Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:10]=[N:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:13]([O:12][N:11]=[CH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(C=NOCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-cyclopentanecarboxylic acid methyl ester (2.26 g, 8.65 mmol) and sodium hydroxide (1.0 g, 25.9 mmol) in THF (15 mL), methanol (15 mL) and water (5 mL) was stirred at room temperature for 18 h. The reaction mixture was acidified to pH 4 with 3N aqueous HCl and was extracted with dichloromethane (50 mL×3). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (1.91 g, 89%). MH+248.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]3[CH2:11][CH2:10][C:9]4([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C:8]3=[O:17])=[C:4]([Cl:21])[CH:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(Cl)c(CN3CCC4(CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 63.5 %

Procedure:
Purge with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.14 g, 0.36 mmol) and 4-methoxycarbonyl phenylboronic acid (0.19 g, 1.05 mmol) in toluene (10 mL) and 2M sodium carbonate (1.25 mL). Treat the reaction with Pd(PPh3)4 (0.041 g, 0.035 mmol) and heat to 90° C. for 4 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.102 g (64%) of the titled product. Rf=0.51 (1/1 hexanes/ethyl acetate). MS (m/z): 446
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][C:7]=1[O:16][CH3:17].Cl>C1COCC1.CO.O>[CH3:3][O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(O)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.5 %

Procedure:
0.1N NaOH (10 mL, 1 mmol) was added to a solution of the product of step 2 (1.10 g, 4.9 mmol) in THF (1 mL) and MeOH (1 mL). Reaction was stirred for three days at room temperature. Reaction solution was concentrated by rotary evaporation and resulting residue was dissolved in water. The solution was neutralized with 1N HCl and a precipitate formed. Collected precipitate and washed with water and hexane. Obtained 0.29 g of 4-Hydroxy-2-methoxy-benzoic acid methyl ester in 33% yield.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](I)=[C:19]([I:21])[N:20]=3)[CH2:13][CH2:14][O:15][C:16]=2[N:17]=1>O1CCCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH:18]=[C:19]([I:21])[N:20]=3)[CH2:13][CH2:14][O:15][C:16]=2[N:17]=1
Reactant: Clc1ccc2c(n1)OCCn1c-2nc(I)c1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Clc1ccc2c(n1)OCCn1cc(I)nc1-2
Temperature: 15 °C

Procedure:
2.0 M of Isopropylmagnesium Chloride in tetrahydrofuran (0.782 mL) was added dropwise to a solution of 0.644 g (1.36 mmol) of 9-chloro-2,3-diiodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine in 12 ml of tetrahydrofuran at −10° C. The mixture was allowed to warm to 15° C. The mixture then was quenched by addition of 20 ml of sat. aqueous NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over Na2SO4 and concentrated to give 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. Yield 448 mg (98%). M/z 348.2, calc. M 346.93. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J=8.2, 1H), 7.16 (dd, J=14.0, 5.9, 1H), 7.10 (s, 1H), 4.61-4.54 (m, 2H), 4.41 (dd, J=5.0, 2.9, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9](=[O:11])[CH:7]([NH2:8])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1
Reactant: CO
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
4-Chloro-DL-phenylalanine (1.00 g, 5.00 mmol) was dissolved in methanol (30 mL) and cooled to 0° C. Thionyl chloride (2.92 mL, 40.0 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was heated at reflux for 4 h. The solvent and reagents were removed in vacuo to yield the hydrochloride salt 1-1 as a white powder in quantitative yield (1.25 g, 5.00 mmol). 1H NMR (300 MHz, CD3OD): δ=7.37 (d, 2H, J=6.6 Hz), 7.27 (d, 2H, J=6.6 Hz), 4.34 (t, 1H, J=6.9 Hz), 3.81 (s, 3H), 3.26 (dd, 1H, J=14.4, 6.4 Hz), 3.18 (dd, 1H, J=14.4, 7.3 Hz); 13C NMR (75 mHz, CD3OD): δ=170.28, 134.87, 134.18, 132.11, 130.19, 54.99, 53.85, 38.81; ESI-MS calcd for C10H13ClNO2 [M+H]+: 214.0635. found 214.0638.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C@@H:15]3[CH2:20][C@@H:19]([OH:21])[CH2:18][C:17](=[O:22])[O:16]3)[C:11]([CH:23]([CH3:25])[CH3:24])=[C:10]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35]CC4C=CC=CC=4)=[CH:31][CH:30]=3)=[O:27])[C:9]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH2:14][C@@H:15]3[CH2:20][C@@H:19]([OH:21])[CH2:18][C:17](=[O:22])[O:16]3)[C:11]([CH:23]([CH3:24])[CH3:25])=[C:10]([C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)=[O:27])[C:9]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)Nc2ccc(OCc3ccccc3)cc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)Nc2ccc(O)cc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1
Temperature: 24 °C
Reaction time: 72 h
Yield: 6887.1 %

