Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:5]=2[CH:4]=1)[CH3:2].[Br:22]Br>CC(O)=O>[Br:22][C:4]1[C:5]2[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[S:21][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1cc2c(NC3CCC(N(C)C)CC3)ncnc2s1
Solvent: CC(=O)O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 4-N-[6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (4.0 g, 13.14 mmol, 1.00 equiv) in AcOH (40 mL), dibromane (4.2 g, 26.28 mmol, 2.00 equiv). The resulting solution was stirred overnight at 70° C. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of water. The pH value of the solution was adjusted to 8.0 with saturated sodium carbonate. The resulting solution was extracted with 4×50 mL of chloroform and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.0 g (60%) of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine as a yellow solid. MS (ES, m/z): 383 [M+H]+ 1H-NMR (400 MHz, DMSO-d6, ppm): δ 8.36 (1H, s), 6.75-6.77 (1H, d), 4.01-4.07 (1H, m), 2.81-2.88 (2H, q), 2.27 (7H, s), 2.09-2.11 (2H, d), 1.86 (2H, d), 1.32-1.40 (4H, q),1.21-1.26 (3H, t).
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl>C1COCC1.O>[C:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)c1csc(C(C)(C)C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)O)cs1
Reaction time: 16 h

Procedure:
Lithium hydroxide (2.8 g, 120.25 mmol) was added to a stirred mixture of ethyl 2-tert-butylthiazole-4-carboxylate (6.56 g, 30.76 mmol) in THF (100 mL) and water (40 mL). After 16 h, HCl (62.5 mL, 125 mmol) was added and the solution concentrated to ˜40 mL. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over magnesium sulphate, filtered and evaporated in vacuo to give the sub-title compound as an off white/yellow solid. Yield: 5.41 g
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]([CH3:28])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:11][C:10]=2[O:29][CH3:30])=[N:6][CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Cl:1][C:2]1[C:3]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]([CH3:28])[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:11][C:10]=2[O:29][CH3:30])=[N:6][CH:7]=1
Reactant: COc1cc(N(C)CCN2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-[2-(4-methylpiperazin-1-yl)ethyl]-5-nitrobenzene-1,4-diamine (0.182 g, 0.33 mmol), iron (0.110 g, 1.98 mmol) and NH4Cl (0.012 g, 0.23 mmol) in EtOH (10 mL) and water (3.33 mL) was heated at reflux for 1.5 h. The mixture was then cooled to r.t., filtered and concentrated in vacuo. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia provided a brown gum (162 mg) after concentration of appropriate fractions. Further purification by FCC, eluting with 2-7% 1M methanolic ammonia in CH2Cl2 gave the title compound (0.148 g, 86%) as a yellow gum; 1H NMR: (CDCl3) 2.28 (3H, s), 2.32-2.63 (10H, m), 2.70 (3H, s), 2.98 (2H, t), 3.84 (3H, s), 4.05 (2H, d), 6.71 (1H, s), 6.95 (1H, td), 7.38 (1H, ddd), 7.52 (1H, d), 7.88 (1H, s), 8.36 (1H, s), 8.57 (1H, d), 8.65 (1H, d), 8.93 (1H, s); m/z: ES+ MH+ 522.57.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4]1.[C:19](#[N:22])[CH:20]=[CH2:21]>>[CH3:1][Si:2]([CH3:18])([CH3:17])[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][CH:4]1[CH:20]([C:19]#[N:22])[CH3:21]
Reactant: C=CC#N
Reactant: C[Si](C)(C)C1C=CN([Si](C)(C)C)c2ccccc21
Product: CC(C#N)C1C=C([Si](C)(C)C)c2ccccc2N1[Si](C)(C)C
Temperature: 100 °C
Yield: 73.6 %

