Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:7]([C:12]([OH:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:15]O.S(Cl)(Cl)=O>CO>[NH2:5][C:6]1[C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: Nc1cccnc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncccc1N

Procedure:
Methanol (75 mL) was cooled to 0° C. and treated dropwise with thionylchloride (3.5 mL, 48 mmol). 3-aminopyridine-2-carboxylic acid (0.9 g, 6.52 mmol, prepared as described by Sucharda, Chem. Ber. 1925, 1727) was added and the mixture brought to reflux. Over the next two days, two more MeOH/thionyl chloride mixtures were made and added to the reaction. The reaction was evaporated to dryness, then treated with thionyl chloride (5.7 mL, 78.3 mmole) in 75 mL of MeOH and refluxed for two more days. The reaction was evaporated to dryness and chromatographed on silica eluting with 9:1:1 EtOH/NH4OH(H2O to give methyl 3-aminopyridine-2-carboxylate as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:6][C:5]=1[NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(N2CCCC2)ccc1[N+](=O)[O-])c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of N-(2-nitro-5-(pyrrolidin-1-yl)phenyl)benzamide and sodium hydrosulfite (9 mmol) (3 mmol) in ethanol (150 mL) was refluxed for 1 h. After cooled to room temperature, the mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuum to give crude N-(2-amino-5-(pyrrolidin-1-yl)phenyl)benzamide.
Reaction SMILES: Cl[Sn]Cl.Cl.[Br:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#N)=[CH:8][C:7]=1[F:15].CC[O:18]CC>O>[Br:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([CH:10]=[O:18])=[CH:8][C:7]=1[F:15]
Reactant: N#Cc1cc(F)c(Br)c(F)c1
Reactant: CCOCC
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: O=Cc1cc(F)c(Br)c(F)c1
Reaction time: 8 h

Procedure:
167 g (0.88 mol) of SnCl2 was added to 880 cm3 of diethyl ether, and dried HCl gas was absorbed to saturation at room temperature. 98 g (0.44 mol) of 4-bromo-3,5-difluorobenzonitrile was added all at once to this mixture, and after stirring for i hour, it was let stand overnight. The reactant was poured into 1,000 cm3 of water, and ether was distilled on a hot water bath at 50° C. The residue was extracted by adding chloroform, and after washing in water the chloroform was removed. The residue was distilled under reduced pressure (b. p. 96° C./73 mmHg) to obtain 88 g (0.40 mol) of 4-bromo-3,5-difluorobenzaldehyde.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[C:11]2[N:10]=[C:9]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:8]=[CH:7][C:6]=2[N:5]([CH3:30])[C:4]1=[O:31])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cl-].[Na+].O>[CH2:1]([CH:3]1[N:12]([C:13]2[CH:14]=[N:15][N:16]([CH3:32])[CH:17]=2)[C:11]2[N:10]=[C:9]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:8]=[CH:7][C:6]=2[N:5]([CH3:30])[C:4]1=[O:31])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cn[nH]c1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cnn(C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 13.4 %

Procedure:
7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one (Example 331, 55 mg, 0.131 mmol) was dissolved in 3 mL of dioxane and Me3PO4 (37 mg, 0.262 mmol) and K2CO3 (90 mg, 0.655 mmol) were added and the reaction mixture was stirred for 18 h at 90° C. The reaction mixture was diluted with brine and extracted with EtOAc. The organic phase was dried with Na2SO4, filtered, concentrated under vacuum and purified by HPLC to give the title compound (7.6 mg). 1H-NMR (CDCl3, 400 MHz): δ: 7.91 (s, 1H), 7.71 (s, 1H), 7.50-7.60 (m, 3H), 7.12 (s, 1H), 7.08-7.10 (m, 2H), 7.01 (s, 1H), 4.57-4.61 (m, 1H), 3.79 (s, 3H), 3.46 (s, 3H), 1.82-1.98 (m, 1H), 1.78-1.82 (m, 1H), 0.82 (t, 3H, J=7.4 Hz); LCMS: 433.2 m/z (M+H)+; ret. Time: 4.36 min (Analytical Method C).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1(/[CH:25]=[CH:24]/[CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC/C=C/c1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C/C=C/c3ccccc3)CC1)O2

