Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:47][C:48]1[CH:53]=[N:52][C:51]([C:54]#[C:55][CH2:56][O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])=[CH:50][N:49]=1.Cl[C:66]1[N:71]=[CH:70][N:69]=[C:68]([NH:72][CH2:73][CH:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)[CH:67]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Si:58]([O:57][CH2:56][C:55]#[C:54][C:51]1[N:52]=[CH:53][C:48]([NH:47][C:66]2[N:71]=[CH:70][N:69]=[C:68]([NH:72][CH2:73][CH:74]3[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:78][CH2:79]3)[CH:67]=2)=[N:49][CH:50]=1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncn2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC#Cc1cnc(N)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#CCO[Si](C)(C)C(C)(C)C)cn3)ncn2)CC1
Temperature: 145 °C

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (56 mg, 0.09 mmol) and palladium acetate (4 mg, 0.015 mmol) were suspended in 5 mL toluene (5 mL) and degassed over 10 minutes under a stream of nitrogen gas. 2-Amino-5-(3-(tert-butyldimethyl-silyloxy)prop-1-ynyl)pyrazine (50 mg, 0.15 mmol) and tert-butyl 4-((6-chloropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate (40 mg, 0.15 mmol), in anhydrous and degassed DMF (500 μL), and sodium tert-butoxide (46 mg, 0.45 mmol) were added and the reaction mixture was heated at 145° C. for 30 minutes by microwave irradiation. The mixture was evaporated to dryness. The residue was partitioned between water and dichloromethane and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated. The residue was redissolved in methanol and filtered through a PS—SH column. The filtrate was evaporated to dryness to give crude tert-butyl 4-((6-(5-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)pyrazin-2-yl-amino)pyrimidin-4-ylamino)methyl)piperidine-1-carboxylate which was used directly for the next step.
Reaction SMILES: [OH-].[K+].[C:3]([C:8]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])([CH2:6][CH3:7])([CH3:5])[CH3:4]>C(O)C>[C:3]([C:8]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:9]=1[O:10][C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])([CH2:6][CH3:7])([CH3:5])[CH3:4]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(OC)cc2C(=O)OC)c(C(C)(C)CC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C)c1ccc(Oc2ccc(OC)cc2C(=O)O)c(C(C)(C)CC)c1
Yield: 90 %

Procedure:
To a solution of potassium hydroxide (5.6 g, 0.1 mol) in ethanol (150 mL) was added methyl 2-(2,4-di-tert-pentylphenoxy)-5-methoxybenzoate (18.0 g, 0.045 mol) and the mixture brought to reflux for 2 hours. TLC indicated the hydrolysis to be complete. The ethanol was removed in vacuo and the residue taken up in water (75 mL) and acidified with 6N HCl. The aqueous mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined and dried over magnesium sulfate, filtered and the solvent removed in vacuo. Recrystallization from heptane yielded the product as a white solid in 90% yield. NMR and mass spectral analysis were consistent with proposed structure.
Reaction SMILES: [C:1]1([C:7]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:15][C:14]3[N:13](COCC[Si](C)(C)C)[N:12]=[C:11]([C:24]4[CH:28]=[CH:27][S:26][CH:25]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(C3C=CC=CC=3)CC3NN(COCC[Si](C)(C)C)C(C4C=CSC=4)C=3C=C2)C=CC=CC=1.Cl>C(O)C>[C:29]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:24]4[CH:28]=[CH:27][S:26][CH:25]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccsc2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: C[Si](C)(C)CCOCN1NC2=C(C=CC(c3ccccc3)(c3ccccc3)C2)C1c1ccsc1
Agent: Cl
Solvent: CCO
Product: C1=CC(c2ccccc2)(c2ccccc2)Cc2[nH]nc(-c3ccsc3)c21

Procedure:
But starting with 0.107 g of a mixture of 6,6-diphenyl-3-thiophen-3-yl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole and 6,6-diphenyl-3-thiophen-3-yl-2-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole, 2.2 cm3 of ethanol and 2.2 cm3 of a 2N ethanolic solution of hydrogen chloride. After flash chromatography on a column of silica [eluent: dichloromethane], 0.024 g of 6,6-diphenyl-3-thiophen-3-yl-6,7-dihydro-1H-indazole is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH:23]=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(CO)cnc2[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(C=O)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of {2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridin-6-yl}methanol (1.0 g) in dichloromethane (50 ml) was added manganese peroxide (2.3 g), and the mixture was stirred at room temperature for 8 hr. The insoluble material was removed by filtration, and the filtrate was concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (0.70 g, yield 69%) as colorless crystals. melting point 170-171° C. purity 87%. M+H: 388. 1H NMR (CDCl3) δ: 1.52 (6H, d, J=6.0 Hz), 4.76-4.85 (1H, m), 5.17 (2H, s), 7.03-7.07 (1H, m), 7.11-7.16 (1H, m), 7.31-7.52 (5H, m), 8.20 (1H, d, J=3.2 Hz), 8.53 (1H, s), 8.88 (1H, d, J=1.5 Hz), 10.19 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[C:7]2[C:12]([C:13](=[O:16])[C:14]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:16])[C:14]([N:28]2[CH2:29][CH2:30][N:25]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:26][CH2:27]2)=[C:5]1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NC1=C(Cl)C(=O)c2ccccc2C1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: CC(=O)NC1=C(N2CCN(Cc3ccccc3)CC2)C(=O)c2ccccc2C1=O
Yield: 89.7 %

Procedure:
A mixture of 500 mg of 2-acetylamino-3-chloro1,4-naphthoquinone, 880 mg of N-benzylpiperazine and 40 ml of absolute ethanol was heated at reflux for 3 hours, then the solvent was removed. The remainder was passed through a small plug of silica gel and eluted with chloroform. The eluate was concentrated to a solid which was recrystallized from dichloromethane/hexane, giving 700 mg of the desired product, mp 153-155°C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[C:10]([CH3:21])[N:9]=1)([CH3:3])[CH3:2].[H-].[Na+].COS(OC)(=O)=O.[CH3:34][O:35][CH2:36]COC>C(CNCC=O)=O.CN(C=O)C>[CH:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][C:8]1[C:13]([C:14](=[CH:34][O:35][CH3:36])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][CH3:20])[N:11]=[C:10]([CH3:21])[N:9]=1)([CH3:3])[CH3:2]
Reactant: COCCOC
Reactant: COC(=O)Cc1c(OC)nc(C)nc1Oc1cccc(C(C)C)c1
Agent: O=CCNCC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC=C(C(=O)OC)c1c(OC)nc(C)nc1Oc1cccc(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of methyl 4-(3-isopropylphenoxy)-6-methoxy-2-methyl-pyrimidin-5-yl-acetate (8.6 g, 26 mol) in 1,2-dimethoxyethane (20 ml) and N,N-diformylmethylamine (8 ml) is added at 5° C. to a suspension of NaH (1.6 g, 80% in oil, 52 mol) in DMF (30 ml). The mixture is stirred for 4 hours at room temperature. Dimethylsulfate (3.7 ml, 39 tool) is added at 0° C and stirring is continued for 3 hours. Dilution with ether, washing with brine and chromatography on silicagel (eluent hexane/ethyl acetate 3:1) gives methyl α-[4-(3-isopropylphenoxy )-6-methoxy-2-methyl-pyrimidin-5-yl]-β-methoxyacrylate as a colorless oil (7.2 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH3:13][O:14][CH2:15]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: COCOC
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COCOc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
To 1.12 g (5.9 mmol) of 2-chloro-4-fluoro-5-nitrophenol in 100 ml CH2Cl2 was added 2 ml of dimethoxymethane followed by 7.48 g (53 mmol) of phosphorus pentoxide. The reaction was stirred at room temperature for 3 hours after which time an additional 100 ml of CH2Cl2 was added. The reaction was poured onto 200 ml ice and the resulting layers were separated. The aqueous phase was extracted once more with water (2×100 ml), dried over MgSO4 and concentrated to afford 1.16 g (95% yield) of the desired product as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:21][CH2:20]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>>[CH:19]1([C:13]2[N:8]3[CH:9]4[CH2:12][CH:11]([C:5]5[CH:4]=[C:3]([F:23])[C:2]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])=[CH:22][C:6]=5[C:7]3=[N:15][C:14]=2[C:16]([NH2:18])=[O:17])[CH2:10]4)[CH2:21][CH2:20]1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CC1

