Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]4[CH2:24][CH2:23][C:22]5([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.[OH-].[Li+].C(O)C.O>>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH:19]3[CH2:24][CH2:23][C:22]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 31.2 %

Procedure:
The mixture of (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)oxazolidin-2-one (324 mg, 0.000823 mol) and lithium hydroxide (294 mg, 0.0123 mol) in ethanol (7.1 mL, 0.12 mol) and water (2.4 mL, 0.13 mol) was heated to reflux for overnight. The solvent was removed under vacuum and the residue was partitioned between water/CH2Cl2. The aqueous was extensively extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into methylene chloride and subjected to chromatography purification with MeOH/CH2Cl2 (10:90 to 80:20) to give the product (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-1-ol as a white powder (94.5 mg, 31.2%). LCMS Rf=1.70 min 351.34 ([M-NH2]+, 100%). 1H NMR (400 MHz, MeOD) δ=7.86 (d, J=1.6 Hz, 1 H), 7.78 (d, J=9.0 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.57 (dd, J=2.0, 8.7 Hz, 1 H), 7.22 (d, J=2.1 Hz, 1 H), 7.14 (dd, J=2.4, 8.9 Hz, 1 H), 4.53-4.44 (m, 1 H), 3.75 (d, J=11.0 Hz, 1 H), 3.70 (d, J=11.0 Hz, 1 H), 2.01-1.88 (m, 2 H), 1.80-1.65 (m, 4 H), 1.55 (s, 3 H), 1.50 (m, 8 H), 1.42-1.30 (m, 4 H).
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=O)([C:3](OCC)=[O:4])=[O:2].C([O-])(=O)C.[NH4+:23]>C(O)(=O)C>[NH:8]1[C:1](=[O:2])[C:3](=[O:4])[NH:23][C:10]2=[C:11]3[C:16]([CH:17]=[C:9]12)=[CH:15][CH:14]=[CH:13][CH2:12]3
Reactant: CCOC(=O)C(=O)NC1Cc2ccccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c2c([nH]c1=O)=C1CC=CC=C1C=2
Temperature: 20 °C
Yield: 76.1 %

Procedure:
1.25 g of 2-ethoxalylamino-1-indanone are added rapidly to a solution of 12.5 g of ammonium acetate in 50 ml of acetic acid brought to reflux under nitrogen. After 18 hours of reflux, the reaction medium is cooled to a temperature in the region of 20° C. The precipitate formed is filtered off, washed copiously with water and dried under a partial vacuum (1 mm Hg; 0.13 kPa) at 50° C. 0.77 g of 1,4-dihydro-5H-indeno[1,2-b]pyrazine-2,3-dione are thereby obtained in the form of a green powder, the melting point of which is above 260° C. (analysis C11H8N2O2 ; 1.18 H2O; % calculated C: 66.00; H: 4.03; N: 13.99; % found C: 65.7; H: 3.9; N: 13.9).
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[C:16]([NH:20][C:21]([NH2:23])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:17][C:16]([NH:20][C:21]1[O:22][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[N:23]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(C)NC(N)=O
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)c1nc(NC(C)(C)C)oc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 37.4 %

Procedure:
By the procedure of Example 50, 12.35 g (50 mmol) of methyl 3-chloro-3-(o-chlorophenyl)pyruvate was reacted with 5.8 g (50 mmol) of tert-butyl urea at 105°-115° C. for 8 hours. The reaction mixture was cooled to ambient temperature and then diluted with methylene chloride, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to yield a yellow oil. This oil was purified by flash chromatography techniques on silic gel using 10% ethyl acetate in hexane as eluent. There was obtained 5.77 g of an orange viscous oil product identified in Table I.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][C:16](OCC)=[O:17]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][C:16](=[O:17])[NH:11][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCl
Reactant: NC(=O)Nc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(c2cccc(I)c2)C(=O)N1
Reaction time: 5 h

Procedure:
A solution of 3-iodophenylurea (2.1 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion; 640 mg), followed by ethyl chloroacetate (0.93 ml) and the mixture was stirred for 5 h. The mixture was partitioned between EtOAc and 2M HCl and the organic solution was washed with NaHCO3, brine, dried and evaporated to dryness to give the title compound (2.08 g) ES+ve 303(MH)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)[CH2:10][CH3:11]>>[CH2:9]([O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:10][CH3:11]
Reactant: Nc1ccc(Br)cc1
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2ccc(N)cc2)c1
Yield: 72.5 %

