Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH3:12])[N:3]=1>[Pd].C(O)C>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH3:12])[NH:3]1
Reactant: CC1=NC(C)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC1Cc2ccccc2C(C)N1
Reaction time: 2 h

Procedure:
A reaction vessel was charged with acetonitrile which was held under a nitrogen blanket. With the reaction vessel cooled in an ice bath, stannic chloride was added gradually below the surface of the acetonitrile with stirring over a period of 2 hours 20 minutes. During the addition period, the temperature of the reaction mixture varied between 3° C. and 39° C. The mixture was allowed to stand overnight at room temperature. With the reaction mixture at 22° C., α-methylphenethyl chloride was added in increments to the reaction vessel over a ten-minute period. With the mixture under reduced pressure and heated, acetonitrile nitrile was gradually stripped from the mixture. The reaction mixture, milky in color, was heated to reflux. The reaction mixture was maintained at reflux for about 61/2 hours. With the temperature of the reaction mixture at about 75° C., the entire amount of previously-stripped acetonitrile was added back to the reaction mixture. The mixture was allowed to cool, stand overnight and was observed to contain a slurry. Methylene chloride was added to the mixture. Then, this mixture was added with stirring to 10% sodium hydroxide previously cooled to about 10° C. The temperature of the mixture reached 40° C. and the mixture was found to be acidic. More 10% sodium hydroxide was added to make the mixture alkaline. The organic phase was separated and washed with water. The organic phase was dried over sodium sulfate, filtered and stripped on a rotary evaporator at a temperature of 35°-40° C. to provide 1,3-dimethyl-3,4-dihyroisoquinoline. An autoclave was charged with a slurry of 50%-wetted 5% palladium-on-carbon catalyst in absolute ethanol. Then, there was added to the slurry a mixture of 1,3-dimethyl-3,4-dihydroisoquinoline. The autoclave was flushed with hydrogen gas. With the reaction mixture being stirred, the autoclave was gradually pressurized with hydrogen over a period of about two hours to a final pressure of about 185 psi (12.5 atm; 12.6×105Pascal) and temperature of about 50° C. The autoclave was maintained in this pressurized condition overnight. The temperature of the autoclave dropped to about 10° C. after venting with stirring of the reaction mixture. The mixture was filtered and stripped of ethanol to provide 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 2.5 g of 1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, 20 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1.1 equivalents dichloro-acetyl chloride was added dropwise to the mixture. The mixture was stirred for 20 minutes, then water was added. The organic extract was dried with magnesium sulfate, and stripped of solvent, and then subjected to Kugelrohr distillation (150° C. @ 0.1 mm Hg) to provide 2.5 g of a yellow oil product having the following elemental analysis:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH:17]([C:23](O)=[O:24])[C:18](=[O:22])[NH:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][CH3:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C1COCC1.O.C(N(CC)CC)C>[CH3:27][N:28]([CH3:29])[C:23]([CH:17]1[CH2:16][C:15]2[C:20](=[CH:21][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:13][CH:14]=2)[NH:19][C:18]1=[O:22])=[O:24]
Reactant: O=C(Nc1ccc2c(c1)NC(=O)C(C(=O)O)C2)OCc1ccccc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1Cc2ccc(NC(=O)OCc3ccccc3)cc2NC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 77.8 %

Procedure:
To a solution of 7-benzyloxycarbonylamino-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid (7.0 g) in acetonitrile (80 ml) and THF (80 ml) were added dimethylamine hydrochloride (2.52 g), WSC(5.92 g), HOBt (3.15 g), and triethylamine (18 ml) subsequently at room temperature. The reaction mixture was stirred at room temperature for 10 hours, diluted with water, and extracted with combined solvent of ethyl acetate and THF. The organic layer was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate, water, saturated aqueous sodium chloride subsequently, dried, and concentrated. The precipitated crystals were washed with IPE to obtain the entitled compound (5.88 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH2:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:14]
