Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:32][CH2:33][N:29]([CH3:28])[C:30]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 78.5 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and 1-methylimidazolidin-2-one (120 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (370 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].I[CH:13]([CH3:15])[CH3:14]>CS(C)=O.O>[CH:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)([CH3:15])[CH3:14]
Reactant: CC1(C)OCC(CO)O1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (2 g), in DMSO (50 mL), powdered potassium hydroxide was added portionwise at 0° C. then warmed to room temperature. 2-Iodo-propane (43 mL) was added to the mixture at 0° C. then stirred for 72 h at room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine (×2) and dried (MgSO4), filtered and evaporated to give the subtitle compound as clear, colourless oil. Yield: 2 g
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[H-].[Na+].[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25]OS(C)(=O)=O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Reactant: O=c1[nH]c2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCn1c(=O)sc2ccccc21)n1cnc(C(N)=O)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
To a stirred solution of 2-oxobenzothiazole (83 mg, 0.549 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 22 mg, 0.549 mmol) at room temperature. After 10 minutes, 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide in DMF (3 ml) was added and the resulting mixture was stirred for 6 hours at 60 to 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(2-oxobenzothiazol-3-yl)-3-pentyl]imidazole-4-carboxamide (63 mg, 52.7%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(=O)(O)[O-].[Na+].[Cl:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])=[O:16]>O.CO>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[CH:19]=1
Reactant: O=C(CCl)Nc1cccc(C(=O)Cl)c1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CNC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a mixture of glycine methyl ester hydrochloride (358 g., 2.85 mole) and 2.4 l. of water is added sodium bicarbonate (239.4 g., 2.85 mole). After stirring at room temperature for 0.5 hr., the mixture is diluted with 1 l. of methanol, cooled at 0° C. while sodium bicarbonate (239.4 g., 2.85 mole) is added followed by portionwise addition of 3-(chloroacetylamino)benzoylchloride (650 g., 2.8 mole) during a 0.75 hr. period. Considerable foaming takes place when approximately one-half of the acid chloride has been added and is controlled by periodic addition of small quantities of methanol. The reaction mixture is stirred for 16 hrs., diluted with 800 ml. of water and then stirred for an additional 0.5 hr. to provide a solid which is collected and sequentially washed with 500 ml. of 50% methanol, 2 l. of water, and 500 ml. of 50% methanol. The washed material is first air dried for 3 days and then for 12 hrs. under reduced pressure at 45° C. to afford 626.7 g. (77% yield) of N-[3-(chloroacetylamino)benzoyl]glycine methyl ester, m.p. 122.0°-124.0° C. Analytically pure N-[3-(chloroacetylamino)benzoyl]glycine methyl ester is obtained by crystallization from methanol, m.p. 122°-127° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([SH:16])([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([S:16][C:13]([CH3:15])([CH3:14])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11])(=[O:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)S
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
2-(tert-butoxycarbonylamino)-3-mercapto-3-methylbutanoic acid (2.96 g, 11.87 mmol) was suspended in water (33 ml) and cooled with an ice/water bath. KOH (1.67 g, 29.7 mmol) dissolved in water (16 ml) followed by acetic anhydride (1.41 ml, 14.9 mmol) were added to the reaction flask and stirred at 0-5° C. for 4 hours (a white precipitated appears after ca. 30 minutes of stirring). The reaction mixture was partitioned between EtOAc and HCl 1M. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and solvent removed under vacuum. Crude compound was used in the next step without further purification. (3.45 g, quantitative yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@H:13]2[N:18]3[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:21][CH2:22][C:23](=[O:24])[N:17]3[CH2:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:48]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:48][C:11]([C@H:13]3[N:18]4[C:19](=[O:36])[C@@H:20]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:21][CH2:22][C:23](=[O:24])[N:17]4[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)NCC(=O)c3ccc(Br)cc3)N2C1=O)OCc1ccccc1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O)OCc1ccccc1
Temperature: 110 °C
Yield: 34.1 %

Procedure:
In a 10 ml, seal tube, benzyl (4S,7S)-4-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (200 mg, 350 μmol) was combined with 1,4-dioxane (5 ml) to give a light yellow solution. Ammonium acetate (270 mg, 3.5 mmol) was added and the reaction mixture was heated at 110° C. for 12 hr. It was cooled and diluted with EtOAc (2×30 ml). The combined organic layers were washed with brine and H2O, dried with MgSO4 and concentrated in vacuo to afford a viscous oil. The crude was purified on a silica gel column (CH2Cl2, 2%, 4%, 6%, 8% MeOH/CH2Cl2) to afford benzyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate as a yellow solid (66 mg, 34.1%). ESI-LRMS m/e calcd for C26H26BrN5O4 [M+] 552. found 553 [M+H+].
