Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[CH3:11]>C(O)CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][CH:20]2[CH2:21][CH2:22][N:17]([CH2:16][C:15]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)[CH2:18][CH2:19]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: OCCO
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)ncc3C)CC2)ccc1OC
Yield: 7 %

Procedure:
A solution of 2,4-dichloro-5-methyl-pyrimidine (16.3 mg, 0.10 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 200° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (7%) of the title compound. MS (ESI): 391.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[OH-].[NH4+:14]>S(Cl)(Cl)=O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:14])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-bromophenyl)propanoic acid (15.0 g) in thionyl chloride (24.5 g) was added catalytic amount of N,N-dimethylformamide (one drop) and refluxed for 1.5 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured slowly into 28% aqueous ammonium hydroxide solution (150 ml) at 0° C. The mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave 3-(4-bromophenyl)propanamide (13.7 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M74) (905 mg, 1.7 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (566 mg).
Reaction SMILES: [OH-].[K+].C(=O)(OC)[O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:6]=1[Cl:18].Cl>CO>[C:14]([C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([OH:4])=[C:6]([Cl:18])[CH:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(Cl)c(O)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Potassium hydroxide (10.1 g, 181 mmol) was added to 4-tert-butyl-2-chloro-5-nitrophenyl methyl carbonate (40.0 g, 139 mmol) in MeOH (100 mL). After 30 min, the reaction was acidified with 1N HCl and extracted with dichloromethane. The combined organic layers were combined, dried over Na2SO4 and concentrated under vacuum. The crude residue was purified by column chromatography (Pet. Ether/EtOAc, 30:1) to give 4-tert-butyl-2-chloro-5-nitro-phenol (23.0 g, 68% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](=[O:42])(=[O:41])[N:26]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11]CC)=O.[NH3:43]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](=[O:42])(=[O:41])[N:26]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([NH2:43])=[O:11]
Reactant: N
Reactant: CCOC(=O)COc1cc(F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc12
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OCC(N)=O)nccc3c2)cc1
Temperature: 60 °C

Procedure:
Ethyl 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetate was dissolved in methanolic ammonia and heated at 60° C. for 16 h in a sealed tube. The reaction mixture was concentrated to obtain 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetamide as light yellow solid. m/z (ESI) 579.2 (M+H)+. This was then dissolved in DCM (1 mL) and 4 drops of TFA were added and the reaction was stirred for 15 min. The reaction mixture was loaded on 10 g silica gel column and eluted with DCM:MeOH (90:10) up to 100% to obtain 2-(5-fluoro-2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetamide (3.9 mg, 8.51 μmol, 2.96% yield) as light yellow solid. m/z (ESI) 459.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[N:26]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:41][CH2:40]2)[N:25]=1.[F-].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([C@H:39]4[CH2:40][CH2:41][C@H:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:43][CH2:44]4)[C:27]=3[CH3:38])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (62.3 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=553.24/555.24 (100/50) [MH+]. HPLC: tR=1.71 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16](C1CCCCO1)[N:15]=[CH:14]2.Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:39][CH3:40])=[C:10](\[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:28][CH:27]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(F)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 164.9 %

Procedure:
A round-bottom flask equipped with a magnetic stir bar was charged with (E)-ethyl 3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (255.9 g, 457.8 mmol; Compound 193) and a solution of HCl (732 mL, 1.25 M in ethyl alcohol). The reaction was heated at 80° C. for 2.5 h, allowed to cool to room temperature, and then concentrated to an orange gel. tert-Butyl methyl ether (2.3 L) was added. After stirring for 5 min, solids began to precipitate. The mixture was stirred at room temperature for 2 h and then filtered. The solids were washed with MTBE (700 mL) and dried to give the title compound (193 g) as an off-white solid. 1H NMR (DMSO-d6): δ 8.11 (s, 1H), 7.69 (s, 1H), 7.57-7.50 (m, 2H), 7.45-7.33 (m, 4H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.48 (d, 1H), 4.14 (q, 2H), 2.38 (q, 2H), 1.19 (t, 3H), 0.90 (t, 3H); LCMS: 475 (M+H)+.
Reaction SMILES: Cl[SiH2:2][SiH3:3].[CH:4]([NH:7][CH:8]([CH3:10])[CH3:9])([CH3:6])[CH3:5]>CCCCCC>[CH:4]([N:7]([SiH2:2][SiH3:3])[CH:8]([CH3:10])[CH3:9])([CH3:6])[CH3:5]
Reactant: CC(C)NC(C)C
Reactant: [SiH3][SiH2]Cl
Solvent: CCCCCC
Product: CC(C)N([SiH2][SiH3])C(C)C
Temperature: 25 °C

