Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[Cl:13])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[N:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[S:28]>>[Cl:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]1[N:29]=[C:27]([N:26]([C:18]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[CH2:30][CH2:31][CH3:32])[S:28][C:2]=1[CH3:14]
Reactant: CCCN(C(N)=S)c1cc([N+](=O)[O-])ccc1OC
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc([N+](=O)[O-])ccc1OC

Procedure:
By carrying out the procedure according to EXAMPLE 12 and by using 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound 1-2) and N-(2-methoxy-5-nitrophenyl)-N-propylthiourea, the expected product is obtained in the form of a powder; m.p.=97° C.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19](=[O:26])[CH:20]([CH2:24]I)[CH:21]([CH3:23])[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:6]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19](=[O:26])[C@H:20]([CH2:24][S:3][C:1](=[O:4])[CH3:2])[CH:21]([CH3:22])[CH3:23])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC([O-])=S
Reactant: CC(C)C(CI)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Potassium thioacetate (19 g) was added to a solution of the 4-(R)-benzyl-3-(2-iodomethyl-3-methylbutanoyl)oxazolidin-2-one (56 g) in N,N-dimethylformamide (200 ml), and the mixture was stirred for 3 h at room temperature, then poured into water (600 ml). The mixture was extracted with diethyl ether (2×500 ml) and the organic solvent washed with water and saturated brine, dried (Na2SO4) and evaporated to give the title compound as a pale amber oil (48.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:18]1([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:22]=[N:21][N:20]=[N:19]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([N:18]4[CH:22]=[N:21][N:20]=[N:19]4)=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(-n2cnnn2)cc1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: O=C(c1ccc(-n2cnnn2)cc1)N(C1CC1)C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-tetrazol-1-yl-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.05 min; Mass spectrum (ESI+): m/z=425 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CN(C=O)C>[CH2:3]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
403 mg (10.1 mmol) of sodium hydride (60% oily) was added to 1.102 g (10.2 mmol) of benzyl alcohol in 15 ml of DMF, and they were stirred for 30 minutes. 2.51 g (9.99 mmol) of ethyl 8-bromooctanoate was dissolved in 5 ml of DMF, and the obtained solution was added dropwise to the reaction mixture in ice bath. After stirring at room temperature for 1.5 hours, 2 N hydrochloric acid was added to the mixture. DMF was evaporated under reduced pressure. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1/) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[OH:17].[CH2:18](I)[CH2:19][CH2:20][CH3:21]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCI
Reactant: CCOC(=O)c1cc2ccccc2c(Br)c1O
Product: CCCCOc1c(C(=O)OCC)cc2ccccc2c1Br

Procedure:
The intermediate was prepared from ethyl 4-bromo-3-hydroxynaphthalen-2-carboxylate and butyl iodide in almost quantitative yield and used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1cnccn1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cnccn1
Reaction time: 0.08 h

Procedure:
A solution of 2-dimethylaminoethanol (1 mL) in THF (20 mL) was treated with potassium tert-butoxide (1.2 g). After 5 min, chloropyrazine (2 g) was added and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold water, the mixture acidified, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 10%-EtOH-1%-NH4OH—CHCl3 to give 2-(2-dimethylaminoethoxy)pyrazine (1.3 g). The HCl salt crystallized from 2-propanol as a white solid, m.p. 151-153° C. (Compound 26).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:31]2[CH:30]=[C:29]([F:28])[CH:36]=[C:35]([F:37])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 507.4(M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]>>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=3)=[O:12])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C(N)=O

Procedure:
2-Acetylamino-4-{4-[(3-(4-trifluoromethoxyphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide may be prepared as described in Example 12 from 4-(trifluoromethoxy)phenyl isocyanate and 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50].Cl>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:23](=[O:25])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:22][CH:21]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
DIPEA (126 mg, 0.17 mL, 0.98 mmol) was added drop wise to 6-(phenyl-amino)-pyridine-3-carboxylic acid (70 mg, 0.32 mmol) in DMF (5 mL). EDCI (74 mg, 0.39 mmol) and HOBT (53 mg, 0.39 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (137 mg, 0.39 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated to afford 110 mg (65% yield) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-6-phenylamino-nicotinamide. LC-MS purity: 93.71%. 1H-NMR (DMSO-d6): δ 9.4 (s, 1H), 8.7 (s, 1H), 8.5 (t, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 7.7 (d, 3H), 7.6 (m, 1H), 6.9 (t, 1H), 6.8 (d, 1H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3](/[CH:8]=[N:18]/[C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ncccc1F
Reactant: COc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(/N=C/c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
3-Fluoro-2-formylpyridine (229 g) and paraanisidine (225 g) were dissolved in toluene (2.29 l). After adding anhydrous sodium sulfate (334 g), the mixture was stirred at room temperature for 1 hour. After filtering off the insoluble matters, the liquid reaction mixture was concentrated under reduced pressure to thereby give the title compound (449 g).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=O)=O.Cl>O>[C:23]([NH:22][CH2:21][CH2:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]([O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]3[C:17]([CH:16]=[CH:15][CH:14]=[C:13]3[CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:19]=1)[CH:19]=[CH:18]2)(=[O:25])[CH3:24]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Agent: Cl
Solvent: O
Product: CC(=O)NCCc1cccc2ccc(OCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc12
Reaction time: 0.33 h

