Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Crude rac-6-chloro-3-hydroxy-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one (0.13 g, 0.43 mmol) (from Example 53a supra) was suspended in a mixture of triethylsilane (0.15 g, 1.29 mmol) (Aldrich) and trifluoroacetic acid (0.73 g, 6.48 mmol) and heated in an 80° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-isopropyl-phenyl)-1,3-dihydro-indol-2-one as a pale yellow solid. (Yield 0.11 g, 91%)
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[S:33]([CH3:32])(=[O:35])=[O:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1S(C)(=O)=O
Yield: 56.8 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 22, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-pyrrolidin-2-ylmethoxy]quinazoline (160 mg, 0.38 mmol), (prepared as described for the starting material in Example 13), was reacted with methanesulphonyl chloride (35 μl, 0.45 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[(2R)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy}quinazoline (108 mg, 57%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2nccnc12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2nccnc12
Temperature: 50 °C

Procedure:
To quinoxalin-5-ol (0.43 g) dissolved in DMF (6 ml) was added K2CO3 (2.5 eq.) and KI (0.2 eq.). To this mixture was then added dropwise iodomethane (1.2 eq.). The resulting mixture then heated to 50° C. overnight. The reaction mixture was subsequently partitioned between satd. NaHCO3 and EtOAc, the EtOAc layer backwashed with water and brine, dried over Na2SO4, and concentrated to dryness under vacuum. The crude material was then purified by SGC (MeOH:DCM) affording 5-methoxyquinoxaline. MS (ESI+) for m/z 160 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[C:29](O)=[O:30])[CH3:27].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:26]([C:28]([OH:34])([CH2:32][CH3:33])[C:29]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:30])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: CCC(O)(CC)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(O)(CC)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (100 mg, 0.27 mmol), 2-ethyl-2-hydroxybutanoic acid (36 mg, 0.27 mmol), and NMM (30 μL, 0.27 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (144 mg, 0.326 mmol). The mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (100 mL). The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN, 0.1% TFA) over 30 min with a flow rate of 18 mL/min. After concentration of desired fractions in vacuo, 1-(2-ethyl-2-hydroxybutanoyl)-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)-L-prolinamide was obtained an amorphous solid (55 mg; HPLC RT=3.32 min, method A; LC-MS m/z=482.2; 1H NMR, 400 MHz, CDCl3, 7.25 ppm (m, 3H), 7.2 ppm (m, 1H), 7.1 ppm (br s, 1H), 5.45 ppm (br s, 1H), 4.55 ppm (m, 2H), 4.3 ppm (m, 3H), 3.7 ppm (m, 2H), 2.2 ppm (m, 2H), 2.0 ppm (m, 2H), 1.8 ppm (m, 2H), 1.7 ppm (m, 2H), 1.4 ppm (s, 9H), 0.8 ppm (m, 6H)).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:14]=[CH:13][C:12]=1[C:23]([OH:25])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([OH:57])[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N:14]=[CH:13][C:12]=1[C:23]([NH:50][CH2:51][C:52]([CH2:58][N:59]([CH2:67][CH3:68])[CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)([OH:57])[C:53]([F:56])([F:55])[F:54])=[O:25]
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(F)cc1
Reactant: CCN(Cc1ccccc1)CC(O)(CN)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCN(Cc1ccccc1)CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 150.6 %

Procedure:
Diisopropylethylamine (0.175 ml, 1 mmol) was added to a mixture of 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (0.119 g, 0.54 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.205 g, 0.54 mmol) in dimethylformamide (1 ml). The resultant mixture was stirred at room temperature for 20 minutes, then a solution of 3-amino-2-{[ethyl(phenylmethyl)amino]methyl}-1,1,1-trifluoro-2-propanol (0.296 g, 1.07 mmol) in dimethylformamide (1 ml) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml) and the separated organic phase washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica (10 g) using 0-100% ethyl acetate in cyclohexane gradient over 15 minutes to give the title compound (0.39 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=[O:3])[CH3:2].Cl.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:40](=[O:47])[C:41]3[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=3)[CH:16]=1)[N:9]=[C:8]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)Oc1ccc2nc(-c3cccc(N)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc2nc(-c3cccc(NC(=O)c4cccnc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
A suspension of tert-butyl 5-(6-acetoxy-2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.50 g, 0.98 mmol), nicotinoyl chloride hydrochloride (0.224 g, 1.26 mmol) and DIEA (0.45 g, 3.48 mmol) in CH2Cl2 (15 mL) was stirred at RT for 7 h. The volatiles were removed in vacuo and the residue was purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the product tert-butyl 5-(6-acetoxy-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.374 g, 0.608 mmol, 62%).
Reaction SMILES: [NH2:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][CH2:5][N:6]([C@H:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[CH3:15])C(=O)OC(C)(C)C.[ClH:29]>C(Cl)Cl.O1CCOCC1>[ClH:29].[ClH:29].[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:6][CH2:5][CH2:4][CH2:3][CH:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH2:1])[CH3:15])=[CH:21][CH:20]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(N)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](NCCCC(N)c1ccccc1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred solution of tert-butyl 4-amino-4-phenylbutyl((1S)-1-(4-bromophenyl)ethyl)carbamate (179 mg, 0.40 mmol) in CH2Cl2 (5 mL) at rt was added 4 M HCl in dioxane (5 mL). The mixture was stirred for 1 h and concentrated to afford N1-((1S)-1-(4-bromophenyl)ethyl)-4-phenylbutane-1,4-diamine dihydrochloride (162 mg, 96%). LC-MS Method 1 tR=0.92 min, m/z=349, 347.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:32])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OCC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of zinc chloride (3.50 g, 25.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.93 g, 51.1 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate (5.50 g, 12.8 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate (4.99 g, 90%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[OH-].[I-:15].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CO>[C:1]([C:5]1[CH:10]=[C:9]([I:15])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: [I-]
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 162.4 %

