Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)Br)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1C[O:18]CC1.O>[N+]([O-])([O-])=O.[Ag+].C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:18])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1C(Br)Br
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
Combine 4-bromo-1-(dibromomethyl)-2-(trifluoromethyl)benzene (6.66 g, 16.8 mmol), silver nitrate (14.8 g, 87.3 mmol), THF (250 mL), and water (35 mL) in a 500 mL flask equipped with a magnetic stir bar, reflux condenser, and N2 inlet. Reflux the mixture while stirring for 2.5 hours then cool to room temperature. Filter the reaction through Celite®, add ethyl acetate (250 mL) and wash with water (2×200 mL) then saturated aqueous sodium chloride solution (1×200 mL). Dry over anhydrous magnesium sulfate, concentrate to an orange oil, and purify the crude product via silica gel chromatography eluting with hexanes to afford 3.46 g (81%) of the product as a clear oil: 1H NMR (300 MHz, CDCl3) δ 10.35-10.33 (m, 1H), 8.0 (d, 1H, J=8.3 Hz), 7.93 (d, 1H, J=1.4 Hz), 7.86 (dd, 1H, J=1.2 Hz, J=8.3 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]=[C:16](NN)[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]([NH2:28])=[O:27].O.Cl>CN1C(=O)CCC1>[F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:25]=[C:26]([OH:27])[N:28]=[C:16]4[C:15]=3[CH2:22][CH2:23][CH3:24])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1NN
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(O)nc12
Temperature: 160 °C
Reaction time: 6 h

Procedure:
To the solution of 131 (3.27, 10 mmol) in anhydrous NMP (3.6 mL) under nitrogen is added urea (1.60 g, 26 mmol). The resulting mixture is heated to 160° C. and stirred for 6 hours. On cooling, the reaction mixture is poured into water (80 mL), pH is adjusted to 7 with hydrochloric acid, and the solution is extracted with dichloromethane (50 ml×4). The organic solution is dried with anhydrous sodium sulfate and concentrated to give the crude product 177 as an oil which is used directly in the next step reaction.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:22][C@@H:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24](O)=[O:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:24](=[O:25])[CH:23]([OH:22])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.3, 28.1, 35.2, 35.3, 47.1, 51.9, 52.7, 56.4, 79.9, 105.0, 131.0, 137.6, 169.3, 170.1, 173.1; MS m/z 411.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[Cl:10][C:11]1[C:20]([NH2:21])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][N:15]=[CH:16]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][C:3]([NH:21][C:20]1[C:11]([Cl:10])=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[N:15][CH:14]=[CH:13]2)=[O:5]
Reactant: Nc1ccc2cnccc2c1Cl
Reactant: O=C(O)CCl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CCl)Nc1ccc2cnccc2c1Cl
Reaction time: 4 h

Procedure:
To chloroacetic acid in DMF is added EDC, DMAP and 5-chloro-6-aminoisoquinoline. This mixture is stirred for 4 hours. The reaction is washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gives 2-chloro-N-(5-chloro-isoquinolin-6-yl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](Cl)=[N:7][OH:8])=[CH:4][CH:3]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[C:18](/N1CCCC1)\[CH3:19])=[O:16].C(N(CC)CC)C>C(O)C>[CH2:13]([O:14][C:15]([C:17]1[C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:7][O:8][C:18]=1[CH3:19])=[O:16])[CH3:12]
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C(\C)N1CCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Yield: 69.8 %

Procedure:
To a suspension of 4-chloro-N-hydroxy-benzimidoyl chloride (1.11 g, 5.88 mmol) in dry ethanol (9 ml) was added a solution of ethyl (E)-3-(1-pyrrolidino)crotonate (1.08 g, 5.88 mmol) and triethylamine (492 μl, 3.53 mmol) in dry ethanol (9 ml) over a period of twenty minutes at room temperature. The suspension was stirred for eighteen hours before the mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic layer was washed with 0.5 N HCl and brine, before it was dried and concentrated in vacuo. The residue was purified by flash column chromatography with a gradient of ethyl acetate and hexanes on silica gel (40 g) to give the title compound as a white solid (1.09 g): 1H NMR (CDCl3, 200 MHz): δ=7.57 (m, 2H), 7.42 (m, 2H), 4.25 (q, J=7.0 Hz, 2H), 2.74 (s, 3H), 1.27 (t, J=7.0 Hz, 3H); MS: (+) m/z 266.31 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:30][CH2:29][CH2:28][O:27][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COCCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COCCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 2-methoxyethylamine.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([C:9]2([CH:19]([CH3:21])[CH3:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[C:22]([OH:25])(=[O:24])[CH3:23].BrC1C=[C:29]([C:33]2(C(C)C)C3C(=CC=CC=3)[C:35]([NH2:42])=[N:34]2)[CH:30]=CC=1.N1C=C(B(O)O)C=NC=1>>[C:22]([OH:25])(=[O:24])[CH3:23].[CH:19]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:29]3[CH:33]=[N:34][CH:35]=[N:42][CH:30]=3)[CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[N:10]1)([CH3:21])[CH3:20]
Reactant: CC(C)C1(c2cccc(Br)c2)N=C(N)c2ccccc21
Agent: Cl
Agent: OB(O)c1cncnc1
Solvent: CC(=O)O
Product: CC(C)C1(c2cccc(-c3cncnc3)c2)N=C(N)c2ccccc21
Yield: 81 %

