Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27]C2C=CC=C3C(NC(=O)C=23)=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:40]N>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27][NH2:40])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2c(OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cccc21
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: NOCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To a solution of 12.0 g of the (2-tritylaminothiazol-4-yl)methoxyphthalimide in 400 ml of dichloromethane was added 1.161 g of hydrazine hydrate with cooling, and the mixture was stirred at room temperature for 5 hours. The formed precipitates were removed by filtration, the dichloromethane layer was washed with 300 ml of 10% ammonia water three times and then with 300 ml of saturated saline twice, dried on anhydrous magnesium sulfate, and concentrated to dryness to obtain 8.74 g of (2-tritylaminothiazol-4-yl)methoxyamine.
Reaction SMILES: [CH:1]1CC[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C[N+]1([O-])[CH2:15][CH2:14][O:13]CC1.[OH2:17]>C(#N)C.[Os](=O)(=O)(=O)=O>[C@@H:14]1([OH:13])[CH2:15][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C@@H:1]1[OH:17]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1=CCCCCCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Product: O[C@@H]1CCCCCC[C@@H]1O
Temperature: 45 °C
Reaction time: 21 h

Procedure:
Cyclooctene (4.41 g) was dissolved in acetonitrile (45 ml) and water (15 ml), and to the solution N-methylmorpholine N-oxide (5.15 g) and microcapsulated osmium tetroxide (1 g, containing 10% osmium tetroxide) were added, and the mixture was stirred at 40 to 50° C. for 21 hours. Insoluble microcapsulated osmium tetroxide was removed by filtration, and was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound (4.97 g) as a colorless solid.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[CH3:31][O:32]C1C=C(C=CC=1)C=O>>[CH3:31][O:32][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][CH:3]=1)[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1cccc(C=O)c1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: COc1cccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-methoxybenzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 422 (M+H) IC50 (p70S6K) “+++”
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]([OH:26])([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:7])[CH3:6].ClC(Cl)C.C(O)(=O)C.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C(OCC)(=O)C.[OH-].[NH4+]>[F:28][C:2]([F:1])([F:27])[C:3]([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)([OH:26])[CH2:4][C:5]([CH3:7])([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH:9]=1)[CH3:6]
Reactant: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)butyl]benzaldehyde (50 mg, 0.13 mmol), 3 mL of dichloroethane, and acetic acid (0.1 mL, 1.6 mmol) in an ice bath was added morpholine (0.28 mL, 3.20 mmol) in one batch. The solution was warmed to room temperature and stirred for 0.5 hours. Triacetoxy sodium borohyride (68 g, 0.32 mmol) was added in a single portion and the reaction stirred at room temperature for 3.0 hours. The solution was diluted with ethyl acetate and 3 mL of 3% ammonium hydroxide solution was added. The biphasic system was transferred to a separatory funnel and the aqueous layer was removed and back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The product was eluted from a flash chromatography column with dichloromethane-methanol, and evaporation of the solvent in vacuo yielded the title compound (27 mg, 45% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:20][C:19]3[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=3[C:13]1=[C:12]([CH3:23])[C:11](=[O:24])[CH2:10][CH2:9]2)(=O)=O.[I-:25].[Na+]>CC(C)=O>[I:25][CH2:6][CH2:7][C:8]12[CH2:9][CH2:10][C:11](=[O:24])[C:12]([CH3:23])=[C:13]1[C:14]1[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=1)[CH2:20]2
Reactant: [I-]
Reactant: COc1ccc2c(c1)CC1(CCOS(C)(=O)=O)CCC(=O)C(C)=C21
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC1(CCI)CCC(=O)C(C)=C21
Temperature: 60 °C

Procedure:
