Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8][CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8][CH:9]([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)O
Reaction time: 16 h

Procedure:
A solution of 51.4 g (0.124 mol) of the R enantiomer of ethyl 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)phenoxy]-propionate in 95 ml of ethanol was added dropwise to a stirred solution of 5.9 g (0.148 mol) of sodium hydroxide in 145 ml of water at 0° C. During this procedure, the reaction mixture foamed to such an extent that, after 2/3 of the ester solution had been added, a further 10 ml of ethanol had first to be introduced into the reaction mixture before the remainder of the ester solution could be added. Stirring was continued for a further 16 hours, while cooling with ice, and working-up was then carried out by acidifying the mixture with hydrochloric acid, extracting the resulting mixture three times with methylene chloride, drying the extracts and evaporating them down. The remaining residue was boiled with petroleum ether, and the hot mixture was filtered under suction. In this manner, 47.6 g (97.1% of theory) of the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)-phenoxy]-propionic acid were obtained in the form of a solid substance of melting point 120° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH2:39][CH2:40]I)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:36])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[Li+].C1(C2(C3C=CC=CC=3)[O:53][C:52]3[CH:54]=[CH:55][C:56]([S:58]([O-:60])=[O:59])=[CH:57][C:51]=3[O:50]2)C=CC=CC=1.C(=O)([O-])O.[Na+].Cl>CN(C)C=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:37]/[O:38][CH2:39][CH2:40][S:58]([C:56]2[CH:55]=[CH:54][C:52]([OH:53])=[C:51]([OH:50])[CH:57]=2)(=[O:60])=[O:59])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:36])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: O=S([O-])c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCCI)c4csc(N)n4)[C@H]3SC2)n2nc(CO)nc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCCS(=O)(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(CO)nc2n1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture of 146 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-iodoethoxy)imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 75 mg of 2,2-diphenyl-1,3-benzodioxol-5-sulphinic acid lithium salt and 24 mg of sodium hydrogen carbonate in 0.5 ml of N,N-dimethylformamide was stirred at 20° C. for 24 hours. The reaction mixture was treated with 5 ml of water and the pH of the mixture was lowered to 3 by the addition of 3N hydrochloric acid. The resulting precipitate was filtered off under suction, washed with a small amount of water and then dissolved in 4 ml of water with the addition of small amount of 2N sodium hydroxide solution. This solution, of pH 7.5, was applied to a MCI gel column (CHP2OP) conditioned with 1% aqueous acetic acid and chromatographed according to the procedure described in Example 16. The fraction eluted with a 1:1 (v/v) water/acetonitrile mixture was concentrated in a vacuum and lyophilized. The lyophilizate was dissolved in 90% aqueous trifluoroacetic acid and the solution was stirred at 20° C. for 20 minutes. The solvents were removed in a vacuum and the residue was partitioned between ethyl acetate and 2% sodium hydrogen carbonate solution. The aqueous phase was chromatographed according to the procedure described in Example 16. After concentration and lyophilization of the pure fractions, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4thiazolyl)-2-[[2-[(3,4-dihydroxyphenyl)sulphonyl]ethoxy]imino]acetamido]-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH:1]1([CH:4]2[CH:13]=[CH:12][C:11]3[C:6](=[C:7]([O:32][CH:33]([F:35])[F:34])[CH:8]=[CH:9][C:10]=3[C:14]3[N:23](COCC[Si](C)(C)C)[C:17]4[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=4[CH:15]=3)[O:5]2)[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CCC1.C(=O)([O-])O.[Na+]>>[CH:1]1([CH:4]2[CH:13]=[CH:12][C:11]3[C:6](=[C:7]([O:32][CH:33]([F:34])[F:35])[CH:8]=[CH:9][C:10]=3[C:14]3[NH:23][C:17]4[CH:18]=[N:19][NH:20][C:21](=[O:22])[C:16]=4[CH:15]=3)[O:5]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c3c2C=CC(C2CC2)O3)cc2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)cc2c(=O)[nH]ncc21
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c4c3C=CC(C3CC3)O4)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
Reaction was carried out in the same manner as in Example 31-(b) except for using 194 mg (0.387 mmol) of 2-(2-cyclopropyl-8-difluoromethoxy-2H-chromen-5-yl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 58-(a) in place of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with a mixed solvent (chloroform/methanol=9/1 (V/V)). The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained solid were added methanol and 28% aqueous ammonia, and the mixture was stirred under room temperature for 3 hours. Then, the solution was concentrated under reduced pressure and the obtained residue was applied to silica gel column chromatography (Eluent; chloroform:methanol=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 81 mg of the title compound as a white solid. (Yield: 56%)
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[N:5]2[C:6]3[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:7]=3[O:8][C:9]([CH3:11])([CH3:10])[C:4]2=[N:3]1>CO.[Pd]>[NH2:16][C:14]1[CH:13]=[CH:12][C:7]2[O:8][C:9]([CH3:11])([CH3:10])[C:4]3[N:5]([C:19](=[O:20])[N:2]([CH3:1])[N:3]=3)[C:6]=2[CH:15]=1
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OC2(C)C
Agent: [Pd]
Solvent: CO
Product: Cn1nc2n(c1=O)-c1cc(N)ccc1OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.4 %

