Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.CN.[CH2:19]([N:21](CC)CC)C.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([NH:21][CH3:19])(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)c(F)cc1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: -50 °C
Reaction time: 6 h
Yield: 39.2 %

Procedure:
A solution of 2,4-difluoro-5-nitrobenzenesulfonyl chloride (21 g, 81 mmol) in THF (400 mL) at −60° C. was treated with methylamine hydrochloride (6.6 g, 97 mmol) and then treated dropwise with triethylamine (22.6 mL, 162 mmol). After stirring for 6 hours at −60 to −40° C. the mixture was adjusted to pH 3 with the addition of 15% aqueous HCl, diluted with water, and extracted with EtOAc. The organic extracts were dried (Na2SO4), concentrated, and subjected to flash chromatography (17% EtOAc-petroleum ether) to give 2,4-difluoro-N-methyl-5-nitrobenzenesulfonamide (8 g, 38%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.66-8.74 (m, 1 H), 7.20-7.25 (m, 1 H), 4.81-4.91 (m, 1 H), 2.78-2.81 (m, 3 H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:16][CH2:15][CH:14]2[CH:11]1[CH2:12][C:13]2=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:30])(=O)=O>C(Cl)Cl>[C:1]([O:9][CH:10]1[CH:11]2[CH:14]([C:13](=[O:17])[NH:30][CH2:12]2)[CH2:15][CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([O:9][CH:10]1[CH:11]2[CH:14]([NH:30][C:13](=[O:17])[CH2:12]2)[CH2:15][CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CCC2C(=O)CC12)c1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Product: O=C1CC2C(CCC2OC(=O)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 133.4 %

Procedure:
To a stirred solution of compound 1H (500 mg, 2.2 mmol) in CH2Cl2 (5 mL) was added a solution of O-mesitylenesulfonylhydroxylamine (650 mg, 3 mmol) in CH2Cl2 (2 mL) at −10° C., and the stirring was continued for 20 min between −10 to 0° C. It was concentrated, added to a mixed solvent of benzene and methanol (30 mL, 3:1) followed by a slurry of basic alumina (25 g) in methanol (20 mL). The reaction mixture was stirred at RT overnight, and alumina solid was removed by filtration. Purification by silica gel chromatography (5% to 100% EtOAc in hexanes, then 5% methanol in EtOAc) provide mixtures of the title compounds 1I and 1J (total 360 mg) as a yellow oil. MS (ES) m/z 246 [M+H]+.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](O)=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].S(Cl)(Cl)=O.Cl.[NH2:23][C:24]([NH2:26])=[NH:25].[OH-:27].[Na+]>>[NH:25]([CH2:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([C:14](=[O:27])[CH3:15])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[C:24]([NH2:26])=[NH:23]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: N=C(N)N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(=O)n1cnc2c1c(=O)n(CNC(=N)N)c(=O)n2C
Temperature: 45 °C

Procedure:
Theophylline-7-acetic acid (TAA) (0.42 moles, 100 grams) is admixed with excess thionyl chloride (SOC12) and slowly heated to 45° C. and refluxed for 2 hours. When reaction is completed, the excess SOC12 is removed under vacuum evaporation at 50° C., in the presence of benzene (80 grams). The vacuum evaporation with benzene is repeated three times to eliminate all residual SOC12. The resultant compound, theophylline-7-acetyl chloride (“TAC”) is added to a solution of guanidine hydrochloride (0.25 mols, 60 grams) and 5 equivalents of 2 normal sodium hydroxide at 0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[C:29]1([CH2:39][NH2:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>O1CCCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:12])[NH:40][CH2:39][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: NCc1cccc2ccccc12
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCCC(=O)NCc1cccc2ccccc12
