Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[CH2:26])[CH2:3][N:4]([CH2:17][CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH:27]S(O)(=O)=O>C(Cl)Cl.O>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C:2](=[O:27])[CH2:3]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3, 6.6 g, 16.6 mmol) was dissolved in 40 mL CH2Cl2 and cooled to −78° C. The resulting solution was treated dropwise with conc. H2SO4 (20 mL) and H2O (2 mL). The reaction was placed in a 0° C. bath and stirred 1 h to completion. The reaction was diluted carefully with CH2Cl2 (200 mL) and H2O (400 mL) and the organic layer was separated, dried (MgSO4) and filtered. Concentration of the organic layer followed by flash column chromatography (SiO2, 0-100% EtOAc-hexanes graident over 40 min) provided 1-[(4-nitrophenyl)sulfonyl]-5-phenylpiperidin-3-one (1-4) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (m, 3H), 7.16 (m, 2H), 4.13 (d, J=15.9 Hz, 1H), 3.98 (m, 1H), 3.42 (d, J=15.9 Hz, 1H), 3.36 (m, 1H), 3.00 (dd, J=12.2, 10.4 Hz, 1H), 2.80 (m, 1H), 2.61 (dd, J=16.2, 11.3 Hz, 1H); MS 361.1 found 361.4 (M+H+) required (ionizes poorly).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C([O-])=O.[Na+].CN(C=O)C.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][N:22]=1>CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:8]([F:12])[F:13])=[CH:23][N:22]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Br)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
Potassium carbonate (2.4 g, 17.3 mmols) and sodium chlorodifluoroacetate (4.2 g, 27.5 mmols) were added to a DMF (20 mL) solution of 2-bromo-5-hydroxypyridine (2.4 g, 13.8 mmols) and stirred overnight at 80° C. The reaction liquid was cooled to room temperature, added ether, washed with water and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; hexane:ethyl acetate=100:1-100:2) to provide the title compound (1.32 g, 43%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2.CN(C)C=O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:8][C@H:9]([C:13]([O:15][CH2:32][C@H:33]([CH2:46][CH2:47][O:48][C:49](=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:34][N:35]1[CH:43]=[N:42][C:41]2[C:40](=[O:44])[NH:39][C:38]([NH2:45])=[N:37][C:36]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Yield: 39.3 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mmol) in dichloromethane (20 ml) was atirred over night at room temperature, dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0.205 mmol), and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, then on aluminum oxide (ethyl acetate methanol: water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:49])[CH2:14][C@@:15]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[O:34])[C@H:19]([CH3:20])[CH2:18][N:17]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:16]1)(C)(C)C>ClCCl>[Cl:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:22]=1[CH2:21][N:17]1[CH2:18][C@@H:19]([CH3:20])[C@@:15]([CH2:14][C:13]([OH:49])=[O:12])([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]2)[CH2:16]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 143.8 %

Procedure:
Trifluoroacetic acid (8 mL) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3c (320 mg, 0.518 mmol) in dichloromethane (dehydrated) (8 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (elution solvent: water/methanol) to give a mixture containing the title compound (344 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[ClH:42].[ClH:42].[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][NH:21][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NCCCN1CCOCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1, N-(3-aminopropyl)morpholine (0.365 mL, 2.50 mmol), 1-hydroxybenzotriazole monohydrate (333 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.75 mL, 6.82 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a free base of Compound 97. Then the free base of Compound 97 was dissolved in ethyl acetate (5.00 mL), and the solution was added with 4 moL/L hydrogen chloride-ethyl acetate solution (1.00 mL), followed by stirring at room temperature for 30 minutes. The precipitate in the reaction mixture was filtered to obtain Compound 97 (340 mg, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([O:34]C)=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>O1CCOCC1.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([C@@H:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[C:32]([OH:34])=[O:33])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)[C@@H]5CCC[C@H]5C(=O)O)cc4)cc3F)oc2c1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF (20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1H), 8.00-7.60 (m, 6H), 7.30 (d, 2H), 7.00 (d, 1H), 4.05 (m, 1H), 3.20 (m, 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m, 4H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([O:6][C:3]1[CH2:4][CH2:5][C:1](=[O:7])[CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)C1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C(OCc2ccccc2)CC1

