Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:5][Si:6]([CH:10]([CH3:12])[CH3:11])([CH:13]([CH3:15])[CH3:14])[CH:7]([CH3:8])[CH3:9])[CH:16]=[CH:17][C:18]=1[NH2:19]
Reactant: CC(C)[Si](Oc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc(N)c(F)c1)(C(C)C)C(C)C
Yield: 101.7 %

Procedure:
A flask with a mixture of (3-fluoro-4-nitro-phenoxy)-triisopropyl-silane (6.74 g, 21.5 mmol) in ethyl acetate (200 mL) is evacuated and filled with nitrogen three times. Palladium 10% by weight on carbon (550 mg) is added. The flask is evacuated and filled with nitrogen three times and then it is evacuated and filled with hydrogen from a balloon. The mixture is stirred under hydrogen atmosphere (balloon) over night. The mixture is filtered over diatomaceoud earth and concentrated to provide the title compound (6.2 g, 100%) as an oil. LC-ES/MS m/e 284.2 (M+1).
Reaction SMILES: [OH:1][CH:2]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:34])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23](=[O:33])[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[C:27]1([CH2:26][CH2:25][CH2:24][C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@H:18]2[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:12]2[C:2](=[O:1])[CH2:3][S:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(CCCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CS(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(CS(=O)c1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Yield: 83.5 %

Procedure:
(2S)-2-[1-Hydroxy-2-(phenylsulfinyl)ethyl]-1-[N-(4-phenylbutyryl)-L-prolyl]pyrrolidine (1.07 g) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 0.89 g of (2S)-1-[N-(4-phenylbutyryl)-L-prolyl]-2-[(phenylsulfinyl)acetyl]-pyrrolidine (See Table 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:16][CH:21]=[C:19]([CH2:18][Cl:17])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1

Procedure:
To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 mL) was added 1,3-dichloroacetone (3.3 g, 26 mmol), MgSO4 (3.6 g, 30 mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (150 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product. 1H NMR (CDCl3): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18].[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: N
Agent: [Na+]
Agent: [OH-]
Product: N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 80 °C
Yield: 73 %

Procedure:
In an autoclave were charged 5.303 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine (20 mmol, optical purity: 100% e.e.), and 42.53 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80° C. whereby an internal pressure of 8 barr was observed. After allowing the reaction for 20 hrs, the reaction mixture was cooled to room temperature, followed by addition of 4.00 g of a 30% by weight aqueous sodium hydroxide solution (1.5 equivalent), and then ammonia was removed by distillation under reduced pressure. The residue was extracted with 30 mL of ethyl acetate three times, and the organic layers were combined. After washing with 3 mL of a saturated brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave 3.6146 g of a dark red oily material (reaction yield: 73%, optical purity: 92.4% e.e.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19](O)=[O:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C=O>[N:1]1([C:19]([C@@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To a solution of pyrrolidine (2.134 g, 30 mmol) in N,N-dimethylformamide (240 mL) was added (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (6.878 g, 30 mmol). Then hydroxybenzotriazole (1.028 g, 6 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (5.751 g, 30 mmol), and triethylamine (7.59 g, 75 mmol) were added sequentially. The mixture was stirred at 30° C. for 16 h. The solvent was removed under reduced pressure and an aqueous solution of sodium bicarbonate (200 mL, 0.1M) was added. The mixture was extracted with ethyl acetate (200 mL×3) and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate, which was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 55 mg of 1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 80 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 62 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[OH:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])(=[O:30])=[O:29])[CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cc(O)c2ccccc2c1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(Oc1cc(O)c2ccccc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
At 0° C. to 1.0 g (6.24 mmol) of 1,3-naphthalenediol in tetrahydrofuran (20 mL) containing 1.5 mL of 2,6-lutidine was added 1.35 g (6.40 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was stirred to ambient temperature overnight, quenched with 3N hydrochloric acid, extracted into methylene chloride, and dried (MgSO4). Purification by flash chromatography (2% ethyl acetate/methylene chloride) gave 277 mg (13% yield) of the title compound as a colorless solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.06 (d, 1H, J=1.7 Hz), 7.78-7.95 (m, 4H), 7.43-7.57 (m, 3H), 7.11 (d, 1H, J=2 Hz), and 6.63 (d, 1H, J=2 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>COCCO>[CH2:11]([NH:18][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2ccsc12
Reactant: NCc1ccccc1
Solvent: COCCO
Product: c1ccc(CNc2ncnc3ccsc23)cc1
Yield: 26.2 %