Procedure:
A mixture of 4.7 g (7.26 mmol) of the benzyl ether from Step D above and 1.0 g of 10% palladium on carbon in 300 mL of ethyl acetate was stirred at 24° C. under hydrogen for 3 days. The mixture was filtered to remove the catalyst, and the solvent was removed by evaporation under reduced pressure to give an oil. The oil was crystallized from fresh ethyl acetate to provide 3.5 g of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(4-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1H-pyrrole-3-carboxamide (containing 0.5 mol of ethyl acetate), mp 130°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:27])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CC(C)(N)c1nccs1
Product: COc1ccc(C(=O)NC(C)(C)c2nccs2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid and (Example 81 c) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: C([C@@H]1CO[C:10](=O)[N:9]1[C:14](=[O:33])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[C:21]=1[F:32])[CH2:16]C=O)C1C=CC=CC=1.[N:34]1[NH:35][CH:36]=[C:37]2[C:42]=1[CH2:41][CH2:40][CH:39](N)[CH2:38]2.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Cl:26][C:25]1[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:39]3[CH2:40][CH2:41][C:42]4[C:37](=[CH:36][NH:35][N:34]=4)[CH2:38]3)[C:14]2=[O:33])=[C:21]([F:32])[C:22]([F:31])=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:24]=1
Reactant: NC1CCc2n[nH]cc2C1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(C(F)(F)F)c(F)c1F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(C(F)(F)F)c(F)c2F)CCN1C1CCc2n[nH]cc2C1
Yield: 46.1 %

Procedure:
Combine a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(6-chloro-2,3-difluoro-4-trifluoromethyl-benzyl)-4-oxo-butyraldehyde (Preparation 46) (0.30 g, 0.6 mmol) and 4,5,6,7-Tetrahydro-2H-indazol-5-ylamine (Preparation 40) (88 mg, 0.64 mmol) in CH2Cl2 (15 mL) and MeOH (1 mL) and treat the solution with HOAc (0.03 mL, 0.6 mmol). Stir the reaction for 30 min at room temperature, treat the reaction with sodium triacetoxyborohydride (0.39 g, 1.8 mmol), and stir overnight at room temperature. Quench the reaction with water and extract with EtOAc. Wash the organic with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by SCX resin exchange column using 2M ammonia in MeOH to elute the pure product. Remove the solvent to afford 0.12 g (46%) of the title compound. MS (m/e): 434 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](O)=[O:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]([CH3:31])=[CH:27][C:28]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=C(C)C
Yield: 76.3 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 3-methylcrotonic acid (1.4 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 77%) as crystals.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: FC(F)(F)c1cc(Oc2ccccc2Br)ccn1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(C(F)(F)F)c3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14F4N4O, 426.11; m/z found, 426.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 58.51 (d, J=5.7, 1H), 8.38 (d, J=1.5, 2H), 7.62 (dd, J=7.6, 1.8, 1H), 7.56-7.42 (m, 3H), 7.38-7.30 (m, 4H), 7.04 (dd, J=5.6, 2.4, 1H), 6.84 (s, 2H).
Reaction SMILES: C([O:8][C:9](=[O:26])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:17]=[N:16][CH:15]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:22]([O:21][C:19]([N:18]1[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:26])=[O:8])=[CH:15][N:16]=[CH:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1cncc1C#CCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cncc1CCCCC(=O)O
Yield: 99.4 %

Procedure:
Vigorously stir a 60° C. solution of tert-butyl 5-(5-benzyloxy-5-oxo-pent-1-ynyl)imidazole-1-carboxylate (0.17 g; 1.0 equiv; 0.48 mmoles) and palladium (10% on carbon; 0.030 g; 0.014 mmoles) in methanol (13 mL) under 1 atmosphere of hydrogen for 16 hours. Filter and concentrate to afford the desired 5-(3-tert-butoxycarbonylimidazol-4-yl)pentanoic acid (0.128 g; 99%) as a white solid: MS (m/z): 213(M-t-Bu+1).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26]Cl)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]>CO.C(OCC)(=O)C>[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:21]=1[CH3:28])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C

Procedure:
To a liquid prepared by dissolving with stirring 7.5 g (0.052 mol, 1.0 eq.) of 2-mercaptobenzimidazole and 61.5 g (0.319 mol, 5.8 eq.) of a 28% sodium methoxide solution in 120 mL of methanol, a liquid prepared by dissolving the whole amount of 4-pentyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 30° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 6.9 g of amorphous solidified product. The product was recrystallized from an ethyl acetate/1-hexane mixed liquid, to obtain 4.3 g of colorless crystals (HPLC: 98.5 Area %, yield 10.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:22](OCC)=[O:23])[F:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([F:21])=[C:19]([CH3:27])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(F)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-2-fluoro-1-methylvinyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-fluoro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 9.99 ppm (s, 1H), 7.84 ppm (d, 1H), 7.37 ppm (d, 1H), 5.26 ppm (m, 1H), 2.18 ppm (d, 3H), 1.38 ppm (d, 3H), 1.36 ppm (d, 3H),
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[F:28]>N1C=CC=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])(=[O:26])=[O:25])=[CH:20][C:19]=1[F:28]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)c(F)c1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-(pyridin-3-yl)-methanone 2 g (8.7 mmol) and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.35 g (8.77 mmol) in 15 ml pyridine. Purification with silica chromatography eluted with dichlorometane:10-ethyl acetate gave a yellow powder.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[C:10]=1[C:11]#[N:12]
Reactant: OC1C=CCCC1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC1C=CCCC1