Procedure:
To a 250 mL round-bottom flask was added 2-tert-butylphenol (3.76 g, 25 mmol) in MeOH (50.0 ml) to give a colorless solution. Sodium hydroxide (1.200 g, 30.0 mmol) was added and the mix was stirred until the hydroxide was completely dissolved. The solution was cooled to 0° C. and treated with sodium iodide (1.75 g, 11.6 mmol) followed by dropwise addition of 10% sodium hypochlorite solution (7.2 ml, 11.6 mmol). The addition of sodium iodide followed by sodium hypochlorite was repeated twice and the mixture was stirred at 0° C. for 30 min. The mixture was treated with 10% w/w solution of sodium thiosulfate, stirred for 30 min and treated with concentrated HCl dropwise to a constant pH of 1. The mixture was extracted 3× with EtOAc. The extracts were combined, washed with brine, dried (MgS04), filtered and concentrated. The crude oil was flash chromatographed on an ISCO 80 g silica cartridge eluting with hexane→4:1 hexane/EtOAc to give a yellow oil (5.2 g, 75%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:21])[CH2:19]Cl)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C)C=O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([CH3:21])[CH2:19][N:26]2[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OC1CCNCC1
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCC(O)CC1
Temperature: 150 °C
Yield: 72 %

Procedure:
106 g of Na2CO3 are added to a solution of 112 g of 3-(4-tert.-butylphenyl)-2-methyl-propyl chloride and 50 g of 4-hydroxypiperidine in 1 liter of dimethylformamide (DMF). The batch is heated at 150° C. for 15 hours and then concentrated, and the residue is taken up in CH2Cl2. The CH2CL2 phase is washed with water, dried over Na2SO4 and concentrated. Distillation of the crude product gives 103 g of N-[3-(4-tert.-butylphenyl)-2-methyl-propyl]-4-hydroxypiperidine [A] as a pale yellowish oil. Boiling point 175°-178° C./0.4 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:33][S:34][C:35]1[O:36][C:37]2[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][C:38]=2[N:39]=1>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:44][C:42]2[CH:41]=[CH:40][C:38]3[N:39]=[C:35]([S:34][CH3:33])[O:36][C:37]=3[CH:43]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CSc1nc2ccc(C=O)cc2o1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (400 mg, 1.84 mmol) and TFA (1.89 mL) in DCM (8 mL) at −5° C. was added NaBH(OAc)3 (1.17 g, 5.52 mmol). Then to the mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (391 mg, 2.03 mmol) in DCM (7 mL), and the mixture was stirred at 0° C. for 2 h. The mixture was diluted with DCM and washed with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 petroleum ether/ethyl acetate to give 4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (704 mg, 97.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (t, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.50-7.60 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (d, J=9.3 Hz, 1H), 4.72 (d, J=6.6 Hz, 1H), 2.73 (s, 3H). LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: Cl.CC(Cl)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:15][CH2:14]1)=[O:12])(C)(C)C>O1CCOCC1>[CH3:6][O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[O:29])[CH:21]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: Cc1ccc(NC(=O)Nc2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2F)cn1
Agent: Cl
Solvent: CC(=O)Cl
Solvent: C1COCCO1
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2)CC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To 1.0 eq of 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (2D) in MeOH (about 0.1 M 2D in MeOH) was added 2 volumes of HCl in dioxane (4 N) and the reaction mixture stirred at 50° C. for 15 min and evaporated to a solid. The solid was combined with DCM and treated with approximately 5 eq of TEA and split into 3 equal portions of reaction mixture A. One portion of the reaction mixture A was treated with 1.2 eq of methyl carbonyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acid methyl ester. MS 402 (M+H). A second portion of the reaction mixture A was treated with 1.2 eq of dimethylsulfamoyl chloride and stirred overnight. The resultant mixture was concentrated and purified by reversed phase HPLC to afford 4-{4-fluoro-3-[3-(6-methyl-pyridin-3-yl)-ureido]-benzyl}-piperazine-1-sulfonic acid dimethylamide. MS 451 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:14]=[C:15]1[C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:34]
Reactant: NCCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 2-(3-(trifluoromethyl)phenyl)ethanamine (0.021 g, 0.112 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.030 g, 0.102 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.029 g, 0.053 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.50 (m, 1H), 7.23-7.40 (m, 13H), 5.84 (t, J=6.1 Hz, 1H), 3.98 (s, 2H), 3.40 (t, J=6.5 Hz, 2H), 3.32-3.40 (m, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.67 (t, J=7.3 Hz, 2H); MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[BH4-].[Na+].O>C1C=CC=CC=1.C1COCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Nc1c(CO)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a suspension of 2-amino-3-nitro benzoic acid (2.12 g, 10 mmol) in benzene (75 mL) was added dropwise thionyl chloride (1.8 mL, 25 mmol). The suspension was heated to reflux overnight. The mixture was cooled to room temperature and concentrated under reduced pressure to afford a golden solid. The crude material was dissolved in THF (40 mL) and cooled in an ice bath. Sodium borohydride (0.83 g, 22 mmol) was added in portions, and the reaction was allowed to come to room temperature with stirring. The ice bath was replaced and H2O (15 mL) was slowly added to the reaction. Once gas evolution had subsided, the solution was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The reside was adsorbed onto silica gel and purified by column chromatography, eluting with a gradient of 25% EtOAc/hexane to 50% EtOAc/hexane to afford the alcohol (0.89 g, 46%) as an orange solid. mp: 100° C. 1H NMR 300 MHz (DMSO-d6): δ=7.92 (dd, 1H, J=8.7, 1.4 Hz), 7.49 (d, 1H, J=6.8 Hz), 7.12 (bs, 2H), 6.66 (dd, 1H, J=8.7, 7.1 Hz), 5.45 (t, 1H, J=5.4 Hz), 4.52 (d, 2H, J=5.4 Hz). MS (ESI-POS): [M+H]+=169.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C=C(CCCC#N)CCCC#[N:18].C1C=CC=CC=1>P(=O)(O)(O)O.O>[C:1]1(=[O:6])[NH:18][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C=C(CCCC#N)CCCC#N
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C1NC(=O)c2ccccc21
Temperature: 240 °C
Yield: 199.4 %

