Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[Cl:6][C:7]1[C:8](=[O:30])[C:9](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[C:28]=[O:29])OC)[C@H:10]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1.Cl.S([O-])([O-])(=O)=[O:33].[NH4+].[NH4+]>CC(C)=O>[Cl:6][C:7]1[C:8](=[O:30])[C:9](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:28]([OH:29])=[O:33])[C@H:10]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=1
Reactant: CCCCCCC=C[C@@H]1C=C(Cl)C(=O)C1=CCCCCC(=C=O)OC
Reactant: O=S(=O)([O-])[O-]
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CCCCCCC=C[C@@H]1C=C(Cl)C(=O)C1=CCCCCCC(=O)O
Reaction time: 100 h
Yield: 68 %

Procedure:
450 ml of 0.1M phosphate buffer (pH8) was added to a solution of 734 mg (2.0 mmol) of (4R)-2-chloro-4-(1-octenyl)-5-(6-methoxy-carbonylhexylidene)-2-cyclopentenone in 45 ml of acetone, and then 45 ml of an aqueous solution of pig liver esterase was added. The mixture was stirred at 30°-35° C. for 100 hours. 0.1N hydrochloric acid was added to the reaction mixture to adjust its pH to 4, and then the mixture was saturated with ammonium sulfate. It was filtered, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 50 mg; eluent, hexane:acetone:acetic acid=10:2:0.05→5:2:0.003) to give 480 mg (yield 68%) of (4R)-2-chloro-4-(1-octenyl)-5-(6-carboxyhexylidene)-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.I[CH2:22][CH3:23]>>[CH2:22]([N:16]1[C:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:9]=2[CH:19]=[CH:18][C:17]1=[O:20])[CH3:23]
Reactant: CCI
Reactant: CSc1nc(-c2ccccc2F)c2ccc(=O)[nH]c2n1
Product: CCn1c(=O)ccc2c(-c3ccccc3F)nc(SC)nc21

Procedure:
Prepared as described above in Example 108 starting from 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one and iodoethane to afford the title compound 8-ethyl-4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=316 (MH+). Rt=2.29 min
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: CN(C)CCN
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 85.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (800 mg, 2.23 mmol) in DCM (45 mL) were added N,N-dimethylethylenediamine (0.36 mL, 3.23 mmol) and triethylamine (0.63 mL, 4.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (730 mg, 85%). LC-MS m/z 383 (M+H)+.
Reaction SMILES: [C:1](=[O:40])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@@H:3]1[CH2:19][C@@H:18]2[C@@:6]([CH3:29])([C@@H:7]3[C@@H:15]([CH2:16][CH2:17]2)[C@:14]2([OH:20])[C@@:10]([CH3:28])([C@@H:11]([C:21]4[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=4)[CH2:12][CH2:13]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:20][C@:14]12[CH2:13][CH2:12][C@H:11]([C:21]3[CH:22]=[CH:23][C:24](=[O:27])[O:25][CH:26]=3)[C@@:10]1([CH3:28])[CH2:9][CH2:8][C@H:7]1[C@H:15]2[CH2:16][CH2:17][C@H:18]2[C@:6]1([CH3:29])[CH2:5][CH2:4][C@H:3]([O:2][C:1]([NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:40])[CH2:19]2
Reactant: C[C@]12CC[C@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Reactant: NCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@]12CC[C@H](OC(=O)NCCCC(=O)O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Yield: 53.9 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 4-nitrophenyl carbonate (20 mg, 0.036 mmol) in CH2Cl2 was added 4-aminobutanoic acid (37.1 mg, 0.36 mmol, 10 eq), DIEA (18.6 mg, 0.144 mmol, 4 eq) and DMAP (16.1 mg, 0.144 mmol 4 eq). The resultant mixture was stirred at 40° C. for 16 h and then purified via preparative TLC to afford 4-(((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)butanoic acid (10 mg, 53.5%) as a white solid. LRMS (M−H+) m/z 514.4 1H NMR (CD3OD, 400 MHz) δ 7.89 (dd, J=9.6, 2.4 Hz, 1H), 7.33 (m, 1H), 6.18 (d, J=9.6 Hz, 1H), 4.82 (m, 1H), 3.03 (m, 2H), 2.44-2.48 (m, 1H), 1.08-2.15 (m, 25H), 0.87 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]=[CH:9][CH:10]=[CH2:11]>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][CH:8]=[CH:9][CH2:10][CH2:11][CH2:11][CH2:10][CH:9]=[CH2:8])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: C=CCCCCC=COC(=O)C(F)(F)F

