Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([C@H:9]([CH2:14][O:15][C:16](=[O:28])[NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]([OH:13])=O)[CH3:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][CH2:69][C:70]1[CH:75]=[N:74][CH:73]=[CH:72][N:71]=1>CCOC(C)=O.CN(C=O)C>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([NH:17][C:16](=[O:28])[O:15][CH2:14][C@@H:9]([N:7]([CH3:8])[C:6]([NH:5][CH2:4][C:3]2[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:2]=2[Cl:1])=[O:29])[CH2:10][C:11](=[O:13])[NH:68][CH2:69][C:70]2[CH:75]=[N:74][CH:73]=[CH:72][N:71]=2)[N:19]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)O
Reactant: NCc1cnccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)CC(=O)NCc1cnccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a mixture of the crude (S)-3-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-(isoquinolin-3-ylcarbamoyloxy)butanoic acid (1.47 mmol) and DMF (5 mL) were added DIEA (0.512 mL, 2.94 mmol) and HBTU (0.667 g, 1.76 mmol). The resulting mixture was stirred at RT for 10 min and 2-aminomethylpyrazine (0.192 g, 1.76 mmol) was added. The resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (100 mL). The organic layer was washed by NaHCO3 solution and concentrated. The resulting residue was purified on silica gel column (DCM/MeOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-oxo-4-(pyrazin-2-ylmethylamino)butyl isoquinolin-3-ylcarbamate (0.65 g, 76.2%). LRMS (M+H+) m/z 580.1
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][CH:4]=[C:3]2[C:2]([F:1])([F:14])[F:15])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2c(C(F)(F)F)ccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 61 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-trifluoromethyl-quinolin-8-ylamine (Intermediate 469) (350 mg, 1.65 mmol), 2-nitrobenzenesulfonyl chloride (474 mg, 12.1 mmol), DMAP (cat), pyridine (2 ml) and DCM (5 ml) gave the title compound (400 mg, 60%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: S(C)C.[C:4]([Li])([CH3:7])([CH3:6])[CH3:5].[C:9]([NH:28][C@@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][C:4]([CH3:7])([CH:30]([OH:31])[C@@H:29]([NH:28][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:32][CH3:33])[CH3:6]
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added tert-butyl lithium (1.5 M in pentane, 8.0 mL, 4 eq, 12.0 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −55° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring, and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane: Et2O (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.47 g (40%). (53% de 3R,4S: 47% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.37 & 0.87 (2×t, 3H, J=7.46 Hz, —NHCH (CH2CH3)CH(C(CH3)3)OH), 0.58 & 0.71 (2×s, 9H, —NHCH(CH2CH3)CH(C(CH3)OH), 1.38-1.52 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.00 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.28 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 2.95 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 4.24 & 4.79 (2×d, 1H, J=5.21 & 6.16 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 7.15-7.53 (m, 15H, 3×Ph).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[C:12](=S)=[S:13]>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C

Procedure:
2-Amino-4-fluorophenol (1.21 g, 9.52 mmol) and potassium hydroxide (0.64 g, 11.4 mmol) were dissolved in carbon disulfide (15 mL) and EtOH (25 mL), and the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was suspended in 1 M aqueous HCl and collected by filtration. This was washed with 1 M aqueous HCl (2×) and water (2×) and was air-dried. This gave 1.115 g (69%) of the title compound as a yellow solid. LC-MS: RT=6.89 min., [M+H]+=169.9.