Procedure:
Compound 139 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, [(1E)-3-bromoprop-1-en-1-yl]benzene and conditions outlined in procedure V. LCMS: 418 [M+H]; Rt=1.05 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([C:31]2[O:36]C(C)(C)[O:34][C:33](=O)[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:33](=[O:34])[CH2:32][C:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccc(Cl)c1
Yield: 71.3 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (205 mg, 0.66 mmol) and 6-(3-chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (174 mg, 0.73 mmol) according to the general procedure K. Obtained as a brown foam (232 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[O:15])[CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[CH:25]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=[O:15])[CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccccn1Cc1cccc(Cl)n1
Reactant: ClC(c1cccnc1)c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ccccn1C(c1cccc(Cl)n1)C(c1cccnc1)c1cccnc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the solution of 1-[(6-chloropyridin-2-yl)methyl]pyridin-2(1H)-one (0.3 g, 1.36 mmol) in THF (6 mL) at −78° C. was added LDA(0.83 mL, 1.8 M) and stirred at −78° C. for 1 h. The solution of 3-[chloro(pyridin-3-yl)methyl]pyridine (0.278 g, 1.36 mmol) in THF (3 mL) was added and the mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give (±)-1-[1-(6-chloropyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridin-2(1H)-one. 1H-NMR (500 MHz, CDCl3) δ 8.58 (d, 1H, J=2.2), 8.53 (d, 1H, J=2.0), 8.42 (dd, 1H, J=4.6, 1.2), 8.35 (dd, 1H, J=4.6, 1.2), 7.92 (d, 1H, 3=6.6), 7.84 (d, 1H, J=8.0), 7.64 (d, 1H, J=8.0), 7.48 (t, 1H, J=7.7), 7.25-7.09 (m, 6H), 6.41 (d, 1H, J=9.0), 6.09 (t, 1H, J=6.7), 5.30 (d, 1H, J=12.2). LRMS m/z (M+H) Calcd: 389.8. found: 389.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]([CH3:35])=[CH:31][C:32](Cl)=[O:33]>CO>[CH3:29][C:30]([CH3:35])=[CH:31][C:32]([N:19]1[CH2:18][CH2:17][N:16]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH2:21][CH2:20]1)=[O:33]
Reactant: Oc1cccc(CC(c2ccccc2)N2CCNCC2)c1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)=CC(=O)N1CCN(C(Cc2cccc(O)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
In methanol (300 ml) is dissolved dl-N-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (3.5 g) and thereto are added water (6 ml) and potassium carbonate (3.3 g). To the mixture is further added dropwise with stirring 3,3-dimethylacryloyl chloride (1.9 g) over a period of about 1 hour. The mixture is stirred at room temperature for 2 hours, and then the solvent is distilled off under reduced pressure. To the residue is added a 10% sodium carbonate aqueous solution and the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give the desired compound (3.6 g), which is recrystallized from methanol to give coloress crystals, melting point: 186°-187° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: CC(C)CCBr
Reactant: O=c1ccc(Br)c[nH]1
Solvent: CC#N
Product: CC(C)CCn1cc(Br)ccc1=O
Yield: 62300 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 0.01 mol, 1.73 g) and 1-isopentylbromide (1 eq, 0.01 mmol, 1.51 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours under reflux in acetonitrile. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column SiO2) using CH2Cl2/AcOEt (80/20) as the eluent to afford 5-bromo-1-isopentylpyridin-2(1H)-one (6.23 mmol, 1.52 g, 62%) as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:4]([I:10])[CH:5]=1
Reactant: OC1CCNCC1
Reactant: Fc1cc(I)c(CBr)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC1CCN(Cc2cnc(F)cc2I)CC1
Temperature: 80 °C