Procedure:
The title compound was prepared as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-isopropyl-1H-isoindol-3-amine hydrochloride (Example 89, Scheme #16, P) (15.0 mg, 0.0410 mmol), 1-(3-bromophenyl)-1-isopropyl-1H-isoindol-3-amine acetate (Scheme #17, Q) (6.5 mg, 0.0167 mmol) and pyrimidine-5-ylboronic acid (15.9 mg, 0.128 mmol) to give 18.2 mg (81% yield): 1H NMR (DMSO-d6) δ 9.19 (d, J=2.14 Hz, 1 H), 9.10 (d, J=2.14 Hz, 2 H), 8.06 (d, J=1.23 Hz, 1 H), 7.85 (d, J=8.58 Hz, 1 H), 7.73 (t, J=9.19 Hz, 2 H), 7.62 (d, J=7.66 Hz, 1 H), 7.48-7.31 (m, 3 H), 3.02-2.91 (m, 1 H), 1.89 (s, 3 H), 0.86 (d, J=6.74 Hz, 3 H), 0.43 (d, J=6.43 Hz, 3H); MS (ES) m/z 329 [M+1]+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[CH2:7]([N:14]1[CH2:20][CH2:19][CH:18](Cl)[CH:17]([CH:22]=O)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]2[CH:22]=[N:5][C:4]([NH2:6])=[N:3][C:18]=2[CH2:19][CH2:20]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CC1CCN(Cc2ccccc2)CCC1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1ncc2c(n1)CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4.60 g (0.20 mol) sodium are dissolved in 250 ml of ethanol and at room temperature combined with 5.90 g (0.10 mmol) guanidine hydrochloride and 24.97 g (0.10 mol) 1-benzyl-5-chloro-azepan-4-carbaldehyde. Then the mixture is refluxed for 5 h, then stirred for 15 h at room temperature. It is then concentrated by evaporation i.vac., combined with 500 ml dichloromethane and washed 3 times with 400 ml of water. It is purified by chromatography through silica gel (eluant: dichloromethane/methanol 95:5), concentrated by evaporation i.vac. And triturated with ethanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([NH2:27])[N:21]=1.Cl>CS(C)=O>[NH2:19][C:20]1[N:25]=[C:24]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])=[CH:15][CH:16]=2)[CH:23]=[C:22]([NH2:27])[N:21]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Nc1cc(Cl)nc(N)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
N-(4-Hydroxymethyl-benzyl)-2,2,2-trifluoro-acetamide (12.0 g, 52 mmol) is dissolved in 80 ml dry DMSO, and NaH (4.08 g, 102 mmol, suspension 60% in mineral oil) is added in portions over 30 min under an argon atmosphere. After stirring at room temperature for 1 h, 2,6-diamino-4-chloropyrimidine (7.52 g, 52 mmol) is added and the reaction mixture heated to 60° C. over night. After cooling to room temperature, the mixture is poured into 1 L of 1 N HCl, and the product extracted with ethyl acetate (500 mL). The combined organic phases are washed with water and brine, dried over MgSO4, and the solvent evaporated. The residue is purified by flash column chromatography (ethyl acetate/methanol 100:0 to 80:20) to yield the title compound as a colorless solid (4.7 g, 13.78 mmol, 27%). 1H-NMR (400 MHz, DMSO-d6): δ=9.99 (t, J=6.1, 1H, CONH), 7.34 (d, J=8.1, 2H, ArH), 7.26 (d, J=8.1, 2H, ArH), 6.02 (s br, 2H, NH2), 5.89 (s br, 2H, NH2), 5.16 (s, 2H, OCH2), 5.01 (s, 1H, 4-H), 4.36 (d, J=6.1, 2H, CH2NCO) ppm.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([C:23]([C:26]1[CH:30]=[C:29]([C:31]2[S:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:37]=3)=[CH:34][CH:35]=2)[N:28]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:52])[N:27]=1)([CH3:25])[CH3:24])=[N+]=[N-]>C1COCC1.O>[Cl:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[N:28]1[C:29]([C:31]2[S:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:37]=3)=[CH:34][CH:35]=2)=[CH:30][C:26]([C:23]([NH2:20])([CH3:24])[CH3:25])=[N:27]1
Reactant: CC(C)(N=[N+]=[N-])c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(N)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Yield: 89 %