A solution of 2-(2-methoxy-5-methyl-6-oxo-6,7,8,9-tetrahydro-8aH-fluoren-8a-yl)ethyl methanesulfonate (49.7 mg, 0.142 mmol) in acetone (2.0 mL) was treated with sodium iodide (85 mg, 0.57 mmol) and the resulting mixture was stirred and heated in an oil bath at 60° C. for 16 hours. After cooling, the mixture was diluted with acetone (2 mL) and filtered through a 0.45 nm Acrodisc filter. The filtrate was evaporated under vacuum and the residue in CH2Cl2 (3 mL) was re-filtered. The filtrate was purified by chromatography on a Biotage Flash 12M KP-Sil column (12 mm×15 cm) which was eluted with 4:1 hexanes-EtOAc, collecting 6 mL fractions every 30 seconds. Fractions 9–11 gave 9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(OC)c1cc(Sc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(OC)c1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenylamine (0.0384 mol) and TEA (0.0578 mol) in THF (q.s.) was cooled to 5° C., and phenylsulfonyl chloride (0.0384 mol) was added dropwise at 5° C. Then, the reaction mixture was reacted at room temperature, and purified by column chromatography over silica gel (eluent: CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[CH2:12]([Mg]Br)[CH3:13].B(F)(F)F.[CH3:20][CH2:21]OCC>C1COCC1>[CH2:20]([C:3]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[CH:12][CH3:13])[CH3:21]
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC=C(CC)c1ccc(F)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 4-fluoro-benzoic acid methyl ester (19.1 g, 114 mmol) in THF (300 mL) at −78° C. is treated with ethylmagnesium bromide (135 mL, 3.0 M). The reaction mixture is allowed to warm to 0° C. over 30 min and quenched with HCl (350 mL, 1.0 M). THF is removed under vacuum, and the residue is extracted with EtOAc (3×100 mL). The organic layer is dried over Na2SO4 and concentrated. The intermediate tertiary alcohol is dissolved in CH2Cl2 (200 mL), cooled to −40° C., and treated with BF3-Et2O (11.5 g, 91.0 mol). The reaction mixture is allowed to warm to 0° C. over 30 min and quenched with water (50 mL). The organic layer is dried over Na2SO4 and concentrated. The residue is purified using silica gel column chromatography (5% EtOAc/Hex) to afford the title compound (16.8 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[CH2:16][CH:17]([CH3:19])[CH3:18].[CH:21]1([SH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.N1CCCCC1.[K+].[Br-]>C(O)C.C(O)(=O)C>[CH:21]1([S:27][CH:15]([C:3]2[C:4](=[O:14])[O:5][C:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:7][C:2]=2[OH:1])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)CC=O
Reactant: O=c1cc(O)cc(-c2ccccc2)o1
Reactant: SC1CCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(C)CC(SC1CCCCC1)c1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6 -phenyl-2H-pyran-2-one (1.5 g, 7.98 mmol), isovaleraldehyde (076 g, 8.78 mmol), cyclohexylmercaptan (2.04 g, 17.56 mmol), piperidine, (1.0 mL), acetic acid (1.0 mL) and ethanol (20 mL).m.p. 210-212° C.; 1H NMR (400 MHz, DMSO-d6) δ0.89 (t, 6 H), 1.36 (m, 6 H), 1.44 (m, 1 H), 1.56 (m, 2 H), 1.69 (m, 2 H), 1.81 (m, 1 H), 2.08 (m, 2 H), 2.61 (brm, 1 H), 4.22 (m, 1 H), 6.67 (s, 1 H), 7.53 (m, 3 H), 7.78 (m, 2 H); IR (KBr) 3106, 2928, 2851, 1659, 1568, 1404, 1125, 766, 569 cm-1 ; MS (CI) m/e 259 (50), 257 (49), 201 (46), 189 (16), 147 (8), 105 (28), 83 (100).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16]>C1COCC1>[O:16]=[C:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[O:9][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: O=C(O)CCCC(=O)ON1C(=O)CCC1=O
Yield: 46.1 %

Procedure:
A solution of 10.0 g (0.088 mol) of glutaric anhydride in 50 mL of dry THF under argon was treated with 10.0 g (0.087 mol) of N-hydroxysuccinimide and heated to reflux for 3.5 hours. The reaction was concentrated at reduced pressure to an oil. The oil was crystallized from 50 mL of ethyl acetate to yield 9.2 g (46%) of 5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxo-pentanoic acid which was treated with 16 mL of thionyl chloride and heated at 45° C. for 3 hours under argon. The reaction mixture was concentrated at reduced pressure to a white solid which was triturated with a small amount of ether and collected by suction filtration. The product was dried overnight at high vacuum to yield 8.7 g (88%) of 18 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CO)cc1Cl
