Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[C@@H:18]([C:19]([OH:21])=O)[CH2:17][CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([C:19]([C@H:18]3[CH2:17][CH2:16][C:13]4([CH2:15][CH2:14]4)[CH2:12][C@@H:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[O:21])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)[C@H]1CCC2(CC2)C[C@@H]1C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1CC2(CC[C@@H]1C(=O)N1CCN(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(5S,6S)-5-((benzyloxy)carbonyl)spiro(2,5)octane-6-carboxylic acid from step 7 (47 mg, 0.16 mmole) was dissolved in DMF (0.7 mL). To the solution, 1-phenylpiperazine (29 mg, 0.18 mmole) was added, followed by BOP (76 mg, 0.17 mmole). DIEA (53 mg, 0.41 mmole) was added after the mixture was stirred at r.t. for 10 min. The mixture was then stirred at r.t. overnight and quenched with sat'd NaHCO3 solution, extracted with EtOAc. The extract was washed with NaHCO3 sat'd solution, brine; dried over MgSO4. After filtration, the filtrate was concentrated. The resulting residue was purified by column chromatography to afford Benzyl(5S,6S)-6-((4-phenylpiperazin-1-yl)carbonyl)spiro(2.5)octane-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32](=[O:34])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(Cl)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3-chloro-4-fluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 480, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)O)cc2)C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)C1

Procedure:
In a similar manner to Referential Example 12 except for the use of 4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([N:22]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:42](=[O:43])[C:41]1[CH:45]=[CH:46][C:38]([Br:37])=[CH:39][CH:40]=1)[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 2 h

Procedure:
A solution of 5-benzyl-3-bromo-6-(1-{[2-(dimethylamino)ethyl]amino}propyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-4, 144 mg, 0.33 mmol, 1 equiv) and N,N-diisopropylethylamine (43 mg, 0.33 mol, 1 equiv) in dichloromethane (5 mL) was treated with 4-bromobenzoyl chloride (73 mg, 0.33 mmol, 1 equiv), and the resulting mixture was stirred under ambient conditions for 2 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, then brine, and dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 10% NH3-EtOH/CH2Cl2 gave N-[1-(5-benzyl-3-bromo-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (1-5) as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 10.9 (bs, 1H), 7.56 (m, 2H), 7.33 (m, 5H), 7.15 (m, 2H), 6.04 (d, J=15 Hz, 1H), 5.94 (m, 1H), 5.03 (d, J=15 Hz, 1H), 3.42 (m, 2H), 2.18 (m, 2H), 2.01 (m, 2H), 1.86 (s, 6H), 0.62 (m, 3H).
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:15]1)=O)(C)(C)C.C1COCC1.O>ClCCl>[NH2:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc2c1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2nc(N3CC(N)C3)sc2c1
Reaction time: 27 h
Yield: 87.8 %