Reactant: CNC
Reactant: N#Cc1ccc(F)cc1CBr
Product: CN(C)Cc1cc(F)ccc1C#N
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 2-(bromomethyl)-4-fluorobenzonitrile (423 mg, 1.9 mmol) and 2.0 M dimethylamine (4 mL) was stirred at room temperature for thirty minutes. The mixture was then concentrated, purified by normal phase flash column chromatography, on a 20 g silica gel column (5-45% ethyl acetate/hexanes gradient), and concentrated in vacuo to yield 2-((dimethylamino)methyl)-4-fluorobenzonitrile (241 mg, 1.35 mmol, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.59, 5.37 Hz, 1H), 7.42 (dd, J=9.94, 2.69 Hz, 1H), 7.35 (td, J=8.46, 2.69 Hz, 1H), 3.56 (s, 2H), 2.19 (s, 6H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=O.CC(=O)[C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](CC(=O)CC2)CC3)CC1.C(Cl)(=O)C([Cl:50])=O>C1C=CC=CC=1>[Cl:50][C:21]([C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][C:12](=[O:20])[CH2:13][CH2:14]1)[CH2:9][CH2:8]3)=[O:23]
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)Cl)CC[C@@H]12

Procedure:
A solution of 5α-androstan-3-one 17β-carboxylic acid (2.1 g., corrected for the presence of 15% 5α-pregnan-3,20 -dione) and oxalyl chloride (4 ml.) in dry benzene (125 ml.) was refluxed for 1.5 hours before evaporation to dryness to afford crude 17β-chlorocarbonyl-5α-androstan-3-one. Morpholinoethanol (5 ml.) was added to a stirred solution of the acid chloride in dry ether (125 ml.) and pyridine (3 ml.) at room temperature. After 1 hour the mixture was diluted with ether (100 ml.) and washed with aqueous 10% sodium hydroxide and water, dried (MgSO4), filtered and evaporated to give a gum (3.275 g.). A sample (2.0 g.) gave, after purification by preparative t.l.c. (ethanol/chloroform 1:19) title compound (900 mg.) as a white froth; [α]D + 54.5°, (c. 0.9).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([C:13](OCC)=[O:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Oc2ccccc2)s1
Solvent: Cc1ccccc1
Product: OCc1cnc(Oc2ccccc2)s1
Temperature: -5 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
54 ml of a solution of 2 moles of diethyl sodium aluminate in toluene were slowly added at -10° C. to a solution of 12 g of the product of Step A in 60 ml of toluene and the mixture was stirred at -5° C. for one hour. The mixture was cooled to -20° C. while adding thereto 80 ml of a solution of aqueous 2N hydrochloric acid and the mixture was filtered. The filtrate was decanted and the organic phase was washed with water, with an aqueous 2N sodium hydroxide solution and then with water and was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-ethyl acetate mixture to obtain 8.15 g of (2-phenoxy-5-thiazolyl)-methanol.
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([CH2:9]O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:31]>>[C:1]([N:5]1[CH2:8][CH:7]([CH2:9][Cl:31])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)N1CC(CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)N1CC(CCl)C1

Procedure:
A mixture of 3.0 g. (0.209 mol.) of N-t-butyl-3-hydroxymethylazetidine, 6.0 g. (0.0229 mol.) of triphenylphosphine and 50 ml. of carbon tetrachloride was refluxed for 48 hours. The mixture was cooled, filtered and the filtrate was extracted three times with 10% aqueous sulfuric acid. The combined extracts were basicified by addition of solid sodium carbonate and the basic solution was extracted with ether. The extract was dried (MgSO4), evaporated to dryness and the residue distilled to give N-t-butyl-3-chloromethylazetidine, b.p. 90°-96° (27 mm.).