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Borane-methyl sulfide complex (10 M; 10 Ml, 100 mmol) was added to a solution of 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 11.98 g, 55.8 mmol) in tetrahydrofuran (100Ml). The solution was heated at reflux for 2 h and then allowed to stand at room temperature overnight. It was poured into water and ethyl acetate (200 Ml each). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 Ml). The combined organic layers were washed with brine (200 Ml), dried (MgSO4), filtered, and evaporated to give 2-chloro-4-(hydroxymethyl)benzoic acid, methyl ester (11.09 g, 99%) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccc(F)cc4)ncnc32)[C@]1(C)F
Yield: 54.8 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added 4-fluorobenzylamine (about 0.39 ml, 3.46 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.13 g) as a colorless gummy mass. Yield: 56%; 1H NMR (300 MHz, CDCl3): δ 8.74 (s, 1H), 8.38 (d, 1H, J=3.9 Hz), 8.06-8.03 (m, 2H), 7.58-7.56 (m, 1H), 7.47-7.42 (m, 2H), 6.46 (d, 1H, J=20.1 Hz), 4.94-4.72 (m, 2H), 4.66-4.59 (m, 1H), 2.11 (s, 3H), 1.79 (s, 3H), 1.41 (m, 3H); Mass: [M+Na]+: 485 (40%), [M+1]+ 463 (45%).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:16](=[S:18])=O>C(Cl)(Cl)Cl>[CH2:2]([NH:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:7][C:16]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:1])=[CH:11][CH:10]=1)=[S:18])[CH3:3]
Reactant: O=C=S
Reactant: Cl
Reactant: CCNC(=O)[C@@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.5 %

Procedure:
3.4 G (0.015 mol) of L-phenylalanine ethylamide hydrochloride was added to 80 ml of chloroform. To the mixture was added 3.3 ml (0.03 mol) of N-methylmorphorine while cooling with ice. To the solution was dropwise added 20 ml of chloroform solution containing 0.9 g (0.015 mol) of carbonyl sulfide at a temperature of from 5°to 10° C. in 20 minutes. After stirred for 30 minutes at the same temperature, 30 ml of chloroform solution containing 2.4 g (0.015 mol) of 4-chlorobenzychloride was dropwise added to the solution in 30 minutes. After this, the solution was stirred at room temperature for 1 hour. The solid material obtained in a similar manner to that described in Example 2 was recrystallized from 50 ml of ethylacetate and 50 ml of n-hexane to give 4.1 g of white crystals.
Reaction SMILES: C[N:2](C)[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC.NCCCCN>CC#N>[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Agent: NCCCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N,N-dimethylphenylalanine (15) (1.19 g, 6.2 mmol), Et3N (1.29 ml, 9.3 mmol), and 1,4-diamino butane (303 μl, 3.0 mmol) were dissolved in CH3CN (50 mL). O-benzotriole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) was added, and the reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The mixture was vacuum filtered (EtOAc), further concentrated under reduced pressure, and subjected to flash chromatography (EtOAc, then 10% Et3N in EtOAc) to afford 1.06 g (80%, non-optimized) of (16a) as white crystals. [α]25−105.7 (c=0.19, CHCl3); FTIR (neat) 1649, 1455, 1384, 748, 700 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.19-7.16 (m, 8H), 6.89 (t, J=5.7 Hz, 211), 6.40 (s, 1H), 5.90 (s, 1H), 3.13-3.04 (m, 6H), 3.12 (dd, J=12.7, 5.3 Hz, 2H), 2.79 (dd, J=13.4, 5.1 Hz, 2H), 2.23 (s, 12H), 1.24 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 171.68, 129.44, 128.88, 127.91, 125.69, 70.61, 41.91, 38.25, 32.84, 26.52; HRMS calculated for C26H39N4O2 (M+H)+ required 439.3073, found 439.3074.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C:34]([CH3:36])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH:34]([CH3:36])[CH3:33])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (30 mg, 0.069 mmol) in 10 mL of dichloromethane is added 1 mL of acetone and NaB(OAc)3H (30 mg, 0.138 mmol). The resulting mixture is stirred at room temperature for 18 h. Following purification by preparative LCMS gave 7-cyclopentyl-2-[5-(4-isopropyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (20 mg, 61%). MS(ESI) m/z 477.3 (M+H)+