Procedure:
2,4,4-Trimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (249 mg) and 10% Pd—C were suspended in methanol (5 mL). The reaction mixture was stirred at room temperature under H2 atmosphere (1 atm) overnight. The catalyst was filtered off over celite and washed with methanol (5×20 mL). The filtrate was evaporated to give 8-amino-2,4,4-trimethyl-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one (245 mg, quant).
Reaction SMILES: C([O:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:8])(C)(C)C.C(O)C>ClC(Cl)C>[OH:5][NH:6][C:7]([C:9]1([N:22]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NOC(C)(C)C)CCN(Cc3ccccc3)CC2)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)NO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[N-t-Butyloxycarbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]piperidine is dissolved in dichloroethane (60 mL) and ethanol (1.0 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 30 minutes at -10° C. The tube is sealed, gradually warmed to room temperature, and stirred overnight. At this point, hydrochloric acid gas is again bubbled through the reaction mixture as done previously and stirred at room temperature for an additional 24 hours. The reaction mixture is reduced to 1/3 volume in vacuo and triturated with diethyl ether. The solid is filtered off and dried in vacuo to provide 4-[N-hydroxy-carbamoyl]-4-[[4-methoxybenzenesulfonyl](benzyl)amino]-1-[benzyl]-piperidine, m.p. 135.5°-142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:4]1[C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=[C:2]([N:39]3[CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37][CH2:38]3)[CH:3]=1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: COC1CCNCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Solvent: O
Product: COC1CCN(c2cnc(N3CCOCC3)c(Nc3c(C)c(-c4ccccn4)nc4cc(F)cc(F)c34)c2)CC1
Temperature: 100 °C
Reaction time: 21.5 h

Procedure:
A stirred mixture of N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.057 g, 0.110 mmol), 4-methoxypiperidine (commercially available from Oakwood Products, Inc.) (0.035 g, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.013 g, 0.014 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (0.012 g, 0.026 mmol), and sodium tert-butoxide (0.056 g, 0.58 mmol) in dry toluene (3.0 mL) was purged three times with argon and placed under vacuum three times, then the mixture was heated to 100° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with DCM:MeOH (95:5), the organics were combined and dried over anhydrous magnesium sulfate. After filtration and concentration the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a light yellow solid as 5,7-difluoro-N-(5-(4-methoxy-1-piperidinyl)-2-(4-morpholinyl)-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine. Mass Spectrum ESI (pos.) m/e: 547.2 (M+H)+.
Reaction SMILES: Cl.Cl.N[C@H]1CCN(CC(C2CCCC[C@H]2O)C2C=CC=C([Cl:17])C=2)C1.[Cl:25][C:26]1[CH:27]=[C:28]([C@@H:32]([C:48]2([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:33]([N:35]2[CH2:39][CH2:38][C@H:37]([NH:40]C(=O)OC(C)(C)C)[CH2:36]2)=O)[CH:29]=[CH:30][CH:31]=1>CO>[ClH:17].[ClH:25].[NH2:40][C@H:37]1[CH2:38][CH2:39][N:35]([CH2:33][C@H:32]([C:48]2([OH:54])[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[CH2:36]1
Reactant: N[C@H]1CCN(CC(c2cccc(Cl)c2)C2CCCC[C@H]2O)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)[C@@H](c2cccc(Cl)c2)C2(O)CCCCC2)C1
Agent: Cl
Solvent: CO
Product: N[C@H]1CCN(C[C@@H](c2cccc(Cl)c2)C2(O)CCCCC2)C1

