Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH2:31][OH:32])[C@@H:27]([O:33][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:30][O:29][C@H:28]([CH:31]=[O:32])[C@@H:27]([O:33][Si:34]([CH2:37][CH3:38])([CH2:39][CH3:40])[CH2:35][CH3:36])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1
Reactant: CC[Si](CC)(CC)O[C@H]1C[C@@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CO[C@@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H]1C[C@@H](Oc2nc3nc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)CO[C@@H]1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ((2R,3 S,5R)-5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-3-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol (56 mg, 0.080 mmol) in anhydrous DCM under nitrogen was added pyridine (13 μL, 12.7 mg, 0.161 mmol) and Dess-Martin periodinane (51 mg, 0.121 mmol). After stirring at room temperature for 2 hours, the mixture was directly loaded onto a Biotage™ 10 g silica gel cartridge and eluted with 0-20% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The desired SEM regioisomeric product fractions were combined and concentrated under reduced pressure to provide the title compound as a clear oil. LC-MS: calculated for C36H48ClN3O5Si2 693.28, observed m/e: 694.25 (M+H)+ (Rt 3.23/4 min, minor isomer), 694.23 (M+H)+ (Rt 3.31/4 min, major isomer).
Reaction SMILES: ClC1C([N+]([O-])=O)=CC=CC=1C=O.C1(NC(C2CCNCC2)=O)CCCCC1.[CH:28]1([NH:34][C:35]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([N+:50]([O-])=O)[C:45]=3[Cl:53])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:35]([CH:37]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([NH2:50])[C:45]=3[Cl:53])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NC1CCCCC1)C1CCN(Cc2cccc([N+](=O)[O-])c2Cl)CC1
Agent: O=C(NC1CCCCC1)C1CCNCC1
Agent: O=Cc1cccc([N+](=O)[O-])c1Cl
Product: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1Cl