Procedure:
Combine 5-(bromomethyl)-2-fluoro-4-iodopyridine (0.2 g, 0.63 mmol), piperidin-4-ol (0.192 mg, 1.9 mmol), and diisopropylethylamine (0.22 mL, 1.27 mmol) in acetonitrile (3.0 mL). Heat the reaction mixture at 80° C. for 2 h and cool to RT. Remove the organic solvent to give crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol. Combine crude 1-((6-fluoro-4-iodopyridin-3-yl)methyl)piperidin-4-ol (0.63 mmol), N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-5-fluoro-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (0.15 g, 0.32 mmol, sodium carbonate (0.102 g, 0.96 mmol), 2-(di-tert-butylphospho)biphenyl (0.006 g, 0.06 mmol) and Pd(dppf)Cl2 (0.026 g, 0.1 mmol) in THF (3 mL) and water (1 mL). Heat the mixture at 120° C. for 10 min in a microwave reactor. Pour the crude reaction mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Purify by reverse phase chromatography (28% isocratic at 85 mL/min for 8 min on a 30×75 mm, 5 mm, C18 ODB MS XBridge™ column, Solvent A: water with 0.01 M ammonium bicarbonate, Solvent B: acetonitrile) to afford the title compound (91 mg, 52%). MS (ES) m/z 549 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+].[CH3:10][C:11]([C:14]([CH2:16]Br)=[O:15])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:14](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: [O-]c1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Na+]
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1

Procedure:
226 g (1 mol) of 1-(4-chlorophenoxy)-3,3-dimethylbutan-2-one (obtained from sodium 4-chlorophenolate and α-bromopinacolone; in this respect, see German Patent Specification No. 2,201,063), together with 120 g (1.07 mols) of glycerol, 19 g (0.1 mol) of p-toluenesulphonic acid monohydrate and 30 ml of butanol, are dissolved in 1,000 ml of toluene, and the mixture is heated under reflux for 16 hours in a water separator. After the mixture has been cooled, the toluene phase is washed with 4 times 250 ml of water, dried over magnesium sulphate, filtered, and evaporated down in vacuo. 186 g (65.4% of theory) of 2-(t-butyl)-2-(4-chlorophenoxymethyl)-4-hydroxymethyl-1,3-dioxolane of boiling point b.p.0.1 : 161° C.-163° C. are obtained by distillation.
Reaction SMILES: COP([CH2:7][C:8](=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:14]=1)(=O)OC.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][C:31]=1[CH:40]=O.[OH-].[Na+]>C1COCC1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:15]2[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:29])[CH:7]=[CH:40][C:31]3[CH:32]=[N:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:30]=3)[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Reactant: O=Cc1cnc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)C=Cc3cnc4ccccc4n3)n2)cc1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a solution of 6-7 (12.0 g, 28.5 mmol) and quinoxaline-2-carbaldehyde 22-1 (4.51 g, 28.5 mmol) in THF (250 mL) at 0° C. was added 4M NaOH (7.49 mL, 29.9 mmol) dropwise. After 15 minutes the ice bath was removed and the mixture stirred for an additional 10 minutes. The solution was diluted with water, extracted with ethyl acetate, and dried (Na2SO4). Following concentration, the residue was triturated with ether to give 11.4 g (88%) of 22-2 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([I:23])=[C:11]([CH2:13][CH2:14][OH:15])[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: OCCc1[nH]nc(-c2ccc(F)cc2)c1I
Yield: 89 %

Procedure:
Analogously to Process step [11], 2-[3-(4-fluorophenyl)-1H-pyrazol-5-yl]ethanol can be reacted with 1.1 eq. of NIS in DMF. In a yield of 89%, the desired product is obtained as a mixture of isomers: log P(HCOOH): 1.99; 1H-NMR (DMSO-d6): 13.29 & 13.19 (s, 1H) 7.78 & 7.69 (dd, 2H), 7.38 & 7.28 (dd, 2H), 4.92 & 4.72 (t, 1H), 3.62 (m, 2H), 2.79 & 2.73 (t, 2H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:19]#[N:20].[Na+]>CS(C)=O.O>[C:1]1([C:7]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccccc2)CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccccc2)CCCCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a stirred solution of methanesulfonic acid 1-phenyl-cyclohexylmethyl ester (252) (20.0 g, 74.52 mmol) in dimethyl sulfoxide (100.0 mL) were added KI (1.24 g, 7.45 mmol) and NaCN (5.48 g, 111.78 mmol) and the reaction mixture was stirred at 140° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 5% ethyl acetate in hexane) to get (1-phenyl-cyclohexyl)-acetonitrile (253) (2.4 g, 16.1%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])=[C:4]([F:23])[CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][C:10]=2[C:21]#[N:22])=[C:4]([F:23])[CH:3]=1
Reactant: COc1ccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2c1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(O)ccc2c1Nc1ccc(Cl)cc1F