Procedure:
As described in the previous experiment 4-chlorothieno[3,2-d]pyrimidine (100 mg, 0.586 mmol) and benzylamine (710 μL, 0.645 mmol) in 2-methoxyethanol (2 mL)yields 4-benzylaminothieno[3,2-d]pyrimidine (37 mg, 26%). 1H NMR (DMSO) δ 8.42 (1H, s), 8.12 (1H, d, J=5.5 Hz), 7.39 (1H, d, J=5.3 Hz), 7.40-7.30 (4H, m), 7.24 (1H, t, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:25][C:26](=[CH2:30])[C:27](Cl)=[O:28]>C(OCC)C>[F:25][C:26](=[CH2:30])[C:27]([O:17][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])=[O:28]
Reactant: OC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C=C(F)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(F)C(=O)OC(c1ccc(F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of 40 g (0.153 mol) of 2-(4-fluorophenyl)-hexafluoro-2-propanol and 15.5 g (0.153 mol) of triethylamine in 75 ml of dry diethyl ether were added dropwise with stirring at a temperature of 25° C. to a solution of 18 g (0.166 mol) of α-fluoroacryloyl chloride (obtained according to Example 4) in 25 ml of dry diethyl ether in the course of 45 minutes. The reaction mixture was then stirred at a temperature of 25° C. for a further 2 hours. The resulting solid was filtered off. The filtrate was distilled under reduced pressure after addition of 0.01 g of hydroquinone monomethyl ether. 42.5 g (83 percent of theory) of 2-(4-fluorophenyl)-hexafluoro-2-propyl α-fluoroacrylate having a boiling point of 70° to 73° C. (under 0.5 mbar) were obtained.
Reaction SMILES: [CH:1](=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Br[CH:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]([O:26][CH3:27])=[O:25].C[Si](C)(C)Cl>[Zn].S(=O)(=O)(O)O>[OH:21][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCCC=O
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Product: CCCCCCCCCCCCCCCCCCCC(O)C(CCCCCCCCCCCCCC)C(=O)OC
Temperature: 85 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
Icosanal (1 g, 3.37 millimole) and methyl 2-bromohexadecanoate (977.8 mg, 2.80 millimole) were dissolved in the same mixed solvent (30 ml). The obtained solution (4 ml) was added dropwise to the reaction vessel containing zinc activated by trimethylchlorosilane as described above, and the mixture was stirred at 85° C. for 1 hour. The progress of reaction was confirmed through thin layer chromatography, and the rest of the solution (26 ml) was gradually added under the same conditions and the mixture was stirred for 8 hours. After cooling the reaction mixture with ice, 20% sulfuric acid (50 ml) was added thereto, and the, mixture,, was stirred for 15 minutes. Then the mixture was extracted twice with benzene, and the organic phase was washed twice with 10% sulfuric acid, and successively washed once with saturated aqueous sodium bicarbonate solution, once with 10% sulfuric acid, then twice with water, and dried over anhydrous sodium sulfate. The solvent was distilled off from the organic phase, and the obtained residue was dissolved in a developing solvent (n-hexane:ether=8:2) and fractionated through silicagel column chromatography (n-hexane:ether=8:2). The fourth and fifth fractions were pooled and the solvent was distilled off to give methyl 3-hydroxy-2-n-tetradecyl-docosanoate (III) (812.8 mg, yield 51%) in the form of white crystals.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[CH:14]=[N:15]O)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[Na+].[Na+]>C(OC(=O)C)(=O)C>[CH:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[C:14]#[N:15])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ON=Cc1cn2c(ccc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cn2c(ccc3ccccc32)n1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A mixture of 2.0 g of the product of Step A in 20 ml of acetic anhydride was stirred at reflux for 3 hours and was cooled to room temperature overnight. The mixture was poured into a saturated sodium carbonate solution and the resulting mixture was extracted with chloroform. The organic phase was washed with sodium carbonate solution and with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ether and was filtered to obtain 1.3 g of imidazo-[1,2-a]-quinoline-2-carbonitrile in the form of pale yellow crystals melting at 244°-246° C. after crystallization from a chloroform-ether mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:30])=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: Cc1noc(C)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2c(C)noc2C)CC1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3,5-dimethylisoxazole-4-carbonyl chloride (0.022 mL, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hr. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (44 mg, 100%). LCMS calculated for C21H22ClN4O3 (M+H)+: m/z=413.1; Found: 413.1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C[Si](C)(C)N[Si](C)(C)C.Cl[Si](C)(C)C>C1(C)C(C)=CC=CC=1>[NH2:2][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: Cc1ccccc1C
Product: N[C@@H]1CCCCNC1=O
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-lysine HCl salt (100 g, 0.68 mol) in xylene (1 L) was added hexamethyldisilazane (1000 mL, 4.76 mol) and chlorotrimethylsilane (10 mL, 78.8 mmol). The mixture was heated to 120° C. for 24 h, then to 180° C. for 48 h. The solvent was then removed under reduced pressure and the crude material was purified by column chromatography (20:1 to 10:1 CH2Cl2/MeOH) to afford (R)-3-aminoazepan-2-one (I-1a).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[C:10]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:21]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(F)cc1CC2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(F)cc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-fluoro-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product (m.p., 116°-118° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: OB(O)c1ccc2[nH]ccc2c1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc3[nH]ccc3c2)s1
Yield: 61.9 %