Procedure:
The title compound is prepared according to the reactions described above starting from 2-chloro-3-nitro-benzaldehyde and piperidine-4-carboxylic acid cyclohexylamide giving after reductive amination 1-(2-chloro-3-nitro-benzyl)-piperidine-4-carboxylic acid cyclohexylamide LC-MS B: tR=0.57 min; [M+H]+=380.14 and reduction with stannous chloride the title compound LC-MS A: tR=0.50 min; [M+H]+=350.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]4[CH:18]=[CH:17][C:16]([C:19]5[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6C(OCC6C=CC=CC=6)=O)=[N:21][CH:20]=5)=[CH:15][C:11]4=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:39]=1.Br.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(OCC)(=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[C:10]4[CH:18]=[CH:17][C:16]([C:19]5[NH:23][C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:47](=[O:48])[C@@H:46]([NH:45][C:43](=[O:44])[O:42][CH3:41])[CH:50]([CH3:52])[CH3:51])=[N:21][CH:20]=5)=[CH:15][C:11]4=[CH:12][CH:13]=3)[O:8][CH2:7][C:6]=2[CH:39]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(Br)cc2CO4)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(Br)cc2CO4)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A solution of (S)-benzyl 2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (485 mg, 0.84 mmol), hydrogen bromide (33% in acetic acid, 1 mL) and dichloromethane (2 mL) was stirred at room temperature for one hour. The reaction was concentrated, suspended in toluene, sonicated for one minute and re-concentrated. The resulting residue was suspended in methanol, sonicated for one minute and concentrated. The resulting residue was suspended in diethyl ether and the solids collected by filtration. This crude amine was dissolved in dimethylformamide (7 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (192 mg, 1.1 mmol), HATU (418 mg, 1.1 mmol) and N-methylmorpholine (0.24 mL, 2.2° mmol). The reaction was stirred at room temperature for one hour, and then diluted ethyl acetate. The organic layer was washed with 5% aqueous LiCl solution, saturated aqueous NaHCO3 solution and brine, then dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-1-((S)-2-(5-(8-bromo-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (466 mg, 92%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:3][CH:4]=[CH2:5]>[Pd].CO>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][CH3:21])[CH:13]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C=CCC(O)c1ccncc1-c1ccc(C#N)c(OC)c1
Agent: [Pd]
Solvent: CO
Product: CCCC(O)c1ccncc1-c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask containing 4-(4-(1-hydroxy-but-3-enyl)pyridin-3-yl)-2-methoxybenzonitrile (140 mg, 0.499 mmol) and MeOH (5 mL) was added 10% Pd/C (53.1 mg, 0.050 umol), and the flask was flushed with H2. The mixture was stirred under H2 at room temperature for 10 min. The mixture was then filtered and concentrated. The residue was purified by Xbridge C18 eluting with a 20 to 70% acetonitrile-water gradient to give 4-(4-(1-hydroxybutyl)pyridin-3-yl)-2-methoxybenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.66 (t, J=7.3 Hz, 3H), 1.04-1.28 (m, 2H), 1.35-1.54 (m, 2H), 3.95 (s, 3H), 4.59 (ddd, J=8.2, 4.3, 4.2 Hz, 1H), 5.35 (d, J=4.0 Hz, 1H), 7.10 (dd, J=8.0, 1.4 Hz, 1H), 7.25 (d, J=1.3 Hz, 1H), 7.60 (d, J=5.3 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 8.39 (s, 1H), 8.61 (d, J=5.1 Hz, 1H). HRMS: (ESI) ink 283.1446 [(M+H)+ Calcd for C17H18N2O2 283.1446].
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 50 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 50%) which was obtained as a colourless oil. MS: m/e=418.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:30])=[N:26][C:27](Cl)=[O:28]>C1COCC1>[CH2:1]([N:8]1[C:27](=[O:28])[NH:26][C:25](=[O:30])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[C:19]([CH3:24])=[N:20][O:21][C:22]=3[CH3:23])[CH:16]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Reactant: O=C=NC(=O)Cl
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (example 95b) (100 mg, 0.31 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (97 mg, 0.92 mmol) was slowly added. After addition, the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinane-2,4,6-trione (112 mg, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.12 (s, 3H), 2.38 (s, 3H), 4.87 (s, 2H), 5.16 (s, 2H), 7.23-7.34 (m, 5H), 7.45 (s, 1H), 7.90 (s, 1H), 11.93 (s, 1H). LC/MS; [M+H] calculated for C19H18N6O4; expected 395.14. Found 395.15. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.14 μM.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][OH:15])=[N:5]/[O:6][CH3:7].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1>C1COCC1.O>[CH3:1][NH:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[N:5]/[O:6][CH3:7]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of (E)-N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (0.10 g) in THF (10 ml), sodium hydride (60% oily suspension) (0.02 g) was added thereto, and the resultant mixture was stirred at room temperature for 10 minutes. To the reaction mixture, 2-chloro-5-trifluoromethylpyridine (0.10 g) was added, and stirring was continued at 60° C. for 1 hour. The reaction mixture was cooled, diluted with water, followed by extraction with dichloromethane. The solvent was dried over anhydrous sodium sulfate, and after removal of the solvent, purified by silica gel column chromatography and recrystallized from n-hexane to give 0.11 g of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:24])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C@H:8]([OH:13])[C@@H:7]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:25]([CH:27]=O)=O.C(OCC)(=O)C>C(O)C>[CH3:12][C:9]1([CH3:11])[O:10][C:5]2[CH:4]=[C:3]3[C:2](=[CH:23][C:6]=2[C@H:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]1[OH:13])[N:1]=[CH:27][CH:25]=[N:24]3
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@H](NCCc2ccccc2)[C@H]1O
Reactant: O=CC=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](NCCc2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of (3R*,4S*)-6,7-diamino-3,4-dihydro-2,2-dimethyl-4-(2-phenylethylamino)-2H-benzopyran-3-ol (1.5 g, 4.58 mmol) in ethanol (30 mL), 40% aqueous glyoxal solution (997 mg, 6.87 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting solution was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated sodium chloride solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 74%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][N:4]=1>Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=1
Reactant: COc1cc(CCc2ccccn2)ccn1
Agent: Cl
Product: O=c1cc(CCc2ccccn2)cc[nH]1
Yield: 96.7 %