Procedure:
In an analogous manner to Example 1, step 2,1-[(1R)-2-[(3S)-3-aminopyrrolidin-1-yl-1-(3-chlorophenyl)ethyl]cyclohexanol dihydrochloride was prepared from tert-butyl {(3S)-1-[(2S)-2-(3-chlorophenyl)-2-(1-hydroxycyclohexyl)acetyl]pyrrolidin-3-yl}carbamate (see Example 387B). MS (ES) m/z 323.1; HRMS: calcd for C18H27ClN2O+H+, 323.18847; found (ESI, [M+H]+), 323.188; [α]D25=+24° (c=0.0105 g/mL, MeOH); CD=−@281 nm.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:20]2[N:11]([C:12](=[O:30])[C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[CH:17][C:18]=3[C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:10][CH2:9][CH:8]=1)(=O)=O>CCO.CCOC(C)=O.O=[Pt]=O>[F:27][C:23]1[CH:22]=[C:21]([C:19]2[C:18]3[CH:17]=[C:16]([O:28][CH3:29])[CH:15]=[CH:14][C:13]=3[C:12](=[O:30])[N:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:20]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(OS(=O)(=O)C(F)(F)F)=CCC3
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)CCCC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 11-(3-fluorophenyl)-9-methoxy-6-oxo-3,6-dihydro-4H-pyrido[1,2-b]isoquinolin-1-yl trifluoromethanesulfonate in EtOH (4 ml) and EtOAc (2 mL) was added PtO2 as a slurry in EtOH. The reaction was stirred at room temp under an H2 balloon for 16 h. The mixture was filtered through celite and concentrated. Flash chromatography (40 g silica, 30-80% EtOAc/hexanes) gave the titled compound.
Reaction SMILES: [OH-].[Na+].[CH:3]([N:6]1[CH2:13][CH:12]2[CH2:14][CH:8]([CH2:9][NH:10][CH2:11]2)[CH2:7]1)([CH3:5])[CH3:4].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl.C(OCC)(=O)C>[C:15]([N:10]1[CH2:11][CH:12]2[CH2:14][CH:8]([CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:13]2)[CH2:9]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N1CC2CC(CN(C(=O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 82.4 %

Procedure:
A three-necked, 50-mL, round-bottomed flask was equipped with a magnetic stirrer, an ice bath, a standard condenser with a N2 inlet, and two glass stoppers. To a solution of 10% NaOH (8.94 g, 22.3 mmol) was added the amine (31, 1.14 g, 6.77 mmol) in CH2Cl2 (15 mL) in one portion. Dropwise addition of a solution of benzoyl chloride (1.05 g, 7.45 mmol) in CH2Cl2 (5 mL) to the mixture over 15 min under N2 was followed by stirring an additional 2.75 h at RT. After the addition of H2O (30 mL), the organic layer was separated. Additional extracts (CH2Cl2, 3×25 mL) were combined with the initial organic layer, dried (Na2SO4, 1 h), filtered, and concentrated (aspirator followed by vacuum pump, 1 h, RT/0.2 mm Hg) to give an orange oil. Chromatography of the oil was performed over neutral alumina (200 g, 2.1 cm×33 cm) with ethyl acetate as eluant. Fractions (Rf =0.70) were combined and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to yield 1.52 g (82.4%) of the amide (32) as an oil which was used without further purification. IR (film) cm-1 3085, 3065, 3035 (Ar C--H), 2970, 2925, 2865, 2805, 2780, 2750 (C--H), 1635 (C=O), 730, 710 (C--H out of plane, mono); 1H NMR (DCCl3) δ0.96 (d, 3 H, CH3, J=6.4 Hz), 1.07 (d, 3 H, CH3, J=6.6 Hz), 1.65-1.78, [m, 3 H, H(5) and H(9)], 1.97 [bs, 1 H, H(1)], 2.41 [d, 1 H, H(4)ax, J=10.3 Hz], 2.50 [d, 1 H, H(6)ax , J=11.0 Hz], 2.62 [m, 1 H, CH(CH3)2, J=6.5 Hz], 2.72 [d, 1 H, H(6)eq, J=10.6 Hz], 3.04-3.07 [m, 2 H, H(2)ax and H(4)eq ], 3.30 [d, 1 H, H(8)ax, J=13.2 Hz], 3.74 [d, 1 H, H(8)eq, J=12.8 Hz], 4.77 [d, 1 H, H(2)eq, J=13.9 Hz], 7.28-7.41 (m, 5 H, Ar--H); 13C NMR (DCCl3) ppm 16.30 (CH3), 19.33 (CH3), 29.06 [C(1)], 29.76 [C(5)], 32.29 [C(9)], 46.55 [C(2)], 52.19 [C(4)], 52.62 [C(8)], 54.34 [CH(CH3)2 ], 54.75 [C(6)], 126.75, 128.24, 128.67, 137.75 (Ar--C), 170.09 (C=O).
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[CH:4][C:5]([NH:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[N:39]=[C:40]=S.CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[NH:39][C:40]1[N:9]([CH3:10])[C:5]2[CH:4]=[C:3]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12]3)[C:2]([F:1])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(F)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(F)c(N3CCC(C(F)(F)F)CC3)cc21

