Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:29]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(S(=O)(=O)On2nnc3ccccc32)c(C)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
In dichloromethane (70 ml) are added 1-hydroxy-1,2,3-benzotriazole (3.4 g) and further triethylamine (3.7 ml). To the solution is added dropwise a solution of 2,4,6-trimethylbenzenesulfonyl chloride (4.5 g) is dichloromethane (20 ml) at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting residue is washed with ethyl acetate-n-hexane (1:1; 50 ml) and dried to give colorless crystals of 1-(2,4,6-trimethylbenzenesulfonyloxy)-1,2,3-benzotriazole (5.5 g), melting point: 128°-130° C. The product is recrystallized from dichloromethane-n-hexane to give colorless prisms, melting point: 130°-131° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:17])[NH:13][NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)[CH3:2].[CH3:18][C:19]([O:21][CH2:22][C@H:23]1[O:28][C@H:27](Br)[C@H:26]([O:30][C:31]([CH3:33])=[O:32])[C@@H:25]([O:34][C:35]([CH3:37])=[O:36])[C@@H:24]1[O:38][C:39]([CH3:41])=[O:40])=[O:20]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[C:12]([O:17][C@@H:27]3[O:28][C@H:23]([CH2:22][O:21][C:19](=[O:20])[CH3:18])[C@@H:24]([O:38][C:39](=[O:40])[CH3:41])[C@H:25]([O:34][C:35](=[O:36])[CH3:37])[C@H:26]3[O:30][C:31](=[O:32])[CH3:33])=[N:13][NH:14][C:15]=2[CH3:16])=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCSc1ccc(Cc2c(C)[nH][nH]c2=O)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Yield: 37.6 %

Procedure:
To a suspension of 4-[(4-ethylthiophenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.6 g) and acetobromo-α-D-glucose (2.9 g) in tetrahydrofuran (30 mL) was added silver carbonate (2.1 g), and the mixture was stirred under shading the light at 60° C. overnight. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran) and further column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3) to give 4-[(4-ethylthiophenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (1.4 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:12]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)c2cc3ccccc3[nH]2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure D using Indole-2-carboxylic acid (Aldrich) and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 3-B), the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]2[C:14]([OH:21])=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[C:11]=2[N:10]=1.OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:19][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[NH:13][C:12]=2[C:14]([OH:21])=[CH:15][CH:16]=1)=[O:20]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Yield: 86 %

Procedure:
2-(2,4-dichloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (1.63 g, 5.03 mmol) obtained in step 3 was dissolved in 30 ml of methanol, and H2SO4 (1.08 ml, 20.12 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (1.5 g, 3.62 mmol) in a yield of 86%.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 2-methoxyphenylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH:6]2[C:11]([CH3:16])([CH3:10])[CH:12]([OH:13])[C:17]3[C:8](=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=3)[NH:7]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)c1ccc(/N=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 4-chloro-3-nitrobenzaldehyde (5.0 g, 27 mmol) in 42 mL of ethonal was added methyl 4-aminobenzoate (4.07 g, 27 mmol), and the reaction mixture was stirred over weekend. The yellow precipitates were filtered, and 8.47 g of (E)-methyl 4-(4-chloro-3-nitrobenzylidenamino)benzoate a yellow solid was obtained. (Yield=98%). (E)-methyl 4-(4-chloro-3-nitrobenzylideneamino)benzoate (8.47 g, 26.6 mmol) and yttrium(III) trifluoromethanesulfonate (800 mg, 1.33 mmol) was dissolved in dry tetrahydrofuran (100 mL), and then cooled below 0° C. Isobutyl aldehyde (2.30 g, 31.9 mmol) was added below 0° C. The reaction mixture was stirred at room temperature overnight. Thin layer chromatography showed most of starting material was consumed. 50 mL of ethyl acetate and 50 mL of water were added to the mixture, and the separated organic layer was washed with brine again. The organic layer was dried over sodium sulfate and purified on silica gel to afford 4.9 g of methyl 2-(4-chloro-3-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield=47%). MS (ESI+APCI) M+1=373.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10]>C(N(CC)CC)C.[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncnc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncnc1
Reaction time: 0.25 h