Procedure:
A mixture of cyclopentane-1,3-dione (2.00 g, 20.4 mmol), benzyl alcohol (2.11 mL, 20.4 mmoL) and para-toluenesulfonic acid (35 mg, 0.20 mmol) in toluene (10.0 mL) is heated at reflux over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to cyclohexane/ethyl acetate 1:4). Yield: 1.66 g; ESI mass spectrum: [M+H]+=189; Retention time HPLC: 0.51 min (X012_S01).
Reaction SMILES: [NH2:1][C:2]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]2[C:20]([CH3:23])=[N:21][N:22]=[C:3]12.[CH3:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.O>O1CCCC1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]3[C:20]([CH3:23])=[N:21][N:22]=[C:3]3[C:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=3)=[O:38])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:8]=2)=[CH:14][CH:13]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)C1(N)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(NC(=O)Nc2cccc(C)c2)N=C(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21

Procedure:
In a nitrogen atmosphere, 4-amino-6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (373 mg) was dissolved in dry tetrahydrofuran (4 ml) and thereto was added 3-methylphenyl isocyanate (139 μl), followed by reaction at room temperature for 3.5 hours. After the completion of the reaction, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of citric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (chroloform:methanol=45:1) and crystallized to give 219 mg of N-[6-(4-chlorophenyl)-4-ethoxycarbonyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N'-(3-methylphenyl)urea as pale yellow needle crystals, mp. 168°-172° C.
Reaction SMILES: Br[CH2:2][CH:3](Br)[C:4](=O)[CH2:5][CH2:6][CH2:7][Cl:8].O.[NH2:12][NH2:13]>C(O)(C)C>[Cl:8][CH2:7][CH2:6][CH2:5][C:4]1[CH:3]=[CH:2][NH:13][N:12]=1
Reactant: NN
Reactant: O=C(CCCCl)C(Br)CBr
Solvent: CC(C)O
Solvent: O
Product: ClCCCc1cc[nH]n1
Reaction time: 16 h

Procedure:
To a solution of 1,2-dibromo-6-chlorohexan-3-one in isopropanol (80% solution in water, 30 mL) at ambient temperature was added hydrazine hydrate (8.4 g, 170 mmol). After 16 hours, the reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 3-(3-chloropropyl)-1H-pyrazole, which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:18][C:19]1[C:20](Cl)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]>CC#N>[Br:18][C:19]1[C:20]([N:4]2[CH2:5][CH:6]([CH3:8])[CH2:7][CH:2]([CH3:1])[CH2:3]2)=[C:21]([C:27](=[O:34])[C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:22]([CH3:26])=[N:23][C:24]=1[CH3:25]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: CC1CNCC(C)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(C)CC(C)C2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.7 %

Procedure:
To a solution of 3,5-dimethylpiperidine (1.1 g, 9.86 mmol) and DIEA (3.1 mL, 18 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.0 g, 8.87 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; cooled, concentrated, and charged (DCM) to a 120 g ISCO silica gel cartridge and gradient eluted (5-15% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-4-(3,5-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate 756 mg (20%) as a mixture of diastereomers. A sample of the product subjected to prep HPLC on Waters-Atlantis column (30×100 mm S5) running 15 min gradient from 10-100% B (MeOH/water/TFA), yielding two bands. The major isomer. 1H NMR (500 MHz, CDCl3) δ 5.21-5.14 (m, 1H), 2.87 (br. s, 4H), 2.70 (s, 3H), 2.41 (s, 3H), 1.77-1.71 (m, 3H), 1.29 (d, J=6.2 Hz, 6H), 0.85 (d, J=6.6 Hz, 6H), 0.68 (q, J=11.9 Hz, 1H). UPLC (M+H)=413.15.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N:39]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2)=[N+:40]=[N-:41]
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(CCO)c([N+](=O)[O-])cc1C2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCCc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)Nc2ncccc21
Temperature: 100 °C

