Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[N:10]=[CH:11]OCC.C(NCCCC)CCC.C([N-]CCCC)CCC.[K+].[NH2-].[K+]>C(O)C>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[NH:10][CH:11]=[CH:1]2)[CH3:9]
Reactant: CCOC=Nc1c(C)cccc1CC
Agent: CCCC[N-]CCCC
Agent: [K+]
Agent: [NH2-]
Solvent: CCO
Solvent: CCCCNCCCC
Product: CCc1cccc2cc[nH]c12
Temperature: 159 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl N-(2-methyl-6-ethylphenyl)formimidate (65.9 g.) in 50 ml. of di-n-butylamine was slowly added, over about 5 minutes, to the potassium di-n-butylamide reaction mixture at 20° C. The metallation and cyclization reactions were substantially instantaneous under these reaction conditions. The transient appearance of a deep red color characteristic of benzyl anion was developed and discharged immediately upon contact of ethyl N-(2-methyl-6-ethylphenyl)formimidate with the potassium amide reaction mixture near the neck of the reactor. All solids dissolved resulting in a light brownish solution. Stirring was continued for another half hour. Then 150 ml. of ethyl alcohol were added to destroy the excess amide and unreacted metal and also to convert potassium indole salt to indole. After the removal of the excess alcohol at reflux temperature (159° C.) through a distillating column packed with Fenske packing materials, a brown oily material separated and settled at the bottom of the flask. The top amine layer was decanted off. The brown oily layer was dissolved in 300 ml. of hexane, then washed with 500 ml. water which was extracted with two 300 ml. portions of hexane. The combined hexane extracts were dried over Na2SO4 and filtered. Evaporation of volatile components furnished 39.8 g. of 7-ethylindole (80.0 percent yield) of over 98.5 percent purity.
Reaction SMILES: C(Cl)(=O)OCC.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH:15]1[C:20](O)=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.C1COCC1>[OH:21][CH2:20][CH:15]1[CH2:16][O:17][CH2:18][CH2:19][N:14]1[C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOCC1CO
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Ethyl chlorocarbonate (149 μL; TCI) was added to a THF (8 mL) solution of morpholine-3, 4-dicarboxylic acid 4-tert-butyl ester (300 mg; Ast) and diisopropylethylamine (560 μL; WAKO) with ice cooling and the resulting mixture was stirred at room temperature for 1 and half hours. Sodium tetrahydroborate (197 mg; WAKO) was added at room temperature, the resulting mixture was stirred for 15 minutes followed by the addition of methanol (1.2 mL) with ice cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture solution was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to extract the reaction mixture, then the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (209 mg).
Reaction SMILES: COC1C=CC([N:9](C(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:34][C@H:33]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C@@H:22]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@:20]4([CH3:44])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=CC=1.CO.C(O)(=O)C>O>[NH2:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([C@@H:19]3[O:34][C@H:33]([CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[C@@H:22]([O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@@:20]3([CH3:44])[OH:21])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N(c4ccc(OC)cc4)C(c4ccccc4)c4ccccc4)ncnc32)[C@]1(C)O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N)ncnc32)[C@]1(C)O

Procedure:
A solution of the compound from Step I (250 mg, 0.31 mmol) in 6:3:1 MeOH:acetic acid:H2O (10 mL) was stirred at 50° C. for 12 h. The reaction mixture was then concentrated to dryness. The residue was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3×15 mL) and water (2×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The crude product (200 mg) was used without further purification in Step K below. Further purification of a small amount was accomplished by silica gel column chromatography using 5% MeOH in CH2Cl2 as the eluent to give the title compound as a white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl.Br[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1ccncc1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: Cl
Product: COc1ccc(-c2ccncc2)cc1C=O

Procedure:
3-Formyl-4-methoxyphenyl boronic acid (393 mg, 2.19 mmol) and 4-bromopyridine hydrochloride (400 mg, 2.19 mmol) were coupled using Method A to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[C:26]([CH:28]=[C:29]1[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27].N12CCCN=C1CCCCC2>>[C:26]([CH2:28][C:29]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:32][CH:31]([C:33]([O:35][CH3:36])=[O:34])[CH2:30]1)#[N:27]
Reactant: COC(=O)C1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.01 g, 0.00637 mol) in acetonitrile (4.0E1 mL, 0.77 mol) was added methyl 3-(cyanomethylene)cyclobutanecarboxylate (1.93 g, 0.0127 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.953 mL, 0.00637 mol). The resulting mixture was stirred at 50° C. overnight. After evaporation to dryness, the residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired Micheal addition product as a mixture of cis- and trans-isomers (2.12 g, 71.3%). LCMS calculated for C23H31N6O3Si(M+H)+: 467.2; Found: 467.4.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[N:27]=[CH:26][C:25]=5[CH2:31][N:32]5[CH2:36][CH2:35][CH:34]([N:37](C)[C:38](=O)OC(C)(C)C)[CH2:33]5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:46])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.Cl.O1CCOCC1>C(Cl)Cl.CO>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[C:25]([CH2:31][N:32]6[CH2:36][CH2:35][CH:34]([NH:37][CH3:38])[CH2:33]6)=[CH:26][N:27]=[C:28]([F:30])[CH:29]=5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:46])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2cnc(F)cc2-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC1CCN(Cc2cnc(F)cc2-c2cccc3cc(-c4nc(NCCn5ccnn5)ncc4F)sc23)C1
Temperature: 35 °C
Yield: 89.3 %