Reaction SMILES: CC1C=C(C=C(C)C=1)C([N:7](C)[C@:8](C)([C:21]([OH:23])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:12][CH:11]=1)=O.Cl.[CH3:31][O:32][C:33](=[O:46])[C@H:34]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH2:35].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:31][O:32][C:33](=[O:46])[C@H:34]([CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][CH:38]=1)[NH:35][C:21](=[O:23])[C@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:14][CH:15]=1)[NH2:7]
Reactant: Cc1cc(C)cc(C(=O)N(C)[C@@](C)(Cc2ccc(-c3ccsc3)cc2)C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)Cc1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine (135 mg, 0.33 mmol) in DMF are successively added tryptophan methyl ester hydrochloride (110 ml, 0.43 mmol), 1-Hydroxybenzotriazole (58 mg, 0.43 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.46M solution) 79μ, 0.43 mmol) at 0° C. under nitrogen atomosphere. The reaction mixture is allowed to stir at 0° C. for 2 h, then at room temperature overnight. The mixture is diluted with ethyl acetate and washed with 10% citric acid twice. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica with hexane/ethyl acetate (1:1) to give (D,L)-isomer (55 mg) and (L,L)-isomer (80 mg: including 15% of (D,L)-isomer) (total 67%) of 3-[4-(3-thienyl)phenyl]alanyl-tryptophan methyl ester. Hydrolysis of (D,L)-isomer (55 mg, 0.09 mmol) with lithium hydroxide hydrate (6 mg, 0.14 mmol) affords N-(3,5-Dimethylbenzoyl)-N-methyl-(D)-2-methyl-3-[4-(3-thienyl)phenyl)-alanyl-(L)-tryptophan FAB-MS m/e 592 (M-H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([CH3:19])=[C:6]([CH:15]=[CH:16][C:17]=1[CH3:18])[CH2:7][NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N
Reaction time: 9 h

Procedure:
A mixture of N-(3-nitro-2,4-dimethyl-benzyl)-2,2-dimethyl-propionamide (500 mg, 1.89 mmol), Pd/C (50 mg) and MeOH (20 mL) is stirred for 9 h under a hydrogen atmosphere (50 psi). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:22](=[O:24])[CH3:23])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=C1CCCC(c2ccc(O)cc2)N1c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To 1.00 g of 1-(4-chlorophenyl)-6-(4-hydroxyphenyl)-2-piperidone was added 25 ml of acetic anhydride and the mixture was stirred at 120° C. for 1 hour. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give 910 mg of 1-(4-chlorophenyl)-6-(4-acetoxyphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:21]I.[OH-].[Na+]>CC(N(C)C)=O.C1COCC1>[C:2]([O:5][C:6]([N:8]([CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1)[CH3:21])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (77.7 mmol) of BOC-tranexamic acid in 162 mL of DMA and 320 mL of THF was cooled to 0° C. and treated with 7.46 g (170.99 mmol, 2.2 eq) of NaH (55% in oil) over 30 min. The mixture was warmed to RT, cooled to 0° C. again and treated with 77.42 mL (1243 mmol, 16 eq) of CH3I and warmed to RT overnight. 230 mL (2487.1 mmol, 32 eq) of aqueous 32% NaOH were added at 0° C., the solution was stirred for 1 h at RT and partitioned between Et2O (×3)/H2O. The organic phase was evaporated to remove the DMA. The residue was dissolved in 100 mL of dioxane and treated with 233 mL (233 mmol) of aqueous 1M NaOH at RT, and the solution was stirred overnight. The reaction was partitioned between Et2O (×3)/H2O, the aqueous phase was acidified with aqueous 10% KHSO4 and partitioned between Et2O (×3), washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 19.2 g (87%) of trans-4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexane-carboxylic acid, MS: 270 (M−H−).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[N:6][C:7](Cl)=[C:8]([C:10]#[N:11])[CH:9]=1)(=[O:3])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[C:1]([C:4]1[C:5]([CH3:13])=[N:6][C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([C:10]#[N:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1cc(C#N)c(Cl)nc1C