Procedure:
1,7-Octadienyl trifluoroacetate was prepared by reacting 1 g of palladium acetate in 20 ml of benzene with 102 g of trifluoroacetic acid and 0.96 M butadiene in a 300 ml autoclave at ambient temperature for 4 days.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)c2ccncc2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=387.1, tR (minutes, Method F)=1.56
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>C(OCC)(=O)C.CN(C)C1C=CN=CC=1.[Pd]>[NH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:3][C:2]=1[CH3:1])[C:26]([CH3:27])=[O:28]
Reactant: Cc1cc(-c2ccccc2C#N)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1C
Reaction time: 1 h
Yield: 51 %

Procedure:
2-(3-Methyl-4-nitrophenyl)benzonitrile (6.3 moles, 1.5 g) was hydrogenated in ethyl acetate (50 ml) over 5% Pd/C (0.50 g). The catalyst was filtered, and the solution concentrated to an oil. The oil was dissolved in 10 ml of methylene chloride and triethylamine (9.4 mmoles, 1.4 ml). Acetic anhydride (9.4 mmoles, 0.960 g) and 4-dimethylaminopyridine (50 mg) were added. The reaction was stirred for 1 hour and poured into 20 ml of 5N HCl. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The product was crystallized from ether and hexane to yield 1.2 g of 2-(4-acetamino-3-methylphenyl)benzonitrile. (MS)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([Cl:36])=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:37]([Cl:42])(=O)C(Cl)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:28][CH:29]=2)=[CH:6][CH:7]=1.[CH2:37]([Cl:42])[Cl:36]
Reactant: COc1cccc(CCNc2ccc(F)cc2)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1cccc(CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2)c2ccc(F)cc2)c1
Product: ClCCl
Yield: 387.7 %

Procedure:
The title compound was prepared as described in Example 1.C, using (4-fluorophenyl){2-(3-methoxyphenyl)ethyl}amine (14.2 g, 58 mmol) and 4-benzyloxyphenylacetyl chloride (15.1 g, 58 mmol) prepared from the corresponding carboxylic acid (14.0 g, 58 mmol) and oxalyl chloride (6.5 mL, 75 mmol) in CH2Cl2 (150 mL) (19.1 g, 70% yield): ES-MS (m/z) 470 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[Mg][CH:21]=[CH2:22].[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]([OH:16])[CH:21]=[CH2:22])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCc2ccccc2)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-phenylpropoxy)benzaldehyde (10.4 g) in dry tetrahydrofuran (100 mL), a solution of bromo(vinyl) magnesium in tetrahydrofuran (14%, about 1 M) was added at 0° C. After stirring for 15 minutes, the reaction mixture was added to a cold saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 3:1) to give the title compound (10.01 g) having the following physical properties.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O.O>C1COCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:19]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[N:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(N)CO
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C2=NC(C)(C)CO2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Triethylamine (23.0 mL) was added to a solution of 2-amino-2-methyl-1-propanol (14.4 g) in THF (200 mL), 3-methoxybenzoyl chloride (25.0 g) was dropped thereinto at 0° C. and the mixture was stirred at room temperature for 1 day. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. Thionyl chloride (25 mL) was dropped into the resulting residue at 0° C. and stirred at room temperature for 3 hours. An aqueous solution of sodium hydroxide was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was evaporated in vacuo to give the aimed compound (22.0 g, 81%) as a colorless oily substance.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[N:11]([C:16]1[CH:21]=[C:20]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[N:19]=[C:18]([CH3:28])[N:17]=1)[CH2:10][CH2:9]2.[CH:29]([O:32]C)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[N:11]([C:16]1[C:21]([CH:29]=[O:32])=[C:20]([NH:22][CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[N:19]=[C:18]([CH3:28])[N:17]=1)[CH2:10][CH2:9]2
Reactant: COC(Cl)Cl
Reactant: CCC(CC)Nc1cc(N2CCc3cc(Cl)cc(Cl)c32)nc(C)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(CC)Nc1nc(C)nc(N2CCc3cc(Cl)cc(Cl)c32)c1C=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
To a suspension of AlCl3 (736 mg, 5.44 mmol) in CHCl3 (5 mL) a solution of 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-2-methylpyrimidine (1.46 g, 4 mmol) in CHCl3 was added at 0° C., followed by Cl2CHOMe (0.4 mL, 4.4 mmol). The reaction was stirred at 0° C. for 2 h and at 20° C. for 16 h. Then an additional amount of Cl2CHOMe was added (0.2 mL, 2.2 mmol) and the reaction was continued for 26 h. The mixture was poured into ice/water (50 mL) and after quenching it was basified with 1 N NaOH, extracted with EtOAc (2×100 mL each) and the combined organic extracts were washed with water, brine, dried over (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel using 10% EtOAc/hexanes as eluent to give the product 4-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-6-(1-ethylpropylamino)-5-formyl-2-methylpyrimidine (470 mg, 30% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#N)=[CH:8][CH:7]=[CH:6]2.[OH-:22].[K+].C[OH:25]>>[CH3:1][O:2][C:3]1[C:4]([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:25])=[O:22])=[CH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(C#N)cccc2c1C(F)(F)C(F)(F)F
Reactant: [OH-]
Reactant: CO
Agent: [K+]
Product: COc1ccc2c(C(=O)O)cccc2c1C(F)(F)C(F)(F)F

