Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:40])[CH:10]([N:19]2[C:23](=[O:24])[CH:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34]C(C)(C)C)=[CH:27][CH:26]=3)[NH:21][C:20]2=[O:39])[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[C:4]([Cl:41])[CH:3]=1.C(#N)C.C[Si](Cl)(C)C.[I-].[Na+]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:40])[CH:10]([N:19]2[C:23](=[O:24])[CH:22]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][OH:34])=[CH:29][CH:30]=3)[NH:21][C:20]2=[O:39])[CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[C:4]([Cl:41])[CH:3]=1
Reactant: CC(c1ccccc1)C(C(=O)Nc1ccc(Br)cc1Cl)N1C(=O)NC(c2ccc(OCCOC(C)(C)C)cc2)C1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(c1ccccc1)C(C(=O)Nc1ccc(Br)cc1Cl)N1C(=O)NC(c2ccc(OCCO)cc2)C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
N-(4-Bromo-2-chloro-phenyl)-2-{4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (300 mg) was dissolved in dichloromethane (2 mL) and acetonitrile (2 mL) in an ice bath. Trimethylsilyl chloride (0.36 mL, 2.8 mmol) was added followed by sodium iodide (352 mg, 2.35 mmol). The mixture was stirred at 0° C. for 1.5 hours and then diluted with ethyl acetate. The mixture was washed with aqueous sodium bisulfite, washed with brine, dried over sodium sulfate and concentrated in vacuo. Trituration of the residue with hexanes gave N-(4-bromo-2-chloro-phenyl)-2-{4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (210 mg, 76%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)C1CCCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and cyclohexanecarboxylic acid chloride, there is obtained ethyl N-cyclohexylcarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 376 (13), 347 (16), 293 (100), 194 (60);
Reaction SMILES: [C:1]([C:4]1[N-:8][N:7]=[N:6][N:5]=1)(O)=[O:2].[K+].[CH3:10][NH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1>>[CH3:10][N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:18][CH2:19]1)[C:1]([C:4]1[N:8]=[N:7][NH:6][N:5]=1)=[O:2]
Reactant: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1nnn[n-]1
Agent: [K+]
Product: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)c1nn[nH]n1

Procedure:
The title compound was prepared from potassium 5-carboxytetrazol-1-ide and 3,5-dichlorobenzyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate (Example 1 step 3) analogously to Example 16;
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:29]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:29]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:14]=[N:13]2)[C:9]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:40])[CH3:38])[N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2cccc3c2OCCO3)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3cccc4c3OCCO4)cc2=O)n1
Yield: 22 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 99) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclohexyl-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid (40 mg, 22%); ES+-HRMS m/e calcd for C28H35N5O6 [M+H+] 538.2660 found 538.2660. 1H NMR (300 MHz, CDCl3) δ ppm 0.73-1.34 (m, 6H), 1.16 (br. s., 3H), 1.16 (br. s., 3H), 1.54-1.85 (m, 5H), 1.96-2.29 (m, 2H), 3.99 (s, 2H), 4.20-4.37 (m, 4H), 5.59-5.79 (m, 1H), 6.00 (d, J=2.7 Hz, 1H), 6.64-6.77 (m, 2H), 6.78-6.95 (m, 2H), 7.32 (s, 1H), 7.96 (d, J=2.7 Hz, 1H), 8.77 (br. s., 1H).
Reaction SMILES: [OH-].[K+].O.[Cl:4][C:5]1[N:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[N:10]=[N:9][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:15][CH2:16]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Yield: 18.6 %

Procedure:
To a stirred solution of 4.5 parts of potassium hydroxide in 50 parts of water was added dropwise a solution of 4 parts of ethyl 4-[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propoxy]benzoate in 160 parts of ethanol. Upon complete addition, stirring was continued over weekend at room temperature. The precipitated product was filtered off, washed with water and then stirred in water. The whole was neutralized with acetic acid. The product was filtered off, washed with water and converted into the hydrochloride salt in methanol. The crystallized product was filtered off and the filtrate was evaporated. The residue and the crystallized product were combined and stirred into water and sodium hydroxide. The precipitate was filtered off and the filtrate was treated with acetic acid. The precipitated product was filtered off, washed with water and crystallized from N,N-dimethylformamide. The product was filtered off and dried, yielding 0.7 parts (18.6%) of 4-[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propoxy]benzoic acid; mp. 209.4° C. (comp. 166).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Li+]>ClCCl>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
In accordance with the method of “Helvetica Chimica Acta”, 2002, vol. 85, no. 11, p. 3616-3623, triethylamine was added under ice-cooling to a mixture of trans-cinnamic acid chloride, (S)-4-benzyl-2-oxazolidinone, lithium chloride and dichloromethane, and then stirred at room temperature for 3Hours. Thereafter, (4S)-4-benzyl-3-[(2E)-3-phenylprop-2-enoyl]-1,3-oxazolidin-2-one was obtained by purifying it in the standard method. FP: 308.
Reaction SMILES: [CH3:1][C:2]([NH:14][C:15]1[C:16](=[O:37])[N:17]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:29][CH:28]=2)[CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:19]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[N:5]=1)[CH3:3].C([BH3-])#N.[Na+]>CC(O)=O>[CH3:3][C:2]([NH:14][CH:15]1[CH2:19][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[N:17]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH:34]([F:36])[F:35])=[CH:31][CH:32]=2)[C:16]1=[O:37])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[N:5]=1)[CH3:1]
Reactant: CC(C)(NC1=CC(c2ccccc2F)N(c2ccc(OC(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(NC1CC(c2ccccc2F)N(c2ccc(OC(F)F)cc2)C1=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Dissolve (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-difluoromethoxy-phenyl)-5-(2-fluoro-phenyl)-1,5-dihydro-pyrrol-2-one (2.06 g; 3.95 mmol) in HOAc (20 mL) and add sodium cyanoborohydride (0.50 g, 7.90 mmol). Stir for 2 hours at ambient temperature. Concentrate under reduced pressure and dissolve the residue in EtOAc. Wash the organic phase with 1N NaOH, water, saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify by silica gel chromatography (5-25% EtOAc-hexane) to yield (±)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(2-fluoro-phenyl)-1-(4-difluoromethoxy-phenyl)-pyrrolidin-2-one (1.5 g, 73%), a racemic mixture, as a clear colorless oil. LC-MS ESI m/z: 524 (M+H)+, Tr=3.18 min., method 1.
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.Cl[C:31]1[C:32]([O:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]2)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=1)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37]>>[CH:15]1([C:31]2[C:32]([O:45][C@H:46]3[CH2:51][CH2:50][C@H:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=2)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])[CH2:10][CH2:9]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide with 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((trans-4-(trifluoromethyl)cyclohexyl)oxy)benzamide, the title compound was obtained (0.24 g, 57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=16.2 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 6.55 (d, J=14.7 Hz, 1H), 4.69-4.65 (m, 1H), 3.39 (s, 3H), 2.24-1.95 (m, 4H), 1.83-1.55 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS (ES−) m/z 422.2 (M−1); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:33]1[N:37]=[C:36]([NH2:38])[S:35][N:34]=1)[C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:28]([OH:30])=[O:29])=[C:13]([CH:16]=[CH:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][N:4]=[C:5]([C:33]1[N:37]=[C:36]([NH2:38])[S:35][N:34]=1)[C:6]([NH:8][CH:9]1[C:31](=[O:32])[N:11]2[C:12]([C:28]([OH:30])=[O:29])=[C:13]([CH:16]=[CH:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3ccc([N+](=O)[O-])cn3)CS[C@H]12)c1nsc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3ccc(N)cn3)CS[C@H]12)c1nsc(N)n1
Temperature: 0 °C
Yield: 82 %

Procedure:
To an ice-cooled solution of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(5-nitro-2-pyridyl)thiovinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer) (1.35 g) in an aqueous solution of sodium bicarbonate (30 ml) was added sodium hydrosulfite (4.05 g) under stirring. The mixture was stirred for 30 minutes at room temperature and cooled in an ice-bath and acidified to pH 3.5 with 10% hydrochloric acid. The precipitate was collected, washed and dried to give 1.05 g of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(5-amino-2-pyridyl)thiovinyl)-3-cephem-4-carboxylic acid (syn isomer) (trans isomer).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:24][O:23][CH2:22]/[CH:21]=[CH:20]/[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1ccc2c(c1)C(=O)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromoindan-1-one (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.3 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was stirred at 100° C. for 1 h. The now black suspension was cooled to RT, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1N.N(OCCCC)=O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: c1ccccc1
Agent: CCCCON=O
Product: Fc1ccc(-c2ccccc2)c(F)c1

Procedure:
The starting material was prepared as follows. 2,4-Difluoroaniline and butyl nitrite were reacted with benzene in a modified Gomberg reaction to give 2,4-difluorobiphenyl, m.p. 63°-65°C. which was reacted with acetyl chloride in a Friedel-Crafts reaction to give 4-acetyl-2',4'-difluorobiphenyl, m.p. 82.5°-83.5°C. This was subjected to the Willgerodt reaction using morpholine and sulphur, followed by hydrolysis, to give 2',4'-difluoro-4-biphenylylacetic acid, m.p. 143°-145°C., which was esterified to give ethyl 2',4'-difluoro-4-biphenylylacetate, b.p. 129°-130°C./0.2 mm. This ester was treated conventionally with diethyl carbonate, and then with dimethyl sulphate, to yield the required ethyl 2-(2',4'-difluoro-4-biphenylyl)-2-methylmalonate, b.p. 172°-175°C./0.5 mm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:4][CH2:3]1.[C:19]([O:23][C:24](=[O:42])[C@@H:25]([NH2:41])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:42])[CH:25]([NH:41][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)N1CCN(C)CC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: CC(C)CC(NC(=O)N1CCN(C)CC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Yield: 60 %

Procedure:
A solution of the product from Example AF (2(S)-[(4-methyl-piperazine-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.25 g, 1.03 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.35 g, 1.03 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, gradient elution 1:1 EtOAc/heptane; 9:1 EtOAc/EtOH; 9:1:0.1 EtOAc/EtOH/NH4OH) to give the title compound as a white foam (0.35 g, 60%).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:11](Br)([CH3:13])[CH3:12]>CS(C)=O>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)Br
Reactant: Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 54.1 g (0.5 mole) of ortho-cresol in 150 ml of DMSO was added portionwise and with stirring 12 g of 57% sodium hydroxide. This addition was exothermic to 45° C. After 2 hours at ambient temperature, 61.5 g (0.5 mole) of isopropyl bromide in 50 ml of DMSO was added dropwise with stirring. After another 2 hours, the reaction mixture was poured into 1000 ml of ice water and extracted with ether. Distillation of the dried extract gave 53.9 g of product as a colorless liquid; b.p. 94°-96° C. (30 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[CH2:13][O:14][C:15]([CH3:20])([CH3:19])[CH:16](O)[OH:17]>C1C=CC=CC=1>[F:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[CH2:13][O:14][C:15]1([CH3:20])[CH2:16][O:17][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[O:6][CH2:19]1
Reactant: CC(C)(OCc1ccccc1F)C(O)O
Reactant: O=Cc1cccc(F)c1
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)COC(c2cccc(F)c2)OC1

Procedure:
Using the procedure of Example 51, 3-fluorobenzaldehyde and 2-(2-fluorobenzyloxy)-2-methylpropanediol were reacted, using benzene as solvent, to give, after separation by column chromatography, c-5-(2-fluorobenzyloxy)-r-2-(3-fluorophenyl)-5-methyl1,3-dioxane, m.p. 86°-87°, and t-5-(2-fluorobenzyloxy)-r-2-(3-fluorophenyl)-5-methyl-1,3-dioxane, m.p. 83°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(B(CC)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)C.Cl.[K].Cl>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(OCC)(=O)C.O>[ClH:1].[N:17]1[CH:18]=[CH:19][C:14]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: CCB(CC)c1ccncc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(-c2ccncc2)nc1

Procedure:
In tetrahydrofuran (20 ml), 6-chloronicotinic acid (535 mg) and diethyl (4-pyridyl)borane (Chem. Pharm. Bull., 33, 4755, 1985) (500 mg) were dissolved. To the resulting solution, tetrabutylammonium bromide (546 mg), potassium hydrochloride (570 mg), tetrakis(triphenylphosphine) palladium (O) (392 mg) and water (0.5 ml) were added under an argon atmosphere, followed by heating under reflux for 6 hours. Dilute hydrochloric acid was added to the reaction mixture to make it acidic. Water and ethyl acetate were poured into the resulting mixture for extraction. The water layer so extracted was distilled off under reduced pressure. The residue was purified by chromatography through a synthetic adsorbent (“Diaion® HP-20”, water˜50% acetonitrile—water). To the resulting fraction, dilute hydrochloric acid was added to make it acidic. The solvent was then distilled off. Tetrahydrofuran was added to the residue and the precipitate was collected by filtration, whereby the title compound (269 mg, 32%) was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[CH:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].P(Br)(Br)[Br:22]>C(OCC)C>[C:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[CH:8]([Br:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc(Cl)cc1C(O)c1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CC(=O)OCc1ccc(Cl)cc1C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 45 g. of 2-acetoxymethyl-5-chloro-benzhydrol in 270 ml. of ethyl ether, 13.7 g. of phosphorus tribromide in 45 ml. ethyl ether is added and the solution is stirred for 3 hours at room temperature. The organic solution is successively washed with a sodium bicarbonate solution and with water. After drying over sodium sulfate and evaporation of the solvent, 43.1 grams of the crude title compound is obtained which may be used for further reaction steps. B.p. 175°-180° C. 0.5 mm Hg.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[F:30])=[N:9][CH:10]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:12]=1)(=O)=O.[CH2:33]([Mg]Cl)[C:34]([CH3:37])([CH3:36])[CH3:35].Cl>C1COCC1.C(OCC)C.CC(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl>[Si:15]([O:14][CH2:13][C:11]1[CH:12]=[C:7]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:8]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[F:30])=[N:9][CH:10]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1C=CN(c2c(C(C)C)cccc2C(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(CO[Si](C)(C)C(C)(C)C)cc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under an argon atmosphere, to a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-fluoro-5-methoxyphenyl)pyridin-3-yl trifluoromethanesulfonate (2.72 g) and PEPPSI-SIPr (trade name) (374 mg) in THF (25 mL) was added dropwise a 1.0 M solution (24 mL) of neopentylmagnesium chloride in diethyl ether, and the mixture was stirred at room temperature for 10 min. 1N Hydrochloric acid was added at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:7]2([O:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][O:8]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CI.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:23][O:19][C:18](=[O:20])[CH2:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:16][CH2:15][C:7]2([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12]2)[CH2:6][CH2:5]1
Reactant: C=CCC1(CC(=O)O)CCC2(CC1)OCC(C)(C)CO2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCC1(CC(=O)OC)CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (9-allyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetic acid (0.50 g), methyl iodide (0.12 mL), K2CO3 (0.37 g), and N,N-dimethylformamide (5 mL) is stirred at room temperature overnight. 10% aqueous K2CO3 solution is then added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated to give the crude title compound that is used without further purification. Yield: 0.36 g (crude); LC (method 6): tR=1.65 min; Mass spectrum (ESI+): m/z=297 [M+H]+.
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[I:13])(=O)C.[Br:15][Si](C)(C)C.N(OCCC(C)C)=O>O1CCCC1>[Br:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([I:13])[N:8]=1
Reactant: CC(=O)n1cnc2c(I)nc(N)nc21
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Brc1nc(I)c2[nH]cnc2n1
Temperature: 22.5 °C
Reaction time: 19 h

Procedure:
9-Acetyl-2-amino-6-iodopurine (1.44 g, 4.72 mmol), bromotrimethylsilane (2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g, 5.67 mmol) were added to tetrahydrofuran (5 ml), and the mixture was stirred 20-25° C. for 19 hr to give 2-bromo-6-iodopurine.