Procedure:
The title compound (280 mg) was prepared from 4-bromoaniline (300 mg, 1.7 mmol) and 3-propoxyphenylboronic acid (408 mg, 2.3 mmol) as a colourless liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:11]
Reactant: CCN
Reactant: Cc1cncc(CCl)n1
Solvent: C1CCOC1
Product: CCNCc1cncc(C)n1

Procedure:
prepared by reaction of 2-chloromethyl-6-methyl-pyrazine (prepared according to Eiermann U. et al, Chem. Ber., 1990, 123, 523-533) with 2M ethylamine in THF.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[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.[CH3:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:31][CH:30]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13) and 4-(methylsulfonyl)aniline (Enamine), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=O)[CH2:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]3[O:13][CH2:1][O:2][C:3]=3[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CC=Nc2cc3c(cc21)OCO3
Product: Clc1ccnc2cc3c(cc12)OCO3

Procedure:
6,7-Methylenedioxy-4-quinolone (5.0 g, 26.5 mmol) was boiled in POCl3 (75 mL) for 45 min and then cooled. Excess phosphohoryl chloride was removed under reduced pressure and ice water (100 mL) was added to hydrolyze any residual phosphoryl chloride. The mixture was basified (pH 9) with ammonium hydroxide, and the solid precipitate was filtered. This material was extracted into ethyl ether (8×100 mL), and the ether solution was dried (MgSO4) and evaporated to provide 4.55 g as a white solid, in 83%; mp 127.5-128° C. (lit. mp 129° C.); 1H NMR (CDCl3) δ 6.15 (s, 2H), 7.35 (d, 1H, J=4.7), 7.39 (s, 1H), 7.49 (s, 1H), 8.56 (d, 1H, J=4.7); 13C NMR (CDCl3) δ 99.8, 102.2, 106.1, 119.9, 123.7, 129.8, 141.2, 147.7, 149.1, 151.4.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:6])[OH:8])=[CH:26][CH:25]=1
Reactant: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)CCCNCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 0.36 g of lithium hydroxide monohydrate in 7 ml of water is added to a solution of 1.61 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester in 3 ml of ethanol, and the mixture is heated at 60° for 24 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The evaporation residue is taken up in water and neutralised with phosphoric acid. A white precipitate forms and is filtered off, and the filtrate is concentrated to dryness by evaporation. The white residue is dried under reduced pressure and crystallised from toluene/diethyl ether. Filtration with suction and drying yield 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having a melting point of 177°-179°.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:25]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(Cl)cc1Cl)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,4-dichlorobenzoyl chloride, there is obtained ethyl N-(2,4-dichloro-benzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 158°-159°-C.;
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4cccn4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-pyrazol-1-yl)benzaldehyde and 2-methyl-N-(3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 402.8 (M+H)+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:31]([NH:35][C:36](=[O:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([CH3:34])[CH3:33])([OH:30])=[O:29])[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:31]([NH:35][C:36](=[O:45])[CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH:32]([CH3:34])[CH3:33])([OH:30])=[O:29])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The benzyl (S)-6-(benzyloxycarbonylamino)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoate (85 mg) obtained in the above step (c) was dissolved in a mixed solvent of dioxane (2.4 ml) and water (0.8 ml) and added with palladium hydroxide (45.8 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered with celite and the filtrate was concentrated. The residue was purified with HP-20 (Diaion, 10 cc, methanol:water=1:4 to 1:1) to obtain the title compound: (S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid (25 mg, 45%) (a diastereoisomeric mixture of 1:1).
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:33])[CH2:20][C:21](=[O:32])[NH:22][C:23]1[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=1)[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:35][C:36]1[CH:43]=[C:42]([CH3:44])[CH:41]=[CH:40][C:37]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[C:28]([C:25]1[S:24][C:23]([NH:22][C:21](=[O:32])[CH2:20][C:19]([NH:18][C@@H:12]([CH2:11][NH:10][CH2:9][C:37]2[CH:40]=[CH:41][C:42]([CH3:44])=[CH:43][C:36]=2[CH3:35])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[O:33])=[N:27][N:26]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (67 mg, 0.43 mmol) was dissolved in 6 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with the lithium salt of N-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamic acid (151 mg, 0.43 mmol, see procedure 21a), N, N-diisopropylethylamine (0.38 mL, 2.1 mmol) and HATU (194 mg, 0.51 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester as a colorless oil (90 mg, 43% yield). MS found: (M+Na)+=510.4. (23b) A solution of {(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamic acid benzyl ester (90 mg, 0.19 mmol) in MeOH (4 mL) was charged with 5% Pd/C, Degussa style (18 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.02 mL, 0.14 mmol) and sodium cyanoborohydride (11 mg, 0.18 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=476.5.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 21 g. of methyl 16-bromohexadecanoate and 20 g. of ethyl 4-aminobenzoate in 150 ml. of hexamethylphosphoramide is stirred at 120° C. for 20 horus, cooled, diluted with water and filtered. A methylene chloride solution of the solid is dried over anhydrous magnesium sulfate, clarified with activated charcoal, and filtered through silica gel. The filtrate is evaporated and the residue crystallized from acetonitrile to yield ethyl 4-(15-carbomethoxypentadecylamino)benzoate as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]([CH2:41][CH3:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:31]=1)[CH3:28].C(OC(=O)C)(=O)C>CO>[CH2:39]([N:36]([CH2:37][CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH2:41][CH3:42])[CH2:27][CH3:28])[CH:35]=[CH:34][C:33]=1[C:8]1([C:7]2[CH:23]=[CH:24][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:13])[O:14]1)[CH3:40]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.85 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol (20 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(diethylamino)-phenyl)-4,5,6,7-tetrachlorophthalide (I: X= Y4 = (CH3CH2)2N, Y2 = H, Z4 = Z5 = Z6 = Z7 = Cl) (7.85 g., m.p. 196°-197° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.4 (br, 1H), 8.75 (s, 1H), 7.79 (m, 1H), 7.62 (d, 1H), 7.27-7.46 (m, 5H), 6.36 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.90 (s and t, 5H), 3.49 (s, 3H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[F:22][C:20]1[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([CH:21]=1)[O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1
Reaction time: 3 h

