Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:33](=[O:34])[N:12]2[C:13]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12)=O.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>[H-].[Ca+2].[H-]>[NH2:9][CH:10]1[C:33](=[O:34])[N:12]2[C:13]([C:17]([O:19][CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Ca+2]
Agent: [H-]
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 2 h

Procedure:
Benzhydryl 7-(2-thienylacetamido)-3-cephem-4-carboxylate (2.45 g. 5 mmol) was dissolved in calcium hydride dried benzene (130 ml) containing dry pyridine (0.59 g, 7.4 mmol). The solution was maintained at 0° and PCl5 (1.54 g. 7.4 mmol.) was added with stirring. The reaction mixture was stirred under nitrogen at 0° for 3 hours and then the solvent was removed in vacuo. Anhydrous methanol (260 ml) was added to the residue and the resultant mixture was allowed to stand 2 hours. The methanol was removed in vacuo and the residue was treated with 20% aqueous tetrahydrofuran. After 15 minutes the tetrahydrofuran was removed in vacuo and the aqueous residue was adjusted to pH 7.5 and extracted with ethyl acetate. The extracts were washed with water, dried over MgSO4 and evaporated to give the solid product which was triturated with chloroform-petroleum ether and dried under high vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl[C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[C:7]([NH:8][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Product: Cc1nc(S(C)(=O)=O)ccc1Nc1ncnc2c1OCCN2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the procedure described in Example 3, with the exception that 2-methyl-6-(methylsulfonyl)pyridin-3-amine was used instead of 2-fluoro-4-(methylsulfonyl)-aniline, tert-butyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 3C was converted into Example 123. 1H NMR (500 MHz, CDCl3) δ ppm 1.45 (s, 9H) 1.55-1.65 (m, 2H) 1.66-1.72 (m, 2H) 2.61 (s, 3H) 2.82-2.90 (m, 2H) 3.15 (s, 3H) 3.45-3.48 (m, 2H) 4.25-4.28 (m, 4H) 4.79-4.88 (m, 1H) 6.86-7.00 (m, 1H) 7.91 (d, J=8.25 Hz, 1H) 8.06 (s, 1H) 8.91 (m, 1H). LRMS (ESI): 505.3 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[CH:6]=1.[Br-].[CH3:9][C:10]1[N:15]=[C:14]([Zn+])[CH:13]=[CH:12][CH:11]=1.C1COCC1>CCOCC.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>[Cl:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1csc(Br)c1
Reactant: Cc1cccc([Zn+])n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(-c2cc(Cl)cs2)n1
Temperature: 40 °C
Yield: 28 %

Procedure:
To a solution of 2-bromo-4-chloro-thiophene (Gronowitz, Rosén Chemica Scripta, 1971, 1, 33) (1.50 g, 7.60 mmol) and 0.5 M solution of 6-methyl-2-pyridylzinc bromide in THF (23.00 mL, 11.39 mmol) is added Pd(PPh3)4 (0.18 g, 0.15 mmol). The solution is heated at 40° C. overnight, diluted with Et2O (50 mL), washed with sat. NH4Cl (40 mL), dried over MgSO4, filtered on concentrated. The residue is purified by ISCO column chromatography (5%-20% EtOAc/hexane gradient) furnish the title compound (0.45 g, 2.15 mmol, 28%). 1H NMR (CDCl3), δ 2.56 (s, 3H), 7.02 (d, 7.7 Hz, 1H), 7.13 (d, J=0.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.54 (dd, J=7.9, 7.7, 1H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]2[C:5]([CH:6]([OH:12])[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CO.[Br:20]N1C(=O)CCC1=O>O1CCCC1.ClCCl.C(O)(=O)C>[Br:20][C:3]1[CH:4]=[C:5]2[C:10](=[N:11][CH:2]=1)[NH:9][CH2:8][CH2:7][CH:6]2[OH:12]
Reactant: OC1CCNc2nc(Br)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: OC1CCNc2ncc(Br)cc21
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 25 %

