Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](O)=[C:20]([C:25]2[NH:26][C:27]3[C:32]([C:33]=2[Cl:34])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]=1>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]2[O:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[N:26]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:33]([Cl:34])=[C:25]3[C:20]=2[CH:19]=1
Reactant: Oc1ccc(Br)cc1-c1[nH]c2ccccc2c1Cl
Reactant: O=CC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1c2n(c3ccccc13)C(C1CC1)Oc1ccc(Br)cc1-2
Temperature: 110 °C
Reaction time: 15 h
Yield: 31.4 %

Procedure:
Cyclopropanecarbaldehyde (70 mg, 1.0 mmol) and PTSA (17 mg, 0.1 mmol) were added to a solution of 4-bromo-2-(3-chloro-1H-indol-2-yl)phenol (110 mg, 0.34 mmol) in toluene (2 mL). The mixture was allowed to stir at 110° C. for about 15 hours. The reaction solution was extracted by EtOAc, and the combined organic layers were washed with H2O (3×10 mL), brine and dried over Na2SO4. The solvent was removed and the crude product was Purified using prep-TLC to provide the desired product of 2-bromo-12-chloro-6-cyclopropyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (40 mg, yield: 31.3%). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (m, 1H), 7.63 (t, J=0.4 Hz, 1H), 7.30˜7.35 (m, 2H), 7.15˜7.24 (m, 2H), 6.93 (m, 1H), 5.62 (d, J=0.8 Hz, 1H), 1.36˜1.45 (m, 1H), 0.50˜0.56 (m, 4H). MS (M+H)+: 374/376.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH:17]1([CH2:16][NH:15][C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:28]([NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)=[O:29])[CH2:19][CH2:18]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)NCC1CC1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)NCC2CC2)c2ccccc2)c1
Yield: 75 %

Procedure:
The procedure is analogous to that described in Example 1, but 0.9 g of 2-(2-amino-N-phenylacetamido)-N-cyclopropylmethylacetamide and 0.45 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from acetonitrile, 1 g of N-cyclopropylmethyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 168° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=4)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Sn](CCCC)(CCCC)CCCC.C(OCC)(=O)C.N>CN(C)C=O.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>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([S:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]1)(=[O:18])=[O:17])=[CH:27]2
Reactant: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ncc(-c2ccccn2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
At room temperature, 1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (500 mg) and (pyridin-2-yl)tributyltin (418 mg) were dissolved in N,N-dimethylformamide (10 ml). To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (69 mg), followed by stirring at 100° C. for 9 hours. After cooling to room temperature, ethyl acetate and ammonia solution were added. The resulting mixture was separated by ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated and the residue was purified by chromatography on a silica gel column (4% methanol—methylene chloride). The resulting fraction was added with ethanol, followed by concentration. Diethyl ether was then added to the concentrate. Colorless powder thus precipitated was collected by filtration and dried, whereby the free form (254 mg) of the title compound was obtained. The resulting free form was dissolved in methylene chloride, followed by the addition of 1N hydrochloric acid (in ethanol) to make the solution acidic. After concentration, ethyl acetate and diethyl ether were added, followed by concentration. Colorless powder thus precipitated was collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([C:16]2[NH:20][N:19]=[C:18]([Cl:21])[N:17]=2)=[C:12]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=2)[NH:11]1>COCCO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[C:13]([C:16]2[NH:20][N:19]=[C:18]([Cl:21])[N:17]=2)=[C:12]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[NH:11]1
Reactant: O=C(Nc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c(=O)c1-c1nc(Cl)n[nH]1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: COCCO
Product: Nc1cccc(C(=O)Nc2[nH]n(-c3c(Cl)cc(Cl)cc3Cl)c(=O)c2-c2nc(Cl)n[nH]2)c1
Yield: 72.3 %

Procedure:
26.4 g of Intermediate H were dissolved in 250 ml of methyl-cellosolve and reduced at 50° C. with H2 at 20 atmospheres and Ni Raney. After cooling, Ni was filtered and the solvent was evaporated under vacuum. The resulting solid was extracted with boiling ethanol and filtered, thus obtaining 18 g of a white solid melting t 252° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[CH2:18]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[O:16]=[C:14]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: O=C1COc2cc(NC(=O)C(=O)N3CCC(CCc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-phenethyl-piperidine [J. Amer. Chem. Soc., 72, 4953. (1950)] according to the method described in Example 1c. Melting Point: 128-132° C. (diethylether)
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:30])([F:29])[C:5]([NH:7][CH2:8][CH:9]1[CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11][N:10]1CC1C=CC=CC=1)=[O:6]>CO.[Pd].O>[F:29][C:4]([F:3])([F:30])[C:5]([NH:7][CH2:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][NH:10]1)=[O:6]
Reactant: O=C(NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NCC1CNCCN1)C(F)(F)F
Yield: 96.8 %

