Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](OS(C(F)(F)F)(=O)=O)=[C:6]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])[CH:5]=1)([O-:3])=[O:2].[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl>[CH3:39][O:38][C:36]([CH:35]([C:34]([O:41][CH3:42])=[O:40])[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23])=[O:37]
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(COC(=O)c2cc([N+](=O)[O-])c3ccccc3c2OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1c(C(=O)OCc2ccc(OC)cc2)cc([N+](=O)[O-])c2ccccc12
Temperature: 20 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
A stirred solution of 4 (13.20 g, 27.2 mmol) and dimethyl malonate (5.39 g, 40.8 mmol) in DMF (85 mL) was cooled to -5° C. and treated with powdered K2CO3 (22.53 g, 163 mmol). The mixture was allowed to warm to 20° C. over a 2 h period, and after stirring for a further 12 h at 20° C. was poured slowly into cold stirred 0.5N HCl (1750 mL). The resulting solid was dissolved in CH2Cl2 and the solution was washed twice with water, dried (Na2SO4) and then evaporated to dryness. The residue was crystallised from CH2Cl2 /iPr2O/petroleum ether to give 4-methoxybenzyl 1-[di(methoxycarbonyl)methyl]-4-nitronaphthalene-2-carboxylate (5) (10.66 g, 84%), suitable for further use. A sample recrystallised from MeOH had mp 124-125° C. 1H NMR (CDCl3) δ 8.62 (s, 1H, H-3), 8.45 (d, J=8.6 Hz, 1H, H-5), 8.21 (d, J=8.7 Hz, 1H, H-8), 7.70 (br t, J=7.7 Hz, 1H, H-6), 7.69 (br t, J=7.8 Hz, 1H, H-7), 7.41 (d, J=8.7 Hz, 2H, H-2',6'), 6.94 (d, J=8.7 Hz, 2H, H-3',5'), 6.62 (s, 1H, ArCH), 5.37 (s, 2H, CH2), 3.83 (s, 3H, PhOCH3), 3.69 (s, 6H, 2×CO2CH3). Anal. Calculated for C24H21NO9 : C, 61.6; H, 4.7; N, 3.1%.
Reaction SMILES: C([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])([O:51][CH2:50][CH:48]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:49]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:53]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) (520 mg, 1.06 mmol) was taken in 20% piperidine in DMF (2 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-D-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×10 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (2 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-L-leucine (38.1 mg, 1.06 mmol), DCC (262.0 mg, 1.27 mmol) and HOBt (171.4 mg, 1.27 mmol) in dry DMF (20 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (3% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 3% MeOH: CH2Cl2 to give 310 mg of the tripeptide Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OH (2a) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]([CH2:29][CH2:30][CH:31](O)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])#[N:28]>>[NH2:28][CH2:27][CH2:29][CH2:30][CH:31]([O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36]
Reactant: Oc1cccnc1
Reactant: COC(=O)CCCC(O)CCC#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)CCCC(CCCN)Oc1cccnc1

Procedure:
Hex-5-enoic acid is first converted to the corresponding epoxide with e.g. m-chloroperbenzoic acid and esterified with diazomethane to the methyl ester which is then condensed with acetonitrile in the presence of lithium diisopropylamide (LDA) to yield methyl 7-cyano-5-hydroxy-heptanoate. Condensation with 3-hydroxypyridine in the presence of triphenylphosphine and reduction of the nitrile yields methyl 8-amino-5-(3-pyridyloxy)-octanoate.
Reaction SMILES: [C:1](=O)([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])[O:2]C(C)(C)C.C(Cl)([Cl:20])=O.ClC1C=C(Cl)C(Cl)=CC=1O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:20][C:1]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=1[Cl:16])=[O:2]
Reactant: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(Cl)Cl
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
T-Butyl 2,4,5-trichlorophenyl carbonate is a known compound and one method for its preparation is described in an article by W. Broadbent, J. S. Morley and B. E. Stone in the Journal of the Chemical Society (C), 1967 pages 2632-2637. Briefly, in this method a solution of phosgene in toluene is treated with 2,4,5-trichlorophenol at -10° C, followed by addition of dimethylaniline at such a rate that the reaction temperature is maintained at 5°-10° C. The mixture is heated to 20°-24° C and maintained at this temperature for 12 hours. The mixture is cooled by addition of ice and the suspension filtered. From the organic layer in the filtrate, 2,4,5-trichlorophenyl chloroformate is isolated. A solution of the crude 2,4,5-trichlorophenyl chloroformate in methylene chloride is reacted with a solution of t-butanol and quinoline in methylene chloride. The reaction mixture is maintained at 20°-24° C for 12 hours. The mixture is cooled by addition of ice and the suspension is filtered. From the organic layer in the filtrate t-butyl 2,4,5-trichlorophenyl carbonate is isolated.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:19])=O)=[C:4]2[CH2:3]1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]#[N:19])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O

