Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cc(F)ccc3OC)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1-c1cc2c(O)c(C(=O)NCCC(=O)O)ncc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 1-benzyl-3-(5-fluoro-2-methoxy-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.062 mmol), β-alanine (737 mg, 8.3 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a white solid. MS: (+) m/z 492.25 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]2)=[C:18]([F:30])[CH:17]=1>>[CH3:28][N:27]([CH3:29])[C@@H:24]1[CH2:25][CH2:26][N:22]([C:19]2[CH:20]=[CH:21][C:16]([N:15]3[CH2:2][CH2:3][C:4]4[C:5](=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[CH:12]=4)[C:6]3=[O:7])=[CH:17][C:18]=2[F:30])[CH2:23]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2F)C1
Reactant: COc1ccc(C(=O)Cl)c(CCCl)c1
Product: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C)C3)c(F)c1)C2=O

Procedure:
2-(2-Chloroethyl)-4-methoxybenzoyl chloride was reacted with [(R)-1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]dimethylamine by method A. The product with the molecular weight of 383.47 (C22H26FN3O2) was obtained in this way; MS (ESI): 384 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:9]
Reactant: c1c[nH]nn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(OCC)n1ccnn1
Yield: 56.8 %

Procedure:
After the addition of 2.5 g of p-toluenesulphonic acid hydrate, 34.5 g (0.5 mol) of triazole in 222 g (1.5 mol) of triethyl orthoforrnate are heated until the internal temperature reaches 150° C., while ethanol is distilled off. 2 g of sodium carbonate are added and the mixture is distilled using high vacuum. 48.6 g (56.8% of theory) of N-diethoxymethyltriazole are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[N:37][NH:38]2)=[CH:34][C:33]=1[NH2:41]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([NH:41][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:32]=1[F:31])[NH:38][N:37]=[CH:36]2)=[O:19]
Reactant: CC1=C(C(=O)O)C(c2cccc(F)c2F)CC(=O)N1
Reactant: Nc1cc2cn[nH]c2cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2cccc(F)c2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
The product of Step 2 (40 mg, 0.15 mmol) was suspended in CH2Cl2 (2 mL) under Ar. DMF (10 μL) was added, followed by oxalyl chloride (13 μL, 0.15 mmol). This mixture was stirred at rt for 30 min, then the resultant yellow solution was added to a −15° C. solution of 6-fluoro-1H-indazol-5-amine (25 mg, 0.17 mmol) in pyridine (2 mL). After stirring at −15° C. for 15 min, the reaction mixture was allowed to warm to rt over 1 h. The mixture was poured into EtOAc (50 mL), washed sequentially with aq. NH4Cl (20 mL), NaOH (10 mL, 2.5 N), HCl (10 mL, 1.0 N) and satd. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was triturated with 10% EtOAc/10% ether/80% hexanes to afford the title compound (34 mg, 57%). MS (ES+) m/e 401 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>O1CCCC1>[CH2:28]([Sn:23]([C:18]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccnnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).
Reaction SMILES: C([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:19]3[C:20]([F:40])=[C:21]([N:25](COC)[S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)[CH:9]=[CH:8][N:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O.O>>[NH2:5][C:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:19]3[C:20]([F:40])=[C:21]([NH:25][S:26]([C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=4[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CCn1cc(-c2ccnc(NC(C)(C)C)c2)c(-c2cccc(N(COC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCn1cc(-c2ccnc(N)c2)c(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 37.8 %