Procedure:
To a stirred solution of (2S)-5-(2-hydroxyethyl)-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′-one from Step E (174 mg, 0.54 mmol) in DMF (4 mL) were added diphenyl phosphoryl azide (177 mg, 0.64 mmol) and DBU (0.096 mL, 0.64 mmol). The mixture was heated at 100° C. for 6 h, then quenched with H2O (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 80:20, to give the title compound. MS: m/z=351 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2R)-5-(2,5-dimethyl-1H-pyrrol-1yl)-2,3-dihydro-2-methyl-1H-indole (Step 2, 0.100 g, 0.442 mmol) in THF/H2O (8:1, 4.5 mL) is added sodium bicarbonate (0.072 g, 0.884 mmol) followed by benzyl chloroformate (80 μL, 0.53 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 mins and at ambient temperature for 2 h and is then concentrated under reduced pressure. The residue is taken up in CH2Cl2 (40 mL), washed with H2O (2×10 mL) and saline (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S 40 g silica gel cartridge (1% EtOAc/Hexanes) to give the title compound, MS (ESI+) for C23H24N2O2 m/z 361 (M+H)+.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29](F)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1.C12(CO)CC3CC(CC(C3)C1)C2.[CH2:48]1[C:50]2([CH2:55][CH2:54][CH:53]([CH2:56][OH:57])[CH2:52][CH2:51]2)[CH2:49]1>>[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:57][CH2:56][CH:53]3[CH2:54][CH2:55][C:50]4([CH2:48][CH2:49]4)[CH2:51][CH2:52]3)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Reactant: OCC1CCC2(CC1)CC2
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide and to replace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.61 g, 53%): 1H NMR (300 MHz, CDCl3) δ 8.70-8.57 (m, 1H), 8.17-8.09 (m, 1H), 6.76-6.66 (m, 1H), 4.32-4.19 (m, 4H), 3.96-3.87 (m, 2H), 2.35-2.20 (m, 2H), 2.03-1.70 (m, 5H), 1.39-1.20 (m, 2H), 1.02-0.86 (m, 2H), 0.38-0.16 (m, 4H); MS (ES+) m/z 431.1 (M+1), 433.1 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[C:49]#[N:50]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:50][CH2:49][C:48]3[CH:51]=[CH:52][CH:53]=[C:46]([C:45]#[N:44])[CH:47]=3)=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CN)c1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Agent: Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)NCc4cccc(C#N)c4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 3-(aminomethyl)benzonitrile-HCl.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]>CCCCCC>[Cl:9][C:10]1[CH:15]=[C:14]([N:6]2[CH:7]=[CH:8][C:4]([CH3:3])=[N:5]2)[CH:13]=[CH:12][C:11]=1[C:17]([N:19]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]2[N:30]=[CH:31][CH:32]=[CH:33][C:21]=2[CH2:20]1)=[O:18]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccnc2Nc2ccccc21
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(Cl)c2)n1
Reaction time: 2 h

Procedure:
Sodium hydride (60% suspension in oil, 1.8 g, 45.19 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (130 mL). Neat 3-methyl pyrazole (3.71 g, 45.19 mmol) was added dropwise at 0° C. After the gas evolution subsided the cooling bath was removed and stirring was continued at room temperature. The (2-chloro-4-fluorophenyl)-(5,11-dihydro-pyrido[2,3-b][1,5]benzodiazepin-6-yl)-methanone of Step D (8.11 g, 22.59 mmol) was added in one portion and the mixture was placed in an oil bath (preheated at 130° C.) for 2 hrs. After cooling, the mixture was partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate, and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 3:2) provided the desired product along with some mixed fractions containing the tide compound and its more polar 5-methylpyrazole regioisomer of Example 2. The title compound crystallized by sonication from hexane-ethanol as a white solid (6.4 g, 68%), m.p. 207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]3[N:34]([CH2:38][CH3:39])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:38]([N:34]1[C:33]2[C:40]([CH3:42])=[CH:41][C:30]([C:28]([C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:23]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37])[CH3:39]
Reactant: CCn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)cc(C)c21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc(C(=O)c3cc(N4CCC(N5CCc6cc(OC)ccc6NC5=O)CC4)ncn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
44 mg (0.20 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 50 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3-ethyl-4-methyl-3H-benzoxazol-2-one and 56 μL (0.30 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried.