Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:12][CH2:13][CH2:14][O:15][CH3:16])(=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21](S)=[CH:20][CH:19]=1.O[O:26][S:27]([O-:29])=O.[K+]>CN(C=O)C.O>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][S:27]([C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)(=[O:29])=[O:26]
Reactant: COCCCOS(C)(=O)=O
Reactant: Sc1ccc(Br)cc1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
Potassium carbonate (2.8 g, 20 mmol) was added to a solution of 3-methoxypropan-1-yl methansulphonate (Method 68; 3.25 g, 19.3 mmol) and 4-bromothiophenol (3.48 g, 18.4 mmol) in DMF (30 ml) and the mixture heated at 40° C. for 4 hours. The mixture was allowed to cool to ambient temperature, poured into water (100 ml) and extracted with EtOAc (2×50 ml). The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and brine (2×50 ml), dried (Chemelut column CE1010) and the volatiles removed by evaporation. The residue was dissolved in MeOH (150 ml) and water (30 ml) and oxone (13.4 g, 21.6 mmol) was added in portions. The mixture was stirred at ambient temperature for 18 hours. The MeOH was evaporated, water (50 ml) added and the solution extracted with DCM (3×50 ml). The extracts were combined, washed with brine (50 ml), dried (Chemelut column CE1010), and evaporated. The residue was purified by flash chromatography on silica gel eluting with iso-hexane: EtOAc (100:0 increasing in polarity to 90:10) to give the title compound (3.32 g, 62%) as a colourless oil. NMR 1.95 (m, 2H), 3.19 (m, 2H), 3.26 (s, 3H), 3.41 (t, 2H), 7.70 (d, 2H), 7.78 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:31](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[C:13]4[N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[CH2:22][CH2:21]3)[CH:9]=[C:4]2[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[NH:31][C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[C:13]4[N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[CH2:22][CH2:21]3)[CH:9]=[C:4]2[N:3]=1
Reactant: Cc1nc2cc(-c3ccc4ncnc(N5CCC(=O)c6ccccc65)c4c3)cnc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(-c3ccc4ncnc(N5CCC(=O)c6ccccc65)c4c3)cnc2[nH]1
Yield: 21.1 %

Procedure:
0.25 g of 1-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]-pyridin-6-yl]quinazolin-4-yl}-2,3-dihydro-1H-quinolin-4-one and 255 μl of trifluoroacetic acid in 2 ml of dichloromethane are stirred at 25° C. in a flask until the reaction is complete (HPLC check, about 72 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of preparative HPLC (gradient water:acetonitrile 1-50% in 16 min.), giving 0.04 g of 1-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one (“A13”) as white solid (yield 23%, content 99%); MS-FAB (M+H+)=407.1; Rf (polar method): 1.50 min;
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:32][CH:29]([CH3:31])[CH3:30])[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Reactant: CC(C)N
Product: CC(C)Nc1nccc(-c2cnc3c(NC(C)C)nccn23)n1

Procedure:
Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and isopropylamine. LC-MS: [M+H]+ 312.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O(7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 6.99 equiv), sodium carbonate (200 mg, 1.89 mmol, 0.26 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 3.19 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath an then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (3R)-3-[4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[O:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:18]([O:23][C:24]3[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=3)=[N:19][CH:20]=[N:21][CH:22]=2)[CH2:13][CH2:12]1>C(O)(C)C>[O:11]1[CH2:12][CH2:13][CH:14]([C:17]2[C:18]([O:23][C:24]3[CH:30]=[CH:29][C:27]([NH:28][C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:26][CH:25]=3)=[N:19][CH:20]=[N:21][CH:22]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(Oc2ncncc2C2CCOCC2)cc1
Solvent: CC(C)O
Product: c1ccc2sc(Nc3ccc(Oc4ncncc4C4CCOCC4)cc3)nc2c1