Procedure:
Dilute tert-butyl 1-((4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-fluoropyridin-3-yl)methyl)pyrrolidin-3-yl(methyl)carbamate (118 mg, 0.18 mmol) in DCM (3 mL) and treat with 4 M hydrochloric acid in dioxane (0.45 mL, 1.8 mmol). Heat the mixture at 35° C. for 2 h. Remove the organic solvent to give the crude deprotected product. Dilute in DCM (3 mL) and methanol. Pour the mixture onto a strong cation exchange (SCX) (10 g) column. Elute the desired product with 2 N methanolic ammonia (40 mL) and concentrate. Dry the concentrated material from 1:1 acetonitrile/water by lyophilizing to afford the title compound (88 mg, 46%). MS (ES) m/z 548 [M+1]+.
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([CH3:18])(=[O:16])=[O:17])[C:9]3=[O:19])=[O:20])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(S(C)(=O)=O)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-1-(methylsulfonyl)-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 495 (M++1). 1H NMR (CDCl3) δ 1.52 (m, 1H), 1.70 (m, 1H), 1.86 (m, 1H), 1.95˜2.05 (m, 2H), 2.15 (m, 1H), 3.09 (m, 4H), 3.45 (s, 3H), 3.48 (m, 1H), 3.65 (m, 4H), 4.45 (m, 1H), 4.81 (m, 1H), 5.17 (br.s, 2H), 5.95 (d, 1H), 6.15 (s, 1H), 7.15 (dd, 1H), 7.60 (d, 1H), 7.69 (d, 1H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][CH:18]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[C:30]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>C1COCC1>[F:17][CH:18]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[C:30]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(C=O)c3)nc2CC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(CC(F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (21 mg) in THF (2.0 mL) was added ethyl diethylphosphonoacetate (117 μL) at 0° C., and the mixture was stirred at room temperature for 5 min. To the obtained colorless solution was added 3-(2-fluoro-2-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)ethyl)benzaldehyde (entire amount) obtained in Example 36, step 0, at 0° C. and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture 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, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (119 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14]C(=O)[C@@](OC)(C3C=CC=CC=3)C(F)(F)F)[CH2:9]2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]2)=[CH:3][CH:2]=1
Reactant: CO[C@](C(=O)O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1)(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1CCC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of compound from Step D in ethanol an excess of NaOH 1N was added and the mixture reaction was stirred at room temperature. The solution was concentrated in vacuo and diluted with brine. Extracted with ether and concentrated to yield the title compound.
Reaction SMILES: CON=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:17]=[C:16]([CH2:18][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[O:15][C:14]=3[C:25]3[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.Cl.CC(C)=[O:36].C(OCC)(=O)C>O1CCOCC1>[CH3:32][S:31][C:27]1[N:26]=[C:25]([C:14]2[O:15][C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:17][C:13]=2[C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:4](=[O:36])[CH2:5][CH2:6]3)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)=O
Reactant: CON=C1CCc2cc(-c3cc(CN4CCCCC4)oc3-c3ccnc(SC)n3)ccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1nccc(-c2oc(CN3CCCCC3)cc2-c2ccc3c(c2)CCC3=O)n1
Temperature: 100 °C

