Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@@H]4CCC[C@H](N)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.[CH3:71][O:72][CH2:73][CH:74]1[CH2:76][O:75]1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:76][CH:74]([OH:75])[CH2:73][O:72][CH3:71])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:71][O:72][CH2:73][CH:74]([OH:75])[CH3:76]
Reactant: COCC1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCC(C)O
Product: COCC(O)CN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (50 mg, 0.09 mmol) in methanol (2 mL) was added 2-(methoxymethyl)oxirane (9.4 mg, 0.11 mmol) and the reaction mixture was heated in the microwave to 140° C. for 10 min. 1M aqueous LiOH (1.0 mL, 1.0 mmol) was added, and the reaction mixture was heated in the microwave to 130° C. for 10 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H2O with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redissolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product 1-[[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2, 3-1)]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol, 610.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH:8]([CH3:13])[C:6]=2[N:7]=1.[CH3:20][Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:30](Br)[CH:31]=C>C1COCC1>[CH2:13]([C:8]1([CH3:20])[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[N:10]([CH3:11])[C:9]1=[O:12])[CH:30]=[CH2:31]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1C(=O)N(C)c2c1nc(Cl)nc2N1CCOCC1
Reactant: C=CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC1(C)C(=O)N(C)c2c(N3CCOCC3)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To 2-chloro-5,7-dimethyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one (92.0 mg, 0.32 mmol) in anhydrous THF (5 mL) under N2 at −78° C. was added dropwise 1.0 M lithium hexamethyldisilazide in THF (0.65 mL, 0.65 mmol). The reaction mixture was stirred at −78° C. under N2 for 60 minutes. Allyl bromide (0.062 mL, 0.72 mmol) dissolved in 0.5 mL of THF was added, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography eluted with 10 to 100% ethyl acetate/heptane gave 84.3 mg (80.3%) of 7-allyl-2-chloro-5,7-dimethyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one. MS(ESI) m/z: 323.1 [M+1]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:33]3[CH:32]=[N:31][CH:30]=[C:29]([F:28])[CH:34]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.71 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.84 Hz, 3H) 3.15 (m, J=7.00 Hz, 2H) 3.32-3.41 (m, 2H) 3.42-3.52 (m, 2H) 4.61 (t, J=5.08 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.83 (d, J=0.78 Hz, 2H) 7.95 (d, J=1.17 Hz, 1H) 8.06 (d, J=1.00 Hz, 1H) 8.52-8.66 (m, 2H) 8.75 (d, J=2.74 Hz, 1H) 10.25 (s, 1H).
Reaction SMILES: [Cl:1]Cl.CS[CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:7]=1[NH2:8].[ClH:17].O>C(Cl)CCl>[Cl-:1].[Cl:17][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:7]=1[NH3+:8]
Reactant: CSCc1cccc(C(F)(F)F)c1N
Reactant: ClCl
Reactant: Cl
Solvent: O
Solvent: ClCCCl
Product: [Cl-]
Product: [NH3+]c1c(CCl)cccc1C(F)(F)F
Temperature: 60 °C
Yield: 92.7 %

Procedure:
Chlorine (76.0 grams, 1.07 mol) was bubbled into a mechanically stirred solution of 221.0 grams (1.00 mol) of 2-(methylthiomethyl)-6-(trifluoromethyl) aniline in 2 liters of ethylene dichloride over 60 minutes while maintaining the reaction temperature below 20° C. The mixture was then heated to 60° C. while maintaining a steady stream of HCl bubbling through. Water (25 ml, 1.4 mol) was added and the HCl treatment was maintained at 60° C. for 15 minutes at which point a clear solution was obtained. Excess water was removed by azeotropic distillation (780 ml of solvent were removed) and the resulting solution was cooled to 0° C. with a steady stream of HCl bubbling through to precipitate the anilinium chloride salt. Filtration, washing of the solids with 150 ml. of cold ethylene dichloride and air-drying gave 228.0 grams (92.7%) of off-white 2-(chloromethyl)-6-(trifluoromethyl) anilinium chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OCc2ccccc2F)c1Cl
Yield: 113.5 %

Procedure:
A solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 3.2 g (0.02 mole) 2-fluorobenzoyl chloride, and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was refluxed for 17 hours. After removal of triethylamine hydrochloride by filtration, the filtrate was concentrated in-vacuo to leave 8.4 g of residue, which, after recrystallization from ligroin, gave 4.6 g (59% yield) of pure product; m.p. 101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([CH2:15][CH2:16][NH:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:11](OC)=[O:12])[C:6]=2[CH:26]=1.C([N-]C(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1>[CH2:19]([O:18][N:17]1[CH2:16][CH2:15][C:7]2([C:6]3[CH:26]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][CH2:8]2)[C:11]1=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1(CCNOCc2ccccc2)CCOc2ccc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1N(OCc2ccccc2)CCC12CCOc1ccc(F)cc12