Procedure:
To a solution of 3.1 g (6.7 mmol) of 2-trifluoroacetylaminomethyl-1,4-diphenylmethyl piperazine dihydrochloride in 100 ml methanol was added a suspension of 0.5 g palladium on carbon in 2 ml water. The mixture was hydrogenized for 30 mn, the catalyst was filtered off and the solvent was removed, taken up in 10 ml absolute ethanol, evaporated again and crystallized in ether to yield 1.37 g of a white powder (72%) as title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH3:16][S:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][S:17]([CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:9]
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of 10.7 grams (0.0525 mole) of m-chloroperbenzoic acid in 150 ml. of chloroform was slowly added to a cool solution (5°-7° C.) of 14.1 grams (0.050 mole) of bis(p-chlorophenyl)methyl methyl sulfide in 500 ml. of chloroform, and the resulting solution stirred for two hours at a temperature of 5° C., while a white precipitate formed. The mixture after warming to ambient temperature and holding at this temperature for a two hour period was then mixed with a solution having 20 grams of potassium carbonate in 200 ml. of water. The chloroform phase was then removed and washed with 100 ml. of water, and the chloroform distilled off; the vacuum distillation leaving 14.7 grams of a crude product which was recrystallized twice from 2,2,4-trimethylpentane-benzene (2:1) mixture to yield 11.7 grams (78 percent) of the white colored solid of bis(p-chlorophenyl)methyl methyl sulfoxide with a melting point of 109.5°-110.5° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][N:13]([CH3:48])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[N:18]=[C:17]1SCC1C=CC(OC)=CC=1)=[O:15]>ClCCl.C(OCC)(=O)C>[CH3:48][N:13]([CH3:12])[C:14]([N:16]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:20]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:19]([CH3:37])[NH:18][C:17]1=[O:6])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(CSC2=NC(C)=C(C(=O)OC(C)C)C(c3cccc([N+](=O)[O-])c3)N2C(=O)N(C)C)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)N(C(=O)N(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperoxybenzoic acid (3 eq, 2.5 mmol, 424 mg) was added to a solution of (+)-3,4-dihydro-3-[(dimethylamino)carbonyl]-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylethyl ester in dry dichloromethane (8.2 ml) at 0° C. under a nitrogen atmosphere. The reaction was stirred overnight at room temperature, and a precipitate formed. The mixture was diluted with ethyl acetate (15 ml) and washed with 1N hydrochloric acid (twice), 1N sodium hydroxide (twice) and water. The combined organic layers were dried over magnesium sulfate, filtered, and reduced in vacuo to afford an oil, 390 mg.
Reaction SMILES: C(OC(=O)[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][N:12]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[O:24])[CH2:11]1)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:17]1[CH:16]=[C:15]([C@H:14]2[C@H:10]([NH:7][CH2:8][CH3:9])[CH2:11][N:12]([C:23]([N:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:29][CH2:30]3)=[O:24])[CH2:13]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester (0.36 g, 0.66 mmol) in CH2Cl2 (10 ml) was added TFA (2 ml) at RT. Stirring was continued over night. The reaction mixture was then concentrated under vacuo, the crude dissolved in CH2Cl2, washed with aq.NaHCO3 and the organic phase was dried over Na2SO4. Purification by flash chromatography (SiO2, CH2Cl2/MeOH 95:5) yielded 0.25 g (84%) of the title compound as light yellow oil. ES-MS m/e: 449.8 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH2:17][CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH2:17][CH3:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1CN(Cc2ccccc2)CCC1O
Reaction time: 0.5 h

Procedure:
Sodium borohydride (0.456 g, 12.0 mmole) was added to the stirred solution of 1-benzyl-3-ethyl piperidin-4-one (5.4 g, 24.0 mmole) in methanol (25 ml) at 0-5° C. over a period of 15 min, and stirring was continued for 30 min at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (25 ml) and extracted with ethyl acetate (2×100 ml). The extract was dried (sodium sulphate) and concentrated to dryness to furnish 1-benzyl-3-ethyl-4-hydroxypiperidine product as oil, which was used as such in the next step. Yield 5.2 g (96%), C14H21NO, m/z 220 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[N:12]O)[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[ClH:15].[H][H]>C(O)C.[Pd]>[ClH:15].[CH2:1]([O:3][C:4](=[O:14])[CH:5]([NH2:12])[C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=NO)C(=O)C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C(=O)C(F)(F)F
Yield: 61.8 %

