Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:33]1([CH2:39][CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][C@@H:19]3[CH2:20][CH2:21][CH2:22][C@H:18]3[C:9]3[O:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:25]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.7 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (140 mg, 0.331 mmol) and 2-phenylethylamine (0.046 ml, 0.364 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (49 mg, 0.364 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (95 mg, 0.495 mmol). After stirring the mixture at room temperature for 2.5 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give N-(2-phenylethyl)-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (172.1 mg, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1O>C[Si](OP(=O)=O)(C)C>[O:8]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:6]1[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: Nc1ccccc1O
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3ccccc3o2)ccc1O
Temperature: 180 °C
Reaction time: 8 h

Procedure:
4-hydroxy-3-methoxybenzoic acid (25 g, 149 mmol) and 2-amino phenol (16.2 g, 149 mmol) were combined in a round bottom flask. Trimethylsilyl polyphosphate (80 mL) was added neat. The mixture was heated at 180° C. for 30 min. The mixture is poured over ice and allowed to stir overnight. The suspension was filtered to afford 4-(1,3-benzoxazol-2-yl)-2-methoxyphenol as a pale green solid. MS (ESI) 242 (M+H)+.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[Cl:12][C:13]1[C:14]([C:34]#[C:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15][C:16]2[N:20]=[C:19](S(C)(=O)=O)[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:17]=2[CH:33]=1>C1COCC1>[Cl:12][C:13]1[C:14]([C:34]#[C:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:15][C:16]2[N:20]=[C:19]([O:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]([OH:4])=[O:11])[N:18]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:17]=2[CH:33]=1
Reactant: COC(=O)C(C)(C)CO
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccccc3)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(COc1nc2cc(C#Cc3ccccc3)c(Cl)cc2n1COCC[Si](C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (18.0 mg, 60% suspension in mineral oil, 0.45 mmol). In a separate vial, a solution of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (79.0 mg, 0.600 mmol) in THF (2.0 mL) was combined with a solution of compound 49-2 (138.0 mg, 0.300 mmol), and added dropwise to the 20 mL scintillation vial containing NaH. The resulting mixture was stirred at rt for 5 min, then cooled in a ice bath (0° C.) and quenched by a dropwise addition of water (6 mL). The mixture was allowed to warm up to rt and stirring was maintained for 5 min. The mixture was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and evaporated to dryness in vacuo. The residue was dissolved in ACN (4 mL) and added to a vial containing 5% aqueous LiOH (1 mL). The resulting mixture was stirred at 65° C. for 1 h, then acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and evaporated to dryness in vacuo. The crude product was used in the next step without further purification. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C26H31ClN2O4Si 498.2, observed m/e 499.0 (M+H)+ (Rt 3.78. 3.87 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=N)[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.Cl.C[OH:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:20])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: N=C1NC(=O)C2(CCOc3ccc(F)cc32)S1
Reactant: CO
Agent: Cl
Product: O=C1NC(=O)C2(CCOc3ccc(F)cc32)S1

Procedure:
2.195 g of (±)-6-fluoro-2,3-dihydro-2'-iminospiro-[4H-1-benzopyran-4,5'-thiazolidin]-4'-one were dissolved in 12 ml of methanol and 12 ml of 37% aqueous hydrochloric acid and the solution was boiled overnight. The colorless crystals which separated were removed and washed with water. After drying in vacuo, there was obtained (±)-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione of melting point 147°-149° C. (95% of theory).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3]1=[O:27].[OH:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3](=[O:27])[C@@H:2]([NH:1][C:37](=[O:38])[C:30]2[C:29]([OH:28])=[C:34]([O:35][CH3:36])[CH:33]=[CH:32][N:31]=2)[CH2:10][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O
Reactant: COc1ccnc(C(=O)O)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)COC2=O)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a mixture of (3S,7S,8S)-3-amino-7,8-bis(benzyloxy)-1,5-dioxonan-2-one (47 mg, 0.127 mmol), 3-hydroxy-4-methoxypicolinic acid (32.1 mg, 0.190 mmol) and HATU (80 mg, 0.202 mmol) in a vial were added CH2Cl2 (1.5 mL), followed by 4-methylmorpholine (0.083 mL, 0.759 mmol), and the resulting suspension was stirred at room temperature for 12 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white foam (32 mg, 48%): 1H NMR (400 MHz, CDCl3) δ 11.90 (d, J=0.6 Hz, 1H), 8.61 (d, J=8.2 Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.43-7.24 (m, 11H), 6.86 (d, J=5.2 Hz, 1H), 5.03 (ddd, J=8.2, 6.8, 6.0 Hz, 1H), 4.80-4.62 (m, 5H), 4.21-4.07 (m, 2H), 3.93 (s, 3H), 3.85 (s, 1H), 3.79-3.65 (m, 2H), 3.55-3.47 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.83, 168.92, 155.37, 148.76, 140.66, 137.97, 137.94, 130.17, 128.48, 128.43, 127.91, 127.89, 127.87, 127.81, 109.61, 81.52, 79.29, 73.80, 73.44, 73.24, 72.97, 63.91, 56.10, 52.25; ESIMS m/z 524.1 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:68][C:69]([N:71]1[CH2:76][CH2:75][N:74]([C:77](=[O:87])[C@@H:78]([NH2:86])[CH2:79][CH2:80][C:81]2[N:82]=[N:83][NH:84][N:85]=2)[CH2:73][CH2:72]1)=[O:70])[CH2:65][CH2:66][CH3:67]>CN(C=O)C>[CH2:64]([O:68][C:69]([N:71]1[CH2:72][CH2:73][N:74]([C:77](=[O:87])[C@@H:78]([NH:86][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:29])[CH2:79][CH2:80][C:81]2[N:85]=[N:84][NH:83][N:82]=2)[CH2:75][CH2:76]1)=[O:70])[CH2:65][CH2:66][CH3:67]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 327 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 415 μl DIPEA, 302 mg HATU and 360 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate. After 30 minutes the reaction mixture was concentrated and the crude product obtained purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 180 mg
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([NH:13][C:14]1[C:18]([Cl:19])=[CH:17][S:16][CH:15]=1)=S.[OH-].[Na+].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1.O>[ClH:19].[Cl:31][C:15]1[S:16][CH:17]=[C:18]([Cl:19])[C:14]=1[NH:13][C:11]1[NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(F)c(F)cc1NC(=S)Nc1cscc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cl
Product: Fc1cc2nc(Nc3c(Cl)csc3Cl)[nH]c2cc1F
Yield: 63.8 %

