Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[O:8]([CH2:26][CH2:27][C:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:37][S:38]([O:36][CH2:35][CH2:34][C:28]1([CH2:27][CH2:26][O:8][Si:9]([C:22]([CH3:24])([CH3:25])[CH3:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCCC1(CCO)CCCCC1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCOS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
After adding triethylamine (2.20 mL, 15.8 mmol) to a solution of 2-[1-(2-tert-butyldiphenylsiloxyethyl)cyclohexyl]ethanol (3.24 g, 7.80 mmol) in methylene chloride (25 mL), methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added dropwise while cooling on ice. The mixture was stirred at room temperature for 40 minutes, and then saturated aqueous sodium hydrogencarbonate (300 mL) was added, extraction was performed with chloroform and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain the title compound as a yellow oil (3.97 g).
Reaction SMILES: [C:1]([C@@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[C:7](O)=[CH:6]1)([O:3][CH3:4])=[O:2].Cl.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1C=C(O)c2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCc2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3

Procedure:
To a solution of 0.5 g (1.3 mmol) of [1 R,8 S,9a R]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (182-3A) in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated aqueous hydrochloric acid was solution was added 0.2 g of 5% palladium supported on carbon and the mixture was shaken under 4 atmospheres of hydrogen until the gas uptake had ceased. The palladium catalyst was removed by filtration through Celite® filter aid and the filtrate concentrated to give a white solid, which was carried on to the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:22])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(R)-Pyrrolidine-2-carboxylic acid tert-butyl ester (16.11 g, 94.1 mmol) in DCM (250 ml) under an inert atmosphere of argon is treated with triethyl amine (26 ml, 188 mmol) and then cooled to 0° C. with a ice bath. To this cooled solution is added dropwise ethyl chloroformate (8.99 ml, 94.1 mmol) and the reaction mixture is left to stir at 0° C. for 3 hours. The reaction mixture is washed with 1M HCl (2×100 ml), water, brine, dried over MgSO4 and concentrated in vacuo to yield the titled compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:10]=[C:11]([CH:32]=[CH:33][N:34]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=[C:20]([O:30][CH3:31])[C:18]=2[N:19]=1)=[O:13]
Reactant: COCCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCOc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 115 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a stirred solution of 0.058 ml (0.74 mmol) 2-methoxyethanol in 2 ml dioxane at room temperature was added 49 mg (1.24 mmol) sodium hydride (60% dispersion in mineral oil) and stirring continued for 10 minutes. 200 mg (0.49 mmol) 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide was then added and the mixture heated at 115° C. for 16 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed sequentially with 1 M hydrochloric acid and saturated brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/toluene) afforded 109 mg (50%) 2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 467 (M+Na+, 16), 445 (M+H+, 100).
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][NH2:4].[CH:6]([CH:8]=O)=O>O>[CH3:1][CH:2]1[NH:5][CH:8]2[NH:4][CH2:3][CH:2]([CH3:1])[NH:5][CH:6]2[NH:4][CH2:3]1
Reactant: O=CC=O
Reactant: CC(N)CN
Solvent: O
Product: CC1CNC2NC(C)CNC2N1
Temperature: 5 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To an ice-cold solution of 148 grams, 2.0 moles, of 1-methylethylenediamine in 150 ml of water was added dropwise 145 grams of 40% aqueous glyoxal (58 grams, 1.0 mole). After the addition was completed, the solution was stirred at 5° C. for one hour, then at room temperature for 5 hours. The solution was evaporated on an open tray, and the resulting semi-solid was stirred in 500 ml of acetonitrile and filtered to give 76 grams (46% of product, m.p. 228°-235° C. (dec). Recrystallization from ethanol gave white crystals, m.p. 246-249 (dec.), literature m.p. 210° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[S:11]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][C:20]#[N:21])(=[O:18])=[O:17])=[CH:12]1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:19](/[S:16]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)(=[O:18])=[O:17])\[C:20]#[N:21])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N#CCS(=O)(=O)c1ccsc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccsc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and thien-3-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-(thien-3-ylsulfonyl)acrylonitrile
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])([OH:3])=O.Cl.[CH3:18][NH2:19]>>[CH3:18][NH:19][C:1]([CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:6])=[O:3]
Reactant: CN
Reactant: CN(CC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-[(N-carboxymethyl-N-methyl-amino)-methyl]-nitrobenzene and methylamine hydrochloride
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]O)[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(O)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Reactant: CN1CCN(CCCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(OCCCN2CCN(C)CC2)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)-acetamide (0.400 g) and 4-methyl-1-piperazinepropanol (0.270 g) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added tributylphosphine (0.64 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.656 g) and the mixture stirred at ambient temperature for 20 hours. The reaction mixture was poured into diethylether and filtered through Celite. After concentration, the residue was purified by NPHPLC (eluting with 75% ethanol in dichloromethane) to afford the title compound (0.334 g).
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=[C:2]1[C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[NH:27][CH3:28]>C(Cl)Cl.CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[N:27]([CH3:28])[C:15]([C:2]1[S:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[O:17]
Reactant: CNc1ccccc1Cl
Reactant: O=C(O)c1nc2c(s1)-c1ccccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)c1nc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 29.8 %