Procedure:
In a 3-necked round bottom flask equipped with a mechanic stirrer, a condenser, and an addition funnel, a solution of 1 equivalent monochlorodisilane in hexane was cooled to −10° C. with a cold bath. With stirring, 2 equivalent of di-iso-propylamine was added dropwise through the addition funnel. After the addition was completed, the reaction mixture was allowed to warm up to room temperature. The reaction mixture was stirred at room temperature for 2 hours, followed by filtration. A distillation removed solvent hexane from the filtrate. The product di-iso-propylaminodisilane was obtained by vacuum distillation. Gas chromatography (GC) showed that it was >99% pure di-iso-propylaminodisilane (DIPADS) (1H NMR (500 MHz, C7D8): δ=4.89 (m, SiH2), 3.31 (t, SiH3), 2.93 (m, CHMe2), 1.00 (d, CHMe2). FIG. 1 shows the TGA/DSC graph of di-iso-propylaminodisilane, wherein the TGA demonstrates that the compound is volatile and the DSC shows it has a boiling point of about 157° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:25]1([CH2:31]Br)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3CCCCC3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CC3CCCCC3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CC3CCCCC3)c3c2CCNCC3)cc1
Yield: 53.5 %

Procedure:
The title compound (0.09 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 170 mg) using cyclohexylmethyl bromide (2 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-cyclohexylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18; found, m/z 344.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=6.6 Hz, 2H), 7.32 (d, J=6.6 Hz, 2H), 3.94 (d, J=7.3 Hz, 2H), 3.44-3.40 (br m, 2H), 3.35-3.32 (br m, 2H), 3.17-3.14 (br m, 2H), 3.01-2.99 (br m, 2H), 1.74-1.53 (m, 4H), 1.52 (d, J=11.2 Hz, 2H), 1.17-1.10 (m, 3H), 0.94-0.90 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](I)=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([O:32][C:33]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][C:34]=2[O:41][CH3:42])[CH3:31])=[CH:26][CH:25]=1>O1CCCC1>[C:1]([Si:5]([CH3:17])([CH3:16])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:37]([C:36]2[CH:39]=[CH:40][C:33]([O:32][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH3:31])=[C:34]([O:41][CH3:42])[CH:35]=2)[OH:38])=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1OC(C)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C)(C)C(C)(C)C)c3ncccc23)ccc1OC(C)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1-(tert-Butyl-dimethyl-silanyl)-3-iodo-1H-pyrrolo[2,3-b]pyridine (636, 647.0 mg, 1.81 mmol) was dissolved in tetrahydrofuran (10.0 mL) at −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.0 M, 0.98 mL) was added to the reaction. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 4-[1-(4-chloro-phenyl)-ethoxy]-3-methoxy-benzaldehyde (644, 420 mg, 1.4 mmol) in tetrahydrofuran (3.00 mL) was added. The reaction was stirred for 2 hours during which time the temperature rose to 10° C. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, ethyl acetate:hexanes, to provide the desired compound, (645, 463 mg, 61%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[O:22][CH2:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:9]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][C:2]1[N:3]=[C:4]([C:21]2[O:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[S:5][C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: Cc1nc(C2=NC(c3ccccc3)CO2)sc1Cc1cccc(N2CCN(C)CC2)c1
Agent: O=[Mn]=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nc(-c3ccccc3)co2)sc1Cc1cccc(N2CCN(C)CC2)c1
Yield: 5.8 %

Procedure:
To a suspension of 2-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-4-phenyl-4,5-dihydrooxazole (17 mg, 0.04 mmol) and MnO2 (21 mg, 0.24 mmol) in toluene (2 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5 mg, 0.02 mmol) was added. The mixture was refluxed for 48 h under N2, and then cooled. The precipitate was filtered and washed with DCM/MeOH (10/1, 30 mL). The filtrate was washed with NaHCO3 (2 M, 10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by prep-TLC (DCM:MeOH=15:1) to afford 2-(4-methyl-5-(3-(4-methylpiperazin-1-yl)benzyl)thiazol-2-yl)-4-phenyloxazole as a light yellow solid (1.0 mg, 5%). MS (ES+) C25H26N4OS requires: 430, found: 431[M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 7.98 (s, 1H), 7.80 (d, J=9.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 6.80-6.82 (m, 1H), 6.72-6.78 (m, 2H), 4.10 (s, 2H), 3.28 (br, 4H), 2.72 (br, 4H), 2.50 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[CH:11][CH:12]=1
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: O
Product: O=C(CC(O)C(=O)O)c1ccc(Cl)cc1