Procedure:
0.5 g of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide is heated to reflux while stirring for 40 hours together with 0.5 g of Sicapent in 150 ml of toluene. The mixture is treated with a 0.5 g portion of Sicapent after 16 hours, 19 hours and 24 hours. The mixture is subsequently cooled and treated with water. The mixture is adjusted to pH 9 with 28 percent sodium hydroxide. After separation of the organic phase, the alkaline-aqueous phase is extracted twice with 250 ml of ethyl acetate each time. The organic extracts are washed twice with saturated sodium chloride solution, dried and evaporated. After recrystallisation of the residue from methylene chloride/hexane, there is recovered a portion of unreacted starting material. The mother liquor is evaporated and chromatographed on 100 g of silica gel while eluting with ethyl acetate and alcohol. After recrystallisation of the thus-obtained substance from acetone, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 184°-185° C.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:26][C:25]=1[F:35].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/[C:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:31])=[CH:26][C:25]=1[F:35]
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2,5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 4-chloro-3-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=464.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=1[O:35][CH3:36])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 ml round bottomed flask is charged with (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid tert-butyl ester (23.9 mg, 0.086 mmol), 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (30.5 mg, 0.095 mmol) and Cs2CO3 (84.6 mg, 0.172 mmol). The mixture is treated with DMF (2 ml) and the solution stirred at RT overnight. Water is added to the mixture giving rise to a solid. This is filtered, dried, and purified via flash column chromatography, eluting with iso-hexane:EtOAc to give the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4cccc(Cl)c4)c3O2)cc1
Product: CNCC1Cc2cc(C)cc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.016 g, 13%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(3-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 181-182° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:35](I)[CH:36]=[CH2:37].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH2:24][CH2:25][CH2:26][N:27]([CH2:37][CH:36]=[CH2:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(N(CCCNCc3ccccc3)C(=O)/C=C/c3ccccc3)cc21
Reactant: C=CCI
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(CCCN(C(=O)/C=C/c1ccccc1)c1ccc2c(c1)N(C(C)=O)CC2)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide (Example 47, 39 mg, 0.090 mmol), allyl iodide (0.01 mL, 0.1 mmol), and diisopropylethylamine (0.03 mL, 0.2 mmol) in CH2Cl2 (3.0 mL) was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified on silica gel (60% EtOAc/hexanes) to provide the title compound (37 mg, 87%). 1H NMR (500 MHz, CDCl3): 8.13 (s, 1H), 7.65 (d, J=15.5 Hz, 1H), 7.31-7.24 (m, 10H), 7.15 (d, J=7.6 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.30 (d, J=16.5 Hz, 1H), 5.84-5.80 (m, 1H), 5.10 (dd, J=17.0, 10.1 Hz, 2H), 4.11 (t, J=7.3 Hz, 2H), 3.84 (br s, 2H), 3.50 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 3.02 (d, J=6.3 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 2.23 (s, 3H), 1.81-1.75 (m, 2H). MS: exact mass calculated for C32H35N3O2, 493.64; m/z found, 494.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([CH:17](Br)Br)=[CH:4][CH:3]=1.C([OH:23])(C)C.O>[N+]([O-])([O-])=O.[Ag+].ClCCl>[C:8]([C:7]1[C:6]([F:16])=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[CH:17]=[O:23])(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1c(Cl)ccc(C(Br)Br)c1F
Reactant: CC(C)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Step 4 A mixture of (6-chloro-3-dibromomethyl-2-fluoro-phenyl)-phenyl-methanone (582 mg, 1.38 mmol), silver nitrate (469 mg, 2.76 mmol), isopropanol (10 ml) and water (2 ml) was stirred at room temperature overnight. Dichloromethane was added and the mixture was filtered under suction washing with isopropanol. The organic liquors were concentrated then purified by silica chromatography eluting with 0-20% ethyl acetate/petroleum ether furnishing 3-benzoyl-4-chloro-2-fluoro-benzaldehyde (222 mg oil, 90% clean). Analytical data as above
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)=[O:2].[H-].[Na+].[C:10]([NH:13][CH2:14][CH:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23](F)=[C:22]([F:27])[CH:21]=2)[CH2:16]1)(=[O:12])[CH3:11]>CN(C)C=O.C(OCC)(=O)C>[F:27][C:22]1[CH:21]=[C:20]([C:17]2[CH2:16][CH:15]([CH2:14][NH:13][C:10](=[O:12])[CH3:11])[O:19][N:18]=2)[CH:25]=[CH:24][C:23]=1[N:5]1[CH:6]=[CH:7][C:3]([CH:1]=[O:2])=[CH:4]1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NCC1CC(c2ccc(-n3ccc(C=O)c3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
3-Formylpyrrole (628 mg) is dissolved in 12 ml dimethylformamide in a 50 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (554 mg), and the mixture is stirred 30 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (1.52 g), and the reaction is stirred 6 hours at 65° C. The reaction is cooled, is diluted with 100 ml ethyl acetate, and is washed with 4×25 ml 50% saturated sodium chloride. The organics are dried over anhydrous potassium carbonate and are concentrated in vacuo to a yellow oil. The crude material is chromatographed over 75 g silica gel (230-400 mesh) eluting with 3% methanol/dichloromethane and after a 200 ml forerun collecting 9 ml fractions. Fractions 48-69 are combined and concentrated to give 1.10 g (56%) of the title compound as a white solid, mp 155-156° C., [α]25D -69° (c 0.61, ethanol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9].[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH3:39])([CH3:30])[CH3:29])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]2[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:7][C:8]=2[CH3:9])=[CH:34][C:33]=1[CH3:39])([CH3:29])[CH3:30])[CH3:25]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C
Yield: 51.8 %