Procedure:
N-{3-[4-(2-tert-Butylamino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (250 mg, 0.436 mmol) was treated with TFA/H2O 9:1 (3 mL) at 70° C. for 4.5 h. The reaction mixture was then evaporated to dryness, taken up with AcOEt and washed with sat, aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (DCM/MeOH/NH3 7M in MeOH 90:8:2) and then treated with ethyl ether, filtered and dried to give 78 mg of N-{3-[4-(2-Amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-benzene-sulfonamide as a white solid. HPLC (254 nm): Rt: 5.13 min; 1H NMR (DMSO-d6) Shift: 10.75 (br. s., 1H), 8.13 (s, 1H), 7.67 (dd, J=0.5, 5.4 Hz, 1H), 7.50-7.59 (m, 1H), 7.41-7.50 (m, 2H), 7.30 (td, J=24, 7.4 Hz, 1H), 7.12-7.26 (m, 2H), 6.27 (d, J=0.7 Hz, 1H), 6.08 (dd, J=14, 5.4 Hz, 1H), 5.82 (br. s., 2H), 4.18 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H); HRMS (ESI) calcd for C22H19F3N5O2S [M+H]+ 474.1206. found 474.1184.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=O)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>N1C=CC=CC=1>[Cl:24][C:10]1[O:11][C:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCc1oc(=O)[nH]c1-c1ccc(F)cc1
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(F)cc1
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[4-(4-fluorophenyl)-2-oxo-4-oxazolin-5-yl]butanoate (7.00 g), phosphorus oxychloride (14.7 g) and pyridine (1.89 g) was heated to 120-130° C. and stirred for 45 minutes. The reaction mixture was poured into ice water (200 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (100 ml) and a saturated aqueous solution of sodium chloride (100 ml), and then dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-4-(4-fluorophenyl)-5-oxazolebutanoate was obtained as a yellow oil (4.23 g, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH2:16]4)[N:9]3[N:8]=2)[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[C:1]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:30]=[C:10]3[N:11]=[C:12]([CH3:29])[C:13]([C:23](=[O:28])[C:24]([O:26][CH3:27])=[O:25])=[C:14]([N:15]4[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20]4)[N:9]3[N:8]=2)[CH:2]=1
Reactant: COC(=O)C(O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1c(C)nc2nc(-c3cccc(-c4ccccc4)c3)nn2c1N1CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a soln. of methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (73 mg, 0.150 mmol) in CH2Cl2 (5 mL) was added Dess-MartinPeriodinane (70.1 mg, 0.165 mmol) and the resulting mixture was stirred at room temp for 1 hr and then diluted with ethyl 5 mL) and washed with sat. NaHCO3 solution (5 mL), dried (Na2SO4), filtered and concentrated and purified by Biotage (90 g, eluted from 3-32% EtOAc/Hexane) to afford methyl 2-(2-([1,1′-biphenyl]-3-yl)-7-(4,4-dimethylpiperidin-1-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (61 mg, 0.124 mmol, 82% yield).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=O)[NH:2]1.O=P(Cl)(Cl)Cl.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH3:23]>>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH3:23])[C:3]1=[N:2][CH2:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4]1
Reactant: O=C1NCc2ccccc2CN1
Reactant: CNCCOC
Solvent: O=P(Cl)(Cl)Cl
Product: COCCN(C)C1=NCc2ccccc2CN1
Temperature: 106 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of 4,5-dihydro-1H-benzo[e][1,3]diazepin-3(2H)-one (Boyer, J. H. et al., J. Chem. Soc., Perkin Trans. I, 2137-2140 (1988)) (70 mg, 0.43 mmol) and POCl3 (805 μL, 8.63 mmol) was heated at 106° C. for 2 h. The reaction mixture was then concentrated in vacuo, dissolved in CHCl3 and azeotroped with PhMe. The residue was dissolved in THF (1.0 mL) and treated with 2-methoxy-N-methylethanamine (70 μl, 0.65 mmol). The resulting reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (29 mg, 28%). 1H NMR (CDCl3) δ 7.38-7.31 (m, 2H), 7.31-7.21 (m, 2H), 5.95 (br s, 1H), 4.61 (d, J=4.6 Hz, 2H), 4.39 (d, J=4.6 Hz, 2H), 3.56-3.51 (m, 2H), 3.42 (s, 3H), 3.40-3.36 (m, 2H), 3.10 (s, 3H); MS(ESI+) m/z 234.1 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]1=[O:23].[Mg+2].[I-].[I-]>>[OH:7][CH2:1][C:2]12[O:6][CH:5]([CH:4]=[CH:3]1)[CH:19]1[CH:20]2[C:21](=[O:22])[CH:17]([C:10]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[CH3:8])[C:18]1=[O:23]
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Reactant: OCc1ccco1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4C=CC(CO)(O4)C3C2=O)c(C)c1
Reaction time: 17 h

Procedure:
Furfuryl alcohol (4 ml, 46.7 mmol) is added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (2.0 g, 9.3 mmol) and MgI2 (520 mg, 1.86 mmol) and the reaction is stirred for 17 hours. The reaction mixture is adsorbed onto silica gel and purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-1-hydroxymethyl-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:8]1>O1CCCC1>[CH2:3]([Si@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)[CH2:2][CH3:1]
Reactant: CCCBr
Reactant: Fc1ccc(-c2ccc(CC[C@H]3CC[Si@H](Cl)CC3)cc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(F)cc3)cc2)CC1