Reaction SMILES: C1(C[O:8][C:9](=[O:57])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:26]=[C:25]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:13]([CH2:12][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH:26]=[C:25]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:24]=1)[CH2:10][C:9]([OH:57])=[O:8])([OH:15])=[O:14]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCC(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 6.5 g of N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 1.5 g of 10% palladium on carbon in 200 ml of THF was stirred in a hydrogen atmosphere at room temperature for 2.5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane. Filtration gave 4.73 g (94% yield, mp 91°-94°) of N-(carboxymethyl)-N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]glycine.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:9]=[C:10]=[O:11])([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[CH2:14]([NH:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:15]>CCCCCC>[CH:17]1([N:16]([CH2:14][CH3:15])[C:10]([NH:9][C:6]([CH3:8])([CH3:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=2)=[O:11])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCNC1CCCCC1
Reactant: CC(C)(N=C=O)c1ccc(F)cc1
Solvent: CCCCCC
Product: CCN(C(=O)NC(C)(C)c1ccc(F)cc1)C1CCCCC1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of 1.8 g of p-fluoro-α,α-dimethylbenzyl isocyanate in 20 ml of n-hexane was added to 1.4 g of N-ethylcyclohexylamine, and the mixture was allowed to stand overnight. The solvent was then removed by distillation and the resulting crystals were washed with cold n-pentane to obtain 2.7 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)(O)[CH3:15].CS(O)(=O)=O.[NH4+].[OH-]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]([C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])=[CH2:15])=[N:18][CH:19]=1
Reactant: CN(C)CCc1sc2ccccc2c1C(C)(O)c1ccc(F)cn1
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: C=C(c1ccc(F)cn1)c1c(CCN(C)C)sc2ccccc12
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-(5-fluoro-pyridin-2-yl)-ethanol in (1.65 g, 4.79 mmol) in methylene chloride (30 mL) at room temperature, methanesulfonic acid (310 uL, 4.8 mol) was added dropwise and the reaction was allowed to stir for 2 hours. Additional methanesulfonic acid (3.1 mL, 47.9 mmol) was added and the reaction was stirred for 2 more hours. The reaction was neutralized with aq NH4OH and was extracted with methylene chloride. Organic layer was concentrated. The reaction mixture was chromatographed on silica gel with 9:1 DCM:MeOH as eluent to afford 923 mg of (2-{3-[1-(5-fluoro-pyridin-2-yl)-vinyl]-benzo[b]thiophen-2-yl}-ethyl)-dimethyl-amine (Compound 7-2) (59%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])=[O:15])=[C:9]([C:26](=[O:43])[NH:27][C:28]3[CH:32]=[CH:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[N:29]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[O:15])=[C:9]([C:26](=[O:43])[NH:27][C:28]3[CH:32]=[CH:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)[N:29]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzoate (300 mg, 0.51 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), water (5 mL), and lithium hydroxide hydrate (300 mg, 12.50 mmol, 24.62 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 2 with hydrochloric acid 1 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined, washed with 1×30 mL of brine, and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 300 mg of crude product as a gray solid.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:20][CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[O:28][C:27]([C:25]([N:23]3[CH2:24][CH:21]([O:20][C:2]4[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=4)[CH2:22]3)=[O:26])=[N:31][N:30]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