Procedure:
To a suspension of 4,5-dihydro-6-oxa-1-thia-3-aza-benzo[e]azulene-2-carboxylic acid (1 eq, 0.38 mmol, 101 mg) in anhydrous DCM (3 ml), 1 drop of DMF was added, followed by 2M oxalyl chloride in DCM (1.7 eq, 0.65 mmol, 330 ul) dropwise. Effervescence was seen and the reaction was stirred at room temperature for 40 mins before evaporating in vacuo. The crude material was dissolved in DCM (3 ml) and 2-chloro-N-methyl aniline (2 eq, 0.76 mmol, 94 ul) was added. The reaction was stirred at room temperature for 16 hr and extracted into DCM, washed with aq K2CO3, the organic layer dried over MgSO4, filtered, and purified on silica (ISCO, gradient 0% ethyl acetate/petrol to 25% ethyl acetate/petrol) to give 326 as a white solid (42 mg, yield 30%). 1H NMR DMSO, 2.89-2.92 (2H, m), 3.43 (3H, s), 4.23 (2H, br. m), 7.02 (1H, d, J=8.4), 7.08 (1H, t, J=7.6), 7.26 (1H, t, J=8), 7.38-7.41 (2H, m), 7.48-7.51 (2H, m), 7.58 (1H, d, J=8.4). MS: (ESI+): MH+ 371, purity >95%.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:20][CH2:19]1
Reactant: FCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CCF)CC2)CC1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:25][CH3:26])[C:8]=1[CH:9]([NH:18]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].Cl.O1CCOCC1>CO>[NH2:18][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[CH:4][N:5]=[CH:6][C:7]=1[O:25][CH3:26])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 6-(3,5-dimethoxypyridin-4-yl)-6-(1,1-dimethylethylsulfinamido)hexanoate (506 mg; 1.30 mmol) in MeOH (9 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.65 ml; 2.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate as a brown solid. LC-MS (conditions A): tR=0.36 min.; [M+H]+: 284.25 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(/C=C/c2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a stirred solution of 2-[(E)-2-(3,5-dimethoxyphenyl)vinyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (1.10 g, 2.61 mmol) in tetrahydrofuran (8 mL)/methanol (10 mL), was added Pd/C (10% w/w, 580 mg, 0.545 mmol). The resulted mixture was stirred under H2 (45 psi) at ambient temperature. After 24 hours, the palladium catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford the desired product (1.05 g, 90%), which was used directly in the next step without further purification. LCMS calculated for C22H22N3O4S (M+H)+: m/z=424.2. Found: 424.2; 1H NMR (400 MHz, CDCl3): δ 8.18-8.15 (m, 3H), 7.97 (d, J=4.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.53-7.48 (m, 2H), 6.80 (d, J=4.4 Hz, 1H), 6.34 (d, J=2.0 Hz, 2H), 6.30 (t, J=2.4 Hz, 1H), 3.73 (s, 6H), 3.19-3.15 (m, 2H), 3.02-2.98 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([OH:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(CC)CC.[N:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([O:12][C:33]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:34])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1O
Reactant: O=C(Cl)N1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2sc(C(=O)OC(C)(C)C)c(N)c2c(C)c1OC(=O)N1CCCC1
Reaction time: 3 h
Yield: 52 %

Procedure:
tert-Butyl 3-amino-5-hydroxy-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylate, prepared in example 1C, Step C, (40 mg, 0.14 mmol) in CH3CN (1 mL) was combined with Et3N (52 mg, 0.52 mmol) and pyrrolidine-1-carbonyl chloride (51 mg, 0.39 mmol) at room temperature. After stirring for 3 h, the mixture was evaporated under reduced pressure, water was added and extracted with ethyl acetate (3 mL), washed with water (3 mL×3), brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to provide tert-butyl 3-amino-4,6-dimethyl-5-(pyrrolidine-1-carbonyloxy)-thieno[2,3-b]pyridine-2-carboxylate (41 mg, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>>[CH3:16][C:4]1[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Br)cnc1NCCN1CCCC1
Product: Cc1cc(C#C[Si](C)(C)C)cnc1NCCN1CCCC1
Temperature: 50 °C

Procedure:
Prepared analogously to Example 15c from 500 mg (1.76 mmol) (5-bromo-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 0.29 mL (2.11 mmol) ethynyl-trimethyl-silane, while the reaction mixture is heated to 50° C. for 12 h.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[C:5]([CH3:16])=[C:4]([C:17]([OH:19])=O)[C:3]1=[S:20].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][NH:26][C:17]([C:4]2[C:3](=[S:20])[N:2]([CH3:1])[C:11]3[C:6]([C:5]=2[CH3:16])=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=3)=[O:19])[CH:27]=[CH:28][CH:29]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1c(C(=O)O)c(=S)n(C)c2cc(C(F)(F)F)ccc12
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(=S)n(C)c2cc(C(F)(F)F)ccc12
Yield: 42 %