Procedure:
The title compound was prepared in analogy to Example 76 using 5-fluoro-2-methylamino-4-(4-trifluoromethyl-piperidin-1-yl)aniline (175 mg, 0.60 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol), DIC (76 mg, 0.60 mmol) and DMF (3 mL).
Reaction SMILES: [C:1](=[O:3])=[O:2].[NH2:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:12])[NH2:11]>O>[C:1](=[O:14])([OH:3])[OH:2].[NH2:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[NH:11])[NH2:12]
Reactant: O=C=O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Product: O=C(O)O
Reaction time: 36 h

Procedure:
Arginine bicarbonate may be produced by bubbling carbon dioxide gas through a saturated arginine aqueous solution at room temperature and pressure. U.S. Pat. No. 6,217,851 describes preparing arginine bicarbonate from arginine hydroxide by bubbling carbon dioxide or by adding dry ice in excess into a solution of arginine free base. However, the efficiency of the existing process needs to be improved. The existing process is slow, requiring 24 to 48 hours to complete the reaction. Carbon dioxide has very limited solubility in water, and releasing the gas into the solution produces a maximum concentration of 1.2×10−5M at room temperature and its natural partial pressure (3.5×10−4 atmosphere). The solubility of arginine in water is only 15% weight/weight at room temperature. Producing a concentrated arginine bicarbonate solution (e.g., 40%) requires the continual addition of arginine to the solution, thereby increasing production time and requiring constant monitoring of the reaction. Thus, there is a need to improve methods to manufacture arginine bicarbonate.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])=[N:16][CH:17]=2)[CH2:7]1.[OH-].[Na+].Cl>CO>[CH3:28][N:2]([CH3:1])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[N:16][CH:17]=2)[CH2:7]1
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3N(C)C)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccccc1CN1CC[C@@H](Nc2cnc(/C=C/C(=O)O)cn2)C1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (2E)-3-[5-({(3R)-1-[2-(dimethylamino) benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate (235 mg) in MeOH (1.9 mL) was added 1N NaOH aq. (1.2 mL), which was stirred at 55° C. for 1 hour. To the reaction mixture was added 1N—HCl aq. (1.2 mL), and evaporated in vacuo to give a crude (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylic acid as, a brown solid (0.310 mg). This was used next reaction without purification.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:28][C:27]1[C:18]([N:17]=[C:8]=[S:9])=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (2.29 g) (Aldrich) and 4-dimethylaminopyridine (DMAP)(0.02 g) in CH2Cl2 (50 mL) is added dropwise a solution of 7-amino-8-methylquinoline (1.3 g) in CH2Cl2 (50 mL). The mixture is stirred for 5 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 8-methyl-7-quinolinylisothiocyanate as a pale yellow solid.
Reaction SMILES: O.C([NH:5][C:6]1[NH:7][C:8](=[O:42])[C:9]([CH2:19][CH2:20][NH:21][C:22]2[CH:41]=[CH:40][C:25]([C:26]([NH:28][C@H:29]([C:36]([O:38]C)=[O:37])[CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:27])=[CH:24][CH:23]=2)=[C:10]([N:12](C(=O)C)C(=O)C)[N:11]=1)(=O)C.C(O)C.SCCO>[OH-].[Na+]>[NH2:5][C:6]1[NH:7][C:8](=[O:42])[C:9]([CH2:19][CH2:20][NH:21][C:22]2[CH:41]=[CH:40][C:25]([C:26]([NH:28][C@H:29]([C:36]([OH:38])=[O:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])=[CH:24][CH:23]=2)=[C:10]([NH2:12])[N:11]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(NCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1)C(=O)OC
Agent: OCCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(N)c(CCNc2ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc2)c(=O)[nH]1
Reaction time: 18 h
Yield: 38 %

Procedure:
A crude preparation of dimethyl N-[4-[2-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamate hydrate (prepared on a 3.3 mmol scale but without recrystallization) was dissolved in 1N sodium hydroxide (100 ml) and ethanol (50 ml) containing 2-mercaptoethanol (0.25 ml). The reaction was heated with stirring to 55° for 18 hours and then spin evaporated in vacuo to a small volume. The pH of the ice bath cooled solution was adjusted to pH 4 with hydrochloric acid (12N) to precipiate the product. Recrystallization from methanol/ether gave 0.52 g (38% of theory) of N-[4-[2-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)ethylamino]benzoyl]-L-glutamic acid, mp 180°-185°.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH2:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:17])[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Product: CN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-benzenesulfonamide (Acros), the title compound was obtained as a pale brown solid after purification by preparative HPLC.