Procedure:
Similar to as described in General Procedure E, 10-bromo-3-cyclopropyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH2:20][C:19]=3[CH:25]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2CO1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc2CO1

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31])(=O)C.O[Li].O>C1COCC1.O.C(Cl)Cl>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:18])[C:11]=2[N:10]([CH3:30])[C:9]1=[O:31]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)c(C)c2n(C)c1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(-c2cccc(OC(F)(F)F)c2)[nH]c2c(=O)n(CCCO)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
To a solution of 3-(1,7-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (40 mg, 0.091 mmol) in THF (5 mL) and water (5 mL) was added LiOH.H2O (7.64 mg, 0.182 mmol). The reaction was stirred at RT for 30 min then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 3-(3-hydroxypropyl)-1,7-dimethyl-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (10 mg, 27.6% yield) as a white solid. 1H NMR (CDCl3) δ: 9.58 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.31 (d, J=9.9 Hz, 2H), 4.30-4.09 (m, 2H), 3.76 (s, 3H), 3.64 (t, J=7.1 Hz, 1H), 3.56-3.41 (m, 2H), 2.42 (s, 3H), 1.92-1.74 (m, 2H). LCMS: MH+ 398 and TR=2.418 min.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([CH:40]=[CH:41][N:42]=2)[C:12]([C:15]2[N:16]=[C:17]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:18]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][C:19]=3[N:20]=2)=[CH:13][CH:14]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:32][N:31]([CH3:33])[CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][C:22]2[S:23][C:18]3[C:17]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:16][C:15]([C:12]4[N:11]5[CH:40]=[CH:41][N:42]=[C:10]5[C:9]([OH:8])=[CH:14][CH:13]=4)=[N:20][C:19]=3[CH:21]=2)[CH2:26][CH2:27]1
Reactant: CN(C)C1CCN(Cc2cc3nc(-c4ccc(OCc5ccccc5)c5nccn45)nc(N4CCOCC4)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCN(Cc2cc3nc(-c4ccc(O)c5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 10 %

Procedure:
A mixture of {1-[2-(8-benzyloxyimidazo[1,2-a]pyridin-5-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]piperidin-4-yl}dimethylamine (381 mg, 0.65 mmol) in TFA was heated at 140° C., for 10 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The appropriate fractions were combined and evaporated. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 689 as a yellow solid (32 mg, 10%). LCMS (Method F) RT 3.98 min; [M+H]+ 494. 1H NMR (400 MHz, CH3OH-d): δ 9.43 (d, J=1.6 Hz, 1 H); 8.04 (d, J=8.2 Hz, 1 H); 7.65 (d, J=1.6 Hz, 1 H); 7.34 (s, 1 H); 6.71 (d, J=8.2 Hz, 1 H); 4.03 (t, J=4.7 Hz, 4 H); 3.87 (m, 7 H); 3.07 (d, J=11.5 Hz, 2 H); 2.37 (s, 6 H); 2.34 (m, 1 H); 2.16 (t, J=11.5 Hz, 2 H); 1.91 (d, J=12.3 Hz, 2 H); 1.66-1.54 (m, 2 H)
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[CH:5][N:4]=1)[NH2:2].[F:14][C:15]([F:20])([F:19])[C:16](O)=O>>[F:14][C:15]([F:20])([F:19])[C:16]1[N:4]2[CH:5]=[C:6]([CH3:13])[C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Cc1cnc(NN)c2ccccc12
Reactant: O=C(O)C(F)(F)F
Product: Cc1cn2c(C(F)(F)F)nnc2c2ccccc12
Yield: 65 %

