Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:6]1[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ncc(Cl)c(Nc2ccccc2)n1

Procedure:
A solution of 2,4,5-trichloropyrimidine (Method 8; 5.5 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidified on standing (3.94 g, 54%). NMR: 7.2 (t, 1H), 7.4 (t, 2H), 7.6 (d, 2H), 8.4 (s, 1H), 9.45 (br s, 1H); MS (MH+): 240, 242, 244.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16]O)=[CH:10][CH:9]=1.[BrH:18]>>[Br:18][CH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][CH:12]=1
Reactant: Br
Reactant: OCCCc1ccc(-c2ccccc2F)nc1
Product: Fc1ccccc1-c1ccc(CCCBr)cn1

Procedure:
230 mg (0.99 mmol) of 3-(6-(2-fluorophenyl)pyridin-3-yl)propan-1-ol were stirred in 10 ml of hydrobromic acid (33% in acetic acid) at 60° C. for 6 h. After concentrating, a sodium hydrogencarbonate solution was added, the resulting mixture was extracted with ethyl acetate, and the organic phase was separated and concentrated. Yield: 707 mg (71%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CN(CCc1ccccc1OCCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
{2-[2-(3-Hydroxypropoxy)phenyl]ethyl}-N-methylcarbamic acid tert-butyl ester (0.587 g, 1.90 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred for 30 min at 0° C. Dichloromethane (50 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (3×70 ml). The aqueous phase was made basic to pH 14 with a 20% aqueous sodium hydroxide solution. It was extracted with tert-butyl methyl ether (3×100 ml). The tert-butyl methyl ether extracts were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 227 mg of crude 3-[2-(2-methylaminoethyl)phenoxy]propan-1-ol. The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C@H:6]2[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]3[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])[N:15]=3)[CH2:8][CH2:7]2)[CH2:3]1.[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N=C=N.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C>C1COCC1>[N+:20]([C:19]1[C:14]([NH:13][CH2:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([N:4]3[CH2:5][CH:2]([NH:1][C:36](=[O:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:3]3)[CH2:7][CH2:8]2)=[N:15][C:16]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][C:32]([F:34])([F:35])[F:33])=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: O=C(O)c1ccccc1
Reactant: NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1
Agent: N=C=N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CN([C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N4-{[Trans-4-(3-aminoazetidin-1-yl)cyclohexyl]methyl}-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (20 mg, 0.04 mmol) was dissolved in THF (1.0 mL). To this solution was added benzoic acid (7.3 mg, 0.06 mmol), Polystyrene-linked Carbodiimide (PS-CDI) (47 mg, 0.06 mmol) followed by triethylamine (0.084 mL, 0.06 mmol). The reaction was allowed to stir at 25° C. for 18 h. The reaction was filtered to remove the PS-CDI and the volatiles were removed in vacuo. The crude was redissolved in CH2Cl2 and extracted with 10% aqueous NaHCO3. The aqueous phase was separated and extracted two more times with CH2Cl2. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The resultant residue was purified via flash chromatography (SiO2, 10-30% (2:18:80, NH4OH:CH3OH:CH2Cl2)—CH2Cl2) to afford 18 mg (74%) of the target compound, m/z 600.34 (M+1)+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([N:12]([CH2:20][C:21](O)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:35][C@@H:36]1[CH2:40][NH:39][C@H:38]([C:41]#[N:42])[CH2:37]1>>[N:1]1([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([N:12]([CH2:20][C:21]([N:39]3[CH2:40][C@@H:36]([F:35])[CH2:37][C@H:38]3[C:41]#[N:42])=[O:22])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@H]1CC[C@@H](Cn2cncn2)C1