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, 0.06 g of sodium is added in small portions. When the sodium has been completely used up, 0.0033 mol of the compound obtained in Preparation 1 is added, and the mixture is stirred for 20 minutes. The methanol is removed by evaporation under reduced pressure, the residue is taken up in 15 ml of DMF, and then 0.0027 mol of the compound obtained in Step B is added. The reaction mixture is then heated at reflux for 12 hours and subsequently cooled and poured into 100 ml of water and 10 ml of 3M HCl. After extraction with ethyl acetate, the organic phase is washed with a 10% sodium hydroxide solution and then with water. After drying over MgSO4 and removal of the solvent by evaporation under reduced pressure, the title compound is obtained by recrystallisation. Beige solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19](O)=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1.Cl.C[N:35](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([O:22][C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][C:16]([C:19]([NH2:35])=[O:20])=[CH:15]3)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(=O)O)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3cccc(Cl)n3)c3[nH]c(C(N)=O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
A mixture of 7-[(6-chloropyridin-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (780 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (632 mg), 1-hydroxybenzotriazole ammonium salt (502 mg) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water and diethyl ether to give the title compound (680 mg, yield 90%) as a white solid. The obtained crystals were recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 259-260° C.
Reaction SMILES: [CH:1]([N:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][C:4]1(C(OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:2].[Cl-].[Na+].O>CS(C)=O>[CH:1]([N:3]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][C:6](=[CH2:14])[CH2:5][CH:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:2]
Reactant: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)(C(=O)OCC)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=C1CC(C(=O)OCC)N(C=O)C(C(=O)OCC)C1
Temperature: 165 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 5 g of the product of Step B, 0.8 g of sodium chloride, 0.26 g of water and 15 ml of dimethylsulfoxide was stirred for 3 hours at 165° C. and the mixture was returned to ambient temperature followed by filtering, washing and evaporating to dryness to obtain 4 g of product which was purified on silica eluting with a cyclohexane-ethyl acetate (9-1) mixture, then by a cyclohexane-ethyl acetate (7-3) mixture to obtain 3.1 g of the desired product with a Rf=0.5.
Reaction SMILES: [Cl:1]C1C=C(Cl)C=CC=1OCCCN1CC=CCC1.[Cl:19][C:20]1[C:35]([Cl:36])=[C:34]([Cl:37])[CH:33]=[CH:32][C:21]=1[O:22][CH2:23][CH2:24][CH2:25]N1CC=CCC1>>[Cl:37][C:34]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][CH2:25][Cl:1])=[C:20]([Cl:19])[C:35]=1[Cl:36]
Reactant: Clc1ccc(OCCCN2CC=CCC2)c(Cl)c1Cl
Reactant: Clc1ccc(OCCCN2CC=CCC2)c(Cl)c1
Product: ClCCCOc1ccc(Cl)c(Cl)c1Cl

Procedure:
IR (CHCl3); 3022, 2968, 2884, 1577, 1448, 1422, 1386, 1285, 1256, 1220; NMR (CDCl3) δ (300 MHz); 2.290 (quint., J=6 Hz, 2H); 3.798 (t, J=6 Hz, 2H); 4.180 (t, J=6 Hz, 2H); 6.824 (d, J=9 Hz, 1H); 7.322 (d, J=9 Hz, 1H). (2) Preparation of 3g; 1-[3-(2,3,4-Trichloro-phenoxy)-propyl]-1,2,3,6-tetrahydro-pyridine
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([NH:16][CH2:17][C:18]([OH:20])=[O:19])(=O)[CH3:14].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:14][C:13]1[O:20][C:18](=[O:19])[C:17](=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]([F:12])([F:11])[F:1])[N:16]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1=NC(=Cc2ccccc2C(F)(F)F)C(=O)O1
Temperature: 0 °C