4-Hydroxybenzaldehyde (1.10 g, 9.17 mmol), cesium carbonate (3.49 g, 10.70 mmol) and 4B (2.70 g, 7.64 mmol) were mixed with DMF (80 mL). The mixture was stirred at 110° C. for 18 h then cooled to RT. The solids were filtered off and the filtrate was evaporated. The residue was treated with methanol and the solid formed was collected by filtration. Drying under vacuum gave 1.8 g (62%) of 9A as a beige solid. 1H NMR (500 MHz, DMSO-d6): δ 3.85 (s, 3H), 4.13 (dd, 1H), 4.57 (dd, 1H), 4.65 (dd, 1H), 5.12 (dd, 1H), 5.29 (m, 1H), 7.10 (d, 2H), 7.16 (d, 2H), 7.90 (d, 2H), 8.00 (d, 2H), 9.90 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](C3C=CC=CC=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH-].[K+].Br[CH2:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]C)=[O:36]>CN(C)C=O.CO>[C:1]1([N:8]2[C:9]([CH2:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: COC(=O)CCCC#CCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)CCCC#CCc1c(-c2ccccc2)nc(-c2ccccc2)n1-c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 2,4,5-triphenylimidazole (1.07 g) in dimethyl-formamide (20 ml) was treated with sodium hydride 50% in oil (0.17 g) and methyl 7-bromohept-5-ynoate (0.95 g). The solution was stirred for 18 hours when the solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluted with chloroform-hexane to give a clear oil which was dissolved in methanol (20 ml) and treated with 10% potassium hydroxide solution (10 ml) for 2 hours. The methanol was removed under reduced pressure and the remaining aqueous was acidified (pH 3) and filtered. The filtrate was extracted with chloroform (3×50 ml). The chloroform extracts were dried over magnesium sulphate, filtered and the solvent removed to give a solid which was recrystallised from acetonitrile to give 7-(1,2,4-triphenyl-imidazolyl)-hept-5-ynoic acid as white prisms, m.p. 144°-145° C.; Found: C, 79.99; H, 5.81; N, 6.40% (C28H24N2O2);Requires: C, 79.97; H, 5.75; N, 6.66%
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[C:2]=[S:3].Cl.[CH:15]([NH2:17])=[NH:16].[OH-].[Na+]>C1COCC1>[NH2:17][CH:15]=[N:16][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[S:3]
Reactant: COc1ccc(N=C=S)cc1OC
Reactant: N=CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NC(=S)N=CN)cc1OC
Reaction time: 3 h

Procedure:
A mixture of 10 g (51.2 mmol) 4-isothiocyanato-1,2-dimethoxybenzene in 51 ml THF at 0° C. was treated with 5.1 g (63.3 mmol) formamidine hydrochloride and 63.3 ml 1N NaOH and allowed to stirr for 3 h after which the mixture was concentrated. 500 ml ethyl acetate and 100 ml water was added and the precipitate was filtered off and dried to yield the intermediate 1-[1-Amino-methylidene]-3-(3,4-dimethoxy-phenyl)-thiourea (MH+ 240.2) which was used without further purification. The thiourea was taken up in 50 ml THF and treated with 8.55 g (51.2 mmol) ethyl bromoacetate and 14.2 ml NEt3 and stirred at room temperature for 16 h and at 50° C. for 8 h. The mixture was concentrated and extracted with CHCl3. The organic layer was washed with aqueous Na2CO3 (1M) and saturated NaCl solution, dried with MgSO4 and evaporated. The residue was purified with reversed phase preparative HPLC to yield 4.04 g (26%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13]OCC1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:9])[C:13]2[CH:8]=[CH:2][CH:3]=[CH:4][C:5]=2[NH2:6])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1

Procedure:
A mixture of benzoxazine-2,4-dione (1.6 g, 10 mmol) and 4-chloroaniline (2.5 g, 20 mmol) in 1,4-dioxane (30 mL) was heated at reflux for 15 hours. After cooling the solid was filtered, and the filtrate was concentrated, washed with ethyl ether. The washing was concentrated further to a solid. Additional washing with cold ethyl ether (10 mL) afforded N-(4-chlorophenyl)-2-aminobenzamide as a tan solid; NMR (DMSO-d6) 10.1 (s, 1), 7.8 (d, 2), 7.6 (d, 1), 7.4 (d, 2), 7.2 (t, 1), 6.8 (d, 1), 6.6 (t, 1), 6.3 (s,2) ppm.