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C#N)c(N2CCOCC2)nc1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
9.5 g (48.8 mmol) of 3-acetyl-6-chloro-5-cyano-2-methyl-pyridine are dissolved in 180 ml of toluene, 9.5 g (0.109 mol) of morpholine are added, and the mixture is stirred at 90° C. for two hours. To work up, the mixture is evaporated, and the residue is suspended in water, filtered with suction and carefully washed with water. Re-crystallization from methanol/water is used for purification.
Reaction SMILES: C[O:2][C:3](=[O:38])[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][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1Cl

Procedure:
(2′-{[(2-Chloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.27 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.7 mL) for 1 hour. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1]I.[NH:3]1[C:10](=[O:11])[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[S:5]>CCO.[OH-].[Na+].O>[CH3:1][S:5][C:4]1[N:6]=[C:7]([OH:8])[CH:9]=[C:10]([OH:11])[N:3]=1
Reactant: CI
Reactant: O=C1CC(=O)NC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (32.64 g, 220 mmol) was added dropwise to a suspension of thiobarbituric acid (29 g, 200 mmol) in EtOH (300 ml) and 2M NaOH solution in water (110 ml) at room temperature. The mixture was stirred at room temperature overnight and then stirred for two hours at 60° C. The ethanol was removed, water was added and the mixture was allowed to stay for 2 hours on an ice bath. The solid title compound was filtered of, washed with ice cold water and dried (30 g, 95%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@:4]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([CH2:21][CH:22]=[CH2:23])[CH2:5][CH2:6][N:7]([C@H:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[CH3:13])[C:8](=O)[O:9]C>C1COCC1.C(Cl)Cl>[CH2:21]([C:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:5][CH2:6][N:7]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH3:13])[C:8](=[O:9])[NH:3]1)[CH:22]=[CH2:23]
Reactant: C=CC[C@](N)(CCN(C(=O)OC)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1

Procedure:
To a mixture of NaH (100 mg, 4 mmol) and anhydrous THF (8 mL) was added dropwise a solution of crude methyl (S)-3-amino-3-(4-fluorophenyl)hex-5-enyl((S)-1-(4-bromophenyl)ethyl)carbamate (39 mg, 0.1 mmol) in anhydrous THF (8 mL) at 0° C. The reaction mixture was refluxed overnight. The reaction mixture was quenched with methanol in an ice bath and evaporated to leave a residue, which was dissolved in CH2Cl2. The combined organic phase was dried, filtered and concentrated to give the crude product, which was purified by TLC to provide (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyptetrahydropyrimidin-2(1H)-one (1.2 mg, 3%). LC-MS Method 1 tR=1.603 min, m/z=419; 1H NMR (CD3OD) 1.36 (d, 3H), 1.81-1.92 (m, 1H), 2.16-2.22 (m, 1H), 2.46-2.53 (m, 1H), 2.61-2.84 (m, 3H), 5.12-5.19 (m, 1H), 5.56-5.69 (m, 1H), 7.06-7.13 (m, 2H), 7.18-7.24 (m, 2H), 7.22-7.29 (m, 2H), 7.42-7.51 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:25])[CH2:9][C:10]([NH:12][C@@H:13]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:14]([O:16]C)=O)=[O:11])[CH3:6].C(OCC)C.[Na]>C(O)C>[CH:19]1([CH2:18][C@@H:13]2[NH:12][C:10](=[O:11])[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:25])=[C:14]2[OH:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CC(=O)N[C@@H](CC1CCCCC1)C(=O)OC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C1=C(O)[C@H](CC2CCCCC2)NC1=O
