Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[CH:4]=[CH:5][C:6]([O-:8])=[O:7])[CH3:2]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([CH:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCC(C=CC(=O)[O-])CC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)CCC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83.2 %

Procedure:
Eethyl 4-ethyl-2-hexenoate (55.3 g) was dissolved in a mixture of tetrahydrofuran (150 mL) and ethanol (150 mL). To the solution was added 5 w/w % palladium on activated carbon (5.5 g). The mixture was stirred at RT for 3.5 hr under hydrogen atmosphere (1 atm). The 5 w/w % palladium on activated carbon was filtered off using Celite. To the filtrate was added aqueous 4 N sodium hydroxide (111 mL). The mixture was stirred at RT overnight. The reaction mixture was washed with hexane. To the aqueous layer was added 4 N hydrochloric acid (113 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with water/brine=1/1 (300 mL) and brine (150 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (47.0 g) as a crude product.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:26]=[N:27][C:28]([CH:31]([NH2:33])[CH3:32])=[N:29][CH:30]=1.O>CS(C)=O>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[CH:30]=[N:29][C:28]([CH:31]([NH:33][C:2]2[N:7]=[C:6]([N:8]3[C@@H:12]([C@H:13]([OH:15])[CH3:14])[CH2:11][O:10][C:9]3=[O:16])[CH:5]=[CH:4][N:3]=2)[CH3:32])=[N:27][CH:26]=1
Reactant: CC(N)c1ncc(-c2cccc(Cl)c2Cl)cn1
Reactant: C[C@@H](O)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: O
Solvent: CS(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1ncc(-c2cccc(Cl)c2Cl)cn1
Yield: 30.8 %

Procedure:
A solution of (R)-3-(2-fluoropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (18.6 mg, 0.082 mmol) and 1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethanamine (22 mg, 0.082 mmol) in DMSO (2 mL) was heated at 100° C. for 2 h. The reaction mixture was poured into water (20 mL), and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography ((25% MeOH in EtOAc)/Heptane to 100%) provided (4R)-3-(2-(1-(5-(2,3-dichlorophenyl)pyrimidin-2-yl)ethylamino)pyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (12 mg, approx 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 4H), 8.15 (d, J=5.7 Hz, 2H), 7.51 (ddd, J=8.1, 2.8, 1.6 Hz, 2H), 7.40-7.11 (m, 6H), 6.07-5.96 (m, 2H), 5.32 (t, J=7.4 Hz, 1H), 5.09 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 4.43 (dd, J=7.3, 4.8 Hz, 2H), 4.33 (dd, J=9.4, 8.3 Hz, 1H), 4.18 (d, J=9.0 Hz, 2H), 3.62 (s, 1H), 3.23 (s, 1H), 1.62-1.58 (m, 6H), 1.07-0.97 (m, 3H), 0.87-0.77 (m, 3H). HRMS m/z 475.1039 and 475.1042 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2cccc(Cl)c2)c1C(=O)OC
Yield: 90.1 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.3 g, 6.3 mmol) in acetone (20 mL) and potassium carbonate (2.1 g, 15.2 mmol) was added 3-chlorobenzyl bromide (1.0 mL, 7.6 mmol) and refluxed overnight. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL), and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(3-chloro-benzyloxy)-phthalic acid dimethyl ester (1.9 g, 92% yield). The product was used in the next step without further purification.
Reaction SMILES: [NH2:1]CCC1C2C(=CC=CC=2)NC=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O>C1(C)C=CC=CC=1>[C:13]1(=[O:18])[NH:1][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Reaction time: 12 h