Procedure:
2.5 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of tetrahydrofuran (hereafter abbreviated as "THF") to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.7 g (20 mmol) of 4-[2-(trans-4-chloro-4-silacyclohexyl)ethyl]-4'-fluorobiphenyl to obtain 4-[2-(trans-4-n-propyl-4-silacyclohexyl) ethyl]-4'-fluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.1 g of the trans isomers (yield 90%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: BrCc1ccccc1
Product: Cc1nc(N2CCCC(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with (bromomethyl)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 26% yield: mp 162-164° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 10H), 6.01 (br s, 1H), 4.57 (d, J=5.3 Hz, 2H), 4.32-4.18 (m, 1H), 4.02-3.88 (m, 1H), 3.47-3.38 (m, 1H), 2.87-2.69 (m, 2H), 2.64 (s, 3H), 2.07-1.45 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 172.2, 162.7, 157.0, 152.2, 138.9, 137.9, 129.2, 128.8, 128.6, 127.9, 127.7, 126.5, 119.4, 48.1, 44.1, 44.0, 37.6, 24.8, 21.2, 17.4; MS (ES+) m/z 420.5 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=1)[CH3:10]
Reactant: CCc1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.9 %

Procedure:
In a 100 mL round-bottomed flask was placed ((3-ethylphenyl)ethynyl)trimethylsilane (3.17 g, 15.66 mmol) and MeOH (31.3 ml) was added to give a yellow solution. Potassium carbonate (21.65 g, 157 mmol) was added and reaction stirred at 25° C. for 1 h. The reaction was partitioned between water (200 mL) and hexanes (200 mL). The organic was washed with water (100 mL) and brine (100 mL). The organic was dried over Na2SO4. The solvent was removed providing 1-ethyl-3-ethynylbenzene (2.24 g, 17.21 mmol, 110% yield) as a dark brown oil that was used as is without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[O:41][C:20]3=[N:21][CH:22]=[CH:23][C:24]([NH:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:19]3[C:18]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[O:41][C:20]3[N:21]=[CH:22][CH:23]=[C:24]([NH:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[C:19]=3[C:18]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(OCCN5CCCCC5)c(F)c4)c(-c4ccccc4)c23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(-c2oc3nccc(NCCN4CCNCC4)c3c2-c2ccccc2)ccc1OCCN1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20437.1 %

Procedure:
A solution of tert-butyl 4-(2-(2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridin-4-ylamino)ethyl)piperazine-1-carboxylate (0.058 g, 0.090 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. Trifluoroacetic acid (1.0 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. for 2 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a yellow oil. This oil was purified via preparative thin layer chromatography (eluting with 90:10:1, dichloromethane/methanol/ammonium hydroxide) to afford 2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenyl-N-(2-(piperazin-1-yl)ethyl)furo[2,3-b]pyridin-4-amine 10 g as a white solid. MS (MH+) 544.3; Calculated 543 for C32H38FN5O2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CN(C)C=O>[F:14][C:13]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1
Reactant: OCC1CCNCC1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (89 g) in N,N-dimethylformamide (1 L) were added 4-piperidinemethanol (50 g) and potassium carbonate (60.0 g), and the mixture was stirred at room temperature for 2 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained oil and triethylamine (242 mL) in dimethyl sulfoxide (1 L) was added sulfur trioxide pyridine complex (138 g), and the mixture was stirred at room temperature for 1 hr. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (85 g).
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9](=[O:44])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][S:18]([N:21]2[CH2:42][CH2:41][C:24]3([N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH:36]=[C:37]([F:39])[F:38])[CH2:31][CH2:30]4)[NH:26][C:25]3=[O:40])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[C:12]([CH3:43])[CH:11]=1.Cl>C(O)(C)(C)C.O1CCCC1.COC(C)(C)C>[F:39][C:37]([F:38])=[CH:36][CH2:35][CH:32]1[CH2:33][CH2:34][CH:29]([C:27]2[NH:26][C:25](=[O:40])[C:24]3([CH2:41][CH2:42][N:21]([S:18]([CH2:17][CH2:16][C:13]4[CH:14]=[CH:15][C:10]([C:9]([OH:44])=[O:8])=[CH:11][C:12]=4[CH3:43])(=[O:20])=[O:19])[CH2:22][CH2:23]3)[N:28]=2)[CH2:30][CH2:31]1
Reactant: COC(=O)c1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCC(CC=C(F)F)CC2)NC3=O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: COC(C)(C)C
Product: Cc1cc(C(=O)O)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(CC=C(F)F)CC1)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.2 %

Procedure:
Potassium t-butoxide (15.6 mg) was added to a solution of 4-(2-{2-[4-(3,3-difluoro-allyl)-cyclohexyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-ethyl)-3-methyl-benzoic acid methyl ester (25.6 mg, 46.4 μmol) in t-butanol (464 μL) and tetrahydrofuran (464 μL), and the mixture was stirred at room temperature for two days. The reaction mixture was diluted with tert-butyl methyl ether and then adjusted to pH 1 with 2 N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was then dried to give 4-(2-{2-[4-(3,3-difluoro-allyl)-cyclohexyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl}-ethyl)-3-methyl-benzoic acid (27.5 mg, 91%).