Procedure:
To 1-(2-amino-4,5-difluoro-phenyl)-3-(4-chloro-thiophen-3-yl)-thiourea (773 mg) in THF (20 ml) a solution of NaOH (240 mg) in water (9 ml) was added followed by a solution of p-toluenesulfonyl chloride (528 mg) in THF (10 ml). Following the analogous description in example 54b) the desired product (275 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].[CH2:29](N(CC)CC)[CH3:30].C(Cl)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][C:29]([CH3:30])=[N:27][N:26]=1
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: Cc1nnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To an ice cooled stirred mixture of 1.0 g (2.50 mmol) of the starting material XVIII, 35 ml of dichloromethane, 0.40 ml (2.75 mmol) of triethylamine and 0.22 ml (2.80 mmol) of acetyl chloride was added. The so obtained solution was left at room temperature for 16 h, then 0.6 g of p-toluenesulfonic acid was added and the mire was stirred at 40° C. for 2 h. Then the reaction mixture was washed with sodium hydrogen carbonate solution and water until neutrality, dried and concentrated. The crude product was treated with methanol, then recrystallized from ethanol to yield 0.99 g (91%) of the title compound. Mp.: 213-215° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([O-:15])(=O)=[O:13].[Na+]>CN(C)C=O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12]([Cl:3])(=[O:15])=[O:13]
Reactant: O=S(=O)([O-])CCCCCCBr
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCCCCCBr
Yield: 32.7 %

Procedure:
Thionyl chloride (10.3 ml, 140.4 mmol) and N,N-dimethylformamide (one drop) were added to sodium 6-bromohexanesulfonate (5.00 g, 18.7 mmol) prepared by a process described in Org. Synth., Coll. Vol. II, 558 or WO95/19345 Pamphlet. The mixture was refluxed for 4 hours. The reaction mixture was concentrated in vacuo. The concentrate was diluted with benzene (50 ml). The resulting solution was washed twice with water (15 ml) and then with brine (10 ml), and thereafter dried over calcium chloride. The solvent was removed by evaporation in vacuo. Crude 6-bromohexanesulfonyl chloride (1.61 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:11](=[O:12])[CH:10]=[CH:9][C:8](=[O:13])[C:6]=2[N:7]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[NH:14]([C:9]1[C:8](=[O:13])[C:6]2[N:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=2[C:11](=[O:12])[CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: CCc1nc2c(o1)C(=O)C=CC2=O
Solvent: CCO
Product: CCc1nc2c(o1)C(=O)C=C(Nc1ccccc1)C2=O
Reaction time: 1 h

Procedure:
A mixture of 2-ethyl-1,3-benzoxazole-4,7-dione (1 eq) and aniline (1.1 eq.) in ethanol is kept under string for 1 hour. The reaction medium turns to dark violet. After concentration, the residue is purified by medium pressure chromatography on silica in order to produce a violet-coloured powder. Melting point: 200° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[Na].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O>O>[N:16]1([C:10]2[C:9]3[C:4](=[C:5]([Cl:14])[CH:6]=[C:7]([Cl:13])[CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: Cc1cc(Cl)c2cc(Cl)cc(Cl)c2n1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)c2cc(Cl)cc(Cl)c2n1
Temperature: 100 °C
Reaction time: 25 h
Yield: 93 %