Procedure:
Dissolve 5-bromopyrimidine (50.0 g, 314.4 mmol) in triethylamine (400 mL), add copper (1) iodide (1.20 g, 6.2 mmol) and stir mixture under nitrogen. After 15 min., add trimethylsilyl acetylene (53.3 mL, 377.3 mmol), followed by dichlorobis(triphenyl-phosphine) palladium (11) (8.82 g, 12.5 mmol) and stir at RT. After 3 h, filter the solution through Celite®, rinsing with ether. Concentrate the filtrate under reduced pressure. Purification by flash chromatography on silica gel eluting first with hexanes (100%), then with hexanes:EtOAc (3:1) gives the title compound: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 8.77 (s, 2H), 0.27 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH2:17][C:18]2[N:19]=[CH:20][N:21]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]=2[CH3:23])[C:15](=[O:16])[N:6]2[C:7]3[C:12]([C:13]([CH3:14])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH-].[Na+].C([OH:47])C>O1CCOCC1>[CH3:1][C:2]([CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:22]=1[CH3:23])([CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH3:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:15]([OH:47])=[O:16]
Reactant: CCO
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C)(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(CCC(C)(Cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C)C(=O)O)[nH]c2ccccc12
Temperature: 90 °C

Procedure:
A mixture of 8,9-dihydro-7,10-dimethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (3.78 g), aqueous 3N sodium hydroxide solution (10 ml), ethanol (10 ml) and dioxane (5 ml) was heated at 90° C. for 30 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with aqueous oxalic acid solution, and extracted three times with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-methyl-4-(3-methylindol-2-yl)-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]butyric acid (3.3 g) as an amorphous powder. The product was used in the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]23[CH2:15][O:14][CH2:13][CH:12]2[CH2:11][O:10][NH:9]3)[CH:7]=1>C(O)(=O)C.[Zn]>[NH2:9][C:8]1([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:16])[CH2:15][O:14][CH2:13][CH:12]1[CH2:11][OH:10]
Reactant: Fc1ccc(Br)cc1C12COCC1CON2
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1(c2cc(Br)ccc2F)COCC1CO
Temperature: 40 °C
Yield: 86.8 %