Procedure:
20 g o-Trifluoromethyl benzaldehyde, 60 g N-acetylglycine and 12 g sodium acetate were stirred in 68.2 g acetic anhydride at 80° C. for 22 hrs. The mixture was poured into 100 ml ice water, the precipitate filtered off and washed with water. Yield 35 g of wet crude product, used without further purification fort the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:30][C:31]([C@H:33](OS(C(F)(F)F)(=O)=O)[CH3:34])=[O:32]>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:25][CH3:26])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[C@H:33]([C:31]([OH:32])=[O:30])[CH3:34])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: COCCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-methoxyethyl)amino]methyl}quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-methoxyethyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.28 (d, 3H); 2.85 (t, 2H); 3.13 (s, 3H); 3.34 (m, 2H); 3.56 (q, 1H); 3.93 (m, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.48 (t, 1H); 7.57 (m, 1H); 8.41 (m, 2H); 9.70 (brs, 1H); Mass Spectrum: (M+H)+ 463.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:17]([OH:19])[CH3:18])[C:14]([NH:29][NH:28][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: NNC(=O)c1ccccc1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (intermediate 61a) (0.62 g, 2.24 mmol), benzoic hydrazide (310 mg, 2.28 mmol), HOBt (308 mg, 2.28 mmol) in THF:DMF (1:1) (30 mL) was added EDC (645 mg, 3.36 mmol) and Et3N (0.47 mL, 3.37 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. After concentration, the residue was purified by flash chromatography to give two fractions. The first fraction (208 mg) contained mainly the title compound and some impurities. The second fraction was the pure desired compound N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (0.58 g, 66%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.95 (m, 2H), 7.84 (d, J 5.7 Hz, 1H), 7.71 (d, J=5.7 Hz, 1H), 7.67 (d, 8.2 Hz, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 6.69 (d, J=8.2 Hz, 1H), 6.37 (d, J=6.9 Hz, 1H), 4.18˜4.26 (m, 2H) 1.41 (d, J=6.3 Hz, 3H),
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.Cl>O1CCCC1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(-c2oncc2CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2oncc2CCC(=O)O)cc1
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of diethyl malonate (11.0 g) in tetrahydrofuran (60 ml) was gradually added sodium hydride (60%, oil, 2.50 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-methylphenyl)isoxazole (6.48 g) in tetrahydrofuran (80 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (80 ml) and acetic acid (120 ml). The mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate-hexane to give a colorless prism (5.03 g, yield 70%) of 3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid. melting point: 121–122° C.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([OH:12])=O)[CH2:2]1.S(Cl)(Cl)=O.C1(C)CCC(C(C)C)C(C(Cl)=O)C1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32].[OH-].[Na+]>>[CH2:31]([N:33]([CH2:34][CH3:35])[C:10]([CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:12])[CH3:32]
Reactant: CCNCC
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Agent: CC1CCC(C(C)C)C(C(=O)Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C1CC(C)CCC1C(C)C

Procedure:
Following the procedure of Example 5, p-menthane-3-carboxylic acid (1.84 g.) was reacted with thionyl chloride and the p-menth-3-oyl chloride then reacted with diethylamine (0.74 g.) in the presence of sodium hydroxide (0.4 g.). The product N,N-diethyl-p-menthane-3-carboxamide was recovered.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)([CH2:4][CH2:5][CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:2]1.[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH2:34])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:21]([O:25][C:26](=[O:37])[C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:32](=[O:36])[C@H:33]([CH3:35])[NH:34][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][C:3]1([O:19][CH2:20][CH2:1][O:2]1)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: CCOC(=O)C(=O)CCCC1(c2cccs2)OCCO1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCCC1(c2cccs2)OCCO1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Ethyl 6,6-ethylenedioxy-2-oxo-6-(2-thienyl)-hexanoate (3 g.) and L-alanyl-L-proline t-butyl ester (2.5 g.) were added to a suspension of freshly activated 4 Å molecular sieve (15 g.) in ethanol (35 ml.) and the mixture was stirred at laboratory temperature for 1 hour. Acetic acid (1.25 ml.) was added, and sodium cyanoborohydride (0.625 g.) was then added in portions during 1 hour. The mixture was stirred at laboratory temperature for 48 hours and then filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on a silica gel column using a 40:1 v/v mixture of dichloromethane and methanol as eluant. There was thus obtained as an oil N-[1-ethoxycarbonyl-5,5-ethylenedioxy-5-(2-thienyl)pentyl]-L-alanyl-L-proline t-butyl ester.