Reactant: N#C[C@@H]1C[C@H](F)CN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N(CC(=O)N1C[C@@H](F)C[C@H]1C#N)[C@H]1CC[C@@H](Cn2cncn2)C1
Yield: 92.4 %

Procedure:
This compound was prepared from [(3R,1S)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentyl-N—BOC-amino]acetic acid (50 g, 154.14 mmol) and (2S,4S)-4-fluoropyrrolidine-2-carbonitrile p-toluenesulfonate (52.96 g, 184.96 mmol) as described in the preparation of its enantiomer (Method C) to give 59.9 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.22-1.36 (m, 2H), 1.44 (s, 9H), 1.62-1.81 (m, 2H), 1.88-2.04 (m, 3H), 2.22-2.27 (m, 1H), 2.34-2.49 (m, 1H), 2.62-2.77 (m, 1H), 3.69-4.01 (m, 3H), 4.13-4.23 (m, 3H), 4.99 (d, J=9.3 Hz, 1H), 5.33 (d, J=51.7 Hz, 0.3H, rotomer), 5.45 (d, J=51.0 Hz, 0.7H. rotomer), 7.92 (s, 1H), 8.08 (s, 0.4H, rotomer), 8.10 (s, 0.6H, rotomer).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[OH:19].[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>C1C=CC=CC=1>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[O:19][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]1)=[O:29])=[O:20]
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: COC(=O)c1cc(Oc2ccccc2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cc(Oc2ccccc2)ccc1OC(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Sodium hydride (0.38 g, 9.93 mmol of a 60% oil dispersion) was added in portions under a nitrogen atmosphere to a solution of 2-hydroxy-5-phenoxybenzoic acid methyl ester (2.0 g, 8.19 mmol) in 30 ml of benzene. The reaction was stirred at room temperature for 30 minutes. 4-Methyl-1-piperidinecarbonyl chloride (1.46 g, 9.03 mmol) was then added and the reaction refluxed for 3.5 hours. The reaction mixture was washed with 1N HCl, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 3.38 g of a clear oil. Purification of this oil on 300 g of silica gel (230-400 mesh) using hexane-methylene chloride as the eluent gave 2.71 g of a white crystalline solid. Recrystallization of this solid from diisopropyl ether-hexane then gave the title compound as a white crystalline solid (2.02 g, 67%), mp 67°-69C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3]([OH:5])=[O:4])=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCN1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
L-Proline (2.5 g, 22 mmol) is dissolved in NaOH (5%, 25 ml, 31 mmol) and, after cooling, treated dropwise, with vigorous stirring, with 4-fluorobenzoyl chloride (3.17 g, 20 mmol). The resulting suspension is again treated with NaOH (5%, 15 ml, 19 mmol) and stirred at RT for 1 h. HCl (20% strength, 10 ml) is added with ice cooling and the mixture is stirred until formation of a crystallizate which can be filtered off with suction. The crystallizate subsequently filtered off with suction is washed with water until HCl-free and dried over P2O5 in a desiccator. 4.21 g (88.8% of theory) of crystallizate remain after drying.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:19])[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:19])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cccc(C(=O)OC)c2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(CCC)C1Cc2cccc(C(=O)O)c2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
A mixture of methyl 3-(dipropylamino)-1,2,3,4-tetrahydro-2-oxo-8-quinolinecarboxylate (1.0 g), methanol (15 mL) and 4.0N sodium hydroxide solution (3.3 mL) was stirred at room temperature for 30 minutes. The methanol was removed and the residue was reconstituted in water (5 mL) and neutralized by addition of 4.0N hydrochloric acid (3.3 mL). The precipitate was filtered off, washed with water and air dried to give 0.67 g of 3-(dipropylamino)-1,2,3,4-tetrahydro-2-oxo-8-quinolinecarboxylic acid, mp 214°-217° C. Anal Calcd for C16H22N2O3 : C, 66.18; H, 7.64; N, 9.65. Found: C, 65.99; H, 7.67; N, 9.62.