Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH3:14][Si:15]([CH2:18][Li])([CH3:17])[CH3:16]>CCCCC>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH3:14][Si:15]([CH2:18][Ti+3:13])([CH3:17])[CH3:16]
Reactant: [Li]C[Si](C)(C)C
Reactant: [Ti+4]
Agent: C[N-]C
Solvent: CCCCC
Product: C[Si](C)(C)C[Ti+3]
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a stirred solution of 4.20 g of titanium tetrakis(dimethylamide) in about 10 ml of pentane was added a solution of 1.77 g of trimethylsilylmethyllithium in pentane. Lithium dimethylamide precipitated immediately. The mixture was stirred for 1 hour and filtered, pentane was removed from the filtrate by rotary evaporation, and the residual pale-yellow oil was distilled through a short still-head under reduced pressure, to give 0.87 g of trimethylsilylmethyltitanium tris(dimethylamide), bp 55° C. (50 μ). Nmr in C6D6 : δ (NMe) 3.07, δ (SiMe) 0.22, δ (CH2) 0.35 ppm downfield from tetramethylsilane.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:37][C:36]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:35][C:34]=1/[CH:44]=[CH:45]/[C:46]1[C:47]([OH:57])=[N:48][N:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:57][C:47]2[C:46](/[CH:45]=[CH:44]/[C:34]3[N:35]=[C:36]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[S:37][C:33]=3[CH3:32])=[CH:50][N:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:48]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14]
Reactant: Cc1sc(N2CCCCC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCCCC5)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.66 g), 4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.44 g), potassium carbonate (0.30 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetate (0.59 g, yield 72%) as crystals. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 131-132° C.
Reaction SMILES: N[C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].[C:17]([O-])(=O)[CH3:18].[Na+]>[OH-].[Na+].[Pd].CO>[CH2:17]=[CH:18][C:2]1[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Nc1ccccc1S(=O)(=O)O
Agent: [Pd]
Agent: Cl
Agent: O=N[O-]
Solvent: CO
Product: C=Cc1ccccc1S(=O)(=O)O
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
10.1 g of aniline-2-sulphonic acid (85%) were dissolved in 40 ml of sodium hydroxide solution (6%) and treated with 40 ml of conc. HCl. 12 ml of aqueous NaNO2 solution were added dropwise to the resulting suspension at a temperature of 0° to 5° C. and the mixture was stirred at this temperature for 30 minutes. 50 g of sodium acetate, 300 ml of methanol and 0.5 g of bis(dibenzylideneacetone-2,2'-disulphonic acid disodium salt)palladium(0) were added successively and the mixture was stirred for 3 hours at 20° C. under an ethylene pressure of 20 bar. It was then filtered and evaporated to dryness, and the residue was stirred with ethanol. The mixture was again filtered and evaporated. 7.4 g (72%) of styrene-2-sulphonic acid, Na salt, were obtained.
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[CH3:36][C:37]1([CH3:43])[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1>C(Cl)Cl.CO>[CH3:36][C:37]1([CH3:43])[NH:38][CH2:39][CH2:40][N:41]([C:9]2[N:10]([CH2:31][C:32]([F:34])([F:33])[F:35])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:14]=[C:13]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[N:12]=3)[CH2:42]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: CC1(C)CNCCN1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Temperature: 120 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
An N-methyl-2-pyrrolidone suspension (5.0 ml) of 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (492.8 mg, 1.19 mmol) and 2,2-dimethylpiperazine (JMC, 1995, Vol. 38, No. 22, 4389) (571.3 mg, 4.75 mmol) was heated at 120° C. to dissolve and the resulting mixture was stirred at 100° C. for 12 hours. The resulting mixture was left standing to cool, poured into methylene chloride-methanol (10:1), and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=49:1 to 13:1) to give the title compound (554.4 mg, 95%) as a pale yellow solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][O:12][C:13]2([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[CH3:18][N:19]1[C:23]([CH:24]=[O:25])=[N:22][C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:20]1>C1COCC1>[CH3:16][C:13]1([CH3:17])[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([CH:24]([C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]=3)[OH:25])[CH:15]=2)[CH2:11][O:12]1
Reactant: CC1(C)OCc2ccc(Br)cc21
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C(O)c1ccc2c(c1)C(C)(C)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
BuLi (0.36 mL, 1.6 M in hexanes, 0.57 mmol) was added dropwise to a solution of Intermediate 388.2 (110 mg, 0.49 mmol) in THF (5 mL) at −78° C. After stirring 5 min, a solution of Intermediate 386.1 (100 mg, 0.54 mmol) in THF (3 mL) was added. The mixture was warmed to 0° C. over 2 h and quenched with sat. NH4Cl (1 mL). The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 63 mg of Intermediate 388.3 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 6 H) 3.48 (s, 3H) 4.90 (s, 2H) 5.68 (s, 1H) 6.01 (s, 1H) 6.93-7.00 (m, 1H) 7.10-7.14 (m, 1H) 7.14-7.19 (m, 1H) 7.28-7.38 (m, 3H) 7.89-7.95 (m, 2H)
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O>[C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][N:39]=[N+:40]=[N-:41])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Yield: 58.1 %

Procedure:
1.26 g of 5-acetyl-2'-deoxyuridine, 1.35 g of triphenylphosphine, 1.52 g of sodium azide and 1.7 g of carbon tetrabromide in 40 ml of dimethylformamide were reacted as described in Example 54 and the product was purified by chromatography on 400 g of silica gel in dichloromethane/ methanol (9:1) to give 0.80 g of 5-acetyl-5'-azido-2',5'dideoxyuridine of melting point 159°-162° C. (decomposition).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.C1COCC1.[Cl:16][C:17]1[CH:18]=[C:19]([Mg]Br)[CH:20]=[CH:21][CH:22]=1.S(=O)(=O)(O)O>C(OCC)C>[CH2:9]([O:8][C:1](=[O:7])[C:2]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1)=[O:4])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Clc1cccc([Mg]Br)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1cccc(Cl)c1
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
Diethyl oxalate (4.4 g, 30.2 mmol) was dissolved in dry ethyl ether (30 mL) and freshly distilled THF (30 mL) and cooled to −78° C. with stirring, under a nitrogen atmosphere. Then added 3-chlorophenylmagnesium bromide (0.5 M in THF, 72.5 mL, 36.2 mmol) dropwise, via an addition funnel, while keeping the temperature between −75 to −78° C. The addition took approximately 90 minutes. After 3 hours, the reaction was quenched by the dropwise addition of 2N sulfuric acid (50 mL, 91 mmol) at −78° C. and upon completion of the addition, the mixture was allowed to return to room temperature. The mixture was extracted with ethyl ether (3×) and the combined ether extracts were washed with brine (2×), dried over magnesium sulfate, filtered, evaporated in vacuo and vacuum-dried to yield ethyl-(3-chlorophenyl)(oxo)acetate (6.5 g, HPLC RT=3.46 min, Method A; LCMS m/z=213).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:28][N:29]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27]
Reactant: CNCCc1ccccc1
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and methyl-phenethyl-amine. The crude product was subjected to preparative HPLC (29%, oil). HPLC-MS: m/z=389.2 (M+1); Rt: 4.15 min.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[C:10]([CH3:13])[N:6]2[C:7](=[O:9])[CH:8]=1.ClCC1N(C)N=C(C)N=1.[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[O:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[O:33][C:32](=[O:34])[C:31]([CH2:2][C:3]3[N:4]=[C:5]4[S:12][CH:11]=[C:10]([CH3:13])[N:6]4[C:7](=[O:9])[CH:8]=3)=[C:30]([OH:35])[CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Agent: Cc1nc(CCl)n(C)n1
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3cc(=O)n4c(C)csc4n3)C(=O)O2)cc1
Yield: 17 %

Procedure:
The title compound was prepared as described in Example B(53), using 7-(chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 17%.
