Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]/[C:29](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)O/C(=C/c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
Oxalyl dichloride (236 μl, 2.78 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (500 mg, 2.78 mmol) in DCM (30 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (40 ml). 1,2-Diphenylethanone (546 mg, 2.78 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (E)-1,2-diphenylvinyl 1-methylpiperidine-4-carboxylate (62 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=O)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])=[O:17])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)O)cs1
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a round bottom flask with 50 mL methylene chloride was added 2-((tert-butoxycarbonylamino)methyl)thiazole-4-carboxylic acid (2.0 g, 7.74 mmole) and methyl 2-amino-2-methylpropanoate hydrochloride salt (1.25 g, 8.13 mmole). To the mixture, triethylamine (5.4 mL, 38.7 mmole) was then added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.97 g, 15.5 mmole) and hydroxybenzotriazole (2.09 g, 15.5 mmole). The resulting mixture was stirred at room temperature overnight. The mixture was then diluted with methylene chloride. The mixture was then washed with water and the aqueous layer was extracted with methylene chloride. The combined organic layer was then dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 1:1 EtOAc/hexane to provide the desired product (2.40 g, 87% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][OH:31]>O.C(O)C>[OH:31][CH2:30][CH2:29][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
A mixture of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.2 g), potassium carbonate (0.1 g) and ethylenebromohydrin (0.1 g) in water and ethanol was stirred under reflux for 10 hours. The reaction mixture was concentrated and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-hydroxyethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 186°-188° C (oxalate).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([C:30]6[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-c2cccnc2)cc1

Procedure:
The title compound, white solid (110 mg, 86%), MS (ISP) m/z=512.5 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyridin-3-yl-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:12]1([O-:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].Cl>O>[O:18]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=1[C:8]([OH:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2
Reactant: [O-]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(COc2ccccc2)c(C(=O)O)c1

Procedure:
Stir a mixture of 1.0 gm of 6-methylphthalide and 0.64 gm of sodium phenolate at a temperature of 200°-210° C. for 1 hour. Cool and dissolve the reaction mixture in water. Acidify with 5% hydrochloric acid and extract with ether. Evaporate to dryness and chromatograph the residue over silica gel eluting with chloroform/methanol (50:1). Evaporate the eluate to dryness and crystallize the residue from ethyl acetate/benzene to obtain the title product.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(Cl)([Cl:25])=O.CN(C)C=O>O>[Cl:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1Cl
Yield: 50 %