Procedure:
A mixture of 2.46 g of 2-methyl-4,6,8-trichloro-quinoline, 1.82 g of the sodium salt of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 25 hours whereupon the reaction mixture is poured into 100 ml of water. The precipitated product is filtered. Thus 2.59 g of the desired compound are obtained, yield 93%. Mp.: 220°-222° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[CH:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[Cl:22])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:13]([C:15]#[CH:16])[CH:14]=1
Reactant: C#Cc1cc(CNC(=O)OC(C)(C)C)c(Cl)cc1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cc(CN)c(Cl)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 74.3 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas and the solution of (2-chloro-5-ethynyl-4-methanesulfonylamino-benzyl)-carbamic acid t-butyl ester (182.6 mg, 0.51 mmol) in methylenechloride was put into the flask. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield brown syrup (98.1 mg, 114.23%).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)C[C@H](C)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C[C@H](C)c2ccccc2)[nH]n1

Procedure:
Hydrazine hydrate (0.126 mL, 2.59 mmol) was added to a stirring room temperature solution of 78 0.0.6895 g, 2.63 mmol) in EtOH (2.6 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (45 min): The reaction was concentrated and purified with 9:1 to 8:1 Hexanes:(3:1 CH2Cl2:2N NH3 in EtOH) to achieve 0.6153 g (90.6%) of 79. HPLC: 10.001 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:6]=2[CH:27]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:36]4[CH:37]=[CH:38][C:39](=[O:42])[NH:40][CH:41]=4)=[CH:27][C:6]=3[N:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(=O)[nH]c2)OC1(C)C
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3ccc(=O)[nH]c3)cc1N(c1ccc(S(C)(=O)=O)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
To a solution of (R)-8-bromo-1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (150 mg, 0.34 mmol) in 1,4-dioxane and H2O (10:1, 5 mL) were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (218.50 mg, 88.95 mmol), Cs2CO3 (218.5 mg, 0.67 mmol) and Tetrakis(triphenylphosphine)palladium(0) (24.5 mg, 0.03 mmol). The mixture was purged with N2 and stirred in the microwave at 130° C. for 20 min. The reaction solution was concentrated and purified by prep-TLC (elute: DCM:CH3OH=15:1) to give (R)-5-(1,4-dimethyl-6-(4-(methylsulfonyl)phenyl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)pyridin-2(1H)-one (70 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21][CH3:22])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].C(#N)C.[OH-].[OH:49][CH2:50][CH2:51][N+:52]([CH3:55])([CH3:54])[CH3:53]>O>[OH:49][CH2:50][CH2:51][N+:52]([CH3:55])([CH3:54])[CH3:53].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21][CH3:22])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O-:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:25])[F:26])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1c(N2CCC(C(=O)[O-])CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (0.63 mmol) of 1-[6-fluoro-8-methoxy-3-({[2-methyl-4-(trifluoromethoxy)benzyl]amino}carbonyl)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylic acid (Example 47) are suspended in 20 ml of deionized water and 20 ml of acetonitrile at RT. 140 μl (153 mg, 0.63 mmol) of β-hydroxyethyltrimethylammonium hydroxide (“choline hydroxide”) are added and the mixture is stirred at RT overnight. The resulting solution is freed from the acetonitrile on a rotary evaporator. The aqueous solution which remains was frozen and lyophilized. 494 mg (100% of theory) of residue, which is found by analysis to correspond to the title compound, are obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH:6]([NH:7][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21])[CH3:8])[CH3:3]
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of L-alanine ethyl ester hydrochloride (50 g, 325 mmol) in anhydrous dichloromethane (800 mL) added triethylamine (65.8 g, 650 mmol) and stirred at room temperature for 30 minutes. To the reaction mixture cyclopropanecarbonyl chloride (50.96 g, 0.487 mole) was slowly added and stirred at room temperature for overnight. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a mixture of ethyl acetate:hexane (1:1) as eluant to give 2-(cyclopropanecarbonyl-amino)-propionic acid ethyl ester (163) (58.0 g, 96% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:8][NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:8][N:9]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:6][CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(CC)CNC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-2-cyclopentylaminomethyl-butanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.3 g of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-butanoic acid ethyl ester (IV-12).
Reaction SMILES: BrC1C=C2C(=CC=1)N=C(S[C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)C=C2.Br[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Br:36])[CH:32]=2)[N:27]=1.SC1C=CC([OH:44])=CC=1>>[Br:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([O:44][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[CH:35]=[CH:34]2
Reactant: Brc1ccc2nc(Br)ccc2c1
Reactant: Oc1ccc(S)cc1
Reactant: CC(Oc1ccc(Sc2ccc3cc(Br)ccc3n2)cc1)C(=O)O
Product: CC(Oc1ccc(Oc2ccc3cc(Br)ccc3n2)cc1)C(=O)O

Procedure:
Also, 2-(4-((6-bromo-2-quinolinyl)thio)phenoxy)propionic acid, m.p. 163°-169° C., was prepared by reacting 2,6-dibromoquinoline with 4-mercaptophenol as described hereinbefore. The corresponding 6-chloro substituted analog is among the preferred embodiments of the invention.