Reaction SMILES: S1C=CN=C1.N1C2C(=CC=CC=2)C=C1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[CH:16]1.N1C2C(=CC=CC=2)CC1.C(O)(C(F)(F)F)=O.[O:44]=[CH:45][C@@H:46]([C@H:48]([C@@H:50]([C@@H:52]([CH2:54][OH:55])[OH:53])[OH:51])[OH:49])O.C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1>[C@@H:54]1([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:24][C:25]([OH:27])=[O:26])=[CH:16]2)[O:55][C@H:46]([CH2:45][OH:44])[C@@H:48]([OH:49])[C@H:50]([OH:51])[C@H:52]1[OH:53]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: c1ccc2[nH]ccc2c1
Agent: c1ccc2c(c1)CCN2
Agent: c1cscn1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C(O)Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12
Yield: 40 %

Procedure:
In order to accommodate need for SAR optimization of the thiazole derivatives, indoles at A ring may be synthesized and evaluated. One isomer of indole may be prepared by adopting the reported procedure [Kai, K. et al. Phytochemistry, 2007, 68, 2512-2522]. First, commercially available indole-3-acetic acid 73 is esterified under acidic conditions. Next, the indole ring of 74 is partially reduced to indoline 75 using triethylsilane and TFA in 77% yield. Condensation of 75 with D-glucose is accomplished in refluxed aqueous methanol in 88% yield. The product 76 is then acylated and oxidized to regenerate the indole ring in 40% over two steps (product 77). After hydrolysis, peracetylation of the tetrahydroxy groups using acetic anhydride and pyridine yields N-β-D-glucopyranosyl indole-3-acetic acid 78 in 40% yield for the two steps. As in Scheme 9, usual coupling between acid 78 and 2-amino-1-(furan-2-yl)ethanone in the presence of EDCI, HOBt, and NMM and then cyclization using Lawesson's reagent produce thiazole 79 in 59% yield for the two steps. Finally, treatment of the tetraacetate 79 with sodium methoxide generates the target compound 80 in 18% yield as shown in Scheme 17.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:6](=[O:7])[C:5]3[CH:16]=[CH:17][CH:2]=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Oc1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Oc1ccc(OC(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
4-Benzoyloxyphenyl 4-benzoyloxybenzoate is prepared from 4-hydroxyphenyl 4-hydroxybenzoate and benzoyl chloride in accordance with the instructions from example 1.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]1([CH:36]2[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:30]1([CH:36]2[CH2:41][CH2:40][C:39](=[CH:2][O:3][CH3:4])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (5.14g) was suspended in anhydrous tetrahydrofuran (THF) (15ml) and stirred under argon at 0° C. A solution of potassium t-butoxide (1.68g) in THF (15ml) was added dropwise and stirring continued at the same temperature for 0.5h. To the resulting dark red near- solution was added a solution of 4-phenylcyclohexanone (2.61g) in THF (4ml), then the mixture was allowed to regain ambient temperature and stirring continued for 16h. Workup and chromatography as described in Example 5(a) gave 4-phenyl-1-(methoxymethylene)cyclohexane (1.59g) contaminated with a little triphenylphosphine; δ(CDCl3,60MHz), inter alia, 3.55 (3H,s), 5.90 (1H,br s), and 7.35 (6H,m). This material in THF (8ml) and water (2ml) was stirred at 20° C. with toluene sulphonic acid hydrate (2.50g) for 8h. Workup as described in Example 5(b) followed by chromatography on silica gel, eluting with ethyl acetate in hexane mixtures, gave the aldehyde (1.29g) as an approximately 2:3 cis:trans mixture; υMax (CHCl3) 1725, 1605, 1495, and 1450cm-1 ; δ(CDCl3,250MHz), 1.3-2.60 (10H,m), 7.15-7.35 (5H,m), 9.68, and 9.79 (1H,d,J=1.5Hz and s). [M. Carissimi et al., Farmaco (Pavia) Ed.Sci., 1965, 20. 106 (Chem.Abs., 1965, 62, 14560)].