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH2:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C:31]1=[O:39]>C1C=CC=CC=1.CCOCC>[O:39]([C:31]1[CH2:32][C:33]2[C:38]([CH:30]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1Cc2ccccc2C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)(C)[Si](OC1=Cc2ccccc2C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of tert-butyldiphenylchlorosilane (42.43 g, 154.4 mmol) and DBU (25.64 g, 168.4 mmol) in benzene (200 mL) was added 2-indanone (18.38 g, 139.1 mmol) in one portion. The reaction mixture was stirred overnight, diluted with Et2O (200 mL), washed with 10% HCl (2×200 mL) and water (2×200 mL) and dried over sodium sulfate. The solvents were evaporated to leave a dark brown oil. Distillation under reduced pressure gave 38.22 g (74.1%) of the title compound as a yellow oil (bp. 172-175° C./0.05 mbar). 1H NMR (CDCl3, δ): 7.77-7.74 (m, 4H); 7.46-7.36 (m, 6H) 7.18-7.16 (m, 1H); 7.11-7.07 (m, 1H); 6.98-6.94 (m, 2H); 5.48 (d, 4J=0.7 Hz, 1H); 3.29 (s, 2H); 1.09 (s, 9H). 13C NMR (CDCl3, δ): 162.13; 145.17; 136.75; 135.53; 132.43; 130.20; 127.99; 126.51; 123.15; 122.49; 119.24; 107.91; 39.43; 26.60; 19.46.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>C(#N)C>[O:21]1[CH2:20][CH:19]1[CH2:17][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc2c(c1)CCN(CC1CO1)C2
Yield: 43.9 %

Procedure:
1,2,3,4-tetrahydroisoquinoline (25.0 g) was dissolved in acetonitrile (100 ml) and sodium carbonate (40.0 g) and epibromohydrin (31.0 g) were added thereto and heated at reflux for 4 hours. After the resultant salt was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Waco Gel C-200, 500 g) and eluted with a mixed solvent of chloroform (99 parts)+methanol (1 part) to give 2-[1-(2,3-epoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (15.6 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC#N.O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:36]5[C:31]([O:30][CH3:29])=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 120 °C
Yield: 55.2 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 2-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (282 mg, 1.2 mmol), Cs2CO3 (650 mg, 2.0 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol) and CH3CN—H2O (1:1, 4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 120° C. for 20 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 271 (270 mg, yield: 46%). 1HNMR (DMSO-d6, 400 MHz): δ8.30-8.26 (m, 2H), 8.15 (d, J=6.8 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.92 (t, J=9.2 Hz, 1H), 7.29-7.18 (m, 2H), 4.33 (s, 2H), 3.96 (s, 3H), 3.16 (s, 2H). ESI-MS: m/z=490 [M+H+]
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=[C:9]=[S:10].[C:23]([O:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:40]#[N:41])([CH3:39])[CH3:38])=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24].C(OCC)C.CC(C)=O>C1COCC1>[C:23]([O:27][C:28](=[O:42])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:37]([CH3:39])([CH3:38])[C:40](=[NH:41])[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:22])[F:21])[CH:12]=3)[C:9]2=[S:10])=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CC(C)(C#N)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
Triethylamine (0.202 g, 2 mmol) was added to a solution of 1a (0.456 g, 2 mmol) and 2b (0.57 g, 2 mmol) in dry THF (5 ml). The reaction mixture was stirred at room temperature for 15 h and then concentrated to yield a dark residue which was subjected to flash chromatography (ethyl ether/acetone, 97:3) to afford {4-[3-(4-cyano-3-trifluoromethylphenyl)-4-imino-5,5-dimethyl-2-thioxo-imidazolidin-1-yl]phenyl}carbamic acid tert-butyl ester, (2c) (0.15 g, 0.3 mmol, 15%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.Br[C:39]1[S:40][C:41]2[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:39]3[S:40][C:41]4[C:47]([C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46][CH:45]=[CH:44][C:42]=4[N:43]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(CC)CC)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(CC)CC)C3)sc12
Yield: 55.8 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-[(1-ethylpropyl)amino]piperidine-1-carboxylate obtained in Example (215a) (16.0 mg, 0.036 mmol), 4 N hydrochloric acid/1,4-dioxane (1 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (11 mg, 0.040 mmol) and sodium carbonate (38 mg, 0.362 mmol), to obtain 11 mg of the title compound (56%) as a pale yellow oily substance.
