) d 10.6 (s, b, 1H), 10.0 (s, b, 1H), 8.6 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:4]=2[N:3]=1>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(C(F)(F)F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H]1O[C@@H](n2c(Br)nc3ccc(C(F)(F)F)cc32)[C@H](O)[C@@H]1O
Yield: 14 %

Procedure:
Starting with 2-bromo-6-trifluoromethyl-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole, this compound was prepared according to general procedure III. Following two flash column chromatographic purifications on silica gel with EtOAc/hexane (3:2), a 14% yield of the title compound was obtained as a foam. 1H NMR (DMSO-d6) δ1.4 (d, 3H, Me), 3.8-3.9 (m, 1H, CH), 3.9-4.1 (m, 2H, 2×CH), 4.45 (q, 1H, CH), 5.3 (d, 1H, OH), 5.5 (d, 1H, OH), 5.91 (d,1H, CH), 7.6 (d, 1H, aromatic), 7.82 (d, 1H, aromatic), 7.9 (s, H, aromatic).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([N:18]=[C:19](SC)SC)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:26][CH2:27][C@@:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[S:15][C:16]([NH:18][C:19]3[O:36][C@:28]4([CH2:27][N:26]=3)[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]4)=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=Nc1nc2ccc(OCc3ccccc3)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COc2ccc3nc(NC4=NC[C@@]5(CN6CCC5CC6)O4)sc3n2)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of dimethyl 5-(benzyloxy)thiazolo[5,4-b]pyridin-2-ylcarbonimidodithioate (500 mg, 1.38 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (317 mg, 1.38 mmol) and cesium carbonate (1.0 g, 3.07 mmol) in DMF (7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-20% [9:1 methanol:ammonium hydroxide]-chloroform) to afford (R)—N-(5-(benzyloxy)thiazolo[5,4-b]pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (390 mg, 67% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.18 (br. s., 1 H) 7.76 (d, J=8.85 Hz, 1 H) 7.50 (d, J=7.32 Hz, 2 H) 7.41 (t, J=7.32 Hz, 2 H) 7.32-7.37 (m, 1 H) 5.42 (s, 2 H) 4.02 (d, J=9.46 Hz, 1 H) 3.68 (d, J=9.46 Hz, 1 H) 3.37-3.44 (m, 1 H) 2.75-3.06 (m, 5 H) 2.13-2.25 (m, 2 H) 1.73-1.82 (m, 1 H) 1.49-1.70 (m, 3 H). MS (LC/MS) R.T.=1.69; [M+H]+=421.98.
Reaction SMILES: [C:1]1([C:7]2([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[C-:20]#[N:21].[Na+].O>CS(C)=O>[C:1]1([C:7]2([CH2:12][C:20]#[N:21])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1(c2ccccc2)CCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (24-01) (6 g, 23.59 mmol) in dimethyl sulfoxide (18 mL) were added potassium iodide (392 mg, 2.59 mmol) and sodium cyanide (1.734 g, 35.384 mmol). The mixture was stirred for 140° C. for 16 h. After completion of the reaction, water was added and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, dried and evaporated to get a crude product which was purified using a normal silica column using 15% ethyl acetate in hexane to afford (1-phenyl-cyclopentyl)-acetonitrile (25-01) (2.25 g, 51.4%) as a yellow liquid.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OC(C#Cc1ncc[nH]1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(C#Cc1ncc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-imidazolyl)ethynyl]-benzenemethanol (297 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12]>C(=O)(O)[O-].[Na+]>[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][N:17]2[C:16]=1[CH:21]=[CH:20][CH:19]=[CH:18]2
Reactant: C=C(C(=O)OC)C(O)c1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccccn2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetic anhydride (80 mL) and 127a (6.68 g, 34.6 mmol). The reaction mixture was heated at reflux under nitrogen for 4 h. After this time the reaction was cooled to room temperature, poured onto the mixture of ice (100 g) and saturated aqueous sodium bicarbonate solution (200 mL), and stirred for 1 h. The resulting solution was neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×200 mL). The combined organic extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 petroleum ether/ethyl acetate (10:1) to afford 127b as a white solid (2.1 g, 35%). MS-ESI: (M+H)+ 176.2. 1H NMR (500 MHz, CDCl3) δ 7.86-7.84 (m, 1H), 7.79 (d, J=1.0 Hz, 1H), 7.36-7.34 (m, 1H), 6.82 (s, 1H), 6.70-6.66 (m, 1H), 6.55-6.51 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:41]([O:43][CH3:44])=[O:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][NH:16][C:17](=[O:39])[C:18]3[C:23]([F:24])=[C:22]([S:25][C:26]4[S:30][C:29]([NH:31][C:32]5[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=5)=[N:28][CH:27]=4)[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:11][N:12]([C:41]([O:43][CH3:44])=[O:42])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(Cl)c(Cl)c5)CCNCC4)c3F)s2)c1
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Following the procedure given for example 81, N-((4-(3,4-dichlorophenyl)piperidin-4-yl)methyl)-3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinamide (compound example 48) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 661. Ret. time: 2.09 min. (Condition I); analytical HPLC Ret. time: 10.35 min (Condition H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].C(OC([C:11]1[CH:12]([CH3:25])[CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH+:17]([CH3:24])[C:16]=12)=O)C.Cl>CC(N(C)C)=O.CCOCC>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:25][CH:12]1[CH2:13][CH2:14][N:15]2[C:16]([NH+:17]([CH3:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=32)=[CH:11]1
Reactant: CCOC(=O)C1=C2N(CCC1C)c1ccccc1[NH+]2C
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CC1C=C2N(CC1)c1ccccc1[NH+]2C
Temperature: 25 °C