Procedure:
PPh3 (3.3 g, 12.58 mmol) was added at rt to a solution of the 3-(2-azidopropan-2-yl)-1-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazole) (3.08 g, 6.185 mmol) in a mixture of THF—H2O (6:1, 70 mL), and the resulting mixture was stirred at it under N2 for 8d. The solvent was removed in vacuo, and the residue was partitioned between water and EtOAc. The two phases were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by flash chromatography (0-60% 20% MeOH/DCM) to give the title compound as a light-yellow solid (2.43 g, 89%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.83-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.56-7.41 (m, 5H), 7.19 9d, 1H), 6.72 9d, 1H), 6.63 (s, 1H), 3.07 (s, 3H), 2.43 (brs, 2H), 1.61 (s, 6H). MS(ES) 455 (M-NH2).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[C:9]([N:13]=[N:14][C:15](Cl)([CH3:24])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>O>[C:9]([N:13]=[N:14][C:15]([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:24])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CCOC(=O)CCC(C)(Cl)N=NC(C)(C)C
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)CCC(C)(N=NC(C)(C)C)OOC(C)(C)C
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of 2.32 grams (0.0352 moles) of 85% potassium hydroxide in 10 ml of water, cooled to 15° C. in a 50 ml erlenmeyer flask was added 4.5 grams (0.045 moles) of 90% t-butyl hydroperoxide slowly and with rapid stirring. After the addition was complete, the reaction was stirred for 15 minutes at 15° C. and then 8.32 grams (0.032 moles) of allyl 4-t-butylazo-4-chlorovalerate was added dropwise over a 15 minute period holding the temperature at 15°-20° C. After the was complete the reaction was stirred for 90 minutes at 0°-5° C. A one gram portion of 50% NaOH was then added and the reaction stirred for 15 minutes to remove the excess t-butyl hydroperoxide. Ice water was then added until the potassium chloride dissolved. The mixture was extracted with 25 ml cold pentane, the pentane extract washed with ice cold water, saturated NaHCO3 solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure at 10° C. to leave 6.6 grams (66% yield) of crude allyl 4-(t-butylazo)-4-(t-butylperoxy)valerate. The product was stored in a dry ice chest.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[CH2:33][CH2:34][S:35][Si](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>CO>[SH:35][CH2:34][CH2:33][C:32]1[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(C(=O)N(C)C)ccc1CCS[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)N(C)C)ccc1CCS
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Citric acid monohydrate (110 mg, 0.523 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) were added to a solution of 3,N,N-trimethyl-4-(2-triphenylsilanylsulfanyl-ethyl)-benzamide (767 mg, 1.59 mmol) in MeOH (27 ml) at room temperature, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in dichloromethane. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-(2-mercapto-ethyl)-3,N,N-trimethyl-benzamide (351 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[Cl:17][C:18]1[CH:19]=[C:20]([C@H:24]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=2[F:39])=[O:29])[CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=1>>[NH2:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][C:30]([C:28]([NH:27][C@@H:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)[CH2:25][OH:26])=[O:29])=[C:31]([F:39])[CH:32]=2)=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:15])[N:12]([CH3:14])[CH2:13]2)=[CH:6][N:7]=1
Reactant: CN1CC(c2cnc(N)c(Br)c2)CCC1=O
Reactant: O=C(N[C@H](CO)c1cccc(Cl)c1)c1ccc(B(O)O)cc1F
Product: CN1CC(c2cnc(N)c(-c3ccc(C(=O)N[C@H](CO)c4cccc(Cl)c4)c(F)c3)c2)CCC1=O

Procedure:
Following Step 6 in Scheme 47, using 5-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one and (S)-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)boronic acid, 4-(2-amino-5-(1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained (33%). LCMS (m/z): 497.2 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.70 (m, 1H), 7.98 (m, 1H), 7.88 (m, 2H), 7.44 (m, 3H), 7.36 (m, 2H), 7.30 (m, 1H), 5.19 (m, 1H), 3.88 (m, 2H), 3.51 (m, 2H), 3.21 (m, 1H), 2.97 (s, 3H), 2.50 (m, 2H), 2.07 (m, 2H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), EtOH+0.1% DEA=40%, 5 ml/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=2.22 min. LCMS (m/z): 497.2 (MH+), 0.61 min. The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was obtained at Rt=3.09 min. LCMS (m/z): 497.3 (MH+), 0.59 min.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH3:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH2:25]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Solvent: Cc1ccccc1
Product: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1Cl
Temperature: 120 °C
Yield: 98 %