Procedure:
5-Bromothiophene-2-carboxylic acid methyl ester (0.5 g, 2.26 mmol), 1H-indol-5-ylboronic acid (0.36 g, 2.26 mmol), tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol) and sodium carbonate (0.48 g, 4.52 mmol) were dissolved in dioxane (30 mL) and refluxed for 5 h. Ethyl acetate (30 mL) was added, and the mixture was washed with sodium bicarbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and purified by column chromatography to give the title compound (0.36 g, 62% Yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22]C)=O)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CC(C)([O-])C.[K+].Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]1[C:20](=[O:22])[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][N:6]12
Reactant: CCOC(=O)CCCn1c(C(=O)OC)cc2c(Br)cc(F)cc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCn2c(cc3c(Br)cc(F)cc32)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of the compound of Step 1 (13.2 g, 34.1 mmol) in THF (100 mL) at 0° C. was added potassium t-butoxide (34.1 mmol, 1M THF solution). The mixture was stirred at 0° C. for 2 h, poured into 1N HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and swished in EtOAc to give 11.6 g of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[C:8](O)(=O)[CH3:9].O>C1(C)C=CC=CC=1>[CH:3]([C@H:2]1[CH2:6][O:7][C:8]([CH3:9])=[N:1]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](N)CO
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=N[C@@H](C(C)C)CO1
Reaction time: 24 h
Yield: 77.8 %

Procedure:
20 g (0.194 mol) valinol are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via NaSO4 and the solvent removed. Distillation (112° C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([OH:5])=O.C(Cl)(=O)OCC.CC[N:49](CC)CC.N.O>C(Cl)Cl>[F:1][C:2]([F:40])([CH2:6][NH:7][C:8]([NH:10][C@@:11]([C:26]1[CH:31]=[C:30]([O:32][C:33]([F:37])([F:38])[CH:34]([F:35])[F:36])[CH:29]=[C:28]([F:39])[CH:27]=1)([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C:3]([NH2:49])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(NCC(F)(F)C(=O)O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: NC(=O)C(F)(F)CNC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To a solution of (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanoic acid (60 mg, 0.1 mmol) in CH2Cl2 (1 mL) at 0° C. was added ethyl carbonochloridate (10 uL, 0.1 mmol), followed by NEt3 (0.021 mL, 0.15 mmol) and NH3.H2O (0.1 mL, 2.6 mmol). The reaction mixture was stirred at rt for 30 min, then concentrated under reduced pressure and purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield (R)-2,2-difluoro-3-(3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)ureido)propanamide as a white solid (12 mg, 21% yield). LCMS: RT=3.85 min [M+H] 576.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[N:16]([O-])=O.[Na+]>S(=O)(=O)(O)O>[C:7]1([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][N:16]=[N:1][C:2]=3[CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1sc(-c2ccccc2)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2cc(-c3ccccc3)sc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To an ice cold solution (0° C.) of 3-amino-5-phenylthiophene-2-carboxamide (0.37 g, 1.7 mmol) in concentrated sulfuric acid (20 mL) was added a cold (0° C.) solution of sodium nitrite (120 mg, 1.86 mmol) in concentrated sulfuric acid (8 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 1 h. The reaction mixture was cooled and poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (3×50 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an off-white color solid (200 mg, 39%), my 178-180° C. 1H NMR (400 MHz, CDCl3): δ 12.30 (1H, br s), 7.86 (1H, s), 7.73-7.75 (2H, m), 7.49-7.54 (3H, m); LC-MS (negative ion mode): m/z 228 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[OH-].[Ba+2].[OH-].S(=O)(=O)(O)[OH:13].C(=O)([O-])[O-].[Ba+2]>O>[NH2:6][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][C:5]([OH:13])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)CCC(=O)O

Procedure:
For example, a mixture of 5,5-dimethyl-2-pyrrolidone, an excess amount of barium hydroxide and a sufficient amount of water is heated under reflux until the reaction is substantially complete. The cooled solution is made slightly acidic with sulfuric acid and neutralized with solid barium carbonate or other bases. After removal of solids by filtration, the filtrate is evaporated under reduced pressure to yield a crude product which after three recrystallizations from an inert solvent such as aqueous ethanol gives an analytically pure product of 4-amino-4,4-dimethyl butanoic acid (4-amino-4-methylvaleric acid). 4-amino-2,4-dimethylvaleric acid is prepared similarly from 3,5,5-trimethyl-2-pyrrolidone.