Procedure:
4-Ethoxycarbonyl-1,2-dihydro-3,5-dimethyl-5H-pyrido[1,2-a]benzimidazolium perchlorate (7.92g; 0.0213 mole) is boiled with stirring for 40 minutes in dimethylacetamide (50ml) containing concentrated HCl (3ml). During the reaction approximately half of the solution is allowed to boil away. The cooled reaction mixture is stirred overnight in a liter of ether. The ether is decanted and the residue is dissolved in hot water (300 ml) and filtered. Upon cooling to room temperature some gummy material separates on the walls of the flask. The clear solution is decanted, cooled with an ice bath, and treated with 30g of sodium perchlorate. The crude product which separates is filtered, washed with a little water then ether, and recrystallized from ethanol to give 3.28g (51.6%); m.p. 206°-210° d.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:18])[CH:15]=NO)[CH:10]=[CH:11][CH:12]=1>>[Br:6][C:7]1[CH:8]=[C:9]2[C:10]([C:15](=[O:2])[C:14](=[O:18])[NH:13]2)=[CH:11][CH:12]=1
Reactant: O=C(C=NO)Nc1cccc(Br)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Br)ccc2C1=O
Temperature: 90 °C
Yield: 98 %

Procedure:
To the concentrated sulfuric acid (275 mL) at 50° C. was added N-(3-Bromo-phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272 mol). The temperature was raised to 90° C. and maintained for 3 h. The reaction mixture was added to ice cold water to get yellow precipitate. The precipitate was filtered and dried to get the title compound as a yellow solid [50 g, 98%]. This material was taken to the next step without any further purification.
Reaction SMILES: N[CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].[Cl-].[Na+]>O>[F:8][C:7]([F:10])([F:9])[CH2:6][CH:2]([OH:12])[C:3]([OH:5])=[O:4]
Reactant: NC(CC(F)(F)F)C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-amino-4,4,4-trifluorobutanoic acid (12-1) (1 g, 6.37 mmol) in 1 N aqueous sulfuric acid (10.00 ml, 10 mmol) was cooled to 0° C. To the cooled reaction mixture was added a solution of sodium nitrite (1.1 g, 15.9 mmol) in water (5 mL) dropwise over 40 minutes via addition funnel. The reaction mixture was then warmed to room temperature and stirred for 16 h. Sodium chloride was added to the reaction until complete saturation was achieved. The resulting aqueous mixture was washed with ethyl acetate (3×50 mL) and the combined organic layer was dried over sodium sulfate, filtered and concentrated to dryness to afford 12-2 as a white crystalline solid. 1H NMR (500 MHz, DMSO-d6) δ 2.51 (m, 1H), 2.67 (m, 1H), 4.24 (dd, J=8.60, 3.60 Hz, 1H), 5.74 (br s, 1H), 12.89 (br s, 1H).