Procedure:
A solution of 3.20 g (20.0 m mol) of tryptamine and 3.10 g (20.0 m mol) of phthalic anhydride in 40 ml of toluene was refluxed under a Dean-Stark water separator for 12 h. Cooling, filtration and concentration of the filtrate gave a crude phthalimide which was recrystallized from ethanol to produce 4.85 g (84%), of phthalimide, mp 164°-165° C.; reported 164°-165° C.3
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:38]([O:42][C:43](=[O:61])[C@@H:44]([NH2:60])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=2)=[CH:48][CH:47]=1)([CH3:41])([CH3:40])[CH3:39]>C1COCC1>[C:38]([O:42][C:43](=[O:61])[CH:44]([NH:60][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=2)=[CH:48][CH:47]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccn2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccn2)cc1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The product from Example Z (1.15 g, 4.50 mmol) was dissolved in 50 mL of THF at room temperature with stirring. To the solution were added O-(7-azabenzotriazol-1-y-)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 3.11 g, 8.18 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 1.11 g, 8.18 mmol), N,N-diisopropylethylamine (DIEA, 2.84 mL, 16.36 mmol) followed by the product from Example M (1.34 g, 4.09 mmol) in 50 mL of THF. After 3 hours, the solution was concentrated under reduced pressure, partitioned between ethyl ether and water (100 mL each), and separated. The organic layer was washed with 5% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a solid. The solid was purified by silica gel chromatography with ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to a solid (2.17 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1>>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:12])[C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)C(=O)NCCO2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(=O)NCCO3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 7-amino-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.42 (d, 1H), 8.11 (s, 1H), 7.88 (d, 1H), 7.71 (dd, 1H), 7.54 (dd, 1H), 7.41 (td, 1H), 7.24 (td, 1H), 7.09 (d, 1H), 4.41 (t, 2H), 3.48 (t, 2H), 2.92 (s, 3H); MS (m/e) 439 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([NH:87][CH2:88][CH2:89][CH3:90])[N:82]=[C:81]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:103]=[CH:102][C:101]([Cl:104])=[CH:100][CH:99]=4)[S:96][CH:97]=3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:64][C@H:65]([C:67]([O:69][CH2:70][CH2:71][O:72][C:73]1[CH:78]=[CH:77][C:76]([C:79]2[C:84]([C:85]#[N:86])=[C:83]([NH:87][CH2:88][CH2:89][CH3:90])[N:82]=[C:81]([S:91][CH2:92][C:93]3[N:94]=[C:95]([C:98]4[CH:103]=[CH:102][C:101]([Cl:104])=[CH:100][CH:99]=4)[S:96][CH:97]=3)[C:80]=2[C:105]#[N:106])=[CH:75][CH:74]=1)=[O:68])[CH3:66])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)N)cc2)c1C#N
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
445 mg (1.284 mmol) of N2,N6-bis(tert-butoxycarbonyl)-L-lysine were initially charged in 12.3 ml of DMF. 268 mg (1.400 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 237 mg (1.750 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 ml (2.917 mmol) of N,N-diisopropylethylamine were added, and 872 mg (1.167 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(propylamino)pyridin-4-yl)phenoxy}ethyl L-alaninate trifluoroacetate (Example 38) were then added and the mixture was stirred at RT overnight. Water was added, and the reaction solution was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated by evaporation. The residue was purified by preparative HPLC (acetonitrile/water+0.1% TFA). For further purification, the product obtained was subjected to column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 1/1). This gave 698 mg (62% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Ca+2].[Br-:34].[Br-].[Br-].C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1.C[N+](C)(C)CC1C=CC=CC=1>ClC(Cl)C>[Br:34][C:9]1[C:10]2[N:11]([C:14](=[O:28])[N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)[N:16]=2)[CH:12]=[N:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)ncn12
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(Cl)Cl
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ncn12
Temperature: 70 °C
Yield: 90 %

Procedure:
To a solution of 7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (40.5 mg, 0.10 mmol) in dichloroethane (5 mL) at room temperature under argon was added calcium carbonate (10.0 mg, 0.10 mmol) and N,N,N-trimethyl-1-phenylmethanaminium tribromide (39.0 mg, 0.10 mmol). The resulting suspension was stirred and heated at 70° C. under argon for 2 h. Analysis by HPLC/MS indicated that most of the starting material had been consumed. After the reaction mixture was cooled to room temperature, the product was purified by silica gel column chromatography eluted with ethyl acetate-dichloromethane. This provided the title compound (43.6 mg) as a solid. HPLC/MS (methanol-water with 10 mM NH4OAc): retention time=3.67 min, [M+H]+486.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:19])[CH3:18])[CH:12]=2)[CH:7]=1)[CH3:2].[Cl:21]N1C(=O)CCC1=O.Cl>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:19])[CH3:18])[CH:12]=2)[C:7]=1[Cl:21])[CH3:2]
Reactant: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1Cl
Temperature: 50 °C

