Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][C@@H:34]1[CH2:38][NH:37][CH2:36][C@H:35]1[OH:39]>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:37]3[CH2:36][C@@H:35]([OH:39])[C@H:34]([F:33])[CH2:38]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CNC[C@H]1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@H](F)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and trans-4-fluoropyrrolidin-3-ol to afford an amorphous white powder. HPLC (Condition 4) tR=5.21 min, UPLC-MS (Condition 3) tR=0.99 min, m/z=468.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.06 (d, J=12.12 Hz, 1H) 3.33-3.49 (m, 2H) 3.53-3.76 (m, 1H) 4.15 (br. s, 1H) 4.77-5.02 (m, 1H) 5.36-5.50 (m, 1H) 6.41 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.79-7.91 (m, 3H) 8.06 (d, J=1.96 Hz, 1H) 8.73 (br. s, 1H) 10.21 (s, 1H) 12.90-13.21 (m, 1H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)([O-:27])=[O:26].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:32](=[NH:33])[C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:35][CH:34]=2)[CH:16]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Anhydrous p-toluenesulfonic acid (6.30 g, 33.1 mmol) was added to 50 ml of benzene and the resulting mixture was refluxed while removing water using a dean-stock trap. Added thereto were 3-amino-4-methoxy benzoic acid methyl ester (3 g, 16.6 mmol) obtained in step 1 of Preparation Example 1 and 4-nitrobenzonitrile (2.94 g, 19.9 mol), followed by stirring at 160° C. for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding NaHCO3 thereto, extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.83 g, 8.59 mmol) in a yield of 52%.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)=[CH:15][N:14]=1>CN(C=O)C>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=[CH:2]3)=[N:14][CH:15]=2)[N:22]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(-n3ccc4cccnc43)nc2)cs1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine (2.0 mmol, 236 mg) in DMF (20 mL) at 60° C. was added sodium hydride (2.5 mmol, 100 mg of 60% wt dispersion in mineral oil). After 30 min, 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.5 mmol, 117 mg) was added and the reaction was warmed to 75° C. and stirred overnight under nitrogen. The reaction was then partitioned with EtOAc:hexanes (1:1, 100 mL) and water (50 mL). The organic layer was washed with 5% NaCl (4×50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 3% MeOH in DCM, to afford the title compound as a white solid that was dissolved in ether and precipitated as the hydrochloride salt with 1N HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 8.88 (m, 2H), 8.65 (d, 1H), 8.54 (d, 1H), 8.30 (dd, 1H), 8.05 (d, 1H), 7.94 (s, 1H), 7.83 (dd, 1H), 7.24 (d, 1H), 2.82 (s, 3H). MS (ESI) 317.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Br:13][CH2:14][C:15](Br)=[O:16]>C(Cl)Cl.O>[Br:13][CH2:14][C:15]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[O:9][CH3:10])=[O:16]
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: O=C(Br)CBr
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) solution of 5-chloro-2,4-dimethoxyaniline (5 g) in DCM under an atmosphere of argon is treated dropwise with bromoacetyl bromide (2.4 ml). After 5 minutes, TEA (7.5 ml) is added dropwise and after stirring for 20 minutes the reaction mixture is diluted with water and extracted with DCM). The organic phase is washed with distilled water, dried over Na2SO4, filtered and evaporated to give a beige solid. This is purified by flash column chromatography on silica, eluting with 20-100% n-hexane in DCM to afford the title compound. [M+H]+ 308.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[N:4].C(N(CC)CC)C.[CH2:12]([S:15](Cl)(=[O:17])=[O:16])[CH2:13][CH3:14]>ClCCCl>[C:3]([CH2:2][NH:1][S:15]([CH2:12][CH2:13][CH3:14])(=[O:17])=[O:16])#[N:4]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CCN
