Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[C:36]([C:46]#[N:47])[CH:35]=2)=O)=CC=1>>[C:46]([C:36]1[CH:35]=[C:34]([NH:33][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([B:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:7][O:6]3)=[CH:13][CH:12]=2)[CH:39]=[CH:38][C:37]=1[S:40]([CH:43]([CH3:44])[CH3:45])(=[O:42])=[O:41])#[N:47]
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2)cc1C#N
Yield: 97 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 9C (600 mg, 1.34 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 9D (625 mg, 97%) as a brown foam. MS (ESI) m/z 413.1 (M−H)− for free boronic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([NH:11][NH2:12])[N:5]=1)[CH3:2].[C:13](=S)=[S:14].[O-]CC.[Na+].Cl>C(O)C.O>[CH2:1]([O:3][C:4]1[N:5]2[C:13](=[S:14])[NH:12][N:11]=[C:6]2[CH:7]=[C:8]([F:10])[N:9]=1)[CH3:2]
Reactant: S=C=S
Reactant: CCOc1nc(F)cc(NN)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(F)cc2n[nH]c(=S)n12
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
A 1.74 g (10 mmol) sample of 2-ethoxy-4-fluoro-6-hydrazinopyrimidine was dissolved in 20 mL of absolute ethanol and 2.84 g (37 mmol) of carbon disulfide and 3.20 g (10 mmol) of 21 percent by weight sodium ethoxide were added. The mixture was heated at reflux with stirring for 3 hours and then was cooled by adding 20 mL of ice water. The mixture was then acidified to a pH of about 2 by adding 2 mL of 6.25N hydrochloric acid diluted to 8 mL with water. The yellow precipitate that formed was recovered by filtration, washed with water, and dried to obtain 0.85 g (40 percent of theory) of 5-ethoxy-7-fluoro-1,2,4-triazolo[4,3-c]pyrimidine-3(2H)-thione. The proton and carbon NMR spectra of this material were consistent with its assigned structure.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[O:24]1[CH2:26][CH:25]1[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:26][CH:25]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[OH:24])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: c1cc(C2CO2)ccn1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccncc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.4 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6,7-triaza-cyclopenta[c]fluorene (600 mg, 2.643 mmol) was dissolved in DMF (18 mL), and cooled to 0° C. Potassium tert-butoxide (444 mg, 3.964 mmol) was added and stirred for 5 min. 4-Oxiranyl-pyridine (639 mg, 5.286 mmol) in DMF (3 mL) was added dropwise into the reaction mixture and the mixture was stirred at RT for 12 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (4×70 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 400 mg of 2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.8 (d, 2H), 8.2 (d, 2H), 8.1 (s, 1H), 7.9 (s, 1H), 5.38 (m, 1H), 5.09 (t, 1H), 4.68 (dd, 2H), 4.4 (m, 1H), 3.75 (m, 4H), 3.43 (m, 2H), 2.7 (m, 2H), 2.46 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC provided diastereomers IV-209a-d.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH2:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[N+:30]([O-])=O)=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:20][CH:21]=1)[CH3:14]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCOc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1
Product: CCOc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 54a (259 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (241 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.31 (t, J=6.99 Hz, 3H) 2.34 (s, 3H) 2.76 (s, 3H) 3.97 (q, J=6.99 Hz, 2H) 6.26 (d, J=7.35 Hz, 1H) 6.83 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.24 (d, J=8.82 Hz, 2H) 7.27 (s, 1H) 7.30 (s, 1H) 7.80 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 11.01 (s, 1H) 14.38 (s, 1H); MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:17]1[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]1=[O:24]>C1COCC1>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][C:18]([OH:24])=[O:17])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(NC(=O)CCCC(=O)O)cc1)n1ccnc1
Yield: 99 %

Procedure:
A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.023 mol) and dihydro-2H-pyran-2,6(3H)-dione (0.03 mol) in THF (200 ml) was stirred and refluxed for 12 hours. When the reaction was complete, the solvent was evaporated, yielding 7.5 g (±)-5-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-5-oxopentanoic acid (compound 218).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH2:5])=[O:4].[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][S:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][S:19][CH2:18][C@H:14]1[C:15]([NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[O:17]
Reactant: CC(C)(C)OC(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Deprotection of 500 mg of Boc-Gly-NH2 was performed similarly to that in Example 28 (Process 3), and the obtained product was dissolved in dichloromethane, and 0.39 ml of tri-ethylamine, 0.67 g of Boc-Thz-OH, 0.47 g of HOBt and 0.64 g of EDC hydrochloride were added under ice cooling and the mixture was stirred overnight at room temperature. The reaction mixture was treated similarly to that in Example 139 (Process 2) to give 0.54 g of the title compound as oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([NH:17][C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[NH2:1][C:2]1[C:7]([O:8][CH2:19][C:18]([NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:21])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)cc1O
Reactant: O=C(CCl)NCc1ccccc1
Product: Nc1ncc(Cl)cc1OCC(=O)NCc1ccccc1