Procedure:
7-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (460 mg) was dissolved in anhydrous tetrahydrofuran (25 mL) and cooled to −78° C. A solution of n-butyllithium in tetrahydrofuran was added (1.6 M, 8.5 mL) (5-7 equiv.) and the reaction was warmed slowly to room temperature. After 2-5 hours, methanol (2 mL) was added and the contents were concentrated to dryness. The residue was dissolved in a mixture of dichloromethane and acetic acid (1:1, v/v, 20 mL) and N-bromosuccinimide (450 mg) (1.2 equiv.) were added. After 45 minutes, the mixture was concentrated to dryness onto silica gel, and purified by silica gel chromatography to give the title compound as yellow solids (25-65% yield). M.p. 125-128° C., LCMS: m/z=229 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.72 (m, 2H), 3.25 (m, 2H), 4.56 (m, 1H), 5.33 (d, J=5.0 Hz, 1H), 6.8 (bs, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=[O:14])[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC#N>[OH:14][CH2:13][CH2:12][C@H:11]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=1
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC#N
Product: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 36 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (0.10 mg, 0.21 mmol) in a 9:1 mixture of dichloroethane in CH3CN (5 mL) was added sodium triacetoxyborohydride (181 mg, 0.854 mmol). After 36 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by silica gel chromatography using a gradient of 0-8% methanol in dichloromethane to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:39])[C:27](=[O:38])[O:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][NH2:37]>>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:37][CH2:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[O:28][C:27](=[O:38])[N:26]([CH3:25])[CH3:39])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Oc1cc(F)ccc1CN
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CN(C)C(=O)Oc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 133, 2-(aminomethyl)-5-fluorophenyl dimethylcarbamate. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.58 (6H, s, gem-Me), 2.92, 3.05 (2s, NMe), 3.96 (2H, m, NCH2), 4.00 (2H, m, OCH2), 4.48 (2H, d, J=5.5 Hz, NCH2), 5.26 (2H, s, OCH2), 6.84 (1H, dd, J=2.5 Hz, 9 Hz, Ar—H), 6.87 (1H, dt, J=2.5 Hz, 8 Hz, Ar—H), 7.25–7.33 (4H, m, Ar—Hs), 7.53 (2H, d, J=˜7 Hz, Ar—Hs), 7.78 (1H, brt, J=5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.68, 36.61, 36.89, 37.97, 42.97, 58.06, 74.73, 76.23, 110.58, 110.77, 113.06, 113.23, 126.55, 126.58, 128.31, 128.45, 128.91, 131.23, 131.31, 136.76, 140.70, 142.00, 150.60, 150.69, 154.50, 156.30, 159.79, 161.40, 163.37, 162.43. HRMS (ESI) calcd for C27H30N4O6F (M+H) 525.2149. found 525.2163.
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]=[C:13]([C:15]3[C:16]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:17][N:18]4[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:19]=34)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:32]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:32]1([NH:24][C:22]2[CH:21]=[CH:20][C:19]3[N:18]([N:17]=[C:16]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:15]=3[C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:3]4[CH2:7][CH2:6][CH2:5][CH2:4]4)[N:14]=3)[CH:23]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCCC1
Reactant: Nc1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(-c2nn3cc(NC4CCCC4)ccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a suspension of 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine dihydrochloride (90 mg, 0.20 mmol) in 1,2-dichloroethane was added cyclopentanone (26 μL, 0.29 mmol), acetic acid (56 μL, 0.98), and sodium triacetoxyborohydride (82 mg, 0.39 mmol). The reaction mixture was stirred at room temperature 16 hours then quenched with water. The resultant mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The organic layer was dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes:ethyl acetate to 7:3 hexanes:ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-6-amine (40 mg, 45%) as a green oil. Rf 0.25 (2:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.25 (d, 1H), 8.00 (d, 1H), 7.79 (s, 1H), 7.61 (m, 2H), 7.13 (t, 2H), 6.86 (d, 1H), 6.32 (d, 1H), 5.23 (br, 1H), 4.36 (m, 1H), 3.72 (m, 1H), 3.54 (d, 1H), 2.14–2.02 (m, 4H), 1.81–1.51 (m, 12H); MS m/z 457 (M+1). To a solution of the product in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:40])C.[OH-].[Na+].Cl>C(O)C>[CH3:40][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:41])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(Oc3ncccc3C(F)(F)F)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 178 mg (72%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.78 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[F:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CC(N(C)C)=O>C1COCC1>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][N:9]2[C:10](=[O:12])[C:11]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=4[F:24])=[C:3]([F:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=3[N:7]=[CH:8]2)[CH2:18][O:17]1
Reactant: Nc1ccc(I)cc1F
Reactant: Cn1c(=O)c(F)c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Combine (R)-5-chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (5.00 g, 14.5 mmol) and 2-fluoro-4-iodoaniline (3.45 g, 14.5 mmol) in THF (25 mL). Cool in an ice-bath. Add lithium hexamethyldisilazide (1.0 M in THF, 36.4 mL, 36.4 mmol) maintaining the temperature below about 10° C. After 10 minutes, warm to ambient temperature. After 30 minutes, heat to 55° C. After 20 hour, cool to ambient temperature, add dimethylacteamide (35 mL) and evaporate in vacuo to remove most of the THF. Cool the remaining mixture in an ice-bath then add water (17.5 mL) to form a solid. Add water (20 mL), then collect the solid by filtration, rinse with water (3×15 mL), heptane (15 mL), and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ10.14 (s, 1H), 8.60 (s, 1H), 7.68 (d, 1H, J=10.4, 2.0 Hz), 7.52 (d, 1H, J=8.8 Hz), 6.96 (td, 1H, J=8.8, 6.0 Hz), 4.41 (m, 1H), 4.25 (dd, 1H, J=13.6, 3.6 Hz), 4.06 (dd, 1H, J=8.8, 6.4 Hz), 3.98 (dd, 1H, J=13.6, 7.6 Hz), 3.78 (dd, 1H, J=9.2, 5.6 Hz), 3.58 (s, 3H), 1.37 (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ161.1 (d, J=4.4 Hz), 155.7 (d, J=8.8 Hz), 155.4, 153.3, 151.1 (d, J=109 Hz), 135.6, 133.6 (d, J=7.3 Hz), 133.1 (d, J=3.7 Hz), 127.9 (d, J=13.2 Hz), 125.2 (d, J=6.5 Hz), 123.9 (d, J=21.9 Hz), 109.1, 95.1 (d, J=4.4 Hz), 87.1 (d, J=7.3 Hz), 72.2, 66.1, 48.9, 28.8, 26.6, 25.0; 19F NMR (376 MHz, DMSO-d6) δ-124.5, −149.3; MS (M+H)+m/z calcd 545.0. found 545.0.
Reaction SMILES: C1(S)C=CC=CC=1.[OH-].[K+].[CH2:10]([N:12]([C@H:25]1[CH2:30][C@H:29]([CH3:31])[S:28][C:27]2[S:32][CH:33]=[CH:34][C:26]1=2)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH3:11]>C(#N)C.O>[CH2:10]([NH:12][C@H:25]1[CH2:30][C@H:29]([CH3:31])[S:28][C:27]2[S:32][CH:33]=[CH:34][C:26]1=2)[CH3:11]
Reactant: CCN([C@H]1C[C@H](C)Sc2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCN[C@H]1C[C@H](C)Sc2sccc21
Temperature: 5 °C
Yield: 72.4 %