Procedure:
To a microwave vial was added 2-chlorobenzo[d]thiazole (68.5 μL, 0.553 mmol) and 4-(5-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yloxy)aniline (150 mg, 0.553 mmol) with isopropanol (1.1 mL). The reaction was irradiated at 120° C. for 3 h with microwave irradiation. The crude reaction was concentrated under reduced pressure. Preparative HPLC afforded the target compound as a salt. The material was washed with sat. aq. sodium bicarbonate and extracted with dichloromethane before concentrating the combined organics under reduced pressure to a pale yellow oil. MS (ESI, pos. ion) m/z: 405.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([C:29]([F:32])([F:31])[F:30])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[C:22]([C:29]([F:32])([F:30])[F:31])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1ccc(N=C=S)c(C(F)(F)F)n1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)nc2C(F)(F)F)c1NCCCO
Yield: 96.9 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 3.87 mmol) and 3-isothiocyanato-6-methoxy-2-(trifluoromethyl)pyridine (1.81 g, 7.73 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give the title compound (1.85 g, 3.75 mmol, 97%) as a pale red amorphous.
Reaction SMILES: C(C(C(C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[O:37][C:38]3[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:39]=3[CH:40]=2)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[Br:45][C:42]1[CH:43]=[CH:44][C:38]2[O:37][C:36]([CH2:35][CH2:34][N:13]3[CH2:14][CH2:15][CH2:16][C@H:12]3[CH3:11])=[CH:40][C:39]=2[CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3o2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
(2R)-2-Methylpyrrolidine tartrate (0.70 g, 3.0 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were combined in acetonitrile (12 mL). The slurry was heated at 60° C. for 1 hour, treated with the product from Example 4B (790 mg, 2.0 mmol). The mixture was heated at about 60° C. for 6 hours, cooled to 25° C., and diluted with toluene (30 mL). The mixture was washed with 5% NaHCO3 (40 mL×2) and extracted with H2O: N-methylpyrrolidinone: MSA (methanesulfonic acid)=70:20:10 (30 mL). The aqueous solution was adjusted to pH about 12 with 50% NaOH and extracted with IPAC (45 mL). The organic phase was washed with 5% NaHCO3 (50 mL×3), water (50 mL, 2×), dried over MgSO4, filtered, and the filtrate was concentrated to dryness to provide 375 mg (60%) of the title compound. MS (esi): 308, 310 (M+H)+; 1H-NMR (CDCl3) δ 7.58 (1H, d, J=1.7 Hz), 7.27 (2H, m), 6.38 (1H, s), 3.20 (2 H, m), 2.95 (2H, m), 2.43 (1H, m), 2.28 (1H, m), 2.19 (1H, q, J=8.8 Hz), 1.95 (1 H, m), 1.75 (2H, m), 1.42 (1H, m), 1.13 (3H, d, J=6.2 Hz); 13C-NMR (CDCl3) δ 158.8, 152.9,130.6, 125.7, 122.6, 115.2,111.9, 101.8, 60.0, 53.9, 51.9, 32.9, 28.4, 22.0, 19.3.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]2[C:21]([CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:22][N:23]=[C:9]12)(C)(C)C.FC(F)(F)C(O)=O.CN(C)C=O>ClCCl>[CH3:20][C@H:11]1[N:10]2[C:21]([CH2:24][C:25]([F:27])([F:26])[F:28])=[CH:22][N:23]=[C:9]2[C@@H:8]([NH2:7])[CH2:13][C@H:12]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2ncc(CC(F)(F)F)n21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2ncc(CC(F)(F)F)n21
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl[(5R,6S,8S)-5-methyl-6-phenyl-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-8-yl]carbamate (18.4 mg, 0.045 mmol) in dichloromethane (900 μL) was added trifluoroacetic acid (104 μL, 1.35 mmol). The mixture was stirred 90 min. N,N-dimethylformamide was added and the dichloromethane was removed under vacuum. The resulting mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid). Product containing fractions were treated with 1 M hydrochloric acid and concentrated to give the hydrochloride salt of the title compound (10.3 mg). MS 310.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>>[N:21]1([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[CH:5]=[N:4][CH:3]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Clc1cncc(Nc2ccc(N3CCOCC3)cc2)n1
Product: c1cn(-c2cncc(Nc3ccc(N4CCOCC4)cc3)n2)cn1
Yield: 33.8 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-morpholin-4-ylphenyl)pyrazin-2-amine (100 mg, 0.34 mmol) and imidazole (126 mg, 0.38 mmol) furnished the product (37 mg, 34%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:4]=1[O:5][CH2:6][C:7]#N)=O.[OH-:14].[K+].Cl.[OH2:17]>CCO>[CH3:13][C:10]1[CH:11]=[CH:12][C:3]2[CH:1]=[C:6]([C:7]([OH:17])=[O:14])[O:5][C:4]=2[CH:9]=1
Reactant: Cc1ccc(C=O)c(OCC#N)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1ccc2cc(C(=O)O)oc2c1
Temperature: 25 °C