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of suberic acid monomethyl ester 6c (376 mg, 2.0 mmol) in anhydrous tetrahydrofuran (5 ml) under argon atmosphere triethylamine (0.36 ml, 2.6 mmol) was added and the resulting solution was cooled in ice bath. To the mixture iso-butylchloroformate (0.3 ml, 2.3 mmol) was added and the reaction was stirred for 20 min, then a solution of 1-naphthylmethylamine 1/89 (314 mg, 2 mmol) in tetrahydrofuran (1.5 ml) was added. The mixture was stirred at ice bath temperature for 15 min and for 1 h at room temperature, diluted with brine (50 ml) and extracted with ethyl acetate (3×25 ml). The organic phase was washed with brine, 5% NaHCO3, brine, saturated KH2PO4, and brine. The organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was purified on silica gel (20 g) with chloroform-ethyl acetate as eluent to give the title compound 7/89, yield 85.4%. 1H NMR (CDCl3, HMDSO) δ: 1.12-1.81 (m, 8H); 2.16 (t, J=8.0 Hz, 2H); 2.25 (t, J=8.0 Hz, 2H); 3.63 (s, 3H); 4.87 (d, J=6.0 Hz, 2H); 5.61 (br s, 1H); 7.32-7.63 (m, 4H); 7.67-8.09 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 3,5-dibromopyridine (32, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and 21.3 mL of sodium methoxide (25% by wt. in methanol, 92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2×200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (33, 14.8 g, 93% theory) afforded a colorless oil after flash chromatography on silica gel (EtOAc:hexane 1:10).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[C:13]([Cl:21])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([OH:39])=O)[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1.CN.C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:21][C:13]1[C:14]([O:19][CH3:20])=[CH:15][C:16]([O:17][CH3:18])=[C:11]([Cl:10])[C:12]=1[C:22]1[N:27]=[CH:26][C:25]2[C:28]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([NH:4][CH3:1])=[O:39])[CH:35]=3)=[N:29][NH:30][C:24]=2[CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)Cn1cc(-c2n[nH]c3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ncc23)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (9.3 μL, 0.054 mmol) was added to a mixture of {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid (8.0 mg, 0.018 mmol), 2.0 M methylamine in THF (9.8 μL, 0.020 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (8.7 mg, 0.020 mmol) in N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at r.t. for 3 h, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=461.0/463.0.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]=[C:42]=[O:43].Cl>C1(C)C=CC=CC=1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][C:42](=[O:43])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccc(CC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid (23 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.152 mmol, 0.0264 mL) dissolved in toluene (2 mL) was added 2,4-difluorophenylisocyanate (0.0796 mmol, 0.0094 mL). The mixture was allowed to stir at room temperature for 72 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), brine (2×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 5% methanol/methylene chloride to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic acid as a clear film (18.5 mg, 54%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH2:14][CH2:15][CH3:16].CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:21]3[CH2:22][CH2:23][C:18]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:20]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)C1(c2ccccc2)CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (177 mg, 1.1 mmole) and 4-butyryl-4-phenylpiperidine (231 mg, 1.0 mmole) were dissolved in 10 ml dichloromethane. To this solution was added catalytic DMAP and EDCI (330 mg, 1.1 mmole). The resulting solution was then stirred at room temperature overnight. The reaction was worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.60 (s, 1H), 7.66 (d, 1H), 7.38-7.18 (m, 8H), 6.53 (d, 1H), 4.28 (bs, 1H), 3.67 (bs, 1H), 3.39 (t, 2H), 2.42 (bs, 2H), 2.18 (m, 3H), 1.88 (bs, 1H), 1.41 (m, 2H), 0.66 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31]([NH:33][CH3:34])=[O:32]>CN(C)C=O.Cl.C(OCC)(=O)C>[ClH:29].