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCS(=O)(=O)NCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Aminoacetonitrile (14.25 g, 92.5 mmoles) was dissolved in 1,2-dichloroethane (150 ml) and the reaction was placed under N2. Triethylamine (32.76 g, 324 mmoles) was added and the reaction was cooled to zero degrees Celsius. A solution of propane-1-sulfonyl chloride (13.19 g, 92.5 mmoles) in 1,2-dichloroethane (20 ml) was added dropwise and the reaction was allowed to warm to room temperature and was stirred for 16 hours. Thin-layer chromatography showed the presence of a new product with a higher Rf. The solvent was removed in vacuo and the crude product was submitted to flash chromatography (methylene chloride:ethyl acetate, 9:1) to yield 10.56 g of propane-1-sulfonic acid cyanomethyl-amide. 1HNMR (CDCl3): 5.40 (s, 1H), 4.11 (s, 2H), 3.15 (m, 2H), 1.89 (q, 2H), 1.10 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:27]=[N:26][C:25]4[C:24]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[N:23][C:22]([C:34]5[CH:35]=[N:36][C:37]([NH:40]C(=O)OC(C)(C)C)=[N:38][CH:39]=5)=[N:21][C:20]=4[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:40][C:37]1[N:36]=[CH:35][C:34]([C:22]2[N:23]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:25]3[N:26]=[CH:27][C:18]([C:14]4[CH:13]=[C:12]([NH:11][S:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=4)=[CH:19][C:20]=3[N:21]=2)=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NS(=O)(=O)c5ccc(F)cc5)c4)cc3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NS(=O)(=O)c5ccc(F)cc5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To a 25 mL flask, tert-butyl (5-(7-(3-(4-fluorophenylsulfonamido)phenyl)-4-morpholino-pyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.00009 mol) and DCM (9 mL) were added. To the same reaction vessel, trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was washed with ether and was dissolved in 10% methanol in DCM. The organic layer was basified with saturated sodium bicarbonate solution (pH 8.0). The organic layer was washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was washed with methanol and diethyl ether to provide the solid. The solid was dried under high vacuum to provide the title compound (0.031 g, 60%). 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1H), 9.20 (s, 2H), 8.92 (d, J=2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.90-7.87 (m, 2H), 7.63 (d, J=7.6 Hz, 1H), 7.55 (br s, 1H), 7.46-7.40 (m, 3H), 7.22 (br s, 2H), 7.20 (s, 1H) 4.52 (br s, 4H), 3.84 (t, J=4.4 Hz, 4H). LC-MS (ESI): Calculated mass: 558.1; Observed mass [M+H]+: 558.9 (RT=1.19 min).
Reaction SMILES: [F:1][C:2]([F:31])([CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@@H:18]([CH2:19][C@H:20]([OH:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[C:3]([OH:6])([CH3:5])[CH3:4].[Br:32]NC(=O)C.C(OCC)(=O)C>C(O)(C)(C)C.O.Br>[Br:32][C@H:19]1[C:20](=[O:30])[CH2:21][CH2:22][C@@:23]2([CH3:24])[C@@H:18]1[CH2:17][CH2:16][C@@H:15]1[C@@H:25]2[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@H:9]([CH3:10])[CH2:8][CH2:7][C:2]([F:31])([F:1])[C:3]([OH:6])([CH3:4])[CH3:5]
Reactant: CC(=O)NBr
Reactant: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Br
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: C[C@H](CCC(F)(F)C(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4[C@@H](Br)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 800 mg of 24,24-difluoro-5β-cholestane-3α,25-diol (Va) in 32 ml of tert-butyl alcohol, 15 ml of water, 200 μl of 48% hydrobromic acid and 800 mg of N-bromoacetamide were added. After stirring at room temperature for 3 days, ethyl acetate was added to the reaction mixture, which was then washed sequentially with 0.5% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified through a short column (5 g of silica gel) to produce 950 mg of a crude product. The product was recrystallized from ether/hexane to produce 4β-bromo-24,24-difluoro-25-hydroxy-5β-cholestan-3-one.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.C([O-])(=O)C.[NH4+].[BH4-].[Na+]>CO>[OH:1][CH:2]([CH3:15])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(CC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1ccc(CC(C)O)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Ethyl 4-(2-oxopropyl)benzoate (2.25 g, 10.9 mmol, 1 eq) and ammonium acetate (8.40 g, 109 mmol, 9.97 eq) were dissolved in MeOH (45 mL). While stirring at room temperature, sodium borohydride (684 mg, 18.1 mmol, 1.65 eq) was added. The resulting reaction mixture was stirred overnight at room temperature. The reaction was concentrated and partitioned between CH2Cl2 and 1M NaOH (aq.). The organic layer was removed and saved and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a residue which was purified via silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes, SiO2) to afford ethyl 4-(2-hydroxypropyl)benzoate (1.18 g, 52%). The same silica gel column was then subjected to a second set of chromatography conditions (gradient elution, 0% to 80% MeOH in EtOAc) to afford racemic ethyl 4-(2-aminopropyl)benzoate (610 mg, 27%).