Procedure:
5.0 g of 2-hydroxy-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 3, 3.55 g of thionyl chloride, and 0.2 ml of dimethylformamide were charged in a flask, and the mixture was allowed to react at 80° C. for 4 hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 2.64 g of a titled compound having a melting point of 53° to 59° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Br:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:22][CH:21]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(Br)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (3.0 g, 11.7 mmol), 6-bromo-pyridin-3-ylamine (2.0 g, 11.7 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (2.4 g, 17.5 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.4 g, 17.5 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a solid. Recrystallization of the crude solid from ethyl acetate/hexane/methanol gave 4.04 g of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide. The mother liquor was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give an additional 200 mg of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-bromo-pyridin-3-yl)-amide (4.24 g in total, 88%) as a light brown solid. LCMS calcd for C16H9BrF3N3O2 (m/e) 412, obsd 413 (M+H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.Br[C:10]1[C:24]2=[C:25]3[C:13]([N:14]([Si](C(C)(C)C)(C)C)[CH2:15][CH:16]3[CH2:17][C@@H:18]3[C@@H:23]2[CH2:22][C@H:21]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:20][N:19]3[CH3:34])=[CH:12][CH:11]=1>>[CH2:29]([N:28]([CH2:31][CH3:32])[C:27]([NH:26][C@H:21]1[CH2:22][C@H:23]2[C@@H:18]([CH2:17][C:16]3[C:25]4[C:13](=[CH:12][C:11]([I:1])=[CH:10][C:24]2=4)[NH:14][CH:15]=3)[N:19]([CH3:34])[CH2:20]1)=[O:33])[CH3:30]
Reactant: O=C1CCC(=O)N1I
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-iodosuccinimide and 3-(12-bromo-1-tert-butyldimethylsilyl-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1diethylurea:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][C:15](SC)=[N:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].CCO>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:22]=[CH:21][C:11]2[C:12]([CH3:20])([CH3:19])[CH2:13][CH2:14][C:15]([NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])=[N:16][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: CSC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2C(C)(C)CC1
Solvent: CCO
Product: COC(CNC1=Nc2cc(NC(=O)OC(C)(C)C)ccc2C(C)(C)CC1)OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(5,5-Dimethyl-2-methylsulfanyl-4,5-dihydro-3H-1-benzazepin-8-yl)-carbamic acid tert-butyl ester (1.281 g, 3.8 mmol), Aminoacetaldehyde dimethyl acetal (0.542 mL, 5 mmol), and EtOH (100 mL, 2 mol) were heated to reflux for 2 hrs and stirred at rt for 72 h. LCMS 392 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:54])[N:6]2[CH2:7][CH2:8][N:9]([CH2:11][C:12]3[CH:13]=[C:14]([C:28]4[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35](CC5C=CC(OC)=CC=5)CC5C=CC(OC)=CC=5)[N:29]=4)[C:15]([NH:18][C:19]4[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=4)=[N:16][CH:17]=3)[CH2:10][CH:5]2[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>>[O:54]=[S:2]1(=[O:1])[N:6]2[CH2:7][CH2:8][N:9]([CH2:11][C:12]3[CH:13]=[C:14]([C:28]4[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH2:35])[N:29]=4)[C:15]([NH:18][C:19]4[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=4)=[N:16][CH:17]=3)[CH2:10][CH:5]2[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN5C(CCS5(=O)=O)C4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(CN3CCN4C(CCS4(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared from 4-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)-2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine via the similar deprotection protocol as described previously in Example 178, Step 4, using trifluoroacetic acid and trifluoromethanesulfonic acid and isolated (61 mg, 30%) as a yellow solid. m/z (ESI, +ve ion) 516 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.95 (s, 1H) 8.73 (d, J=2.15 Hz, 1H) 8.42 (d, J=2.15 Hz, 1H) 8.37 (dd, J=12.81, 2.05 Hz, 1H) 8.26 (d, J=2.15 Hz, 1H) 7.91 (br. s., 1H) 7.76 (br. s., 1H) 3.93 (s, 3H) 3.45-3.62 (m, 1H) 3.00-3.30 (m, 5H) 2.80-3.00 (m, 2H) 2.62-2.74 (m, 1H) 2.44 (s, 3H) 2.23-2.36 (m, 1H) 2.06-2.16 (m, 1H) 1.81-1.96 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][C:23]([OH:25])=O)[CH:16]=3)=[N:9][C:8]=2[N:7]([CH2:26][CH:27]=[CH2:28])[C:5]1=[O:6])[CH:2]=[CH2:3].[C:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:20][N:19]1[NH:18][C:17]([O:21][CH2:22][C:23]([N:38]2[CH2:39][CH2:40][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[O:25])=[CH:16]/[C:15]/1=[C:10]1\[N:11]=[C:12]2[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[N:7]([CH2:26][CH:27]=[CH2:28])[C:8]2=[N:9]\1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2c(n(CC=C)c1=O)=N/C(=C1/C=C(OCC(=O)N3CCN(c4ccccc4)CC3)NN1C)N=2
Yield: 27 %

Procedure:
Condensation of 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (0.5 mmol) and N-phenyl-piperazine (1.3 mmol) in the presence of EDCl (1.12 mmol) and HOBt (1.14 mmol) in anhydrous dimethylformamide afforded the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:18]=1)[C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:18]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2F)nc(N2CCOCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3CCOCC3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of methyl 2-(2-fluoro-4-methylphenyl)-6-morpholin-4-ylisonicotinate (0.31 g, 0.94 mmol) in DMA (4 mL) was added sodium hydroxide (1.0 M solution in water; 1.87 mL, 1.87 mmol). The mixture was stirred at ambient temperature. After 1 h, HCl (1.0 Min water; 1.87 mL, 1.87 mmol) was added and the mixture was concentrated. Methanol was added and the mixture was filtered and the filtrate was concentrated. The mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid). HCl (1.0 M) was added and fractions were concentrated to give the hydrochloride salt of the title compound (129 mg). MS 317.0 (M+1).
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[F:10][C:6]1[C:7]([F:9])=[CH:8][C:2]2[S:15][C:14]([SH:16])=[N:4][C:3]=2[CH:5]=1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2nc(S)sc2cc1F
Temperature: 95 °C
Yield: 39.8 %

Procedure:
A mixture of 1 g (6.80 mmol) 2,4,5-trifluoroaniline and 1.33 g (8.16 mmol) potassium ethylxanthogenate in 5 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 7 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 0.55 g (40%) of the titled compound as a light yellow solid. MS(m/e): 201.9 (M−H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:26](N1CCOCC1)=[O:27]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:26]=[O:27])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.73 g; 5.21 mmol) in THF (25 mL) was added dropwise n-BuLi (2.08 mL; 2.50 mol/l; 5.21 mmol), at −78° C. The resulting mixture was stirred for one hour, and subsequently a solution of N-formylmorpholine (0.90 g; 7.81 mmol) in THF (5 mL) was added dropwise, at −78° C. The reaction was quenched by the addition of an 5% aqueous NaHCO3 solution, at −70° C. The resulting mixture was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O: hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-benzaldehyde (1.21 g).
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1([CH2:19][CH3:20])[CH2:18][O:17][CH2:16]1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([C:15]1([CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:18][O:17][CH2:16]1)[CH3:20]
Reactant: CCC1(COCCCCCCBr)COC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Yield: 66.4 %