Procedure:
2-Methoxy-4-(2-(pyridin-2-yl)ethyl)pyridine (200 mg, 0.93 mmol) was stirred in concentrated hydrochloric acid (5 mL) at 120° C. for 18 h and then concentrated. The residue was dissolved in MeOH (5 mL) and passed down an Isolute SCX-2 column (10 g). Elution with 7 N NH3 in MeOH and concentration of the eluent provided the title compound (180 mg, 96%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 8.45 (d, J=4.7 Hz, 1H), 7.75-7.71 (dd, J=7.8, 1.8 Hz, 1H), 7.32 (d, J=6.9 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.27-7.23 (dd, J=7.8, 5.1 Hz, 1H), 6.34-6.29 (m, 2H), 3.08 (t, J=7.3 Hz, 2H), 2.92 (t, J=7.9 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>CCO.[Pt]=O>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccccn2)cc1
Agent: O=[Pt]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C2CCCCN2)cc1
Reaction time: 72 h

Procedure:
2-Phenylpyridine, Intermediate 14, (4.0 g, 25.81 mmol), and concentrated HCl (3 mL) in EtOH (15 mL) were treated with platinum oxide and subjected to catalytic hydrogenation (˜1 atm, balloon), at room temperature for 72 hours. After removal of the catalyst by filtration, the solution was evaporated in vacuo to a pale yellow HCl salt of the product. The free base is obtained by treating the residue with 10% aqueous sodium hydroxide. The aqueous is then extracted with Et2O several times and the extracts dried (MgSO4) and evaporated to an oil to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:25]1[C:30]([Cl:31])=[N:29][C:28]([Cl:32])=[CH:27][C:26]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[Cl:32][C:28]1[CH:27]=[C:26]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:25]=[C:30]([Cl:31])[N:29]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)nc(Cl)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2,6-dichloropyridin-4-isocyanate (230 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 287 mg (81.1%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.COCCOC.C([O-])(O)=O.[Na+]>CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[C:11]([Cl:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1-c1cccnc1Cl
Temperature: 80 °C

Procedure:
To 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol), 2-chloropyridine-3-boronic acid (707 mg, 4.49 mmol), Pd(PPh3)4 (346 mg, 0.30 mmol) was added DME (9.0 mL) and 1 M NaHCO3 (3.0 mL). The mixture was heated overnight in a sealed tube at 80° C., cooled to RT, diluted with EtOAc, and washed with water and saturated Na2CO3. The organic layer was dried over Na2SO4, filtered, concentrated and purified by reverse-phase HPLC to provide 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine. MS m/z=244, 246 [M]+ and [M+2]+. Calc'd for C9H4Cl2FN3: 244.06.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=1.CN(C)[CH:23]=[O:24]>>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:23]=[O:24])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(-c2cc3ccccc3[nH]2)no1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2[nH]c3ccccc3c2C=O)no1
Reaction time: 4 h