Procedure:
225 g (1.52 moles) of phthalic anhydride, 121.5 g (0.75 mole) of 5-methylene-1,9-nonanedinitrile, 300 cc of benzene, 40 g of water and 2 g of phosphoric acid were placed in a 1-liter autoclave. The autoclave was closed, then purged with dry nitrogen. Following purging, the reactor was heated to 240° C for a period of 4 hours. After cooling, the reaction mixture was filtered. The filter solid, after being washed in 300 cc of benzene, filtered and dried, yielded 220 g of phthalimide having a melting point of 234°-238° C. Yield 100 percent.
Reaction SMILES: [NH3:1].[CH3:2][CH:3]([N:5]1[S:15](=[O:17])(=[O:16])[NH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]1=[O:7])[CH3:4]>ClCCCl>[CH3:4][CH:3]([N:5]1[S:15](=[O:17])(=[O:16])[NH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]1=[O:7])[CH3:2].[NH4+:1]
Reactant: N
Agent: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Solvent: ClCCCl
Product: [NH4+]

Procedure:
1.7-3 g of ammonia were introduced as a gas with stirring at 20°-50° C. into a solution of 24 g of bentazone (IIa) in 2376 g of 1,2dichloroethane, a suspension being formed. The solid was separated off at 20° C. by filtration and freed from solvent residues under reduced pressure. 25.4 g of bentazone-ammonium (m.p. 180° C.) were obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:17])[CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH2:15][CH3:16].[C:18](O)(=[O:21])[CH2:19][OH:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[C:10]([C:9]1[CH:12]=[C:13]([CH3:14])[C:6]([O:5][CH2:4][C@@H:3]([OH:17])[CH2:2][NH:1][C:19](=[O:20])[CH2:18][OH:21])=[C:7]([CH2:15][CH3:16])[CH:8]=1)#[N:11]
Reactant: CCc1cc(C#N)cc(C)c1OC[C@@H](O)CN
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a solution of (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6.23 g, 26.59 mmol) in THF (150 mL), glycolic acid (2.43 g, 31.9 mmol), HOBt (4.31 g, 31.9 mmol), and EDC hydrochloride (6.12 g, 31.9 mmol) are added. The mixture is stirred at rt for 18 h before it is diluted with sat. aq. NaHCO3 and extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC with DCM containing 8% of methanol to give (S)—N-[3-(4-cyano-2-ethyl-6-methyl-phenoxy)-2-hydroxy-propyl]-2-hydroxy-acetamide (7.03 g) as a yellow oil; LC-MS: tR=0.74 min; [M+1]+=293.10; 1H NMR (CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.48-3.56 (m, 3H), 3.70-3.90 (m, 3H), 4.19 (s, br, 3H), 7.06 (m, 1H), 7.36 (s, 1H), 7.38 (s, 1H).