Procedure:
Reaction of 220 mg (0.73 mmol) 1,4-dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid with 3-fluoro-benzylamine according to the method described under example 2 Section a) yielded 125 mg (0.3 mmol, 42%) N-[(3-fluorophenyl)-methyl]-1,4-dimethyl-2-thioxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 3). MS: m/z 409.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:5]1[CH2:9][CH2:8][O:7][CH:6]1[C:10]1[CH:11]=[C:12]([NH:16][C:1](=[O:3])[CH3:2])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C2OCCO2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(C2OCCO2)c1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A solution of acetyl chloride (3.75 g, 0.048 mol, 3.4 mL) in CH2Cl2 (6.5 mL) was added dropwise over 15 min to an ice-bath chilled solution of 3-[1,3]dioxolan-2-yl-phenylamine (7.18 g, 0.043 mol) and pyridine (3.40 g, 0.043 mol, 3.5 mL) in CH2Cl2 (85 mL). The solution was then brought to room temperature, stirred for 1 hr, and poured onto ice-water (60 mL). The phases were separated, and the organic layer washed with water, saturated NaHCO3, brine and dried with MgSO4. Removal of the solvent in vacuo afforded N-(3-[1,3]dioxolan-2-yl-phenyl)-acetamide (8.01 g, 90%). 1H NMR (CDCl3) δ 2.08 (s, 3H), 4.03 (d of mult., ethylenedioxy), 5.71 (s, 1H), 7.17 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.62 (s, 1H), 8.32 (br s, 1H). 13C NMR (CDCl3) δ 168.9, 138.8, 138.3, 129.1, 122.3, 120.8, 118.1, 103.5, 65.4, 24.4.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([F:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:22][C:11]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(F)(c1ccccn1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(c2ccccn2)CC2CCC(C1)N2
Reaction time: 2 h
Yield: 84.9 %

Procedure:
3-Fluoro-3-pyridin-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (PA Isomer 1) (0.056 g) was dissolved in DCM (1 mL) and TFA (5 mL). The solution was stirred for 2 hours then the solvent was removed by evaporation under vacuum. The residue was loaded onto an SCX-2 cartridge and washed with DCM, methanol and then eluted with ammonia (2 M in methanol). The solvent was removed by evaporation under vacuum to afford the title compound as a white solid (0.032 g). LCMS m/z 207 [M+H]+. R.T.=0.37 min (Analytical Method 3).
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[CH:6]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)([OH:3])=O.Cl.[C:23]1([N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]1([N:29]([NH:30][C:1]([CH2:4]/[CH:5]=[C:6]2\[CH2:7][CH2:8][CH2:9][C:10]3[C:15]\2=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:3])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1CCCC2/C=C/C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCC/C2=C\CC(=O)NN(c1ccccc1)c1ccccc1
Yield: 70.8 %

Procedure:
A solution of the carboxylic acid (prepared in reference example 5, 150 mg), 2-chloro-N-methylpyridinum iodide (197 mg). 1,1-diphenylhydrazine hydrochloride (147 mg) and triethylamine (0.216 ml) in methylene chloride (6 ml) was stirred overnight at room temperature. The mixture was poured into 1N hydrochloric acid, and extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was crystallized from crystallized ethyl acetate to give the title compound (as pale yellow powder; 167 mg) having the following physical data.
Reaction SMILES: [Li].[Li].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].C([Li:26])CCC.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>CCCCCC>[Li:26][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([Li:26])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[CH3:14][N:15]([CH3:21])[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]
Reactant: c1cc[cH-]c1
Reactant: [Li]CCCC
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]
Solvent: CCCCCC
Product: [Li][c-]1cccc1
Reaction time: 0.17 h

Procedure:
During a first step, ferrocene dilithium complexed with tetramethylethylenediamine (TMEDA) was prepared: In a glove box under argon, there is added 37 ml of freshly distilled TMEDA (247 mmoles) and 40 ml of anhydrous hexane in a 1 1 flask. There is then added drop wise 154 ml of a 1.6 M solution of butyllithium in hexane (247 mmoles, commercially available from Aldrich). After 10 min, there is added drop wise 18.6 g of ferrocene (100 mmoles) in solution in 500 ml of anhydrous hexane while keeping a strong stirring of the solution. After one night, orange crystals appeared in the solution, which were recovered by filtering the solution on a fritted glass of porosity No 4. After drying under vacuum, there is obtained 28.4 g of 1,1′-dilithio-ferrocene&Circlesolid;2 TMEDA (66% yield) which was preserved under argon.