Procedure:
With vigorous stirring, POCl3 (1.4 mL, 15 mmol) was added slowly to dimethylformamide (2 mL) at 0° C. 2-(5-Methyl-isoxazol-3-yl)-1H-indole (1.0 g, 5.04 mmol) dissolved in N,N-dimethylformamide (8 mL) was added. The reaction mixture was allowed to come to room temperature, stirred for 4 h, and quenched with ice cold water followed by a 10% sodium hydroxide solution. The resulting precipitate was washed with water, dried in vacuo, and purified via silica gel column chromatography (30% ethyl acetate in petroleum ether) to obtain 2-(5-methyl-isoxazol-3-yl)-1H-indole-3-carbaldehyde (0.6 g, 2.65 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]=[CH2:15])[CH:7]=[C:6]([C:16]([O:18]CC)=[O:17])[C:5]2=[O:21].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(#N)C>>[F:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[N:8]([CH:14]=[CH2:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:21]
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2c(C)c(F)c(F)c(F)c21
Reactant: C1CNCCN1
Solvent: CC#N
Product: C=Cn1cc(C(=O)O)c(=O)c2c(C)c(F)c(N3CCNCC3)c(F)c21
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A solution of 0.69 g (1.80 mmol) of ethyl 6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-1-vinyl-3-quinolinecarboxylate, 0.62 g (7.2 mmol) of anhydrous piperazine, and 20 mmol of acetonitrile was refluxed for 18 hours, cooled, and concentrated. The residue was suspended in 25 ml of 1N sodium hydroxide and heated at 80° C. for 90 minutes. The clear yellow solution was cooled to room temperature, filtered, and neutralized (pH 6.8) with 6N hydrochloric acid. The solids were filtered, washed with water and ether, and dried to give 0.32 g of the title compound, mp 222°-225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH:15]1(O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[CH:15]1([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OC1CCCC1
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1C1CCCC1
Yield: 74.4 %

Procedure:
To a solution of 3-nitrophthalimide (3.85 g, 20.0 mmol), cyclopentanol (2.24 g, 26.0 mmol) and triphenylphosphine (6.87 g, 26.2 mmol) in tetrahydrofuran 30 ml was dropwise added 40% toluene solution (11.4 ml) of diethyl azocarboxylate under stirring in a nitrogen stream. The mixture was concentrated in vacuo, and the precipitate formed upon addition of ether was filtered off. After the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (hexane-ethyl acetate, 3:1) to give the title compound (3.87 g) as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([S:13](Cl)(=[O:15])=[O:14])[CH2:11][CH3:12]>>[CH:1]1([CH2:7][CH2:8][NH:9][S:13]([CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCC1CCCCC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCCC1CCCCC1

Procedure:
The desired product was prepared using the method described in Example 1174A starting with cyclohexylethylamine and 1-propanesulfonyl chloride.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[C:41]([O:43][CH3:44])=[O:42]>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:41]([O:43][CH3:44])=[O:42])[C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
Methyl 4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-2-(R)-(hydroxymethyl)piperazine-1-carboxylate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one (example 139) and Methyl chloroformate.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH:26][C:27]([NH2:29])=[S:28])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:29]=[C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[S:28][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)(C)NC(N)=S
Solvent: CCO
Product: CC(C)(C)Nc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.406 g, 1.09 mmol) in ethanol (11 mL) in a 25 mL round bottom flask was added N-(t-butyl)thiourea (0.144 g, 1.09 mmol) and the solution heated to reflux (14 hours). The reaction was cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), sodium carbonate solution (10%, 3×20 mL), dried over sodium sulfate, filtered and concentrated. The crude product was recrystallized from methylene chloride and isooctane yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-tert-butylaminothiazole (0.226 g, 51%) as a yellow crystalline plates: mp 250°-253° C.; 1HNMR (DMSO d6) 400 mHz 7.78 (d, J=8.32 Hz, 2 H), 7.70 (s, 1 H), 7.46-7.35 (m, 4 H), 7.15 (t, J=9.05 Hz, 2 H), 3.19 (s, 3 H), 1.40 (s, 9 H); MS m/z 405 (M+H). HRMS Δ=4.78 mmu.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)[CH2:31][CH3:32].O>C1COCC1>[CH2:30]([Si:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH:36]([CH:2]=[O:4])[CH2:35][CH2:34]1)[CH2:31][CH3:32]
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[Si]1(c2ccccc2)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 23 g of 4-n-propyl-4-phenyl-4-silacyclohexanone in 50 ml of THF was added to the ylide solution and agitated at room temperature for 2 hours. Thereafter, the mixture was poured into iced water and extracted with methylene chloride, followed by washing, drying and concentration by a usual manner. n-Hexane was added to the residue, and the resultant crystals of triphenylphosphine oxide were removed by filtration. The filtrate was concentrated, and the resultant residue was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-n-propyl-4-phenyl-4-silacyclohexane carbaldehyde.