Yield: 99.8 %

Procedure:
Sodium ethoxide, 21 weight percent in ethanol, 204 g (0.63 mol) (5% less than theory to prevent racemization), is added to a solution of 200 g (0.67 mol) of (S)-α-[[3-ethoxy-1,3-dioxopropyl]amino]cyclohexanepropanoic acid, methyl ester in 650 ml of absolute ethanol. The solution is heated to reflux for 5 minutes, cooled and treated with about 1.5 liters of diethyl ether to precipitate the sodium salt of the product. The mixture is filtered, washed with 500 ml of diethyl ether and then with 100 ml of petroleum ether. The cake is dried on the funnel using a rubber-dam to prevent moisture from condensing to afford 178.8 g of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester, sodium salt. The previous sodium salt is dissolved in 1 liter of water and 325 ml of 2N hydrochloric acid is added to precipitate a large taffy-like clump of material which gradually crystallizes. The clumps are broken up in a mortar and the mixture filtered, washed with water and dried to afford 143.2 g of (S)-5-(cyclohexylmethyl)-2,5-dihydro-4-hydroxy-2-oxo-1H-pyrrole-3-carboxylic acid, ethyl ester after dissolution in 105 methanol-chloroform at room temperature, charcoaling and concentration; mp 176°-180° C.; [α]D23 =-68.9° (c=1.02% methanol).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N+:13]1[C:18](Cl)=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N+:13]1[CH:18]=[CH:17][C:16]([NH2:20])=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cn[n+](Cc2ccccc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: Nc1cc[n+](Cc2ccccc2)nc1

Procedure:
The procedure of Example 4 is repeated but 13 parts of 1-benzyl-4-amino-6-chloropyridazinium perchlorate is used and 10 parts of sodium bicarbonate is used instead of triethylamine. 9.6 parts (67.3% of theory) of 1-benzyl-4-aminopyridazinium perchlorate is obtained from the filtrate from the reaction mixture; C11H12O4N3Cl, melting point 127° to 129°C after having been recrystallized from water.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: OCCCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(OCCCCCCO)cccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
Prepared as in Example 197c from hexane-1,6-diol and 2,6-dinitrobenzonitrile in 88% yield as a pale yellow solid. MS 265 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[CH2:24]([OH:27])[C:25]#[CH:26]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([C:26]#[C:25][CH2:24][OH:27])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#CCO
Reactant: Cn1cc(C(=O)NCCO)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Yield: 79 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with propargyl alcohol in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (79%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.26 (s, 1H), 8.44 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.38 (dd, J=11.6, 1.8 Hz, 1H), 7.27 (dd, J=8.3, 1.4 Hz, 1H), 5.70 (s, 1H), 5.35 (t, J=5.9 Hz, 1H), 4.76 (t, J=5.7 Hz, 1H), 4.30 (d, J=6.0 Hz, 2H), 3.50 (q, J=5.8 Hz, 2H), 3.38 (s, 3H), 3.31-3.26 (m, 2H). LCMS (APCI+) calcd for C18H18FN3O4 360 (MH+), found 360.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=5[F:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC)cc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-4-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.92 min; Mass spectrum (ESI+): m/z=505 [M+Na]+.