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:12]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:16]([C@@H:25]([CH:34]3[CH2:36][CH2:35]3)[CH2:26][NH:27][S:28]([CH:31]3[CH2:33][CH2:32]3)(=[O:30])=[O:29])[C:15](=[O:37])[C@@:14]([CH2:41][CH3:42])([CH2:38][CH:39]=[O:40])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C([OH:47])(C)(C)C.C1COCC1>O.OP([O-])(O)=O.[K+]>[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:12]2[C@@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]([C@@H:25]([CH:34]3[CH2:36][CH2:35]3)[CH2:26][NH:27][S:28]([CH:31]3[CH2:32][CH2:33]3)(=[O:30])=[O:29])[C:15](=[O:37])[C@:14]([CH2:38][C:39]([OH:47])=[O:40])([CH2:41][CH3:42])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)O
Reactant: CC[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CNS(=O)(=O)C2CC2)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium chlorite (58.9 mg, 0.651 mmol) in 0.25×1.25 M potassium phosphate monobasic in water (1 mL) at 0° C. was added to a clear solution of N—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide (Example 254, Step C, 94 mg, 0.163 mmol) in 1.25 M potassium phosphate monobasic in water (1 mL)+t-butanol (1 mL)+2 M 2-methylbut-2-ene in THF (4.07 mL, 8.14 mmol). After stirring at ambient temperature for 4 hours, the reaction was quenched with 0.6 mL of 1 M sodium thiosulfate solution. After stirring for 10 min at ambient temperature, the mixture was acidified with 1.2 mL of 1 M potassium bisulphate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water then sat. aq. NaCl solution and dried over sodium sulfate. Purification by reverse phase HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 20% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) afforded the title compound.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, is charged with 50 mL of DMF, 3.50 g (10 mmol) of (R)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 6.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture is stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicates complete reaction. The mixture is transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture is then added hexanes, 50 mL. The formed white solid is collected by filtration to afford the title compound of Formula 203 (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers are separated and the organic is concentrated to dryness. The residue is chromatographed to afford an additional yield of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C.CCCCCC>O1CCCC1.C(OCC)(=O)C>[CH3:15][N:16]([CH3:17])[S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(S(=O)(=O)N(C)C)cc2s1
Yield: 93 %

Procedure:
A solution of Compound 2 (5.0 g, 20.2 mmol) from step (b) of Example 1 dissolved in tetrahydrofuran (THF, 30 ml) was added drop wise to a mixture of 2M N,N-dimethyl amine in THF (12 mL, 24.2 mmol) and triethylamine (5.6 ml, 40.4 mmol). The resultant mixture was stirred at room temperature for 3 hours. Solvents were removed by rotary evaporation and the residue thus obtained was partitioned between chloroform (100 ml) and water (100 ml). The organic layer was then washed with water (2×, 100 ml) and brine (1×, 100 ml), dried over sodium sulfate and evaporated. The oily residue thus obtained was dissolved in ca. 5 ml of hot ethyl acetate and this solution was then slowly added to 45 ml hexane. The mixture was cooled in the refrigerator overnight and the white solid that precipitated was collected, washed with hexane and dried to yield 4.8 g (93%) of Compound 24 whose structure is given below:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=1.[OH-].[Na+].[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:36][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]3)=[CH:35][CH:34]=2)=[O:16])=[N:11][N:10]=1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1nnc(Nc2ccccc2F)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCN(c2ccc(NC(=O)c3nnc(Nc4ccccc4F)o3)cc2)CC1
Reaction time: 1 h
Yield: 43.9 %

Procedure:
Ethyl 5-[(2-fluorophenyl)amino]-1,3,4-oxadiazole-2-carboxylate (Intermediate 40, 94 mg, 0.37 mmol) was stirred in water (1 mL). Sodium hydroxide (37 mg, 0.925 mmol) was dissolved in water (0.5 mL) and added to the reaction mixture. After stirring for 1 h the reaction was concentrated in vacuo to give a yellow solid which was dissolved in DMF (1 mL). [4-(4-Isopropylpiperazin-1-yl)phenyl]amine (WO02/057261) (89 mg, 0.41 mmol) dissolved in DMF (1 mL), HOBt (100 mg, 0.74 mmol), and EDAC (142 mg, 0.74 mmol) were added. The reaction was allowed to stir for 3 h then water (20 mL) was added and the reaction mixture thoroughly shaken to give a precipitate. After filtration and drying under in vacuo the title compound was obtained as a cream solid (69 mg, 44%):