Procedure:
The crude 6-MPCN product of Example I was dissolved in 135 ml of methanol and 40 ml of a potassium hydroxide solution (4.5 g of KOH in 40 ml of water) and heated to 125° C./70 psi for seven hours. The reaction mixture was then worked up and acidified to yield 6.6 g of 6-methoxy-5-pentafluoroethyl-1-naphthoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.[OH-].[Na+].I[CH3:12]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:12])[N:3]=1
Reactant: Cc1ccnc(S)n1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Methylpyrimidine-2-thiol (79.4 g. 488 mmol) was added to 1M aqueous sodium hydroxide (NaOH) (1.02 L, 1.02 mol). To the stirring mixture was added iodomethane (76.2 g, 540 mmol) and the reaction-stirred at room temperature overnight. The mixture was extracted with dichloromethane (3×300 mL). The organic phase was dried over magnesium sulfate and concentrated to yield 66.8 g (98%) of 4-methyl-2-(methylsulfanyl)pyrimidine. 1H NMR (CDCl3): δ 8.39 (d, 1H), 6.84 (d, 1H), 2.59 (s, 3H), 2.48 (s, 3H); MS m/z 141 (M+1).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]=[CH:9][CH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.C[SiH](C)O[SiH](C)C.[CH:23]1([CH2:29][CH2:30][Si:31]([CH3:37])([CH3:36])[O:32][SiH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]1>C(O)(CC)(C)C.C(C(C)=O)C>[CH:10]1([CH2:9][CH2:8][Si:33]([CH3:34])([CH3:35])[O:32][Si:31]([CH2:30][CH2:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH:25]=[CH:24]2)([CH3:37])[CH3:36])[CH2:11][CH2:12][CH2:13][CH:14]=[CH:15]1
Reactant: C[SiH](C)O[Si](C)(C)CCC1C=CCCC1
Reactant: C=CC1CC=CCC1
Agent: C[SiH](C)O[SiH](C)C
Solvent: CCC(C)(C)O
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(CCC1C=CCCC1)O[Si](C)(C)CCC1C=CCCC1

Procedure:
To a 20 ml toluene solution of 51.93 g (0.48 mole) of 4-vinylcyclohexene-1 and 0.37 g of 5% H2PtCl6 in t-amyl alcohol is added 33.6 (0.23 mole, 90% purity) of 1,1,3,3-tetramethyldisiloxane at 45° C. to 50° C. for 1 hour and 30 minutes. The reaction is complete after maintaining the reaction at 55° C. for 5 hours. To this mixture is added 250 ml methyl ethyl ketone. After washing successively with four 100 ml portions of H2O, 78 g (>95% purity by GC) of 1,3-bis-((2-cyclohexenyl)-ethyl)-1,1,3,3-tetramethyldisiloxane having a light yellowish color is obtained after stripping off solvent at 120° C. and <10 mm Hg. The structure of the product, 1,3-bis-((2-cyclohexenyl)ethyl-1,1,3,3-tetramethyldisiloxane, is confirmed by IR and 1H NMR as follows:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:35])[CH2:21][NH:22][C:23]([CH3:34])([CH3:33])[CH2:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl>C(O)(C)C>[CH3:32][C:27]1[CH:26]=[C:25]([CH2:24][C:23]([NH:22][CH2:21][CH:20]([C:11]2[C:12]3[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=[C:9]([OH:8])[CH:10]=2)[OH:35])([CH3:34])[CH3:33])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(O)cc3c2OCC(=O)N3)c1