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:30][C:31]([NH:33][CH3:34])=[O:32])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: c1ccc(COc2cccc(CCNCC3CC3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CN(CCc1cccc(OCc2ccccc2)c1)CC1CC1
Temperature: 120 °C
Yield: 72.6 %

Procedure:
A mixture of 0.24 g (0.85 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.14 ml (1.00 mmol) of triethylamine, 0.11 g (1.02 mmol) of 2-chloro-N-methyl-acetamide in 3 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed and the crude residue was purified by flash chromatography (dichloromethane/methanol/NH3 100:0:0→95:5:0.5 gradient). The product obtained was dissolved in anhydrous hydrochloric acid in ethyl acetate, the solvent was removed under vacuum and the residue was triturated with diethyl ether. 0.24 g (80% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1>>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: Nc1cccnc1
Reactant: NC(=O)c1cc(Br)cc(Br)c1
Product: NC(=O)c1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3,5-Dibromo-benzamide and pyridin-3-ylamine were coupled to give 3-bromo-5-(pyridin-3-ylamino)-benzamide as described for Example 44. 3-Bromo-5-(pyridin-3-ylamino)-benzamide was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzamide as described in Example 75. 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.62 (d, J=2.9 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:34]=[C:33]([O:42][CH3:43])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(NS(C)(=O)=O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(NS(C)(=O)=O)c1
Temperature: 80 °C
Yield: 23 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (117 mg, 0.38 mmol), 4-amino-6-chloro-N-(3-methoxy-5-(methylsulfonamido)phenyl)pyrimidine-5-carboxamide (266 mg, 65% purity, 0.46 mmol), DIEA (404 μl, 2.32 mmol) and cesium fluoride (175 mg, 1.14 mmol) were suspended in tert-butanol (12 ml) and the mixture was heated at 80° C. in a sealed tube for 3 days. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 54 mg (23% yield) as a solid. Purity 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(F)c2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-8-fluoro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([Li])CCC.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[C:38]1[S:39][C:40]2[C:45]([N:46]=1)=[CH:44][CH:43]=[C:42]([C:47]1([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48]1)[N:41]=2)C=O>C1COCC1>[F:29][C:30]1[CH:31]=[C:32]([CH:24]=[CH:4][O:3][CH3:2])[CH:35]=[CH:36][C:37]=1[C:38]1[S:39][C:40]2[C:45]([N:46]=1)=[CH:44][CH:43]=[C:42]([C:47]1([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:48][CH2:49]1)[N:41]=2
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (methoxymethyl)triphenylphosphonium chloride (1.0 g, 2.93 mmol) was added THF (26 mLl) before it was cooled to 0° C.; butyllithium (2.5 M in hexanes, 1.28 ml, 3.20 mmol) was then added and stirred for 15 min before 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (1.00 g, 2.67 mmol) in THF (26 ml) was added to the reaction mixture. The reaction mixture was allowed to warm to ambient temperature and stir for 1 h to give 2-(2-fluoro-4-(2-methoxyvinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine after flash chromatography. MS (ESI) m/z: Calculated: 402.1; Observed: 403.1 (M++H).