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[CH:10][C:9]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:2][C@@H:3]([CH3:6])[CH2:4][OH:5])=[CH:10][C:9]=1[CH3:16]
Reactant: C[C@@H](CO)CBr
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Temperature: 25 °C

Procedure:
(S)-3-Bromo-2-methyl-1-propanol (150 mg), 4-bromo-3,5-dimethylphenol (98.5 mg) and potassium carbonate are stirred in 5 mL of acetonitrile at 80° C. for 4 h. The reaction mixture is cooled to room temperature, water is added and the reaction mixture is extracted with diethyl ether. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give a solid, used in the next step without further purification. Yield: 130 mg.
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][C:30](Cl)=[O:31]>C1COCC1>[O:31]=[C:30]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:28](=[O:33])[CH2:29]1
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 35.9 %

Procedure:
To 20 mL of THF at 0° C. is added dropwise over 10 min simultaneously a solution of 1.97 g (5.48 mmol) of N-isopropyl-N-phenyl-2-(2-phenylamino-phenylamino) acetamide in 20 mL of THF and 0.53 mL (5.48 mmol) of malonyl dichloride in 20 mL of THF. The resulting red-brown solution is stirred at RT for 5.5 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash chromatography (50 to 75% ethyl acetate/petroleum ether) followed by recrystallization from ethyl acetate/petroleum ether gave 0.84 g of the title compound as a white powder: mp. 199°-200° C.; 1H NMR (CDCl3, 300 MHz) δ7.6-7.2 (m, 12H), 7.09 (t, 1H, J=8), 6.90 (d, 1H, J=8), 5.05 (m, 1H), 4.38 (d, 1H, J=17), 4.04 (d, 1H, J=17), 3.54 (dd, 2H, J=5, 22), 1.10 (d, 6H, J=7); low resolution MS (FAB) m/e 428 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[CH3:43])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (362 mg, 1.2 mmol) and 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H8) (300 mg, 1.0 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (302 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:21]O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)c(Cl)c1
Agent: Cl[Fe]Cl
Solvent: O
Solvent: COCCOC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
To a suspension of 1-(3-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (15.56 g, 46.8 mmol) in DME (64 ml) at 5° C. was added TFAA (6.6 ml, 46.8 mmol) and the mixture stirred for 10 minutes. Triethylamine (19.6 ml, 140.4 mmol) was then added dropwise over 15 min. After the addition was complete, the reaction was then warmed to room temperature. After stirring for 1 hour, iron (II) chloride (60 mg) was added and the mixture was then heated to 75° C. for 1 hour then allowed to cool. The mixture was poured into water (500 ml) and extracted with dichloromethane (300 ml). The organic extracts were dried over MgSO4 and concentrated under reduced pressure to ca. 50 ml. This residue was purified by filtration through a layer of silica gel washing with further dichloromethane. The filtrate was concentrated to dryness to give 12 g (82%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][NH:1][C:12](=[O:14])[CH3:13])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The synthesis was performed with reference to the known literature (International Patent Publication WO2000/75139). 5-Aminomethyl-1H-indole (0.50 g, 3.4 mmol) was added with acetic anhydride (2.0 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was azeotroped twice with toluene under reduced pressure, and the residual solid was washed with ethyl acetate to obtain N-[(1H-indol-5-yl)methyl]acetamide (0.62 g, 96%).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:7][NH2:8].