Procedure:
1-Hydrazino-4-methylisoquinoline (5.0 g.) and trifluoroacetic acid (70 ml.)were heated at reflux for three hours. After removal of the excess trifluoroacetic acid, the residue was dissolved in chloroform and extracted with sodium carbonate solution. The organic layer was dried and concentrated and the residue was recrystallized from a cyclohexane-benzene(70/30) mixture to provide the product in a yield of 65%, m.p. 162°-164°C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([CH3:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)c(C)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2c(cc1C)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCC=CC[C@H](C)O2

Procedure:
Prepared in 69% from methyl(2S)-2-(tert-butoxy)-2-[(22S)-4,17,18,22,28-pentamethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure of (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.06-7.97 (m, 3H), 7.50 (t, J=7.7 Hz, 1H), 7.31-7.26 (m, 2H), 7.10 (s, 1H), 7.00 (s, 1H), 6.10 (dd, J=14.3, 7.3 Hz, 1H), 5.92 (br. s., 1H), 5.77 (d, J=15.4 Hz, 1H), 4.57 (s, 1H), 4.03-3.89 (m, 3H), 3.64 (t, J=10.8 Hz, 1H), 3.10 (d, J=7.7 Hz, 1H), 2.63 (d, J=8.1 Hz, 1H), 2.56-2.53 (m, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 2.23 (d, J=7.7 Hz, 1H), 2.20 (s, 3H), 1.98-1.91 (m, 1H), 1.87 (d, J=13.2 Hz, 1H), 1.77-1.67 (m, 2H), 1.25 (s, 3H), 1.18 (s, 9H), 1.01 (d, J=5.9 Hz, 3H); LCMS (ESI, M):651.4.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:46][CH2:47]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-[3-(methylsulfonyl)propyl]-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3'25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H47Cl2N6O4S [(M+H)+] 729.2751, observed 729.2749.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:17])[CH2:13][N:14]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:17])[CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCc1ccccc1
Yield: 103.8 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 6.5 g of 3-(3-phenylpropoxy)-2-hydroxypropylazide (prepared as described in Preparation 53), 2.1 g of lithium aluminum hydride and 250 ml of anhydrous tetrahydrofuran were used, to give 6 g of the title compound as a pale yellow oil having an Rf value of 0.09 (on silica gel thin layer chromatography, using a 10:2:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][NH:16][N:15](Cl)[CH:14]=1.[Cl-].[NH4+]>CS(C)=O>[CH2:3]([S:10][N:15]1[CH:14]=[C:13]([O:12][CH3:11])[CH:18]=[CH:17][NH:16]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: COC1=CN(Cl)NC=C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COC1=CN(SCc2ccccc2)NC=C1
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
843 mg (21 mmol, 55% oily) of sodium hydride was suspended in dimethyl sulfoxide (30 ml). Under ice-cooling, 2.0 ml (16.7 mmol) of benzylmercaptan was added thereto, followed by stirring for 10 minutes. To the reaction mixture was added 2.5 g (17.6 mmol) of 4-methoxy-2-chloropyridazine, followed by stirring at room temperature overnight. To the reaction mixture was added an aqueous saturated ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel chromatography, to give 1.63 g of the title compound.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH:6]=[O:7]>CO.CCCCC>[Cl:3][C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1c(F)cc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CO
Product: OCc1c(F)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) was added in portions to an ice-cooled solution of 2-chloro-4,6-difluorobenzaldehyde (6.70 g, 38.0 mmol) in methanol (56 ml); once addition was complete the reaction was warmed to rt over 1 h and then concentrated in vacuo. The residue was partitioned between ether and saturated sodium bicarbonate solution, the phases were separated and the aqueous phase extracted with more ether. The combined organic phases were washed with H2O, dried with MgSO4 and concentrated in vacuo to yield the crude product as an oil which was diluted with pentane (20 mL) and allowed to stand in a freezer overnight. The liquors were decanted from the resultant white crystals which were then dried in vacuo to yield the title compound (5.60 g, 31.4 mmol).