Procedure:
To a solution of methyl 2,3-dihydro-6-fluoro-4-(2-(benzyloxyamino)ethyl)-4H-1-benzopyran-4-carboxylate (3.1 g) in anhydrous tetrahydrofuran at -78° C. was added a solution of 1-M lithium diisopropylamide (9.0 mL) in tetrahydrofuran. After 1 hour acetic acid (1 mL) was added, and the solution concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N HCl, and organic layers washed with 1N HCl, saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to afford the title compound as an oil, 2.9 g. (1H NMR (CDCl3, 60 MHz): 1.9-2.5 (m, 4H), 3.2-4.6 (m, 4H), 5.0 (s, 2H), 6.3-6.8 (m, 3H), 7.3-7.5 (m, 5H).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]>CO.N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:4][O:2][CH3:3])[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of methoxylamine hydrochloride (23 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-methoxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (68 mg, 81%) was a white foam: EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1364.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 28m was prepared from compound 2 (75 mg, 0.30 mmol), p-cyanobenzyl bromide (65 mg, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in a manner similar to that described for 28d in 81.5% (89 mg) yield as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CN(C=O)C.C(O)(C)C>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([F:12])[CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(F)c1
Solvent: CCCCO
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Fc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
2 g (10.58 mmol) of 2,6-dichloro-purine and 5.9 g (52.9 mmol) of 3-fluoro-aniline (Fluka, Buchs, Switzerland) are stirred in 60 ml of n-butanol and 3 ml of DMF at 80° C. for 5 h. The cooled reaction mixture is treated with isopropanol and the crystal mass which has precipitated out is filtered off and dried. 2-Chloro-6-(3-fluoro-phenyl-amino)-purine is obtained; m.p.>250° C.; FAB-MS: (M+H)+=264; Rf=0.3 (CH2Cl2:methanol 9:1).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].Br[CH2:39][C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=1>CN(C=O)C.CCOCC.Cl>[CH3:34][C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:39][C:40]3[CH:49]=[CH:48][C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:35]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc3ccccc3c2)CC1CCOc1ccc(CC(C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 minute Then 89 mg of 2-bromomethyl naphthalene is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 51 mg (51%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.81-7.77 (m, 3H), 7.66 (s, 1H), 7.48-7.45 (m, 4H), 7.35 (dd, 1H, J=8.8, 1.6 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.4 Hz), 6.69 (d, 2H, J=8.4 Hz), 6.20 (bs, 1H), 4.51 (s, 2H), 3.92-3.90 (m, 2H), 3.72-3.64 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.29, 3.13 (ABq, 2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.86 (s, 3H), 2.22-2.15 (m, 1H), 1.93-1.84 (m, 1H), 1.46 (s, 3H). HRMS (ES+) m/z exact mass calcd for C34H34N2O5F3 (m+1) 6072420, found 6072417.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:19]1([OH:18])[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Fc1ccccc1-n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nccn2-c2ccccc2F)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1-(2-Fluorophenyl)imidazole (484 mg, 2.99 mmol) was dissolved in a tetrahydrofuran (5 mL) under an atmosphere of argon. The reaction mixture was cooled to −78° C. n-Butyllithium (2.2 mL of 1.6 M, 3.58 mmol) in hexanes was slowly added and the resulting mixture was stirred at −78° C. for 1 hour. tert-Butyl 4-oxopiperidine-1-carboxylate (892.2 mg, 4.48 mmol) was then added as a solution in tetrahydrofuran (2 mL). The reaction mixture was allowed to slowly warm to room temperature and stir for 10 days. The crude material was evaporated to dryness and taken to the next step without further purification. ESI-MS m/z calc. 361.2. found 362.1 (M+1)+. Retention time 1.12 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:12][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from (2,4-Dichloro-phenyl)-piperidin-4-yl-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (m/e): 483.4 (M+H+)