Procedure:
Prepared as in Example 22b from cyclohex-2-enol and 2-amino-6-fluorobenzonitrile as a colorless oil (78%). 1H NMR (400 MHz, CDCl3) δ 1.64 (m, 1H), 1.96 (m, 4H), 2.15 (m, 1H), 4.39 (s, 2H), 4.82 (m, 1H), 5.87 (m, 1H), 5.98 (m, 1H), 6.30 (d, 2H), 7.20 (t, 1H). MS 215 (MH+).
Reaction SMILES: C(Cl)Cl.[NH2:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Na+]>C(N(CC)CC)C>[C:24]([NH:4][CH:5]([CH:11]([OH:23])[C:12]1[S:13][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N)C(O)c1ccc(CN2CCCC2)s1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccccc1)C(O)c1ccc(CN2CCCC2)s1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To methylene chloride solution (5 ml) of 180 mg ethyl 2-amino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate diastereomers (A form and B form) was added triethylamine (300 μl), followed by dropwise addition of 80 mg of benzoyl chloride. After 30 minutes, a saturated sodium chloride aqueous solution was added to effect separation of layers, the thus separated organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Then, the residue was subjected to silica gel column chromatography and elution was carried out with chloroform:methanol (30:1) mixed solution to obtain 110 mg of ethyl 2-benzoylamino-3-hydroxy-3-[5-(1-pyrrolidinyl)methyl-2-thienyl]propionate (diastereomer A form and B form).
Reaction SMILES: [N:1]1([C:52](OC(C)(C)C)=O)[CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH3:29])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:28]([C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:31])[CH3:29])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (1.31 g.) and HDAla-Leu-MetNH2 (0.85 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-DAla-Leu-MetNH2 in 66% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-DAla-Leu-MetNH2 (1.10 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-DAla-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 66% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:15][C:14](=[O:16])[N:13]([CH3:17])[CH2:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCOCC1.[Pt]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:15][C:14](=[O:16])[N:13]([CH3:17])[CH2:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CN1CN=C(c2ccc([N+](=O)[O-])cc2)OC1=O
Agent: [Pt]
Solvent: C1COCCO1
Product: CN1CN=C(c2ccc(N)cc2)OC1=O

Procedure:
3 g of 6-(4-nitro-phenyl)-3-methyl-3,4-dihydro-2H-1,3,5-oxadiazin-2-one in 60 ml of dioxan are hydrogenated with 0.3 g of platinum/charcoal (5%) as catalyst until the uptake of hydrogen has ceased. The hydrogenation is carried out at room temperature and under normal pressure. The catalyst is then filtered off, the solvent evaporated off in vacuo and the residue is recrystallised from ethyl acetate to yield 6-(4-amino-phenyl)-3-methyl,3,4-dihydro-2H-1,3,5-oxadiazin-2-one which melts at 173°-174°C with decomposition (compound 83).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: CCO
Product: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Yield: 99.1 %

Procedure:
The procedure of Example 4, step (a) was followed using 0.950 g (5.43 mmol) of 4-chloro-2-fluoronitrobenzene and 1.93 mL (16.3 mmol) of 4-methylpiperidine in 10 mL of EtOH to afford 1.37 g (99%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C12H15ClN2O2, 255.1 (M+H), found 255.0.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[NH:14][C:13](=[O:23])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27]>CC1CCCO1>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]2[CH2:11][CH2:12][C:13](=[O:23])[N:14]([C@@H:25]([CH2:30][CH3:31])[C:26]([O:28][CH3:29])=[O:27])[C@@H:15]2[C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: CCC(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC[C@@H](C(=O)OC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1.25 h

Procedure:
To a 50° C. solution of 33.8 g (60% in mineral oil, 845 mmol) of sodium hydride in 2-methyltetrahydrofuran (550 mL) was added a solution of 240 g (750 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 2-methyltetrahydrofuran (550 mL) over a period of 45 min. After an additional 1.25 h at 50° C., 105 mL (912 mmol) of methyl 2-bromobutyrate was added over a 20 min period. The resulting slurry was stirred at 50° C. for 3.5 h, and then was cooled to room temperature and quenched with saturated aq. NH4Cl solution. Water was added to dissolve the precipitate and the resulting mixture was extracted with ethyl acetate (4×). The combined organic layers were washed with sat. aq. NaCl solution (1×), dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 35% EtOAc/DCM, gradient elution) provided the title compound as a white oily solid.