Reaction SMILES: O[CH2:2][CH:3]1C(CO)CC(C)=CC1.Cl[C:13]1C=CC=C(C(OO)=O)[CH:14]=1.[OH:23][CH2:24][CH:25]1[CH:30]([CH2:31][OH:32])[CH2:29][C:28]2([O:34][CH:27]2[CH2:26]1)[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC.C(OC=C)(=O)C>C1(C)C=CC=CC=1>[CH:2]([O:23][CH2:24][CH:25]1[CH:30]([CH2:31][O:32][CH:13]=[CH2:14])[CH2:29][C:28]2([O:34][CH:27]2[CH2:26]1)[CH3:33])=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCC(CO)C(CO)C1
Reactant: CC12CC(CO)C(CO)CC1O2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Solvent: CCC(=O)O
Product: C=COCC1CC2OC2(C)CC1COC=C
Reaction time: 1 h
Yield: 80 %

Procedure:
4,5-di(hydroxymethyl)-1-methylcyclohexene was epoxidized with m-chloroperbenzoic acid and thereby yielded 4,5-di(hydroxymethyl)-1-methylcyclohexene oxide. A mixture (280 mL) of sodium carbonate 24.9 g (0.23 mol) and toluene was heated to 95° C., and 1.4 g of propionic acid was added dropwise to the mixture. Maintaining the temperature of the reaction mixture, the mixture was combined with 19 g of vinyl acetate added dropwise, and fifteen minutes later, further combined with 1.27 g (1.9 mmol) of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir (cod) Cl]2. Next, 30 g (0.19 mol) of 4,5-di(hydroxymethyl)-1-methylcyclohexene oxide was added dropwise for three hours, and a reaction was carried out in a nitrogen atmosphere while adding dropwise 62 g of vinyl acetate and holding the reaction temperature at 95° C. After the completion of dropwise addition, the mixture was stirred for one hour. As the result of gas chromatography analysis of the mixture, it is confirmed that there were produced 4,5-di(vinyloxymethyl)-1-methylcyclohexene oxide represented by following Formula (13) in a yield of 80%. In 1H-NMR (CDCl3) analysis, signals specific to vinyl group were observed at 6.2-6.5 ppm, 4.1-4.3 ppm, as an isomer mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using 4'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]-propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 205° C.; 1H NMR (400 MHz, DMSO-d6) δ2.37 (s, 3 H), 3.99 (s, 2 H), 6.69 (s, 1 H), 7.26 (m, 7 H), 7.68 (m, 2 H), 11.83 (bs, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:16][C:15]3[C:10](=[N:11][CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:4][CH2:3]1.[OH-].[Na+].C(Cl)[Cl:28].CO>C(Cl)Cl.CCO>[ClH:28].[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([CH2:16][C:15]3[C:10](=[N:11][CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:6][CH2:7]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C)CC1)C(=O)N2
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of (E)-ethyl 3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate (95 mg, 0.288 mmol) in DCM (2 mL) and EtOH (2 mL) was added 1N aqueous sodium hydroxide (1 mL, 1.000 mmol) and the reaction was stirred at rt overnight, after which TLC (DCM/MeOH, 9:1) showed full conversion. Next, the mixture was concentrated and the residue acidified with 1N HCl (5 mL) and stirred for 1 h. The resulting white solids were isolated by filtration, washed with H2O and Et2O and dried on the filter. The product (47 mg, 48%) was obtained as an off-white solid.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3](=[CH2:5])[CH3:4].[C:7]([CH:10]1[C:15]([CH3:17])([CH3:16])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)(=[O:9])[CH3:8].[Cl-].[NH4+]>C(OCC)C>[CH2:2]([C:7]([CH3:8])([CH:10]1[C:15]([CH3:16])([CH3:17])[CH:14]2[CH2:18][CH:11]1[CH:12]=[CH:13]2)[OH:9])[C:3](=[CH2:5])[CH3:4]
Reactant: C=C(C)CCl
Reactant: CC(=O)C1C2C=CC(C2)C1(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C(C)CC(C)(O)C1C2C=CC(C2)C1(C)C
Yield: 106.5 %

Procedure:
Into a 1 liter reaction flask equipped with a reflux condenser, thermometer, stirrer, dropping funnel and nitrogen inlet tube are placed 12 g (0.5 moles) of magnesium turnings and 250 cc anhydrous diethyl ether. Over a 2 hour period, 45.3 g (0.5 moles) of methallyl chloride is added. The Grignard solution is stirred for one-half hour and 28 g of 2-acetyl-3,3-dimethyl-5-norbornene is added over a 20 minute period. The mixture is stirred at reflux for one-half hour and then is hydrolyzed by the addition of saturated ammonium chloride solution. The organic layer is washed with water and dried over magnesium sulfate. The mixture is then filtered and the solvent evaporated to yield 40 g of an oil, which is then fractionated on a micro Vigreux column after adding thereto 5 g Primol® and a trace quantity of Ionox®.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cc(F)ccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)-1,4-difluorobenzene (1.06 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.88 g, 54%).