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](O)(=O)=O)=[CH:8]C=1>CO>[CH2:10]([C:9]1[S:12][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:8]=1)[CH2:11][CH2:6][CH2:16][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCCCCCCCc1ccc(CCO)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydrofuran (20 ml) and p-toluenesulfonic acid (0.3 g) were added to a solution (80 ml) of the above-mentioned compound (6.5 g) in methanol and the mixture was stirred at room temperature for 1 hour. The solvent was distilled away and ethyl acetate was added to the resulting mixture. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue obtained was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to give 4 g of the subject compound as an oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][O:44][CH2:45][C:46]([CH2:51][O:52][CH3:53])([NH2:50])[CH2:47][O:48][CH3:49]>>[CH3:49][O:48][CH2:47][C:46]([NH:50][C:28]([C:25]1[C:24]2[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]3[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]3)=[C:22]([F:34])[C:23]=2[O:27][N:26]=1)=[O:29])([CH2:51][O:52][CH3:53])[CH2:45][O:44][CH3:43]
Reactant: COCC(N)(COC)COC
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: COCC(COC)(COC)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 1,3-dimethoxy-2-(methoxymethyl)propan-2-amine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[NH:13][C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][N:25]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:12]3[N:13]([CH2:31][CH2:30][C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=4)[C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][C:19]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCc3[nH]c4ccc(C)cc4c3C2)cc1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCc3c(c4cc(C)ccc4n3CCc3ccc(C)nc3)C2)cc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=O)=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O=[C:24]([CH3:35])[CH2:25][CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl[Si](C)(C)C.O>CN(C=O)C>[C:1]([N:4]1[CH2:5][C:6]2[S:12][C:11]3[N:13]=[C:24]([CH3:35])[C:25]([CH:26]([CH2:32][CH2:33][CH3:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=4)[C:10]=3[C:7]=2[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCC(CC(C)=O)C(=O)OCC
Reactant: CC(=O)N1CCc2c(sc(N)c2C(=O)c2ccc(C)cc2)C1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C(=O)OCC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCN(C(C)=O)C3
Temperature: 100 °C
Yield: 94.4 %

Procedure:
To a solution of (6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (2 g; 6.36 mmol) and ethyl 4-oxo-2-propylpentanoate (1.3 g; 7 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added chlorotrimethylsilane (3.25 mL; 25.45 mmol). The mixture was stirred in a sealed tube and heated at 100° C. for 48 h. After cooling, water (25 mL) was added and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of methanol (0-20%) in dichloromethane furnished 2.79 g (94%) of the title compound.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[CH3:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][O:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[O:11][CH3:10])[CH3:6]
Reactant: COc1cccc(O)c1OC
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cccc(OC)c1OC)OCC
Temperature: 140 °C
Reaction time: 24 h
Yield: 87.7 %

Procedure:
2-bromo-1,1-diethoxyethane (0.097 mol) was added to a mixture of 2,3-dimethoxy-phenol (0.097 mol) and potassium carbonate (0.097 mol) in N,N-dimethylacetamide (200 ml). The reaction mixture was stirred for 24 hours at 140° C. The solvent was evaporated. The residue was partitioned between 1,1'-oxybisethane and a solution of NaOH in water. The organic layer was separated, washed with a saturated NaCl solution, dried (MgSO4), filtered and the solvent was evaporated, yielding 23 g (87.7%) of 1-(2,2-diethoxyethoxy)-2,3-dimethoxybenzene (interm. 1).