Procedure:
Zinc powder (190 g, 2.91 mol) is added to a mixture of racemic (3aSR,6aSR)-6a-(5-bromo-2-fluorophenyl)hexahydrofuro[3,4-c]isoxazole (84 g, 290 mmol) in acetic acid (1.4 L) at a rate maintaining the temperature below 30° C. The reaction is heated at 40° C. for 5 h. The reaction is cooled to room temperature and is filtered through a pad of diatomaceous earth, washed with acetic acid and water (200 mL). The solvent is removed under reduced pressure. Water (500 mL) is added to the residue, and the pH is adjusted to pH 10 with 2 M aqueous sodium hydroxide. The basic aqueous suspension is extracted three times with 15% isopropyl alcohol in dichloromethane (3×500 mL). The combined organic layer is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the title compound as a white solid (73.0 g, 86%). ES/MS m/e (79Br/81Br) 290, 292 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([NH:48][C:49]2[CH:54]=[C:53]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][CH2:62][C:63]4[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=4)[N:56]=3)[C:52]([Cl:70])=[CH:51][N:50]=2)[CH2:44][CH2:43]1>CS(C)=O.CN1C(=O)CCC1>[Cl:70][C:52]1[C:53]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([NH:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([F:69])[CH:64]=3)[N:56]=2)=[CH:54][C:49]([NH:48][C@H:45]2[CH2:44][CH2:43][C@H:42]([NH:41][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH2:47][CH2:46]2)=[N:50][CH:51]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-(dimethylamino)acetic acid (6.05 mg, 0.059 mmol), NMP (0.5 ml), Huenig's Base (0.023 ml, 0.132 mmol), and HATU (24.55 mg, 0.065 mmol) was stirred at ambient temperature for 5 minutes, followed by addition of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine (Example 1) (12.5 mg, 0.029 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was diluted with 0.25 ml of DMSO, filtered, purified by prep LC and then lyapholized to yield 6.8 mg of the title compound, as a TFA salt. LCMS (m/z): 511.3 (MH+), retention time=0.62 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32-1.53 (m, 4H) 1.98-2.07 (m, 2H) 2.07-2.18 (m, 2H) 2.92 (s, 6H) 3.60-3.68 (m, 1H) 3.70-3.82 (m, 1H) 3.90 (s, 2H) 4.63 (s, 2H) 6.83 (d, J=8.79 Hz, 1H) 6.86 (s, 1H) 6.93 (d, J=7.03 Hz, 1H) 6.99 (s, 1H) 7.10 (d, J=9.67 Hz, 1H) 7.18 (d, J=7.62 Hz, 1H) 7.28-7.40 (m, 1H) 7.68-7.77 (m, 1H) 8.01 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(F)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(F)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
To a solution of 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (53 mg, 0.203 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (78 mg, 0.203 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.18 ml, 1.02 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (95 mg, 0.203 mmol) in one portion. The solution stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (106 mg, 0.129 mmol, 63.5% yield) as a clear oil; LCMS (ES) m/e 591, 593 (M, M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=C[C:17]=2OC)[C:10]1=[O:24].C([NH:28]C1C=NC=CC=1)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[N:28][CH:19]=[CH:20][CH:21]=2)[C:10]1=[O:24]
Reactant: C=CCNc1cccnc1
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCCN(c2cccnc2)C1=O

Procedure:
(S)-3-Amino-1-(pyridin-3-yl)azepan-2-one trifluoroacetate (36 mg, 0.11 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allylpyridin-3-amine in step A. Anal. Calcd. for C11H15N3O m/z 205.2. found: 206.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=[C:2]1[C:14]([O:16]C)=O.CO.[NH3:20].C(OCC)C>CN(C=O)C>[NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=[C:2]1[C:14]([NH2:20])=[O:16]
Reactant: COC(=O)c1cc2c([nH]1)-c1ccncc1CC2
Reactant: N
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1cc2c([nH]1)-c1ccncc1CC2
Yield: 50 %

Procedure:
A solution of methyl 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-2-carboxylate L1 (0.44 mmol) in DMF (5 mL), MeOH (5 ml) and 30% aq NH3 (10 mL) was heated at 80° C. in a close vessel for 8 h. The solvent was evaporated, the residue was dissolved with DCM and washed with water. The organic layer was dried (Na2SO4) and concentrated to provide, after trituration with diethylether, the title compound (50% yield). ESI (+) MS: m/z 214 (MH+). 1H NMR: 2.69 (m, 2H), 2.84 (m, 2H), 6.72 (d, J=2.19, 1H), 7.08 (bs, 1H), 7.74 (d, J=5.12, 1H), 8.33-8.44 (2m, 2H), 12.01 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][O:32][C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[C:39]=[O:40])=[CH:35][CH:34]=1>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:39]([NH:38][CH2:37][C:36]4[CH:41]=[CH:42][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[O:40])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: COc1ccc(CN=C=O)cc1
Product: COc1ccc(CNC(=O)NC[C@H]2C[C@@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(4-methoxy-benzyl)-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 4-methoxybenzyl isocyanate (Aldrich, Buchs, Switzerland). Analytical HPLC: tR=7.21 min (Grad 2); ES-MS: m/eo=562.9.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1.I[CH3:19]>CN(C=O)C.[Cl-].[NH4+]>[CH3:19][N:10]1[CH2:9][CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][C:4]1=[O:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCNC(=O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 1 h