Procedure:
A mixture of glyoxylic acid monohydrate (4.6 g, 50 mmol) and 4-chloroacetophenone (15.4 g, 0.1 mol) are heated at +95° C. under reduced pressure (50 mbar) for 3 hours. During this time, water is continually removed. After cooling, the reaction mixture is taken up in aqueous sodium carbonate solution and extracted with diethyl ether. The aqueous layer is acidified with 15% hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated, the residue is crystallized from ethyl acetate/hexane to obtain 4-(4-chloro-phenyl)-2-hydroxy-4-oxo-butyric acid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[S:10]1(=[O:21])[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]>CS(C)=O>[CH3:17][C:16]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][S:10]2(=[O:21])=[O:9])([CH3:20])[CH3:19])[CH2:4][O:18]1
Reactant: CC(=O)C(C)(C)N1CCCS1(=O)=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C(C)(C)N2CCCS2(=O)=O)CO1
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred suspension of 60% sodium hydride in mineral oil (0.039 g, 1.0 mmol) in anhydrous dimethyl sulfoxide (5 mL), under nitrogen, was added trimethylsulfoxonium iodide (0.214 g, 1.0 mmol). The mixture was stirred at 70° C. for 1 hr and then cooled to room temperature. 3-(1,1-Dioxidoisothiazolidin-2-yl)-3-methylbutan-2-one (0.100 g, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs and then heated at 70° C. for 4 hrs. The mixture was cooled to 0° C. and quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes) to afford the product as a thick oil (0.065 g, 61%). 1H NMR (300 MHz, CDCl3) δ 3.52-3.12 (m, 4H), 2.76 (d, 1H, J=4.5 Hz), 2.54 (d, 1H, J=4.5 Hz), 2.42-2.20 (m, 2H), 1.60 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])=[CH2:2].S(Cl)([Cl:14])=O>>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])=[CH2:2]
Reactant: C=Cc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: C=Cc1ccccc1C(=O)Cl

Procedure:
Reaction of 2-ethenylbenzoic acid with thionyl chloride affords 2-ethenylbenzoyl chloride, which on reaction with diethylamine, affords 2-ethenyl-N,N-diethylbenzamide. Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-ethenylsaccharin.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4](O)=[O:5].[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:19])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:15][CH2:16]2)=[CH:7][C:3]=1[C:4]([NH:36][CH2:35][C:25]12[CH2:34][CH:29]3[CH2:28][CH:27]([CH2:33][CH:31]([CH2:30]3)[CH2:32]1)[CH2:26]2)=[O:5]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared as described in Example 5c) using 2-chloro-5-[4-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]-benzoic acid (Example 6b, 0.065 g), N,N′-carbonyldiimidazole (0.030 g), 1-adamantanemethylamine (0.032 ml) and dimethylformamide (3 ml) to give the subtitle compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH2:19])=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:21]1[CH:22]=[CH:23][N:24]=[C:25]2[C:30]=1[N:29]=[CH:28][C:27]([O:31][CH3:32])=[CH:26]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]3[C:15]([CH2:18][NH:19][C:21]4[C:30]5[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][N:29]=5)[N:24]=[CH:23][CH:22]=4)=[CH:16][O:17][C:12]3=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NCc1coc2ccc(-c3cc(F)cc(F)c3)nc12
Reactant: COc1cnc2c(Cl)ccnc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: COc1cnc2c(NCc3coc4ccc(-c5cc(F)cc(F)c5)nc34)ccnc2c1
Temperature: 100 °C
Yield: 36.1 %

Procedure:
A sealable microwave vial was charged with (5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methanamine (177.6 mg, 682 μmol), 8-chloro-3-methoxy-1,5-naphthyridine (146 mg, 751 μmol), and potassium phosphate (435 mg, 2047 μmol). A septum was attached and the vial was flushed with N2, then toluene (5 mL) and H2O (1 mL) were added and the was solution sparged with N2 for 5 min. The septum was then quickly removed and tris(dibenzylideneacetone)dipalladium (0) (15.6 mg, 17.1 μmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (42.5 mg, 68.2 μmol) were added together as solids. The vial was then sealed and the resulting purple solution was sparged again for 5 min. The mixture was then heated at 100° C. for 20 h. The mixture was concentrated in vacuo for purification by MPLC (Teledine Isco combiFlash Companion). The crude residue was taken up in minimal CH2Cl2 and absorbed onto a 25 g loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) using 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2: MeOH gradient to afford a tan amorphous solid. This solid was additionally triturated with CH2Cl2 (2×0.5 mL) to give N-((5-(3,5-difluorophenyl)furo[3,2-b]pyridin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (103 mg, 36.1% yield). LRMS (ESI) m/z calcd for C23H17F2N4O2 (M+H) 419.1. found 419.2.
Reaction SMILES: [I-:1].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>CN(C=O)C.Cl>[I:1][C:19]1[CH:18]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:22]=[CH:21][C:20]=1[OH:23]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium iodide (3.32 g) then chloramine-T (5.91 g) were added to a stirred solution of 4-trifluoromethylphenol (3.0 g) in DMF (30 ml) at O° C. The mixture was warmed to RT, stirred for 1 h, diluted with dilute hydrochloric acid then extracted with diethylether. The organic layer was washed with aqueous sodium thiosulphate solution, dried and the solvent removed under reduced pressure. Yield 5.25 g
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH2:24]([Mg]Cl)[CH2:25][CH3:26]>O1CCCC1>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CCC[Mg]Cl
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
A mixed solution of 3.7 g (10 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and 30 ml of tetrahydrofuran (hereafter abbreviated as "THF") was prepared, and a 5 ml THF solution of 2.5M n-propylmagnesium chloride (12.5 mmol) was dripped into this solution. The silacyclohexane rings of the target product thus obtained were a mixture of trans isomers and cis isomers. Following a conventional after treatment, they were separated by means of chromatography to obtain 2.9 g of the trans isomers of the target product (yield 80%). The results of its analysis are shown below.