Reaction SMILES: C[O:2][CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:5][CH3:6].Cl>C1COCC1>[F:20][C:19]([F:21])([F:22])[C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:4]([CH2:5][CH3:6])[CH:3]=[O:2])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1
Reactant: CCC(=COC)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(1-methoxymethylenepropyl)-4′-trifluoromethylbiphenyl (278 mg, 0.908 mmol) in THF (9.1 mL) is treated with concentrated hydrochloric acid (0.456 mL), and the reaction is heated at reflux overnight. The reaction mixture is cooled to RT, and extracted with EtOAc (3×). The combined organic layers are dried and concentrated, giving 2-(4′-trifluoromethylbiphenyl-4-yl)butyraldehyde as a crude residue to be used as is (weight in excess of theoretical yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.Cl.[CH:21]12[CH2:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]2[NH2:28].C(N(CC)CC)C.O1CCOCC1>O>[C@H:21]12[CH2:27][C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@H:22]2[NH:28][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1cnc(N[C@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (150 mg), rac-(1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (300 mg), triethylamine (354 μL), and 1,4-dioxane (1.5 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained colorless oil was solidified from hexane-ethyl acetate to obtain rac-N-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-yl]-5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-amine (132 mg) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[CH:21][N:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:33]1[N:42]=[CH:41][C:40]2[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:34]1=[O:48])(=O)C.[OH-].[Na+].C(OCC)(=O)C.O>O1CCOCC1>[C:43]([C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([F:47])[CH:37]=1)[C:34](=[O:48])[N:33]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[N:15]=[CH:14][N:13]=3)[C:6]=1[CH2:5][OH:4])[N:42]=[CH:41]2)([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)ncn2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)ncn4)c3CO)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(6-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyrimidin-4-yl)benzyl acetate (90 mg, 0.14 mmol) in 1,4-dioxane (5 mL) was added 1N NaOH (10 mL). The mixture was stirred at room temperature for 2 hrs. The mixture was acidified to pH=2, followed by addition of ethyl acetate (50 mL) and H2O (20 mL). The organic phase was washed with H2O (2×20 mL), then brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified by prep-HPLC to afford 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(6-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyrimidin-4-yl)phenyl)-phthalazin-1(2H)-one (30 mg, 36%). 1H NMR (300 MHz, CD3OD): δ 8.98 (s, 1H), 8.52-8.48 (m, 2H), 8.39 (s, 1H), 7.99-7.95 (m, 1H), 7.85 (s, 1H), 7.73-7.68 (m, 5H), 4.55 (s, 2H), 3.72 (brs, 8H), 1.46 (s, 9H). LC-MS (ESI): 610.3, [M+1]+ HPLC: 97.17% at 214 nm, 99.01% at 254 nm, tR=5.761 min.
Reaction SMILES: C(OCC)(=O)C.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH:8]=1.CS(C)=O>C(N(CC)CC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]=[O:16])[CH:8]=1
Reactant: OCCCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CCCc1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To an ethyl acetate (30 mL) solution of 3-(3-pyridyl)propanol (1.5 g) were added dimethyl sulfoxide (15 mL) and triethylamine (9 mL), a pyridine sulfur trioxide complex (5.2 g) was added while the mixture was stirred at 0° C., and the mixture was stirred as it was for 2 hours. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=30:70→0:100) to obtain a titled compound (1:1 g) having the following physical property values.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:40])/[CH:15]=[CH:16]/[C@H:17]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@@H:18]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([OH:40])/[CH:15]=[CH:16]/[C@H:17]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[C@@H:18]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/C(=O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(S)-binal-H (0.5 M tetrahydrofuran solution, 335 μL, 0.167 mmol) was added dropwise to a tetrahydrofuran solution (500 μL) of (12S,13S)-(E)-12,13-di-tert-butyldimethylsiloxy-9-oxo-10-octadecaenoic acid t-butyl ester (11) (31.1 mg, 0.0508 mmol) at −78° C. over 5 minutes under the argon atmosphere, and the mixture was stirred at −78° C. for 1 hour. Hydrochloric acid (1.0 N, 1 mL) was added to the reaction solution, the mixture was extracted with chloroform (5 mL) three times, and the organic layer was washed successively with 1.0 N sodium hydroxide (5 mL×3), and saturated brine (5 mL), dried over magnesium sulfate, and concentrated. The resulting colorless oily crude product (32 mg) was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain (9S,12S,13S)-(E)-12,13-di-tert-butyldimethylsiloxy-9-hydroxy-10-octadecaenoic acid t-butyl ester (12) as a colorless oily substance (31.0 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([N+:13]([O-:15])=[O:14])=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:7]=1.[NH3:17]>C(O)C.CO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH2:17])[CH:3]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1-n1cccn1
Reactant: N
Solvent: CO
Solvent: CCO
Product: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86 %

Procedure:
To a solution of 1-(5-bromo-3-fluoro-2-nitro-phenyl)-1H-pyrazole (240 mg, 0.84 mmol) in ethanol (3 mL) was added ammonia (3 mL, 2N in methanol. The resulting mixture was heated in a sealed tube at 80° C. for 16 hours then concentrated in vacuo. The residue was purified by column chromatography over silica gel eluted with ethyl acetate:hexanes (1:3) to afford 205 mg (86%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 5.20 (br s, 2H), 6.50 (t, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.7 (d, 1H), 7.8 (d, 1H). MS M+1 283, M+1+2 285.