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[C:26]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[N:27][O:28][C:29]=2[CH2:30][OH:31])=[N:19][CH:18]=1>O1CCOCC1>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:26]2[C:25]([CH2:24][O:23][C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:8][CH2:7][C:6]([F:13])([F:5])[C:9]([F:12])([F:11])[F:10])=[O:15])=[CH:18][N:19]=3)=[C:29]([CH2:30][OH:31])[O:28][N:27]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reactant: NCC(F)(F)C(F)(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)C(F)(F)F)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.84 mL, 1.67 mmol) was added to a solution of 2,2,3,3,3-pentafluoropropylamine (121 μL, 1.12 mmol) in dioxane (4 mL). After stirring for 45 min at 50° C. a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.28 mmol) in dioxane (4 mL) was added and stirring was continued overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane 1:1) to yield the title compound (103 mg, 77%) as a white solid. MS: m/e=474.2 [M−H]−.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:7]=2[N:8]=1.[O:15]1CCC[CH2:16]1>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: Cc1nc2cc(C=O)ccc2s1
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2sc(C)nc2c1
Reaction time: 0.5 h

Procedure:
3.83 g of silver nitrate was dissolved in 10 mL of water, to which a solution of 1.81 g of sodium hydroxide in 10 mL of water was added dropwise and then a solution of 2.00 g of 2-methyl-1,3-benzothiazole-5-carbaldehyde in 20 mL of tetrahydrofuran was added dropwise at room temperature, and this solution was stirred for 30 minutes at the same temperature. The reaction mixture was filtered through Celite, and 6M hydrochloric acid was added to the filtrate to adjust its pH value to 3.5 followed by addition of ethyl acetate, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was dissolved in 30 mL of methylene chloride, to which 20 μL of N,N-dimethylformamide and 1.5 mL of oxalyl chloride were added successively, and this solution was stirred for 30 minutes at room temperature. The reaction mixture, to which 20 mL of methanol was added dropwise, was stirred for 30 minutes at room temperature, and after water was added thereto, the pH value of this mixture was adjusted to 7 with a 5M solution of sodium hydroxide in water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 1.90 g of methyl 2-methyl-1,3-benzothiazole-5-carboxylate as light yellow solid.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].O=[C:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>C1COCC1.O>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:40]2[CH2:41][CH2:36][CH2:37][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]2)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2cccc(F)c2)C1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
(3-Fluorobenzyltriphenylphosphonium bromide (Intermediate 228, 5.3 g) was added in portions to a solution of sodium tert-butoxide (1.06 g) in anhydrous THF (20 mL) at room temperature and the mixture was stirred for 30 minutes. A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g) in anhydrous THF (10 mL) was added dropwise at room temperature and the mixture was stirred for 24 hours. The mixture was diluted with water (100 mL) and extracted with ether (100 mL), washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexxane with a gradient of 0-20% to give tert-butyl 3-[1-(3-fluorophenyl)-methylidene]piperidine-1-carboxylate (1.42 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:17]=[N:16][C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH3:18])(=[O:3])[CH3:2].[Se](=O)=[O:20]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:17]=[N:16][C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH:18]=[O:20])(=[O:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: CC(=O)OCc1cnc2[nH]c(=O)[nH]c(=O)c2c1C
Solvent: CC(=O)O
Product: CC(=O)OCc1cnc2[nH]c(=O)[nH]c(=O)c2c1C=O
Yield: 89.4 %

Procedure:
A mixture of 6-acetoxymethyl-5-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.14 g, 12.5 mmol) and selenium dioxide (2.09 g, 18.9 mmol) in glacial acetic acid (100 mL) is heated at reflux for 20 hours, and then the mixture is filtered through a Celite pad while hot. The filtrate is concentrated in vacuo, and the residue is crystallized from methanol to give 6-acetoxymethyl-5-formylpyrido[2,3-d]-pyrimidine-2,4(1H, 3H)-dione (2.94 g, 86.6%), mp 263°-264° C. (decomposition). 1H NMR (Me2SO-d6) d 2.02 (3H, s, Ac), 5.03 (2H, s, CH2), 8.75 (1H, s, H-7, 10.49 (1H, s, CHO).