Procedure:
85% phosphoric acid (0.23 mL, 1.96 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl)-1,3-benzothiazole-6-carboxylate obtained in Example (225b) (296 mg, 0.78 mmol) in dichloromethane (2 mL) at room temperature, followed by stirring for 27 hours. Then, THF (1 mL) and 85% phosphoric acid (0.23 mL, 1.96 mmol) were added, and the mixture was further stirred for five hours. Water was added to the reaction solution, and the mixture was washed with ethyl acetate. Then, a 1 N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 190 mg of the title compound as a milk white solid (87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12](=O)N(C)C)=[C:7]([Cl:17])[CH:6]=1.C[O-].[Na+].[Br:22][C:23](Br)(C)[CH3:24]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:24][CH2:23][Br:22])=[C:7]([Cl:17])[CH:6]=1
Reactant: CC(C)(Br)Br
Reactant: COC(=O)Cc1ccc(SC(=O)N(C)C)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(SCCCBr)c(Cl)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-4-dimethylcarbamoylthiophenyl acetic acid methyl ester (10.028 grams; 34.848 mmol) in dry MeOH (90 mL) was treated with a solution of sodium methoxide (4.37 M; 11.16 mL; 48.788 mmol). The reaction was refluxed for 2 hours. The reaction mixture was cooled to 20 ° C. and transferred to a dropping funnel. The dropping funnel was placed atop a flask containing a solution of dibromopropane (14.15 mL; 139.392 mmol) in dry MeOH (50 mL). The contents of the dropping funnel were added to the flask dropwise, and the solution stirred for 2 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The layers were separated and the organic washed once with water. The organic was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography afforded 3-chloro-4-(3-bromopropyl)thiophenyl acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH2:66])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH2:32]([C:36]1[N:37]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[S:65](=[O:68])(=[O:67])[NH:66][C:5]([C@H:3]3[CH2:4][C:2]3([CH3:8])[CH3:1])=[O:6])=[CH:55][CH:54]=2)[C:38](=[O:51])[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)[C@H]2CC2(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of (S)-2,2-dimethylcyclopropanecarboxylic acid (194 mg, 1.70 mmol), and carbonyldiimidazole (275 mg, 1.70 mmol) in THF was stirred at 50° C. for 3 hrs. To this was added dropwise a solution of DBU (258 mg, 1.7 mmol) and 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (300 mg, 0.57 mmol) (from Example 16, Step C) in THF. After stirring at 50° C. overnight, the reaction mixture was quenched by addition of 5% citric acid and extracted with EtOAc. The organic layers were combined and washed with water, 5% NaHCO3, and brine, and dried over anhydrous Na2SO4. The crude material obtained after filtration and evaporation of volatiles was flash chromatographed over 60 mL silica gel (gradient elution using 0.5-5.0% MeOH/CH2Cl2) to afford the title compound in 74% yield (263 mg) as a white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 627 (M+1)+, 649 (M+Na)+ ; mp 93°-95° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH2:9])=[N:7][N:8]=1.[CH3:10][C:11](=O)[CH2:12][CH3:13].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6]([NH:9][CH:11]([CH3:10])[CH2:12][CH3:13])=[N:7][N:8]=1
Reactant: COCc1nnc(N)[nH]1
Reactant: CCC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)Nc1nnc(COC)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution (5 mL) of 5-(methoxymethyl)-4H-1,2,4-triazol-3-amine (0.3 g) and butan-2-one (0.25 mL) in acetic acid was added sodium cyanoborohydride (0.6 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.2 g, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].[CH3:29][CH2:30][O:31][C:32](C)=[O:33].O>C1COCC1.CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([NH:21][C:32]([O:31][CH2:30][C:29]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[O:33])=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 0 °C
Yield: 67 %

Procedure:
The 1-(tert-butoxycarbonyl)-4-(2,6-difluoro-4-nitrophenyl)piperazine (44.7 g, 130 mmol) was dissolved in 20% THF/MeOH (600 mL) in a 2 L flask. Ammonium formate (41 g, 651 mmol) was added portionwise, followed by 10% Pd-C (1.12 g, 2.5 weight %), with cooling in an ice bath. When the addition was completed the ice bath was removed. The flask became slightly warm, and the yellow color disappeared. The reaction mixture was filtered through Celite (washing the filter cake with 500 mL MeOH). The filtrate was concentrated under reduced pressure to give a solid which was then treated with 1 L EtOAc and 500 mL H2O. The layers were separated and then the organic layer was washed again with H2O (500 mL) and once with brine (500 mL). The aqueous portions were back-extracted with more EtOAc (2×300 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow solid. The crude material was recrystallized from hot EtOAc/hexane to afford 39.11 g (67%) of the title compound as a pale yellow crystalline solid with mp 171°-172° C.
Reaction SMILES: [CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2OS(C(F)(F)F)(=O)=O)[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([CH:36]=[O:37])C.[CH3:38][OH:39]>>[CH:1]([N:4]([C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:38]([O:37][CH3:36])=[O:39])[O:10][CH2:9]1)[CH2:5][CH2:6][CH3:7])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCCN(C(C)C)[C@H]1COc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN(C(C)C)[C@H]1COc2cccc(C(=O)OC)c2C1
Temperature: 70 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
(R)-3-(N-Isopropyl,N-n-propylamino)-5-trifluoromethanesulfonyloxychroman (4.0 g, 10.5 mmol), triethylamine (2.3 g, 23.1 mmol) and a mixture of DMF/MeOH (18 mL, 6:2) was mixed in a three necked round-bottom flask. The flask was evacuated followed by inlet of CO-gas (repeated two times). Finally 1,3-bis(diphenylphosphino)propane (0.11 g) and palladium(II)acetate (0.07 g) was added. The mixture was stirred at 70° C. for 17 hours. The reaction mixture was diluted with diethyl ether, washed with 2M NH3 and dried (MgSO4). Removal of solvent in vacuo gave a brown oily residue which was purified by flash chromatography (SiO2, CH2Cl2 /EtOAc; 10:1) to give the title compound in 82% yield (2.5 g). [α]D21 =-131.6° (MeOH, 0.1M) GC-MS(70 eV)=291 (M+), 262 (100%)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[Cl-].[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34](Cl)=O)[CH3:29].CC[O-].[Na+]>C1COCC1.CCO>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][C:34]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[CH3:29]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CCc1nc(O)c2ccc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (0.5 mmol) and pyridine (0.55 mmol) in THF (5 ml), add 3-chlorocarbonyl-propionic acid ethyl ester chloride (0.55 mmol). Stir the mixture for 20 minutes at room temperature, add 20 ml of 21% NaOEt in EtOH, and stir for 30 minutes at 50° C. Concentrate, add water, filter, acidify to pH 6, and collect the precipitate to give 3-[4-hydroxy-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-yl]-propionic acid ethyl ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>>[OH:10][C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: Ic1ccncc1
Reactant: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Product: CC(O)(c1ccncc1)c1ccc(-c2ccc(C#N)nc2)cn1
Yield: 18.4 %