Procedure:
A stirred solution of 4,4,4-trifluoro-2-hydroxyimino-3-oxo-butyric acid ethyl ester (55 g, 0.258 mol) in ethanol (140 ml) was added with palladium on activated carbon and 4N hydrochloric acid (90 ml) accordingly. The reaction mixture was stirred in a Parr shaker under 0.3 MPa of hydrogen at room temperature for 2.5 hours. The reaction mixture was filtered, the filtrate was concentrated to give 2-amino-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester hydrochloride (37.56 g, 61.8%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH:24]([CH2:35][N:36]=[N+]=[N-])[CH2:25][C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:39])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH:24]([CH2:35][NH2:36])[CH2:25][C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][CH:27]=4)[CH:22]=3)=[CH:14][CH:15]=2)[C:10]([CH3:39])=[N:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(-c3cncc(OC(CN=[N+]=[N-])Cc4c[nH]c5ccccc45)c3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(-c3cncc(OC(CN)Cc4c[nH]c5ccccc45)c3)cc12
Reaction time: 4 h
Yield: 97.1 %

Procedure:
To a solution of Example 406A (480 mg) in ethanol was added 10% Pd/C (160 mg) under nitrogen. This suspension was purged with hydrogen (3 circles) and was stirred under hydrogen (balloon) for 4 h. The solid material was filtered off and the filtrate was concentrated to give the desired product (443 mg, 97%). MS (APCI) m/z 498 (M+1)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].Cl>O.C(O)C>[OH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCCCCCCl
Reactant: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)COc1ccc(-c2ccc(OCCCCCCO)cc2)cc1

Procedure:
4.5 g of KOH and 15 g of 4-hydroxy-4'-(2-methylbutoxy)-biphenyl are dissolved in 150 ml of a 1:1 water/ethanol mixture, the solution is raised to the boil and 9 g of 6-chloro-1-hexanol are slowly added dropwise, whilst stirring, after which the batch is refluxed for about 10 hours. When the reaction solution has cooled, it is acidified with HCl and the product is extracted with CHCl3 in a separating funnel. The CHCl3 is then stripped off and the crude product is recrystallized from ethanol (melting point 118° C.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[S:12](=[O:13])(=[O:14])[N:11]([CH2:41][C:40]3[CH:43]=[CH:44][C:37]([O:36][CH3:35])=[CH:38][CH:39]=3)[C:10](=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(c2cccc(I)c2)S(=O)(=O)N1
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(c3cccc(I)c3)S2(=O)=O)cc1
Reaction time: 0.58 h

Procedure:
The title B compound, 5-(3-iodo-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (932 mg, 2.76 mmol) is dissolved in tetrahydrofuran (20 mL) in a 40 mL capacity septum capped vial, stirred under argon balloon. Triphenylphosphine (1.47 g, 5.51 mmol) is added as a solid and stirred until dissolved, then 4-methyoxybenzyl alcohol (0.688 mL, 5.51 mmol) is added by syringe. The stirred reaction is cooled in an ice bath, and diethyl azodicarboxylate (0.867 mL, 5.51 mmol) is added slow dropwise by syringe. The reaction is stirred 16 h and then recooled and added more diethyl azodicarboxylate (0.433 mL, 2.26 mmol). After 5H, the reaction is concentrated in vacuo, then taken up in CH2Cl2 and chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) for 5 min, then to 5:95 over 35 min. Fractions containing product are combined, concentrated and recrystalized with EtOAc/hexanes to yield 5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a white solid: 1H-NMR (300 MHz, DMSO-d6) δ 3.76 (s, 3H), 4.79 (s, 2H), 4.88 (s, 2H), 6.92 (d, J=7.5, 2H), 7.27 (t, J=7.5, 1H), 7.33 (d, J=7.5, 2H), 7.39 (d, J=7.5, 1H), 7.63 (d, J=7.5, 1H), 7.67 (s, 1H).
Reaction SMILES: C(N[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:16][C:17]1[O:18]C(=O)C(=CC2C=CC=CC=2)[N:21]=1>O>[NH:21]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5][C:13]([OH:15])=[O:14])[C:17]([CH3:16])=[O:18]
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: CC(=O)Nc1ccccc1C=CC(=O)O