Procedure:
To a solution of 2-(2-formyl-5-methylphenoxy)acetonitrile (11.12 g, 63.5 mmol) in 244 mL of EtOH was added KOH (14.85 g, 265 mmol), and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated until a thick slurry was obtained, which was diluted with 204 mL H2O. To the resulting solution was added concentrated HCl, a white precipitate formed, and the mixture was filtered, the solid was washed with H2O and dried under the vacuum oven at 50° C. to yield 6-methylbenzofuran-2-carboxylic acid (11.2 g). LCMS retention time=1.00 minutes (LC method 3); MS (m−1)=175.0. 1H NMR (400 MHz, DMSO-d6) δ 2.45 (s, 3H), 7.13-7.18 (m, 1H), 7.47 (s, 2H), 7.62 (d, J=8.0 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1CS([C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=O.[CH2:19]([SH:22])[CH2:20][CH3:21].[ClH:23]>O1CCCC1>[Cl-:23].[N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:10]=1[N+:11]1[CH:12]=[CH:13][CH:15]=[CH:21][C:20]=1[CH2:19][S:22][S:22][CH2:19][CH2:20][CH3:21]
Reactant: O=S(Cc1ccccn1)c1nc2ccccc2[nH]1
Reactant: Cl
Reactant: CCCS
Solvent: C1CCOC1
Product: CCCSSCc1cccc[n+]1-c1nc2ccccc2[nH]1
Product: [Cl-]
Reaction time: 0.08 h

Procedure:
2.6 g of 2-[(2-pyridylmethyl)sulphinyl]benzimidazole are dissolved in 30 ml of tetrahydrofuran and treated with 1.0 ml of n-propyl mercaptan. 10 ml of 3N hydrochloric acid are added at an internal temperature of 40°. The mixture is stirred at 40° for 5 minutes and then evaporated in vacuo. The residue is crystallized from ethanol/ether. There is obtained 1-(2-benzimidazolyl)-2-[(propyldithio)methyl]pyridinium chloride of melting point 144°-145°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[NH4+].[OH-]>>[CH3:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:1]=[C:4]([CH2:5][CH2:6][CH3:7])[NH:8][C:7]=12
Reactant: Cc1ccnc(N)c1N
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 174.5 %

Procedure:
A mixture of burytic acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline (8.05 g, 65.4 mmol), and polyphosphoric acid (50 g) was heated to 100° C. with stirring for 3 hours, and monitored by t1c of NH4OH neutralized aliquots. Basification (NH4OH), extraction (CH2Cl2, 4×50 mL), drying (K2CO3), purification (by filtering through 100 g silica gel, EtOAc solution), and concentration gave 10.0 g (87%) of the title compound as an amorphous tan solid which was judged pure by 1H NMR and t1c: mp 110°-112° C. (without recrystallization).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][C:28]#[CH:29]>O1CCCC1>[CH3:25][N:26]([CH2:27][C:28]#[CH:29])[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3]
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: C#CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CCN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
A mixture of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine and 3 g (0.022 mole) of potassium carbonate in 50 ml of tetrahydrofuran was treated while stirring with 1.52 g of N-methylpropargylamine. After stirring for 15 min. 10 g of ice was added and stirring continued for an additional 72 hr. The tetrahydrofuran was decanted from the salt paste and concentrated on a rotary evaporator to yield an amber oil, 5.9 g. This oil solidified when cooled to -70° C. and was recrystallized from hexane to yield 4.6 g (74.2%) of fine white crystals, m.p. 71°-73° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:13][CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>C(#N)C>[C:19]([S:21][C@H:11]1[CH2:12][CH2:13][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:10]1)(=[O:22])[CH3:20]
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2nc(C(N)=O)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1CCN(c2nc(C(N)=O)cs2)C1
Yield: 76.3 %