Procedure:
A mixture consisting of 27.5 g (0.1 mol) of 1,4-bis-(trimethylsilyl)-1,4-dihydroquinoline and 6 g (0.1 mol) of acrylonitrile is heated in an inert atmosphere at 100°C for 150 hours. Fractional distillation yields 24.2 g (72%) of 1,4-bis-(trimethylsilyl)-2-(1-cyanoethyl)-1,2-dihydroquinoline: yellow-green oil, b.p. 106°-108°C/0.001 mm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=O)[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])=[O:22])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycartonylamino-2-(4-chlorophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(4-chlorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 13, 2.50 g, 6.04 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.39 g, 6.34 mmol), WSCI hydrochloride (1.39 g, 7.25 mmol) and HOBT (1.63 g, 1.21 mmol) in DMF (20 mL) to give 3.72 g (100%) of the target compound as colorless crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH:21]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: CCCCC(c1cc(F)ccc1F)S(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After addition of 3-chloroperbenzoic acid (98.8 mg, 0.571 mmol) to a solution of 2-[1-[(4-chlorophenyl)sulfinyl]pentyl]-1,4-difluorobenzene (Isomer 2-B) (150 mg, 0.439 mmol) in methylene chloride (5 ml), the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride, washed successively with a 1N aqueous solution of sodium hydroxide, water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane), whereby the title compound (122 mg, 77%) was obtained as a colorless oil.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH2:21]C=O>C(O)C.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]2[C:6]=1[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[CH:13]2[CH:21]=[N:2][OH:3]
Reactant: NO
Reactant: COc1c(C)cc(C)c2c1C(CC=O)C1=C2CCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1c(C)cc(C)c2c1C(C=NO)C1=C2CCCC1

Procedure:
500 Milligrams of hydroxylamine hydrochloride was added to an ethanol-chloroform (5:1) solution containing 910 mg of 5,7-dimethyl-8-methoxy-9-formylmethyl-1,2,3,4-tetrahydro-9H-fluorene in 18 ml of ethanol-chloroform and the mixture was refluxed with heating for 2 hours. The reaction mixture was diluted with chloroform and then washed with saturated aqueous sodium chloride solution and subsequently the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) to obtain 670 mg of 5,7-dimethyl-8-methoxy-9-hydroxyiminomethyl-1,2,3,4-tetrahydro-9H-fluorene
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9][OH:10])=[CH:5][CH:6]=1.[OH-:11].[K+:12]>C1(C)C=CC=CC=1>[C:9]([O-:11])(=[O:10])[CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1.[K+:12]
Reactant: [OH-]
Reactant: OC/C=C/c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C([O-])C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g (0,36 mol) of cinnamic alcohol are dissolved in 180 ml of dry toluene. 20 g (0,36 mol) of KOH are added to the solution, and the resulting mixture is kept under stirring for one hour at room temperature. During this phase, potassium cinnamate is obtained. Then, a solution prepared starting from 18 g (0,10 mol) of 2,4,6-trichloro-s-triazine in 150 ml of toluene is added, allowing to react at room temperature for further 90 hours under stirring.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[S:13]([Cl:12])(=[O:15])=[O:14])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCc1cc2ccccc2o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-Ethylbenzo[b]furan-3-sulfonyl chloride was prepared by the method of Example 82C with 2-ethylbenzo[b]furan (6.9 mmols, 1.0 g), chlorosulfonic acid (8.9 mmols, 0.6 ml) phosphorous oxychloride (21 mmols, 1.9 ml), phosphorous pentachloride (6.9 mmols, 1.4 g) and CH2Cl2 (10 ml). Flash chromatography (2% ethyl acetate/hexanes) provided 0.71 g (42%) of an orange solid.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]3[C:6](=[CH:7][N:8]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[N:9]=[C:10]2[C:6]=1[CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:12]([N+:13]([O-:15])=[O:14])=[CH:11]2
Reactant: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3cc([N+](=O)[O-])c(C4CC4)cc3c2Br)nc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (v) (1.08 g, 3.67 mmol) in DMF (15 mL) was added N-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried (MgSO4) and the volatiles removed in vacuo to give (vi) (1.37 g, >99%). ESI-MS: calculated [M+H]+ 373.0/375.0, observed [M+H]+ 373.1/375.1
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C2C(=CC=CN=2)C=[CH:15][CH:14]=1.S(Cl)(Cl)=O>C(O)C>[CH2:14]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:12])[C:9]([Cl:11])=[N:10][C:2]=1[Cl:1])[CH3:15]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: c1cnc2ncccc2c1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)c(Cl)nc1Cl