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:48]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[C:63]([CH3:64])=[CH:62][C:61](O)=[CH:60][C:59]=2[CH3:66])=[CH:54][CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>C1COCC1.C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:2]([O:1][C:61]2[CH:62]=[C:63]([CH3:64])[C:58]([C:55]3[CH:56]=[CH:57][C:52]([C:48]([CH3:50])([CH3:49])[CH3:51])=[CH:53][CH:54]=3)=[C:59]([CH3:66])[CH:60]=2)[CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
Methyl 4-(1-hydroxy-3-methylbutyl)benzoate, Isomer 1 (Preparation 4) (2.00 g, 9.01 mmol) is stirred in THF/toluene and 1,1′-(azodicarbonyl)dipiperidine (ADDP) (3.41 g, 13.51 mmol) at a temperature of 0-5° C., followed by addition of tri-n-butylphosphine (3.36 mL, 13.51 mmol) and 4′-tert-butyl-2,6-dimethylbiphenyl-4-ol (Preparation 2) (2.75, 10.81 mmol). The reaction is allowed to warm to room temperature with stirring for 24 to 48 h. The reaction is loaded on silica gel, and eluted with hexanes using a gradient of 0-100% ethyl acetate to obtain 2.90 g (70%) of product. 1H NMR.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl.[CH3:42][NH:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][N:43]([CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34])[CH3:44]
Reactant: CNC
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)Cc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 120 (1) was dissolved in 10 mL of dimethylformamide, 558 mg (6.85 mmol) of dimethylamine hydrochloride and 945 mg (6.85 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 727 mg of 7-dimethylaminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:58][CH3:59])[C@H:42]([NH:46][C:47]([N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1)=[O:48])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:43](=[O:44])[C@H:42]([CH:41]([CH2:58][CH3:59])[CH3:40])[NH:46][C:47](=[O:48])[N:49]([CH3:57])[CH2:50][C:51]1[N:52]=[C:53]([CH3:56])[S:54][CH:55]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 109E (0.018 g, 0.061 mmol), DEPBT (0.021 g, 0.071 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.235 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 0-10% methanol in ethyl acetate, to give the title compound (0.030 g, 78% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.78 (m, 16 H), 1.01 (m, 1 H), 1.36 (m, 1 H), 1.50 (m, 2 H), 1.70 (m, 1 H), 2.61 (s, 3 H), 2.73 (m, 3 H), 2.86 (s, 3 H), 3.49 (s, 3 H), 3.62 (m, 1 H), 3.83 (d, J=9.93 Hz, 1 H), 3.98 (t, J=7.91 Hz, 1 H), 4.11 (m, 2 H), 4.43 (m, 2 H), 4.86 (d, J=5.88 Hz, 1 H), 6.19 (d, J=8.09 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.16 (m, 8 H), 7.31 (m, 1 H), 7.42 (d, J=9.19 Hz, 1 H), 7.77 (d, J=8.09 Hz, 1 H), 7.85 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:21])[C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>C(O)CCC>[C@@H:32]1([NH:31][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH3:21])[C@H:9]3[C@@H:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]4[C@@H:11]([CH2:19][OH:20])[CH2:10]3)[CH:3]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1cc(N[C@H]2CCc3ccccc32)ncn1)[C@@H]1C[C@H](CO)[C@H]2OC(C)(C)O[C@H]21
Temperature: 200 °C
Yield: 24.1 %

Procedure:
{(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)(methyl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (130 mg, 0.41 mmol) was weighed into a microwave reaction tube and dissolved in 1-butanol (1.50 mL). To this solution was added N,N-diisopropylethylamine (0.22 mL, 1.24 mmol) and (S)-(+)-1-aminoindan (0.16 mL, 1.24 mmol) and the mixture was heated in a sealed tube under microwave irradiation at 200° C. for 4 h. The reaction mixture was concentrated under vacuum, and the residue was purified via silica gel column chromatography eluting with a gradient of 2 to 5% methanol in DCM to afford the title compound (40.5 mg, 24%) as a colorless oil. LC/MS: Rt=1.49 min, ES+ 411.5 (AA standard).