Procedure:
A solution of 350 mg (1 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]), 235 mg (1 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 417 mg (1 mmol) cesium carbonate in 5 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 283 mg of pure 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[Cl:26][C:27]([Cl:33])([Cl:32])[C:28](=[NH:31])OC.O>CC(O)=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:31]=[C:28]([C:27]([Cl:26])([Cl:32])[Cl:33])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(Cl)(Cl)Cl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (270 mg) in AcOH (3 ml) was added methyl 2,2,2-trichloroacetimidate (0.196 ml) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. Water was added to the mixture. The resulting precipitate was collected by filtration and dried to give the title compound (220 mg) as an ivory solid.
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:11]([C:23]1[S:24][C:25]([CH:3]=[O:4])=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCc1cccs1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C=O)s1
Temperature: 5 °C
Yield: 75.9 %

Procedure:
In a 1 liter-four-necked flask, 93.7 (1.28 mol) of N,N-dimethylformamide was placed and cooled to 5° C., followed by addition of 107.4 g (7.00×10-1 mol) of POCl3 in 15 min. below 10° C. under stirring. After stirring for 30 min. below 10° C., 160 g (6.35×10-1 mol) of 2-dodecylthiophene was added dropwise to the mixture in 10 min. at room temperature, followed by stirring for 1.5 hours and further stirring for 2.5 hours at 60° C. After the reaction, the reaction mixture was poured into 2 liters of iced water, subjected to 3 times of extraction with 500 ml of chloroform and washed 6 times with 500 ml of water. The organic layer was dried on CaCl2, followed by distilling-off of the solvent to obtain 237 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 135 g of a product (yield: 75.9%). b.p.: 160° C./0.6 mmHg
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCBr)cc1
Yield: 43.9 %

Procedure:
A mixture of 1,2-dibromoethane (3.9 mL, 45 mmol), 4-hydroxybenzaldehyde (1.8 g, 15 mmol) and K2CO3 (10.4 g, 75 mmol) in acetone (40 mL) was heated to reflux for 18 hr. The mixture was cooled, diluted with ethyl acetate (200 mL) and washed with brine (200 mL). Then organic layer was dried (MgSO4), filtered and then concentrated. The resulting residue was subjected to flash chromatography (25% ethyl acetate/hexane) to provide 1.51 g (44%) of 4-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=[N:28][S:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH:36]=[CH2:37]>C1COCC1.[NH4+].[Cl-]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21]([NH:28][S:29]([C:31]([CH3:33])([CH3:32])[CH3:34])=[O:30])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:37][CH:36]=[CH2:35])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=NS(=O)C(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(CCCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)(NS(=O)C(C)(C)C)c1ccccc1
Reaction time: 3 h
Yield: 99 %

Procedure:
A stirred solution of tert-butyl (S)-1-(4-bromophenyl)ethyl(4-(tert-butylsulfinylimino)-4-phenylbutyl)carbamate (926 mg, 1.69 mmol) in dry THF (25 mL) was cooled in a dry ice/i-PrOH bath and 1 M allylmagnesium bromide (4.2 mL, 4.2 mmol) was added dropwise over 2 min The mixture was stirred in the cooling bath for 3 h, diluted with satd aq NH4Cl (50 mL) and extracted with EtOAc (2×50 mL). The combined EtOAc extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated to afford tert-butyl (S)-1-(4-bromophenyl)ethyl(4-(1,1-dimethylethylsulfinamido)-4-phenylhept-6-enyl)carbamate (990 mg, 99%) as an oil. LC-MS Method 1 tR=2.47 min, m/z=593, 591.