Procedure:
A mixture of the product from Step 3 (0.310 g, 0.692 mmol) and 5M HCl (3 ml) in dioxane (3 ml)/acetone (1 ml) was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The ethyl acetate was then dried and the solvent evaporated in vacuo and the residue chromatographed on silica gel eluting with a mixture of 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to furnish the title compound (0.145 g, 0.345 mmol); MS(ES+) m/e 420 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]#[C:23][CH3:24]>>[C:1]([O:5][C:6](=[O:19])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)(=[O:9])=[O:10])([CH2:16][C:11]#[C:12][CH3:13])[CH2:21][C:22]#[C:23][CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)CC(=O)OC(C)(C)C)cc1
Reactant: CC#CCBr
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Yield: 90 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-methoxy-benzenesulfonyl)-acetic acid tert-butyl ester (2.86 g, 10 mmol) and 1-bromo-2-butyne (2.68 g, 20 mmol), 3.50 g of the product was isolated. Yield 90%; white solid; mp 85-87° C.; MS: 391.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:47])[C:32](=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].O>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:47])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1ccccc1)(c1ccccc1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.75 g of fluorene (10.5 mmol) was dissolved in 40 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 7.0 ml of an n-butyl lithium/hexane solution (1.58M: 1.1 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. The solvent was distilled off under reduced pressure and thereby a reddish orange solid was obtained. In a glove box, to the reddish-orange solid, 3.17 g of 3-tert-butyl-1-methyl-6,6-diphenylfulvene (10.6 mmol) was added and dissolved in 50 ml of dehydrated diethyl ether. The solution was stirred for 120 hr while intermittent refluxing in a 50° C. oil bath and stirred at room temperature for 496 hr. To the resulting reaction mixture, 50 ml of a distilled water was gradually added dropwise in an ice bath and diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with distilled waster and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red oil. The red oil was re-crystallized from ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 0.648 g (1.39 mmol) as a pale yellow solid (yield: 13%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=O)[N:14]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:15]2=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:15]2
Reactant: COc1cccc2c1C(=O)N(Nc1ccncc1)C2=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of lithium aluminum hydride (9.96 g) in dry tetrahydrofuran (150 ml) was stirred at ambient temperature, under nitrogen, as 4-methoxy-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride monohydrate (17.0 g) was added in portions. The reaction mixture was stirred, under nitrogen, at ambient temperature overnight and sodium sulfate decahydrate was added in portions, with cooling. The precipitate was collected, washed with ethyl acetate, and the filtrate was evaporated. The residue was chromatographed on silica, eluting with 8-10% methanol-dichloromethane. The appropriate fractions were collected and concentrated. The residue was crystallized, then recrystallized from ethyl acetate to give 7.2 g (57%) of product, mp 144-146° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([CH3:26])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([CH3:26])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Reactant: Cc1ccc(CO)c(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (110 mg) and THF (dry) (5 mL) were added (2,6-dimethylpyridin-3-yl)methanol (58.8 mg), tri-n-butylphosphine (0.159 mL) and ADDP (130 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (139 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])S(C)(=O)=O)[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])[S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(C(=O)O)cc(-c2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N(C)c1cc(C(=O)O)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1

Procedure:
Prepared using a procedure similar to that employed for the synthesis of Intermediate VI, substituting isopropyl sulfonyl chloride in the place of methanesulfonyl chloride in Step A of the Intermediate III synthesis.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])CCC.CCCCCC.O>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COc2ccccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (3.3 g, 14.53 mmol) in tetrahydrofuran (30 mL) was added dropwise, at −78° C., under an atmosphere of argon, a solution of n-butyllithium in hexane (8.8 mL, 22 mmol). The mixture was stirred at −78° C. for 5 minutes, then water was added and the mixture was warmed up to room temperature and stirred for 30 minutes. The layers were separated. The aqueous layer was extracted twice with ethyl acetate and the organic combined extract was washed with water, brine, dried (MgSO4), and filtered. The solvent was evaporated to afford 2.13 g of 3,3-dimethyl-2,3-dihydro-benzofuran. 99% yield. 1H-NMR (300 MHz, CDCl3): 1.35 (s, 6H), 4.23 (s, 2H), 6.79 (d, J=7.6 Hz, 1H), 6.88 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.6 Hz, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([OH:40])=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].O[C@H:42]1[CH2:46][CH2:45][O:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:40][C@@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)=[C:29]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O[C@H]1CCOC1
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Nc2ncnc3cc(O[C@@H]4CCOC4)c(OCc4ccccc4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.03 ml Diethyl azodicarboxylate are added dropwise to a solution of 8.00 g 4-[(3-chloro-4-fluoro-phenyl)amino]-6-benzyloxy-7-hydroxy-quinazoline (see WO 0055141 A1) and 2.42 ml (S)-(+)-3-hydroxy-tetrahydrofuran and 7.95 g triphenylphosphine in 160 ml tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and subsequently concentrated by evaporation in the rotary evaporator. The flask residue is purified chromatographically on a silica gel column with methylene chloride/ethyl acetate (gradient from 2:1 to 1:2) as eluant.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14](NC(=O)CC)[C@@H:13](O)[C@H:12]2O)=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.ClC1N=C2C(N=CN2[C@@H]2C[C@H]([N:53]3[N:57]=[N:56][C:55]([CH2:58][CH3:59])=[N:54]3)C=C2)=C(Cl)N=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:53]3[N:57]=[N:56][C:55]([CH2:58][CH3:59])=[N:54]3)[CH:13]=[CH:12]2)=[C:4]([NH:23][CH2:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)n1
Product: CCc1nnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)n1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (AA7) by replacing N-[(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) with 2,6-dichloro-9-[(1R,4S)-4-(5-ethyl-tetrazol-2-yl)-cyclopent-2-enyl]-9H-purine (EA1). MS (ES+) m/e 512.2 (MH+)