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:10]([Cl:12])[Cl:11])[SiH:7]([Cl:9])[Cl:8])[Cl:5]>>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH:6]1[SiH:10]([Cl:12])[Cl:11]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[SiH](Cl)Cl
Reactant: C#C
Product: Cl[SiH](Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Hydrosilation of acetylene with tris(dichlorosilyl)methane in the presence of H2PtC6. Into the same apparatus as described in Example 1 were placed 220 μl of a 0.1 M H2PtCl6 /IPA solution and the flask placed under a dry nitrogen atmosphere. The IPA was removed from the flask under vacuum and 5.31 g of tris(dichlorosilyl)methane and 30 ml of dried benzene added to form a mixture. Acetylene gas was blown into the mixture at a rate of 90 ml per minute for 8 hours. The resulting mixture was vacuum distilled at 67 Pa to yield a mixture comprising 4.51 g of 1,1,3,3-tetrachloro-2-dichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC area 31.7%) and 3,3,5,5-tetrachloro-4-dichlorosilyl-3,5-disilahepta-1,6-diene (TCD-GC area 8.6%). 1,1,3,3-Tetrachloro-2-dichlorosilyl-1,3-disilacyclopent-4-ene =1H-NMR (CDCl3, ppm):1.33 (d, 3.9 Hz, 1H, SiCHSi), 5.73 (d, 3.9 Hz, 1H, SiH), 7.43 (s, 2H, CH=CH).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Yield: 8.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-6-(2-methoxy-ethoxymethyl)-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.86 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.10 g, 3.95 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and purified by silica gel chromatography to give 4-{6-[8-cyclopentyl-6-(2-methoxy-ethoxymethyl )-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (0.140 g, 14.7%). 1H NMR δ(400 MHz, CDCl3) 8.60 (s, 1H), 8.34 (m, 1H), 7.95 (s, 1H), 7.69 (t, J=1.4 Hz, 1H), 7.42 (m, 1H), 5.91 (m, 1H), 4.53 (d, J=1.2 Hz, 1H), 3.78 (m, 1H), 3.63 (m, 6H), 3.43 (s, 3H), 3.11 (m, 4H), 2.35 (m, 2H), 2.08 (m, 2H), 1.88 (m, 2H), 1.69 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[CH2:20]([O:22][C:23](=[O:32])[C@@:24]([CH3:31])([C:27]([NH:29][CH3:30])=[O:28])[NH:25][CH3:26])[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23](=[O:32])[C:24]([N:25]([CH3:26])[C:15]([C:14]1[CH:18]=[CH:19][C:11]([I:10])=[CH:12][CH:13]=1)=[O:16])([CH3:31])[C:27]([NH:29][CH3:30])=[O:28])[CH3:21]
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98 %

Procedure:
DIPEA (0.34 mL) and 4-iodobenzoyl chloride (0.13 g) were added to a chloroform (2.3 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.25 g) under ice cooling, and the mixture was stirred for 40 minutes at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→35/65) to obtain 1-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 10-1, yellow oil) (0.20 g, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C1(C)C=CC=CC=1>[CH3:12][S:13]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of (4-nitrophenyl)methanol (2 g, 13.06 mmol) in toluene (10 mL) was slowly added methane sulfonylchloride (1.21 mL, 15.67 mmol) at room temperature. The reaction mixture was heated to 80° C. for 4 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give 4-nitrobenzyl methanesulfonate (2.2 g, 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.C[Si]([C:30]#[CH:31])(C)C.C(N(CC)CC)C.CO>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:30]([C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1)#[CH:31]
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc2c(c1)-c1c3c(c4c([nH]c5ccccc54)c1C2)C(=O)NC3
Temperature: 25 °C
Reaction time: 24 h
Yield: 8.2 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7-(7H)one (Compound I-9) (435 mg, 1.1 mmol), trimethylsilylacetylene (0.47 ml, 3.3 mmol) and triethylamine (1.0 mL) in DMF (11 mL) was added bis(triphenylphosphine)palladium(II)chloride (17 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 24 h. The mixture was cooled to ambient temperature, filtered through a pad of celite then the solvent concentrated at reduced pressure. The product was dissolved in DMF (8 mL), MeOH (8 mL) cesium fluoride (370 mg, 2.4 mmol) added and the mixture stirred at ambient temperature 24 h. The solvent was concentrated at reduced pressure to give a dark solid. Purification by column chromatography (silica gel, EtOAc:MeOH; 10:1, Rf=0.53) give 30 mg of a tan solid. The compound was further purified by preparative TLC (silica gel, EtOAc:hexane; 3:1) to give Compound I-36 as a tan solid, mp>300° C. 1H NMR (DMSO-d6, 300 MHz): d 4.2 (s, 2H), 5.0 (s, 2H), 7.38-7.46 (m, 3H), 7.58-7.75 (m,4H), 8.15 (s, 1H), 8.63 (s, 1H), 9.42 (d, 1H, J=9Hz), 12.19 (s, 1H); MS m/e=335 (m+).