Procedure:
10 ml of a solution of HCl in dioxane (4 M) were added to 1.19 g trans-[4-(5-fluoro-2-nitro-phenoxy)-cyclohexyl]-carbamic acid tert-butyl ester in methylene chloride. The mixture is stirred for 3 hours and 2 ml of HCl in dioxane (4 M) were added. The reaction mixture was stirred for 1 hour and concentrated in vacuo.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](Cl)=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35]([N:24]([CH2:23][C:14]2[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=2[C:7]2[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=2)[CH2:25][CH3:26])=[O:36])=[CH:31][CH:30]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COc1ccc(Cl)cc1

Procedure:
[2′-({[2-(4-Chloro-phenoxy)-acetyl]-ethyl-amino}-methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid (Compound 1-93) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: Cl[O-:2].[Na+:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([O:25][CH:26]([F:28])[F:27])[CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[O:29][CH3:30]>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S+:15]([O-:2])[C:16]2[N-:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:27])[F:28])=[CH:21][C:19]=3[N:20]=2)[C:9]=1[O:29][CH3:30].[Na+:3]
Reactant: [O-]Cl
Reactant: COc1ccnc(CSc2nc3ccc(OC(F)F)cc3[nH]2)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC

Procedure:
The intermediates (V) pantoprazole sulfide and pantoprazole base as shown in the scheme were not isolated during the process of the present invention. In particular, they were not subjected to any purification. Further, the pantoprazole sulfide obtained in situ was oxidized using aqueous sodium hypohalite solution preferably an aqueous solution of sodium hypochlorite with a strength from 2-14%, and having a sodium hydroxide content from 0.5 to 10%, more preferably from 1.0 to 3.0%. We prefer that the sodium hydroxide content is at least 2%. Most preferably, the sodium hydroxide content is from 2.0 to 2.3%. The oxidation of the pantoprazole sulfide is preferably carried out at a temperature ranging from 0° C. to ambient temperature, more preferably 5-8° C. The resulting reaction mass was cooled to afford pantoprazole sodium.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][CH:8]=1)C.[CH3:29][NH:30][CH3:31]>>[CH2:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4](=[O:3])[N:30]([CH3:31])[CH3:29])=[CH:8][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNC
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Product: CN(C)C(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 55 °C
Yield: 52 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid ethyl ester 23 (0.50 g, 1.3 mmol) and dimethylamine (2.0 M in THF, 10 mL, 20 mmol) in a sealed tube was heated at 55° C. for 48 h. The solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/CH2Cl2, 1:4, 1:3, v/v) to provide [4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 28 (0.26 g, 52% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 4H), 2.55 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 3.20 (m, 2H), 4.65 (s, 2H), 5.08 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.35 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O>>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCc1[nH]nc(N)c1C#N
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)ccnc2c1C#N

Procedure:
As for Example 1, 3-amino-5-ethylpyrazole-4-carbonitrile is reacted with 3-dimethylamino-3'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 144°-146° C.