Procedure:
Sodium hydride (103 mg) was added to a stirred solution of tert-butyl hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate in DMF (5 mL) at 0° C. After 1 h, iodomethane (0.15 mL) was added, and the resultant mixture was stirred at 0° C., then room temperature overnight. It was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to give the product, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:6]1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[NH:24][N:23]=[N:22][N:16]=3)=[CH:11][N:10]=2)[CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OC2CN(c3cnc(-c4nnn[nH]4)cn3)C2)c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carbonitrile (0.48 g, 1.36 mmol), sodium azide (0.18 g, 2.7 mmol), and ammonium chloride (0.73 g, 1.36 mmol) in DMF (4 mL) was heated at 130° C. After a period of 4 h, the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The resulting solid was filtered and washed with water and ether. The solid was taken up in toluene and the solvent evaporated to provide the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:18][CH3:19])[CH:8]=2)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].CCO>O>[Cl:17][CH2:16][CH2:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:18][CH3:19])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2
Reactant: COC(=O)c1cc2cc(OCCCl)c(OC)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: COc1cc2[nH]c(C(=O)O)cc2cc1OCCCl
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of ester 17 (2.00 g, 7.05 mmol), Cs2CO3 (3.45 g, 10.6 mmol), 95% EtOH (40 mL), and water (20 mL) was heated at reflux for 8 h. After cooling to room temperature the solvent was removed in vacuo, the residue was treated with water (50 μL), and the resulting solution was acidified with 2 M HCl. The formed precipitate was isolated by filtration, washed with water (100 mL), and dried in vacuo to give 18 (1.80 g, 95%) as a beige solid. 1H NMR (300 MHz, DMSO-d6): δ=3.81 (s, 3 H, OMe), 3.93 (t, J=5.3 Hz, 2 H, 2′-H2), 4.21 (t, J=5.3 Hz, 2 H, 1′-H2), 6.91 (s, 1 H, 7-H), 6.96 (d, J=2.1 Hz, 1 H, 3-H), 7.15 (s, 1 H, 4-H), 11.44 (sbr, 1 H, NH), 12.57 (sbr, 1 H, CO2H) ppm; 13C NMR (50.3 MHz, DMSO-d6): δ=43.0 (C-2′), 55.6 (OMe), 69.5 (C-1′), 94.9 (C-7), 105.8 (C-4), 107.5 (C-3), 119.8 (C-3a), 126.8 (C-2), 133.0 (C-7a), 143.9 (C-5), 149.5 (C-6), 162.4 (C═O) ppm; MS (70 eV, EI): m/z (%)=269 (100) [M]+, 206 (58) [M-(CH2)2Cl]+; C12H12ClNO4 (269.68): calcd. C, 53.44; H, 4.49; found C, 53.54; H, 4.29.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([Cl:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[F:17][B-](F)(F)F.[H+]>Cl>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[C:6]([F:17])[CH:7]=[CH:8][C:9]=1[Cl:16]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: F[B-](F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Product: COC(=O)c1cc(F)ccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of NaNO2 (3.69 g, 53.4 mmol in 50 mL water) was added dropwise to a stirred suspension of methyl 5-amino-2-chlorobenzoate (9 g, 48.5 mmol) in HCl (10%, 90 mL), keeping the temperature between 0-5° C. The reaction mixture was stirred for 10 min. and a solution of fluoroboric acid (70%, excess) was added to the mixture. The precipitate of diazonium fluoroborate salt was filtered, washed with water and dried. The pyrolysis of this salt was then carried out at 140° C. for 15-20 min. The residue was purified using a silica gel column and 10% CHCl3 in petroleum ether (60-80° C.) as an eluant to furnish the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:13]([C:14]([O:16]C)=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
The product of Step A above is suspended in 8.0 ml. of aqueous sodium hydroxide (5%) and refluxed for 30 minutes. The mixture is acidified with aqueous hydrochloric acid and extracted three times with 15.0 ml. of toluene. The combined toluene extracts are concentrated to afford 2.3 mmole of 5-(2,4-difluorophenyl)salicylic acid.