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:32]([CH2:36][C:37](Cl)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:37](=[O:38])[CH2:36][C:32]([CH3:35])([CH3:34])[CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CC(C)(C)CC(=O)Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and tert-butylacetyl chloride as a pale yellow oil (97%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (dd, J=6.0, 1.9 Hz, 1H), 7.44 (m, 4H), 7.16 (m, 4H), 7.08 (m, 1H), 6.99 (m, 1H), 4.88 (s, 2H), 3.94 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 2.00 (s, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.99 (s, 9H), 0.94 (t, J=7.3 Hz, 3H). M+ (ESI): 514.0, HPLC, Rt: 5.92 min (Purity: 100.0%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11]>CC(C)=O.Cl.O>[CH:2]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][C:10]#[N:11])=[O:1]
Reactant: CC(C)(CCC#N)CC1OCCO1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(CC=O)CCC#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.2 %

Procedure:
50 g of 5-(dioxolan-2-yl)-4,4-dimethylvaleronitrile, prepared in D], are dissolved in 1.3 l of acetone in the presence of 140 ml of concentrated hydrochloric acid and 700 ml of water. The mixture is stirred at room temperature for 5 hours, the acetone is concentrated under vacuum and the residue is taken up with ether, washed with water and then evaporated to dryness to give 35 g of 5-formyl-4,4-dimethylvaleronitrile.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=2)[C:16](O)=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].O1CCCC1.C[Si]([Cl:31])(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=[O:21])[C:15](=[CH:19][CH:20]=2)[CH2:16][Cl:31])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
From 5.0 g. of 6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 250 ml. of tetrahydrofuran, 2.26 ml. of triethylamine, 2.05 ml. of trimethylsilyl chloride and 2.33 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(methylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([N:27]4C(=O)C5C(=CC=CC=5)C4=O)=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.NN>O1CCCC1.C(O)C>[CH:1]([O:4][C:5](=[O:39])[NH:6][C@@H:7]1[CH2:38][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N3C(=O)c4ccccc4C3=O)c3ccc(C#N)cc23)C1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Temperature: 24 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Alternate procedure: Dissolve (S)-{7-cyano-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylmethyl]-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl}-carbamic acid isopropyl ester (20 g; 34.64 mmoles) in tetrahydrofuran (170 mL) and ethanol (30 mL). Add hydrazine monohydrate (3.37 mL, 69.29 mmoles) using a syringe pump over 30 min. Stir the mixture at 22/24° C. for 3 h and then filter. Wash the cake with additional tetrahydrofuran (50 ml). Evaporate the combined mother liquors and purify the resulting residue by silica gel chromatography eluting with dichloromethane/(2M NH3 in methanol/) (98:2). Combine the fractions containing pure product and evaporate the solvent. Dry the solid to constant weight and then add over ethanol (50 mL). Heat the mixture to reflux until complete dissolution occurs and then allow to cool to room temperature overnight. Filter the solid and dry under vacuum to constant weight to provide 11.45 g (84%) of the title compound. MS (m/z): 390 (M+1). Chiral HPLC: ee>98% (Isomer 1, Chiralpak AD, EtOH/0.2% dimethylethylamine)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: Brc1ccncc1
Reactant: C1CC2(CCN1)OCCO2
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 91 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (5.0 g, 34.9 mmol, 1.0 eq.), 4-bromopyridine HCl (7.46 g, 38.46 mmol, 1.1 eq.) and DIPEA (18.2 ml, 104.7 mmol, 3.0 eq.) were dissolved in n-butanol (100 ml) and refluxed for 36 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 91% (7.0 g, 31.81 mmol)