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:49]>ClCCl>[CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[CH:42][N+:41]([O-:49])=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3ccncc3)C3CC3)cc2)c(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cc[n+]([O-])cc3)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (3-[cyclopropyl(pyridin-4-ylmethyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 110, Step 1 (1 eq.) in dichloromethane (0.12 M) was added 3-chloroperoxybenzoic acid (1.3 eq.). The reaction mixture was stirred at RT for 1.5 h. The reaction was then quenched with 10% aq. Na2S2O3 and sat. aq. NaHCO3. The organic layer was separated and the aqueous layer were back extracted with ether. The combined organic extracts were washed with water, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, EtOAc→4:1 (v/v) EtOAc:MeOH) afforded the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30](ON3C(=O)CCC3=O)=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.O>C(=O)([O-])[O-].[Na+].[Na+]>[CH:15]1[C:27]2[CH:26]([CH2:28][O:29][C:30]([NH:1][C@@H:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=3)[C:3]([OH:5])=[O:4])=[O:31])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
(S)-2-Amino-3-(3-fluoro-4-hydroxyphenyl)propanoic acid (H-Tyr(3-F)-HH, SP449) (7.2 g, 36.2 mmol) was dissolved in a 10% aqueous sodium carbonate solution (250 ml), N-(9-fluorenylmethoxycarbonyloxy)-succinimide (12.2 g, 36.2 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. Water (120 ml) was added to the reaction solution, and the mixture was then washed with 200 ml of diethyl ether twice and with 100 ml of diethyl ether once. The aqueous layer was made acidic (pH=2) by adding a 6 N aqueous HCl solution thereto, and then extracted with 250 ml of ethyl acetate twice and with 200 ml of ethyl acetate once. The resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (SP450, 15.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:18])[CH3:21]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1cccc(C(=O)O)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 3-aminobenzoic acid (20 g), 1 M aqueous sodium bicarbonate solution (730 cc) and ethyl chloroformate (14 cc) is left with stirring for 30 minutes at 5° C. 2.5 N hydrochloric acid (300 cc) is then added to the reaction mixture. The precipitate formed is separated by filtration, washed with water (3×200 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 3-Ethoxycarbonylaminobenzoic acid (25 g), m.p. 198° C., is thereby obtained.
Reaction SMILES: [Na].[C:2]([O:7][CH2:8][CH3:9])(=[O:6])[C:3]([O-:5])=O.[C:10]([NH:14][C:15]1[C:16]([CH3:28])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25](=[O:27])[CH3:26])[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11]>CCO.O>[C:10]([NH:14][C:15]1[C:16]([CH3:28])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25](=[O:27])[CH2:26][C:3](=[O:5])[C:2]([O:7][CH2:8][CH3:9])=[O:6])[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Temperature: -10 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
To a 25-mL round-bottomed flask was added EtOH (4 mL) and sodium ethoxyde (1.01 g of 21% in EtOH, 3.11 mmol). The reaction mixture was cooled to −10° C. and added ethyl oxalate (0.21 mL, 1.55 mmol, Sigma-Aldrich) and 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (0.4 g, 1.55 mmol) slowly. The reaction mixture was warmed to RT and stirred at RT for 18 h. The reaction mixture was diluted with water (10 mL) and partially concentrated under vacuum. The reaction mixture was diluted with HCl (1 N, 5 mL) and extracted with EtOAc (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate as an orange oil (135 mg, 24% yield). m/z (ESI, +ve) 358.1 (M+H)+. To a 15-mL glass tube was added ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate (135 mg, 0.38 mmol), hydrazine (12 μL, 0.38 mmol), and AcOH (2 mL). The tube was sealed and heated at 85° C. for 1 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The mixture was diluted with EtOAc (10 mL) and NaOH (1 N, 5 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (102 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.97 (m, 1H), 7.74 (d, J=7.82 Hz, 1H), 7.51-7.60 (m, 1H), 7.40 (t, J=8.90 Hz, 1H), 6.00-6.07 (m, 1H), 4.31 (q, J=7.11 Hz, 2H), 2.56 (s, 3H), 1.53 (s, 9H), 1.33 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 354.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([C:6]([O:8]C)=[O:7])[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[F:16][C:2]1([F:1])[CH2:5][C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: COC(=O)C1(c2cccnc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccnc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate 311D (250 mg, 1.100 mmol) in THF (2 mL) and water (1 mL) was added NaOH (132 mg, 3.30 mmol) and the reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated; the pH of the residue was adjusted to 2 with a 1.5N aq. solution of HCl and extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford Intermediate 311E as a colorless semi-solid (160 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br. s., 1H), 8.65-8.54 (m, 1H), 8.53-8.46 (m, 1H), 7.83-7.74 (m, 1H), 7.46-7.35 (m, 1H), 3.47-3.35 (m, 2H), 3.23-3.08 (m, 2H).