Procedure:
Benzenethiol (3.2 mL) is dissolved in acetonitrile (15 mL). It is cooled under 5° C. and a mixture of potassium hydroxide (1.73 g) in water (4.2 mL) is added, maintaining the temperature under 10° C. The temperature is allowed to rise to 20-25° C. and a solution of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran (4.9 g) in acetonitrile (10 mL) is added. The resulting mixture is heated at 50° C. and is maintained until completing the transformation. Water (80 mL) is added and it is vacuum distilled until the volatiles are removed. It is extracted with ethyl acetate (80 mL). The resulting organic phase is vacuum distilled to dryness and the obtained residue is chromatographed in a column (methylene chloride/methanol 94/6), obtaining 1.9 g of trans-4-(N-ethylamino)-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran.
Reaction SMILES: [CH2:1]([S:13][C:14]1[S:18][C:17]([SH:19])=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+].Cl[C:23]1[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:13][C:14]1[S:18][C:17]([S:19][C:23]2[C:24]([C:29]#[N:30])=[N:25][CH:26]=[CH:27][N:28]=2)=[N:16][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to Example 1 by using 5-(dodecylthio)-1,3,4-thiadiazole-2-thiol (319 mg, 1.00 mmol), NaH (60% dispersion in mineral oil, 44 mg, 1.10 mmol), and 3-chloropyrazine-2-carbonitrile (140 mg, 1.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere overnight.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.ClC1C=CC(S(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1.[OH-].[Na+].[N+]([C:40]1[CH:41]=[C:42]([C:48]#[N:49])[C:43](=[CH:46][CH:47]=1)[C:44]#[N:45])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:48](#[N:49])[C:42]1[C:43](=[CH:46][CH:47]=[CH:40][CH:41]=1)[C:44]#[N:45]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccccc1C#N
Temperature: 150 °C
Yield: 98 %