Procedure:
A mixture of N-(6-acetyloxy-2-naphthyl)carbamic acid ethyl ester (670 mg, 2.45 mmol), N-chlorosuccinimide (326 mg, 2.45 mmol) and 1 M HCl in acetic acid (2.45 mL, 2.45 mmol) in acetic acid (10 mL) is heated at 50° C. under N2 atmosphere for 1 hour. After cooling to room temperature the mixture is partitioned between EtOAc and water. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator to give N-(6-acetyloxy-1-chloro-2-naphthyl)carbamic acid ethyl ester as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH2:24])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:12])[CH2:9][CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl.CN(C=O)C>[CH3:12][C:8]([C:13]1[S:17][C:16]([NH:18][C:19](=[O:25])[CH:20]([NH:24][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH2:21][CH2:22][CH3:23])=[N:15][N:14]=1)([CH3:7])[CH2:9][CH2:10][CH3:11]
Reactant: CCC(=O)CC
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)CCC)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(NC(CC)CC)C(=O)Nc1nnc(C(C)(C)CCC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of pentan-3-one (0.3 mmol), 2-Amino-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide (0.3 mmol), sodium triacetoxy borohydride (0.3 mmol) and acetic acid (0.3 mmol) in 1.0 mL of anhydrous dichloromethane and 1 ml DMF was stirred at room temperature (rt) overnight. The reaction was not complete. The mixture was treated with NaBH3CN (40 mg) and heated at 45° C. for 4 hr. All starting material was consumed. The crude solution was diluted with dilute NaOH and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through Shimadzu HPLC to give 2-(1-Ethyl-propylamino)-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide. LC-MS (retention time, M+1): 1.70 min, 355.3 [M+1]
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4]O.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:1][C:2]([F:17])([F:16])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][N:22]1[C:18](=[O:28])[C:19]2[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21]1=[O:23]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(NC(CO)C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reaction time: 0.67 h
Yield: 80.6 %

Procedure:
To a solution of 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propan-1-ol (C14, 171 mg), phthalimide (201 mg) and triphenylphosphine (305 mg) in tetrahydrofuran (7 mL), a 40% solution of diethyl azodicarboxylate in toluene (526 μL) was added under ice cooling, and the mixture was stirred at the same temperature for 40 minutes. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 70% hexane in ethyl acetate) to obtain 2-(3,3,3-trifluoro-2-((3-nitrophenyl)amino)propyl)isoindoline-1,3-dione (C15, 209 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)[CH:22]=[CH:21][N:20]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>CO.C(O)(=O)C.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)=[CH:16][CH:17]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc([N+](=O)[O-])cc4)n3)cc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(N)cc4)n3)cc2)CC1
Reaction time: 6 h

Procedure:
To a solution of 1-acetyl-4-[(4-{[4-(4-nitrophenyl)pyrimidin-2-yl}amino}phenyl)carbonyl}piperazine (150 mg, 0.34 mmol) in methanol (5 mL) containing a few drops of acetic acid, is added 100 mg of 10% Palladium-Charcoal. The solution is then hydrogenated at 50 psi for 6 h at which time there remains no starting material. The solution is then filtered through a pad of Celite which gives 135 mg (95%) of essentially pure reduced material as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(#N)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:6]=[C:5]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:4]=1
Reactant: C1COCCN1
Reactant: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(S(C)(=O)=O)n1
Solvent: CC#N
Product: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Temperature: 100 °C

Procedure:
Compound 19 (150 mg, 0.405 mmol) was dissolved in acetonitrile (2 mL) and morpholine (0.282 mL, 3.24 mmol) was added, The solution was sealed and heated to 100° C. for 18 h. The solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a colorless oil. 1H NMR (CDCl3) δ 5.13 (s, 1H), 4.52-4.51 (m, 1H), 3.82 (s, 3H), 3.72 (s, 8H), 3.62-3.59 (m, 2H), 3.14-3.10 (m, 2H), 1.94 (m, 1H), 1.72-1.70 (m, 1H), 1.55-1.53 (m, 2H), 1.43 (s, 9H); LCMS 2.02 min, 394 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[S:8][C:9](C(O)=O)=[CH:10][C:6]=2[CH:5]=1.N12CCCN=C1CCCCC2>CC(N(C)C)=O.Cl>[F:17][C:2]([F:1])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1
Reactant: O=C(O)c1cc2cc(OC(F)(F)F)ccc2s1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)Oc1ccc2sccc2c1
Temperature: 200 °C
Yield: 31.1 %