Procedure:
The target compound was obtained after hydrogenolysis of 0.90 g (1.71 mmol) of 6-benzyloxy-8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-4H-benzo[1,4]oxazin-3-one and recrystallization of the crude product from isopropanol. White solid. Yield: 0.50 g (69%, hydrochloride); melting point: 235° C.–238° C.; mass spectroscopy: [M+H]+=385.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[N:14][CH:13]=1>>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:18][C:16]2[CH:17]=[N:12][CH:13]=[N:14][CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cncnc1
Product: N#Cc1cc(C=O)ccc1Oc1cncnc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and pyrimidin-5-ol.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1>>[C:2]([S:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: Sc1cccc(Br)c1
Product: CC(C)(C)Sc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isobutylene was bubbled through 75% H2SO4 solution at -5 degrees C. until 2.65 g (47.2 mmol) of isobutylene had been absorbed. The mixture was treated with 3.8 g (20.1 mmol) of 3-bromothiophenol and then allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was then poured into 40 of an ice/water mixture and then extracted with ether. The ether extracts were combined and washed successively with 5% NaOH, water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the residue distilled (69-75 degrees C., 0.6 mm) to give the title compound as a pale yellow oil. PMR (CDCl3): & 1.30 (9H, s), 7.23 (1H, t, J~8.0 Hz), 7.45-7.54 (2H, m), 7.72 (1H, t, J~1.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=1[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[F:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccccc1F
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCOc4ccccc4F)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 46.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (71 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (100 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-fluorophenoxy)-1-propanol (61 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 42%).
Reaction SMILES: C([O:8][C@H](C)C(N[C@H]1C[C@@H](N2C=NC3C2=NC(N2CC[C@@H](NC(NC4C=NC=CC=4)=O)C2)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O)=O)C1C=CC=CC=1.[NH2:60][C@@H:61]1[CH2:65][CH2:64][N:63]([C:66]2[N:74]=[C:73]3[C:69]([N:70]=[CH:71][N:72]3[C@@H:75]3[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[C@H:82](OCC4C=CC=CC=4)[CH3:83])[C@@H:77]([OH:93])[C@H:76]3[OH:94])=[C:68]([NH:95][CH2:96][CH:97]([C:104]3[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=3)[C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[N:67]=2)[CH2:62]1.C1([O:116][C:117](=O)[NH:118][C:119]2[CH:124]=[CH:123][CH:122]=[C:121]([S:125](=[O:128])(=[O:127])[NH2:126])[CH:120]=2)C=CC=CC=1.C1(OC(=O)NC2C=NC=CC=2)C=CC=CC=1>>[C:104]1([CH:97]([C:98]2[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=2)[CH2:96][NH:95][C:68]2[N:67]=[C:66]([N:63]3[CH2:64][CH2:65][C@@H:61]([NH:60][C:117]([NH:118][C:119]4[CH:124]=[CH:123][CH:122]=[C:121]([S:125](=[O:127])(=[O:128])[NH2:126])[CH:120]=4)=[O:116])[CH2:62]3)[N:74]=[C:73]3[C:69]=2[N:70]=[CH:71][N:72]3[C@@H:75]2[CH2:79][C@H:78]([NH:80][C:81](=[O:92])[CH2:82][CH2:83][OH:8])[C@@H:77]([OH:93])[C@H:76]2[OH:94])[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: NS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Agent: O=C(Nc1cccnc1)Oc1ccccc1
Product: NS(=O)(=O)c1cccc(NC(=O)N[C@@H]2CCN(c3nc(NCC(c4ccccc4)c4ccccc4)c4ncn([C@@H]5C[C@H](NC(=O)CCO)[C@@H](O)[C@H]5O)c4n3)C2)c1

Procedure:
The title compound was prepared analogously to (R)-2-benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide (Example 181, step 5), by substituting N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-3-hydroxy-propionamide (Intermediate ZG) for (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4) and (3-Sulfamoyl-phenyl)-carbamic acid phenyl ester (Intermediate ZF) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:22][Si:23]([CH3:42])([CH3:41])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[N:36]=[C:31]2[CH:30]=[CH:29]1.BrC1N=C2C=CN(COCC[Si](C)(C)C)C2=NC=1>>[CH3:9][S:8][C:5]1[N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH2:12]2)[C:2]([C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:42])([CH3:41])[CH3:22])[C:32]3=[N:33][CH:34]=2)=[CH:7][N:6]=1
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(C(=O)CC#N)C2)n1
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Agent: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(C(=O)CC#N)C2)n1

Procedure:
The 3-[(S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-piperidin-1-yl]-3-oxo-propionitrile from above (226 mg, 609 μmol) was cross-coupled with 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine prepared from 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.61 mmol) and tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) in a manner similar to step 3, Example 76 to give 3-((S)-3-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-ylamino}-piperidin-1-yl)-3-oxo-propionitrile (−40 mg). MS (ES+): 539.