Procedure:
Using 4-iodo pyridine (0.22 g, 1.076 mmol), and 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile (0.12 g, 0.54 mmol) and procedure described for example 7 and step 4, crude product was obtained. The crude product was purified by preparative TLC (5% methanol in ethyl acetate) to obtain 6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile as off-white solid (30 mg, 18% yield) in 98% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.94 (s, 1H), 8.46 (d, 2H), 8.38 (dd, 1H), 8.23 (dd, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.49 (d, 2H), 6.27 (s, 1H), 1.9 (s, 3H); LC-MS m/z calculated for [M+H]+ 303.12, found 303.1.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
To a stirring mixture of the 2-(4-tert-butylbenzoylamino)benzoic acid (9.5 g, 32 mmol), CH2Cl2 (200 mL) and 2 drops of DMF was added 2 M oxalyl chloride in CH2Cl2 (19 mL). After stirring at ambient temperature for 45 minutes, the mixture was concentrated under vacuum to an oil, redissolved in 100 mL CH2Cl2 and cooled to 0° C. To this was added triethylamine (3.3 g, 33 mmol) at 0° C. for 1 hour. The solvent was removed in vacuo and the residue purified by flash chromatrography using hexanes/EtOAc to give 8.6 g (96%) of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:5]2.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[Cl:42])=[O:32])[CH2:17][NH:18][C:19](=[O:29])[CH2:20][NH2:21])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNC(=O)CN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a solution of (S)-3-(2-tert-butoxycarbonylaminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (0.87 g, 1.37 mmol) in DCM (30.0 mL) was added TFA (3.0 mL). The mixture was stirred for 1 h. The mixture was concentrated and dissolved in EtOAc. The EtOAc solution was washed with Na2CO3, brine, dried over Na2SO4, and filtered. To the filtrate was added HCl (4 M in dioxane, 0.7 mL, 2.8 mmol). The organic solvent was removed under reduced pressure to give (S)-3-(2-aminoacetamido)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)propyl 6-fluoroisoquinolin-3-ylcarbamate (730 mg, 93%) as a HCl salt. LRMS (M+H+) m/z 535.2.
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[NH:24][N:23]=3)[N:20]=2)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[H-].[Na+].Cl.Br[CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH3:1][CH:2]([NH:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[C:30]4[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=4)[N:24]([CH2:44][CH2:45][N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)[N:23]=3)[N:20]=2)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH:14]=1)=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrCCN1CCCC1
Reactant: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCCC4)c4cc(F)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
2-(6-Fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide (70 mg, 0.13 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 14 mg, 0.385 mmol) was added and the reaction was stirred at 0° C. for 10 min. 1-(2-Bromoethyl)pyrrolidine hydrochloride (41 mg, 0.19 mmol) was added and teh reaction was stirred at 0° C. for 30 min then warmed to room temperature. The reaction mixture was stirred for 2 h then quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 75 mg (91%) of 2-[6-fluoro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methyl-2-pyridin-2-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=643.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][CH:29]([CH3:33])[C:30]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:31])(=[O:27])[CH3:26]
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Reactant: CC(=O)OC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(C)C(=O)NCCC1CCc2ccc3nc(C)oc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (150 mg, 0.593 mmol) and triethylamine (166 μL, 1.19 mmol) were dissolved in tetrahydrofuran (5 mL), 2-chloro-1-methyl-2-oxoethyl acetate (108 mg, 0.712 mmol) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) to give the title compound (78.4 mg, yield 40%).