Procedure:
In the process for the preparation of N-acetylphenylalanine by opening the ring of 2-methyl-4-benzylidene-1,3-oxazolin-5-one with water to give 2-acetaminocinnamic acid and subsequently catalytically hydrogenating the latter, both reaction stages are carried out in a mixture of an aliphatic C3 -ketone to C10 -ketone or a water-miscible ether and water as the solvent, and the hydrogenation of the 2-acetaminocinnamic acid is carried out at temperatures of 10° to 50° C. and pressures of 1 to 15 bar in the presence of a supported palladium catalyst.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([Sn](CCCC)(CCCC)COCC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CCC.C(OCC)C.[F-].[K+]>C(Cl)(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:9])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(=O)C(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
Diphenylacetyl chloride (4.6 g), tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (12.6 g; Example 1a, (Method Ai)and benzylchlorobis(triphenylphosphine) palladium (II)(80 mg)were dissolved in chloroform (10 ml) and the solution heated at 80° C. for 6h. On cooling diethyl ether and saturated aqueous potassium fluoride were added and after 30 minutes the solution was filtered through Hiflo™. The organic layer was washed with water, saturated brine and dried (MgSO4). After evaporation in vacuo the residual oil was purified by chromatography on silica gel (eluting with 0 to 10% ethyl acetate in petroleum ether bp=60°-80° C.) to give 1-(3,5-bis(trifluoromethyl)phenyl)methyloxy)-3,3-diphenyl acetone as an oil. 1H NMR (CDCl3, 360MHz) δ7.80 (1H; s; 4-aryl CH) 7.71 (2H; s; 2,6-aryl CH), 7.43-7.24 (10H; m; phenyl), 5.30 (1H; s; Ph2CH), 4.56 (2H; s), 4.31 (2H; s). m/e Found 452.1191, C24H13F6O2 requires 452.12110.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@@H:21]1[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][C@@H:24]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[NH:23][CH2:22]1)S(C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C1COCC1>[CH2:1]([O:4][NH:5][C@@H:21]1[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][C@@H:24]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[NH:23][CH2:22]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C(N)=O
Yield: 78.6 %

Procedure:
To a reddish-brown, stirred suspension of (3R,6S)-3-(N-(allyloxy)-2,4-dinitrophenylsulfonamido)-6-((tert-butyldimethylsilyloxy)methyl)-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 106, 1.1 g, 1.9 mmol) and cesium carbonate (3.1 g, 9.5 mmol) in THF (about 45 mL), at ambient temperature under a blanket of argon, was added benzenethiol (polymer-bound reagent, 1.55 mmol/g) (4.5 g, 7.0 mmol). This mixture was stirred overnight at ambient temperature. Analysis by LCMS in the morning indicated complete consumption of starting material, as did analysis by TLC (5% methanol in methylene chloride). The mixture was filtered and the filtered material was rinsed with THF until no material remained that was responsive to UV or I2 stain on a silica plate. The red-orange solution obtained was concentrated and redissolved in methylene chloride. Normal-phase chromatography (0-6% methanol in methylene chloride, 80-g, 25 min.) afforded the desired compound (510 mg, 80%, orange-brown solid).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=2)=[O:8])[CH:32]=[C:31]([C:44]([OH:47])([CH3:45])[CH3:46])[CH:30]=1
Reactant: CC(C)(O)c1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: CC(C)(O)c1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 2-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol and to afford a yellow resin. HPLC (Condition 4) tR=5.18 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=520.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=1.96 Hz, 6H) 1.65-1.75 (m, 1H) 1.76-1.89 (m, 1H) 2.86 (d, J=10.95 Hz, 1H) 3.13-3.28 (m, 2H) 3.34-3.50 (m, 1H) 4.03-4.22 (m, 1H) 4.82 (d, J=2.74 Hz, 1H) 5.19 (d, J=0.78 Hz, 1H) 7.09 (d, J=9.38 Hz, 1H) 7.18-7.28 (m, 2H) 7.33 (d, J=8.99 Hz, 2H) 7.77-7.88 (m, 2H) 7.98 (m, J=2.30, 0.80 Hz, 1H) 8.67-8.76 (m, 1H) 10.16 (s, 1H).