Procedure:
A mixture of 5-trifluoromethoxy-benzo[b]thiophene-2-carboxylic acid (2.00 g, 7.63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 32 mmol) in DMA (12 mL) was heated via microwave irradiation at 200° C. for 1 h. The reaction was cooled to rt, diluted with HCl (1 N aq., 15 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and concentrated. The residue was taken up in Et2O (25 mL) and washed with water (25 mL). The aqueous layer was extracted with Et2O (10 mL×2). The combined Et2O layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (518 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:28])([F:27])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([C:13]([F:28])([F:27])[F:12])=[N:19][CH:18]=1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-trifluoromethyl-pyrimidin-5-yl)-3-cyclopropyl-propylamine. LCMS (MH+): m/z=418.1, tR (minutes, Method G)=2.55
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[CH:19]([OH:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:23])([CH3:22])[C:19](=[O:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 0.75 h
Yield: 102.1 %

Procedure:
4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-ol (15 mg, 0.038 mmol) in DCM (1 ml) was treated with commercially available Dess-Martin periodinane (25 mg, 0.058 mmol). The reaction was complete in 45 minutes and was filtered through a plug of SiO2 using DCM/hexane (3:1) and concentrated to give the crude product. The crude material was purified via chromatography on silica gel eluting with 14% ethyl acetate in hexane to afford 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3,3-dimethyl-4-phenylbutan-2-one as a white foam (15 mg, quantitative yield). 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, s) 7.81 (1 H, s) 7.70 (2 H, dd, J=9.16, 4.58 Hz) 7.60 (1 H, d, J=8.65 Hz) 7.38 (1 H, dd, J=8.65, 1.53 Hz) 7.23-7.35 (6 H, m) 7.19 (1 H, t, J=7.12 Hz) 4.67 (1 H, s) 2.05 (3 H, s) 1.26 (6 H, d, J=5.09 Hz). LC/MS (m/z) 387.20 [(M+1)+]; HPLC Rt: 3.758 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:21]([CH3:22])[CH:20]=[CH:19][C:7]=2[C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:9][CH:10]=1)=[O:4].[OH-].[Na+]>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:8]2[C:7]3[CH:19]=[CH:20][N:21]([CH3:22])[C:6]=3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Yield: 83.7 %

Procedure:
4-(3-Chloro-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid methyl ester (0.6 g) and 2N sodium hydroxide (2 ml) in methanol were irradiated at 120° C. for 3 minutes with microwaves. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer washed with dilute citric acid solution and saturated brine solution then dried (MgSO4), filtered and evaporated to yield the title compound as an off-white solid (0.48 g).
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:17]([O-])=O.[Na+].[F:21][B-:22]([F:25])([F:24])[F:23].[Na+]>O>[F:21][B-:22]([F:25])([F:24])[F:23].[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([N+:11]#[N:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+]#N)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A stirred solution of concentrated hydrochloric acid (1.7 mL) in water (5 mL) from 0° C. and 5° C. is treated with 3-cyclopentyloxy-4-methoxyaniline (0.83 g), followed by a solution of sodium nitrite (0.29 g) in water (0.6 mL), at such a rate that the temperature remains from 0° C. and 5° C. The resulting solution is stirred for a further 10 minutes, while keeping the temperature below 5° C. The stirred solution, while still maintained at below 5° C. , is then treated dropwise with a solution of sodium tetrafluoroborate (0.88 g) in water (1.8 mL). The resulting precipitate is filtered off, washed with cold water (3 mL) and dried in vacuo, to give 3-cyclopentyloxy-4-methoxyphenyldiazonium tetrafluoroborate (1.24 g) in the form of a gray solid, m.p. 120° C.