Procedure:
A dimethylformamide (3 L) solution of 3-[(6-bromohexyloxy)methyl]-3-ethyloxetane 500 g, 4-hydroxybenzoic acid 297 g and potassium carbonate 490 g was stirred at 90° C. for 8 hours. Water 4 L was added to the reaction mixture, and then it was extracted with toluene 4 L. The organic layer was washed with water, and the solvent was distilled off. Sodium hydroxide 200 g, water 1 L and ethanol 2.5 L were added to the resulting residue and refluxed for 4 hours. Ethanol (1 L) was distilled off at atmospheric pressure, and then the solution was acidified by hydrochloric acid to obtain a slurry. The slurry was filtered and dried to thereby obtain 400 g of 4-[6-(3-ethyloxetane-3-ylmethoxy)hexyloxy]benzoic acid. Melting point: 58.5° C.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in Example 54, 2-oxo-4-phenylbutyric acid and L-histidyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-histidyl-L-proline. The product is purified by gel filtration chromatography in methanol (LH-20). The nmr spectrum is consistent with structure. The mass spectrum shows a molecular ion at 657 for the disilylated species.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]([N:16]([CH2:31][CH3:32])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=1[CH3:30])=[O:21])[CH3:15]>>[CH2:31]([N:16]([CH2:14][CH3:15])[CH2:17][CH2:18][NH:19][C:20]([C:22]1[C:26]([CH3:27])=[C:25]([CH:28]=[C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[NH:24][C:23]=1[CH3:30])=[O:21])[CH3:32]
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(C(=O)O)ccc32)c1C
Yield: 92 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid (80 mg, 0.45 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide to give 210 mg (92%) of the title compound as a yellow orange solid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[N:5]1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>C(Cl)Cl>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:9]([C:6]3[CH:7]=[CH:8][N:4]([CH:3]=[C:2]([CH3:1])[CH3:12])[N:5]=3)=[O:11])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: CC(C)=Cn1ccc(C(=O)O)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: ClCCl
Product: CC(C)=Cn1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 75.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1-(2-methylprop-1-en-1-yl)-1H-pyrazole-3-carboxylic acid (1.151 mmol, 191 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.959 mmol, 250 mg) using DCM (5 ml) as the solvent. The mixture was diluted with DCM and washed with 1 M Na2CO3. The organic phase was dried, filtered and evaporated. The crude product was purified flash chromatography. 297 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H), 1.80 (d, 3H), 1.85 (d, 3H), 4.25-4.52 (m, 3H), 6.66 (d, 1H), 6.77-6.81 (m, 1H), 6.95 (d, 1H), 7.83 (t, 2H), 7.94-7.97 (m, 2H), 8.06-8.10 (m, 1H), 8.18 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[CH3:34][O:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:37][CH2:36][O:35][CH3:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: COCCBr
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Temperature: 115 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (100 mg, 73 μmol; purity 32%) was suspended in DMF (0.5 ml). 2-Bromoethyl methyl ether (148 mg, 1.06 mmol) was then added, and the mixture was heated in a closed tube at 115° C. for 15 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (27.3 mg, 73% of theory).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[NH2:1][CH:2]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: NC(CC(=O)O)c1cccnc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(N)c1cccnc1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirred suspension of 114 g (0.69 mole) of β-amino-β-(3-pyridyl)propionic acid in 2,850 ml of ethanol was added a 5° C. solution of 417 g of sulfuric acid in 240 ml of ethanol. After stirring for 1 hour, the resultant clear solution was left standing at room temperature for 48 hours and then concentrated to incipient crystallization in vacuum at a temperature below 50° C. The solution was added to a suspension of 715 g of sodium bicarbonate in 1430 ml of water over 1 hour. The temperature of the solution was maintained between 0° to 5° C. After stirring an additional 30 minutes, 300 ml of carbon tetrachloride was added and the admixture stirred for 10 minutes. The by-product salt was removed by filtration and the aqueous layer was extracted thoroughly with carbon tetrachloride. The combined organic extracts were dried and concentrated under vacuum to yield 87.11 g (65% yield) of crude ethyl β-amino-β-(3-pyridyl)propionate as a slightly viscous green liquid.