Procedure:
2,6 Dichloro-5-fluoro-nicotinic acid was selected as a starting material to make the compounds of structure (Ia) with fluoro substitution at 6-position of naphthyridine moiety. 2,6 Dichloro-5-fluoro-nicotinic acid was esterified by treating with thionyl chloride followed by refluxing with dry ethanol to yield 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester, depicted by formula 21 in Scheme 10. This ester gave 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, depicted by formula 22 in Scheme 10, when reacted with ethanethiol and sodium hydride. 6-Ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 23 in Scheme 10, was prepared by amination of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester, which was converted into 5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester, depicted by formula 24 in Scheme 10, by refluxing with ethanol and raney nickel. 5-Fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester was then reacted with trichloromethylchloroformate to yield 6-fluoro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione, depicted by formula 25 in Scheme 10. The sequence of reactions is shown in Scheme 10.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=2[CH3:18])[CH2:4][O:3]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:22])[C:11]=2[CH3:18])[CH2:4][O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCC2COC(C)(C)OC2)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OCC2COC(C)(C)OC2)ccnc1CO
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
The 4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (3.84 g, 14.4 mmol) obtained in the step (12a) was mixed with acetic anhydride (50 ml, 530 mmol). The mixture was stirred at 85° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was concentrated. To the residue, methanol (50 ml) and a 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) were added and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous sodium hydroxide solution twice, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (2.97 g, yield: 77.2%) as a brown solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([N:15]1[CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]1[CH2:9][OH:8])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(CO)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.58 mL, 4.2 mmol) was added to a mixture of racemic tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (0.60 g, 2.8 mmol, racemic, AstaTech) and benzyl bromide (0.36 mL, 3.0 mmol) in acetonitrile (5.0 mL). The mixture was heated to 80° C. in an oil bath for 4 h, then allowed to cool and stir at ambient temperature overnight. Solvent was removed in vacuo and the residue was dissolved in methylene chloride. The solution was washed with 0.1N NaOH, dried over sodium sulfate and concentrated. Flash chromatography, using a 40 g silica gel cartridge and eluting with a gradient from 0-60% EtOAc in hexanes afforded product as a viscous oil (630 mg, 71%). 1H NMR (300 MHz, CDCl3): δ 7.37-7.22 (m, 5H), 4.02 (d, 1H), 3.87 (dd, 1H), 3.69 (dd, 1H), 3.63-3.50 (m, 2H), 3.41 (d, 1H), 3.41-3.27 (br m, 1H), 3.22-3.06 (br m, 1H), 2.84-2.71 (br m, 1H), 2.64-2.50 (br m, 1H), 2.27 (ddd, 1H), 1.45 (s, 9H); LCMS (M+H)+: 307.2.
Reaction SMILES: [C:1](=[O:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([OH:19])(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[I-].[Na+]>C(OCC)C>[C:1](=[O:13])([S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:2][CH:3]([O:19][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:4]
Reactant: CC(C)C(=O)O
Reactant: CC(Cl)OC(=O)Sc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(OC(=O)Sc1ccccc1)OC(=O)C(C)C
Temperature: 50 °C
Yield: 97 %

Procedure:
A mixture of compound (4) (10 g, 46 mmol), isobutyric acid (30 mL), triethylamine (30 mL) and sodium iodide (2 g) was stirred and heated in an oil bath at 50° C. for 3 days. The reaction mixture was diluted with diethyl ether (200 mL) and washed successively with water (3×100 mL), saturated aqueous sodium bicarbonate (2×100 mL) and 0.1 M aqueous potassium bisulfate (2×100 mL). The organic phase was separated, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (9) as a pale yellow liquid (12 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 1.2 (d, 6H), 1.5 (d, 3H), 2.55 (m, 1H), 6.95 (q, 1H), 7.4-7.5 (m, 5H).
Reaction SMILES: [SH:1][CH2:2][CH:3]1[O:7][C:6]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:5][CH2:4]1.[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Br)[CH2:23][CH3:24]>>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH2:29][CH2:30][S:1][CH2:2][CH:3]2[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:5][CH2:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OC(CS)CS1
Product: CCCc1c(OCCCSCC2CSC(CCC(=O)OCC)(CCC(=O)OCC)O2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 64 (1.0 g, 0.003 mol), (3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopropane (described in U.S. Pat. No. 4,565,882, Example 14) (1.1 g, 0.0033 mol) and anhydrous potassium carbonate (1.6 g) in methyl ethyl ketone (15 ml) The crude product was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to give 1.54 g (90%) of the product as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[C:6]([CH3:15])([CH3:14])[C:5]1=[O:16])(=O)C.Cl>C(O)(C)C.O>[F:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][C:5](=[O:16])[C:6]2([CH3:15])[CH3:14]
Reactant: CC(=O)N1C(=O)C(C)(C)c2cc(F)ccc21
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C(=O)Nc2ccc(F)cc21

Procedure:
2.10 g (9.49 mmol) 1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one in 20 mL isopropanol were refluxed with 50 mL of a 6M aqueous HCl solution for 1 h. After cooling the isopropanol was eliminated i. vac. The residue was diluted with water and cooled with ice. The precipitated substance was suction filtered and washed with water. The solid was dried i. vac.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[C:8](=[O:13])[C:9](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:10][CH2:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1=CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CCC=C(O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 115 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(tert-butyl-dimethyl-silanyloxy)-cyclohex-2-enone (6.9 g, 30.48 mmol) in dry toluene (50 mL) was treated with Bredereck's reagent (9.44 ml, 45.72 mmol) was stirred at 115° C. for 24 hours. The mixture was concentrated under reduced pressure to give 2-(tert-butyl-dimethyl-silanyloxy)-6-dimethylaminomethylene-cyclohex-2-enone as a semi-solid brown residue which was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[CH2:50][CH2:49][CH2:48][C@@H:45]1[CH2:46][OH:47]>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][N:44]4[CH2:50][CH2:49][CH2:48][C@@H:45]4[CH2:46][OH:47])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: OC[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC[C@@H]2CO)C1

Procedure:
The title compound is prepared in analogy to Example 116 from cis-{3-[4-amino-5-(3-benzoyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol of Example 124, p-toluenesulfonyl chloride and D-prolinol (Fluka, Buchs, Switzerland). Analytical HPLC-MS: tR=1.48 min; ES-MS: m/eo=512.48.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C1COCC1>[C:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])(=[O:16])[CH:14]=[CH2:15]
Reactant: OCCCO
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCCO
Yield: 50 %

Procedure:
1,3-Propanediol (by Tokyo Kasei) and triethylamine were dissolved in THF, and in an ice-water bath, acryloyl chloride was added thereto. After the reaction, the reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution added thereto, and then the organic layer was washed with 1 N hydrochloric acid and saturated saline water. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography to obtain 32 g of 3-hydroxypropyl acrylate (yield: 50%).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:31][C:32]([CH3:39])([CH3:38])[CH2:33][NH:34][C:35]([NH2:37])=[NH:36]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:37]=[C:35]([NH:34][CH2:33][C:32]([CH3:39])([OH:31])[CH3:38])[N:36]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: CC(C)(O)CNC(=N)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), 1-(2-hydroxy-2-methylpropyl)guanidine and potassium carbonate (107 mg, 0.773 mmol) were added and the reaction mixture was stirred at 120° C. for 2 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (23.8 mg, 39%).