Procedure:
To a solution of (3R)-1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxypyrrolidine (190 mg, 0.652 mmol) (obtained as described in Reference Example 18(7)) in acetonitrile (6 ml) was added potassium thioacetate (223 mg, 1.96 mmol) at room temperature. The mixture was heated under reflux for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate→2% methanol in ethyl acetate as the eluant to afford (3S)-3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)pyrrolidine (135 mg, yield 77%) as a pale brown solid.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O>>[CH3:26][O:25][C:22]1[CH:21]=[C:18]2[C:17]([C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2](=[CH:19]2)[C:3]=34)=[CH:24][CH:23]=1
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Product: COc1ccc2c(c1)cc1c3c(cccc32)C(=O)OC1=O

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-5-methoxybenzaldehyde (Handford, B. O.; Whalley, W. B. J. Chem. Soc. 1963, 3896):
Reaction SMILES: N1C=CC=CC=1CN1CCC([S:18]([N:21]2[CH2:26][CH2:25][CH:24](OC3C=CC(OC(F)(F)F)=CC=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])(C(OC)=O)CC1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52]Cl.C[N:55](C)C=O>>[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH2:52][NH:55][S:18]([N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)(=[O:19])=[O:20]
Reactant: ClCc1ccccn1
Reactant: CN(C)C=O
Reactant: COC(=O)C1(S(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)CCN(Cc2ccccn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=S(=O)(NCc1ccccn1)N1CCCCC1
Temperature: 35 °C
Yield: 72 %

Procedure:
Part I: Preparation of methyl 1-(2-pyridinylmethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate. The unsubstituted piperidine sulfonamide from part H (7.9 g, 16.95 mmol) was dissolved in dry dimethylformamide (35 mL) and potassium carbonate (7.05 g, 51.1 mmol) and 2-picolyl chloride hydrochloride (4.21 g, 25.67 mmol) were added. The reaction was stirred at 35° C. for sixteen hr and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the N-picolyl piperidine sulfonamide as a white solid (6.8 g, 72%).
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:7][CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[C:28]2[CH3:32])[N:23]=[N:24][CH:25]=1>>[ClH:19].[F:18][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:20]2[CH:21]=[C:22]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[N:23]=[N:24][CH:25]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2cccc(C(F)F)c2)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2cccc(C(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=301.3 (M+H+), was prepared from 2-(3-difluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][O:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][CH2:2][C:3]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16])=[O:4]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(Br)CBr
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromoacetylbromide (17.9 ml; 0.20 moles) in CH2Cl2 (30 ml) was slowly added to a mixture of 4-methoxy-2-nitroaniline (30 g; 0.18 moles) and triethylamine (28 ml; 0.2 moles) in CH2Cl2 (300 ml). The reaction mixture was stirred at room temperature overnight, then poured into water. The aqueous layer was extracted with additional CH2Cl2, dried over MgSO4 and evaporated under vacuum. The crude product was crystallized from a 7/3 Et2O/EtOH mixture to give the title compound as a white solid. 31.5 g; m.p. 94-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>CO.O.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc3n2CCN=C3C)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COc1ccc(-c2ccc3n2CCNC3C)cc1
Yield: 47 %

Procedure:
3,4-Dihydro-6-(p-methoxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine (1.0 g) was dissolved in a mixture of 60 ml of methanol and 6 ml of water under argon. The solution was treated portionwise with 0.5 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 45 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 50 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.0 g of brown solid, was dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.7 g (47%) of 1,2,3,4-tetrahydro-6-(p-methoxyphenyl)-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:0.9); m.pt.: 162°-165° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(-c2ccc(Cl)cc2)cc1Br

Procedure:
Prepared from crude 5-(4-chloro-phenyl)-pyridin-2-ylamine (example C.27 step 1) (ca. 50 mmol) in acetonitrile (100 mL) and NBS (9.34 g, 53 mmol) as described in example C.25 step 2. Obtained the crude 3-bromo-5-(4-chloro-phenyl)-pyridin-2-ylamine a dark brown solid (76% pure).