Procedure:
In the manner of Example 302 reaction of 4-(4-chloro-2-fluorophenylamino)-7-methoxy-3-quinolinecarbonitrile with pyridine hydrochloride at 210° C. gave the title compound, mp 295-305° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:12][N:11]=1)(C(C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[F:16][C:14]1[C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:12][N:11]=[C:10]([CH2:9][OH:8])[CH:15]=1
Reactant: COCOc1cnc(CO[Si](C)(C)C(C)(C)C)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1cnc(CO)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 2-(((tert-butyl(dimethyl)silyl)oxy)methyl)-4-fluoro-5-(methoxymethoxy)pyridine (8.04 g) in THF (60 mL) was added 1 M tetrabutylammonium fluoride THF solution (34.7 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate/methanol) to give the title compound (3.59 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40]C3CCCCO3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1([CH2:16][N:14]([CH3:15])[C:12]2[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]3[NH:24][C:25](=[O:48])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[C:38]([CH2:39][OH:40])=[CH:37][N:36]=[N:35]5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(cyclopropylmethyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M67) (939 mg, 1.37 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (544 mg).
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:21](=[O:27])[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:30]([C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C:21](=[O:27])[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C@@H:7]([CH3:20])[C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)#[N:31]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc2N1C(=O)CS(C)(=O)=O
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2cc(C#N)ccc2N1C(=O)CS(C)(=O)=O
Temperature: 110 °C
Yield: 94 %

Procedure:
A solution of tert-butyl(2S,3S)-7-bromo-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (124 mg, 253 μmol) in DMF (2.53 ml) was sparged with Ar for 10 min, then zinc cyanide (59.4 mg, 506 μmol) and tetrakis(triphenyl-phosphine)palladium(0) (29.2 mg, 25.3 μmol) were added. The mixture was sparged with Ar for an additional 5 min, then sealed and heated in the microwave at 110° C. for 20 min, then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (104 mg, 94%) as a white solid. MS m/z 459 (MNa)+.
Reaction SMILES: CN(CC1[C:6]([OH:24])=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]1=[O:23])C.[OH-].[K+].C[CH2:28][O:29][CH2:30][CH3:31]>>[OH:24][C:6]1[C:31]([CH2:30][O:29][CH3:28])=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:23])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1
Reactant: CN(C)Cc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Product: COCc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a suspension of 2-dimethylaminomethyl-3-hydroxyestra-1,3,5(10)-trien-17-one (72, 2.0 g, 6.1 mmol) in Et2O (200 mL) was added iodemethane (10 mL, 161 mmol) and stirred for 20 h at room temperature. The precipitate was collected by filtration and washed with Et2O. The solid was dissolved in MeOH (50 mL) and added potassium hydroxide (5.0 g, 85%, 76 mmol), and stirred for 3 h at reflux condition. After the reaction mixture was cooled to room temperature, solvent was evaporated at reduced pressure until half volume. The reaction mixture was acidified with 5 N HCl at 0° C., and extracted with Et2O. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using CHCl3 :EtOAc (15:1→10:1, v/v) to afford 1.34 g of 74 (88% yield) mp: 149-151° C.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]1=[O:23])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[CH3:9][C:2]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]1=[O:23])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(c1ccccc1)N1CCC(=O)C(c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(c1ccccc1)N1CCC(O)C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
4.0 g (0.013 mol) of 1-(α,α-dimethylbenzyl)-2,4-dioxo-3-phenylpiperidine prepared by the method of Reference Example 18, was dissolved in 50 ml of ethanol, and 0.27 g (0.007 mol) of sodium borohydride was added thereto at room temperature. The mixture was stirred at room temperature for 30 minutes, and then ethanol was distilled off under reduced pressure. Water was added to the residue, and precipitated crystals were collected by filtration. The crude product thereby obtained was recrystallized from ethanol to obtain 3.6 g (yield: 90.0%) of the desired compound.