Procedure:
68.3 gm of 2-chloro-4-nitro-1,3-diphenoxy-benzene were dissolved in 300 ml of toluene, and the solution was admixed with 100 ml of concentrated aqueous ammonia in an autoclave. The autoclave was then closed, the internal pressure was increased to 3 bar with gaseous ammonia, and the contents were heated for 12 hours at 120° C., whereby the internal pressure rose to about 13 bar. Thereafter, the contents were allowed to cool, and the organic phase was separated, extracted with dilute hydrochloric acid, dried with sodium sulfate and the toluene was distilled off. The reaction product was obtained with virtually quantitative yield (54 gm). Gas-chromatographic analysis revealed that the reaction product contained 98% of the title compound, m.p. 81°-82° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[O:23][CH3:24])[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2OC)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2OC)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(2-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide (232 mg, 696 μmol) in a mixture of MeOH (30 mL) and AcOH (2.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 50° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate H4 as an impure oily liquid; Rt 1.08 min (Method 2); m/z 304 (M+H)+ (ES+). This material, containing residual acetic acid was used directly, without further purification, in the next step (below).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)[N:6]=[CH:5][CH:4]=1)#[N:2].OO.NC(N)=[O:24].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][N+:6]([O-:24])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: CCn1cc(-c2nccc(C#N)c2C(=O)OC)cn1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCn1cc(-c2c(C(=O)OC)c(C#N)cc[n+]2[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (207 mg, 0.808 mmol) in ACN (2 mL) was added urea hydrogen peroxide (380 mg, 4.04 mmol) and trifluoroacetic anhydride (0.456 mL, 3.23 mmol) at 0° C. The resulting mixture was stirred at RT overnight. Next, saturated aq NaHCO3 solution and chloroform were added. The aqueous phase was extracted with chloroform (3×200 mL). The organic layers were combined and washed with brine, dried over MgSO4, and evaporated to give the title compound which was used without further purification (210 mg, 95%). [M+H] calc'd for C13H12N4O3, 273.5. found, 273.5.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].Cl.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]([CH3:14])[CH2:20]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A mixture of crude 1-(bromomethyl)-2-chloro-4-nitrobenzene (D102) (0.391 g), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (0.407 g, 1.72 mmol) and Hunig's base (0.625 mL, 3.59 mmol) in dry DMF (3 mL) was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to give an orange oil which was dissolved in DCM and washed with water (×2) and brine, then dried and concentrated to give an orange oil. Purification by column chromatography eluting with 0-30% EtOAc/pentane gave the title compound as a yellow oil (0.199 g). δH (CDCl3, 400 MHz) 8.24 (1H, d), 8.12 (1H, dd), 7.77 (1H, d), 4.24 (1H, br.s), 3.85 (1H, d), 3.63 (2H, s), 3.14 (1H, td), 2.76 (1H, m), 2.59 (1H, m), 2.33 (1H, dd), 2.18 (1H, m), 1.47 (9H, s), 1.28 (3H, d). MS (ES): MH+ 370/372,
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[Br:29][CH2:30][CH2:31]Br>C1COCC1>[Br:29][CH2:30][CH2:31][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCCBr
Reactant: CCOC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(CCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF (85 mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0° C. for 30 min, cooled to a bath temperature of −65° C. and ethyl cyclopentanecarboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 h, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at −65° C. for 3 h and then was allowed to warm to room temperature overnight. After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with 1:1 brine:water (250 mL) and were dried (Na2SO4). The solution was filtered, concentrated in vacuo then the residue was diluted with toluene (100 mL) and concentrated. The dilution and concentration cycle was repeated twice to give ethyl 1-(2-bromoethyl)cyclopentanecarboxylate (52.5 g).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COc1cccc2oc(C(C)=O)cc12
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)c2oc(C(C)=O)cc12
Yield: 93 %

Procedure:
There was reacted 0.95 g (5 mmole) of 2-acetyl-4-methoxybenzofuran with chlorosulfonic acid as in Example 1, yielding 1.3 g of 2-acetyl-4-methoxy-7-chlorosulfonylbenzofuran (yield: 93%, MS (m/z): 288 (M+), 273, 253 and 189). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hydrochloride to give an ester compound (yield: 97%, MS (m/z): 354 (M+), 281, 252 and 188), which was then hydrolyzed to give 2-acetyl-4-methoxy-7-(N-carboxymethylsulfamoyl)benzofuran (yellow plates, yield: 84%). The physical constants are shown in Table 4.