Procedure:
The title compound was prepared by the method of P. Nedenskov, N. Clauson-Kaas, J. Lei, H.-N. Heide, G. Olsen and G. Jansen (Acta Chemica Scandinavica, 1969, 23, 1791) from 2-amino-5-chloro-3-pyridinol (G. Mattern, Helv. Chimica Acta, 1977, 60, 2062) and N-benzyl-α-chloroacetamide. Sand coloured solid:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[CH:12][C:13]([F:34])=[C:14]([N:16]2[CH2:33][CH2:32][C:19]3([C:23](=[O:24])[N:22]([C@H:25]4[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[CH:15]=1.[N:35]1([C:40]([C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1>O.O1CCOCC1.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>[F:34][C:13]1[CH:12]=[CH:11][C:10]([C:45]2[CH:44]=[N:43][C:42]([C:40]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:41])=[CH:47][CH:46]=2)=[CH:15][C:14]=1[N:16]1[CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)[CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCCC3)nc2)OC1(C)C
Reactant: O=C1N([C@H]2CC[C@@H](O)CC2)CCC12CCN(c1cc(Br)ccc1F)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccc(F)c(N3CCC4(CC3)CCN([C@H]3CC[C@@H](O)CC3)C4=O)c2)cn1)N1CCCC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
Potassium phosphate (0.017 g, 0.078 mmol) in water (0.10 mL) was added to a mixture of 8-(5-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (15.0 mg, 0.0353 mmol), 2-(pyrrolidin-1-ylcarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (16 mg, 0.053 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol) in 1,4-dioxane (0.30 mL). The resulting mixture was heated and stirred at 120° C. for 20 min. The mixture was filtered. The filtrate was diluted with methanol, and was purified by mass-guided reverse phase chromatography to afford the desired product. LCMS: (M+H)+=521.2.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].CC(C)([O-])C.[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O.C(#N)C>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[C:24]([F:23])([F:33])[F:34])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide ((for a preparation see Intermediate 9)(31.9 mg, 0.1 mmol) in dimethylformamide (0.4 ml) was treated with potassium t-butoxide (11.3 mg, 0.1 mmol) and allowed to stand at room temperature for 10 min. A solution of 2-(trifluoromethyl)benzyl bromide (22.3 mg, 0.1 mmol, Aldrich) in acetonitrile (0.2 ml) was finally added and the solution left to stand for 16 h at room temperature. The solvent was removed using a Genevac and the crude mixture dissolved in a 1:1 mixture of dimethylsulphoxide:methanol (0.6 ml) and the solution purified by MDAP on SUNFIRE C18 (Method D). The appropriate fraction was concentrated in vacuo using a Genevac to give the title compound (2.3 mg);
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@@H:7]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][NH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([N:9]1[CH2:10][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:12][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 0.50 g (1.4 mmol) (3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine and 0.15 g (1.5 mmol) triethylamine in 30 ml of THF was added dropwise a solution of 0.26 g (1.5 mmol) benzyl chloroformate in 2 ml of THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature during 30 min. Quenching with a saturated aqueous solution of sodium hydrogencarbonate was followed by extraction with three portions of dichloromethane. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.62 g (90%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[O:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([C:15]4[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=4)[CH:18]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNc3ccc4c(c3)OCO4)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,3-benzodioxol-5-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 450.4. HPLC (Condition A), Rt: 5.12 min (HPLC purity: 95.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[F:15]>CCO.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[F:15]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)c1cc(N)c(N)c(F)c1F

Procedure:
To a stirred solution of 4-amino-2,3-difluoro-5-nitrobenzoic acid methyl ester (500 mg, 2.2 mmol) in EtOH (20 ml) was added PtO2 (50 mg, 10% w). The suspension was hydrogenated with a H2 balloon overnight. The catalyst was filtered through Celite and washed with EtOH The solvent was removed under reduced pressure to give 4,5-diamino-2,3-difluorobenzoic acid methyl ester as a light yellow solid.
Reaction SMILES: [OH:1][C@@:2]1([C:33]([F:36])([F:35])[F:34])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=O)[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O[N:38]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N.Cl>CN(C)C=O.O>[OH:1][C@@:2]1([C:33]([F:35])([F:34])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:32])([CH3:31])[C:28]([NH2:38])=[O:30])[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: On1nnc2ccccc21
Reactant: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(N)=O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Under a nitrogen atmosphere, 2-{4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionic acid (66.7 g) was dissolved in N,N-dimethylformamide (480 ml), 1-hydroxybenzotriazole (HOBt) 1 hydrate (27.6 g), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (34.6 g) and 28% aqueous ammonia (24.5 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled, water (630 ml) and 2N hydrochloric acid (330 ml) were added dropwise, and the mixture was extracted with ethyl acetate (800 ml). The obtained aqueous layer was extracted again with ethyl acetate (500 ml). The obtained organic layers were combined, and washed successively with water (500 ml, twice), saturated aqueous sodium hydrogen carbonate (500 ml), and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated to give the title compound (60.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NCc2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(N(Cc2cccnc2)S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
A 3.5 g. portion of 3-(4-methylphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 2 ml. of methanesulfonyl chloride were added. The mixture was stirred overnight under reflux, and was then extracted with 20 ml. of water and evaporated under vacuum. The residue was triturated with diethyl ether and dried to obtain 4.5 g. of the desired product, m.p. 143°-146°.
Reaction SMILES: Cl.[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][C:11]2([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[C:10]3=[N:23]S(C(C)(C)C)=O)[CH2:4][CH2:3]1>O1CCOCC1>[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][C:11]4([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]4)[C:10]3=[NH:23])=[CH:14][CH:15]=2)[CH2:3][CH2:4]1
Reactant: COC1CCC2(CC1)Cc1ccc(C#CC3CC3)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(C#CC3CC3)cc1C2=N
Reaction time: 1 h
Yield: 104.8 %