Procedure:
To a 500 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A (50 g, 219 mmol), bis(4-chlorophenyl) sulfone (22.0 g, 76.7 mmol), sodium hydroxide (20.0 g, 500 mmol), toluene (50 mL), and dimethylsulfoxide (DMSO) (250 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 145-155° C. under a nitrogen atmosphere for 8-16 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (50.6 g, 292 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile and the bisphenol A phthalonitrile composition (100 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)([CH2:13][CH:14]=O)[CH2:9]1)=[O:7].[CH2:29]([O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])[CH3:30]>>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:35]3[N:34]([CH2:33][CH2:32][O:31][CH2:29][CH3:30])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)=[O:44])[CH2:50][CH2:49]2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CC=O)(c3ccccn3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccccn4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 68.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(pyridin-2-yl)-3-(2-oxo-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound
Reaction SMILES: [CH2:1]([Sn:11]([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(C1C=CSC=1)[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:32]Br>>[CH2:1]([Sn:11]([Br:32])([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(c1ccsc1)c1ccsc1)c1ccccc1
Reactant: BrBr
Product: CC(C)(C[Sn](Br)(CC(C)(C)c1ccccc1)c1ccsc1)c1ccccc1

Procedure:
In substantial accordance with the procedure described in Example 1(2), dineophyl-di(3-thienyl)tin (80 g, 0.145 mol) obtained above was reacted with bromine to give crude dineophyl-3-thienyltin bromide, which was then reacted with sodium fluoride. The resulting product was recrystallized from n-hexane to provide 21.5 g of dineophyl-3-thienyltin fluoride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[C:19]([NH2:22])(=[S:21])[CH3:20]>>[CH3:1][O:2][C:3]([C:4]1[N:22]=[C:19]([CH3:20])[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:18]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.98 min; [M+H]+=302.2.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[C:15]1=[O:32])[CH3:13].[H-].[Na+]>CN(C=O)C.CO>[CH2:12]([N:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[N:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:27][CH:26]=2)[C:15]1=[O:32])[CH3:13]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(C#N)cc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncc(C#N)cc21
Temperature: 180 °C
Yield: 13.5 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (15 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (25.5 mg) and sodium hydride (4.0 mg) in DMF (1.0 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carbonitrile (5 mg) as white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:18][CH2:19][O:20][CH3:21])[S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[CH3:21][O:20][CH2:19][CH2:18][C:8]1[S:9][C:10]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1nc(CCOC)sc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Temperature: 55 °C
Reaction time: 0.67 h
Yield: 51.1 %

Procedure:
A solution of 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.17 g, 0.56 mmol) in methanol (1.00 ml) was treated with a 2.55 N solution of KOH in water (0.66 ml). The mixture was stirred at 55° C. for 40 min, then the volatiles were evaporated. The residue was redissolved in water (1.30 ml) and acidified to pH 3 with 1N HCl. Filtration and drying under vacuum afforded 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.08 g, 50%), MS (ISP): m/e=278.1 (M−H)