Procedure:
4 M HCl in dioxane (1.5 mL, 6.00 mmol) was added to a solution of N-(5′-(cyclopropylethynyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Example 20i Step 2, 470 mg, 1.18 mmol) in dry dioxane (5 mL) at 5° C. The reaction mixture was allowed to come to r.t. and stirred for 1 h, then it was stored at 0° C. overnight and then concentrated. The product (as the hydrochloride salt) was dissolved in DCM and washed with aq. sat. NaHCO3, dried over Na2SO4 and concentrated to give 363 mg of the title compound (quantitative yield). 1 H NMR (500 MHz, CDCl3) δ ppm 0.78-0.85 (m, 2 H), 0.85-0.91 (m, 2 H), 1.34-1.49 (m, 3 H), 1.54-1.63 (m, 2 H), 1.68-1.84 (m, 2 H), 2.08-2.19 (m, 2 H), 2.98 (s, 2 H), 3.23-3.33 (m, 1 H), 3.38-3.43 (m, 3 H), 7.27 (m, 2 H), 7.46 (dd, 1 H), 7.69 (br. s., 1 H). MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.[H-].[Na+].Br.Br[CH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.BrCC1C(O)=CC=CN=1>CN(C=O)C>[OH:21][C:20]1[C:15]([CH2:14][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cccnc1CBr
Reactant: CC(=O)Nc1cc[nH]n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(Cc2ncccc2O)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
Intermediate 1 (200 mg, 1.598 mmol) was dissolved in 2 mL of anhydrous DMF at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and mixture of reaction was stirred at 0° C. for 20 minutes. 2-(Bromomethyl)-3-pyridinol hydrobromide (ALFAAESAR, 301 mg, 1.598 mmol) was dissolved in 2 mL of DMF (anh) at 0° C. Sodium hydride (ALDRICH, 48.5 mg, 1.920 mmol) was added and this solution was stirred at 0° C. for 20 minutes. Solution of 2-(bromomethyl)-3-pyridinol was added dropwise to reaction mixture. Reaction was stirred at 80° C. for 24 h. Solvent was evaporated to dryness. Residue was partitioned between EtOAc and NH4Cl. Organic layer was dried over MgSO4 (anh), filtered and concentrated to dryness. Residue was purified using silica chromatography column using a linear gradient of DCM/MeOH as eluents to give the title compound (48.5 mg, 0.207 mmol, 13% yield). 1H NMR (300 MHz, CDCl3) δ ppm: 9.70 (br s, 1H), 8.04 (m, 1H), 7.46 (d, 1H), 7.33 (m, 1H), 7.24 (m, 1H), 6.53 (d, 1H), 5.42 (s, 2H), 2.27 (s, 3H). [ES+MS] m/z 233 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:15][CH2:14][C:9]2[N:10]([CH3:13])[N:11]=[N:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:20][CH:21]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (380 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 88 mg, 2.02 mmol) in THF (2.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (346 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (449 mg, 72%) as a white solid. MS: m/e=343.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].O=S(Cl)[Cl:17].CN(C=O)C>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
To a mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2 g, 9.61 mmol) and SOCl2 (21.04 mL, 288 mmol) was added DMF (0.074 mL, 0.961 mmol). Then the mixture was stirred at 80° C. for 16 h. The mixture was concentrated and extracted with EA (2×100 mL) and washed with H2O (100 mL) to give the organic layer. The combined organic extract was washed with brine, dried over Na2SO4 and concentrated to yield a brown solid of 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (2 g, 5.30 mmol, 55.1% yield): 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=2.43 Hz, 1H), 9.42 (d, J=2.43 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:7]=[CH:6][C:5]=1[NH2:20])([O-:3])=[O:2].[O:21]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:24][C:23]([C:31](O)=[O:32])=[N:22]1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[N:7]=[CH:6][C:5]=1[NH:20][C:31]([C:23]1[CH2:24][C:25]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[O:21][N:22]=1)=[O:32])([O-:3])=[O:2]
Reactant: Nc1cnc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Product: O=C(Nc1cnc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-])C1=NOC2(CCCCC2)C1

Procedure:
The title compound was prepared from 4-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine (as prepared in the previous step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedure described in Example 16, step D. 1H-NMR (400 MHz, CDCl3) δ: 9.45 (s, 1H), 8.93 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 2.97 (s, 2H), 1.73-1.90 (m, 5H), 1.62-1.73 (m, 3H), 1.40-1.54 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H19F3N4O4: 449.1 (M+H). found: 449.2.