Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(N(CC)CC)C.O>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(N2CCS(=O)(=O)CC2)nc(Cl)n1
Yield: 39.2 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (579 mg, 3.55 mmol), thiomorpholine-1,1-dioxide (480 mg, 3.55 mmol) and triethylamine (0.99 mL, 7.10 mmol) in 7 mL isopropanol was refluxed overnight. Water was added and the mixture of the regioisomers were extracted with ethyl acetate. Chromatography on on Si—NH2 gel (Isolute) using cyclo-hexane/ethyl acetate(gradient 30 to 60% ethyl acetate) gave the title compound as a colourless solid (364 mg, 39%). MS ISP (m/e): 201.2 (33) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.39 (s, 1H), 4.20 (t broad, 4H), 3.08 (t broad, 4H), 2.41 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][NH:8][C@H:7]1[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CCN(CC)CC.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[CH3:33])[C@H:7]1[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCN[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a 0° C. solution of the (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-piperidine-3-carboxylic acid ethyl ester prepared above (600 mg, 1.72 mmol) in dry CH2Cl2 (5 mL) containing Et3N (480 μL, 3.44 mmol) was added 2-methylbenzoyl chloride (266 mg, 1.72 mmol) and the mixture was stirred at room temperature for over night. The reaction mixture was then diluted with CH2Cl2 (20 mL), washed with 1 N aqueous HCl, water, and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester in quantitative yield and the crude product was used as such in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([C:19]2[N:20]=[C:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]4[N:32]=[CH:33][CH:34]=[CH:35][C:23]=4[N:22]3[C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)=[CH:37][CH:38]=1)(=[O:43])=[O:44]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(S(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 86.2 %

Procedure:
tert-Butyl[1-(4-{2-[4-(methylsulfonyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (51 mg) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 23 hours. The mixture was concentrated, then sat.NaHCO3 aq. was added. The mixture was extracted with AcOEt+MeOH, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated to afford the desired product (37 mg, 72%, 2 steps) as a pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.60 (s, 1H), 8.09 (dd, J=4.6 Hz and 1.7 Hz, 1H), 7.98 (dd, J=8.0 Hz and 1.7 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.37 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.30 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 7.14 (td, J=7.4 Hz and 1.7 Hz, 2H), 6.92 (dd, J=8.0 Hz and 1.7 Hz, 1H), 6.74 (dd, J=8.0 Hz and 5.2 Hz, 1H), 3.21 (s, 3H), 2.45-2.39 (m, 2H), 2.18-2.13 (m, 2H), 2.08-2.00 (m, 1H), 1.75-1.67 (m, 1H). LCMS: 534 [M+H].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:20]>>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=3)=[CH:11][CH:12]=2)=[O:29])=[CH:23][CH:22]=1)[CH3:20]
Reactant: Nc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc1
Reaction time: 4.5 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(2-trifluoromethyl-pyridin-4-yloxy)-phenylamine (Example 108) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4.5 h. The title compound is obtained as a white solid: ES-MS: 401.9 [M+H]+; single peak at tR=9.33 min (System 2); Rf=0.37 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:35]=2)[CH2:27][CH2:26]1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:37]2[CH:36]=[N:35][C:34]([NH:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[CH:39][CH:38]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(NCCN3CCOCC3)nc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and N-(2-morpholinoethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (62 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid was purified by HPLC to yield 5-chloro-3-((5-(6-(2-morpholinoethylamino)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=451).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH2:15]1[C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][O:17][CH:16]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(N(CC)CC)C>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][C:20]3([CH2:15][CH2:16][OH:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: OC1CC2(CCCCCCC2)CCO1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCCCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate (synthesized in Preparation Example 4-5) (1.31 g) in 1,2-dichloroethane (6 mL) was added triethylamine (0.96 mL). The suspension was stirred at room temperature for 5 minutes. Then, a solution of 3-oxaspiro[5.7]tridecan-2-ol (synthesized in Example 72) (0.62 g) in 1,2-dichloroethane (3 mL) was added to the suspension, and it was stirred at room temperature for additional 10 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (0.70 g) was added thereto. The reaction solution was then allowed for its temperature to rise to room temperature, and the solution was stirred for additional 4.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, methanol-chloroform (3:97 to 1:9)] to give the title compound (0.53 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[N:16]=[CH:17][S:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.COCCOC>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[N:16]=[CH:17][S:18][CH:19]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1cscn1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cscn2)cc1C=O
Temperature: 80 °C
Yield: 55 %

Procedure:
(3-Formyl-4-methoxyphenyl)boronic acid (309 mg, 1.71 mmol), 4-bromothiazole (250 mg, 1.52 mmol, prepared as described by J. Trybulski and H. J. Brabander, U.S. Pat. No. 4,990,520, 1991), and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mmol) were added to a mixture of water (3.5 mL), ethylene glycol dimethyl ether (3.5 mL), and sodium carbonate (805 mg, 7.6 mmol). The mixture was heated in an oil bath at 80° C. for 3 h, allowed to cool to 25° C., and partioned between ethyl acetate (40 mL) and water (20 mL). The aqueous layer was extracted with 2×40 mL of dichioromethane and the combined organic layers dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate in hexane to give 182 mg (55% yield) of the title compound as a white solid. NMR (400 MHz, CDCl3): δ 10.51 (s, 1H), 8.88 (d, 1H, J=2 Hz), 8.32 (d, 1H, J=2 Hz), 8.24 (dd, 1H, J=9,2 Hz), 7.54 (d, 1H, J=2 Hz), 7.09 (d, 1H, J=9 Hz), 3.99 (s, 3H). Mass spectrum (NH3 /CI): 220 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([NH2:36])=N)=[O:30].[OH2:37]>C(#N)C.[OH-].[Na+]>[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:29]([NH:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:37])=[O:30]
Reactant: O
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3C)cn2C)cc1C(=O)NCCC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc([N+](=O)[O-])nn3C)cn2C)cc1C(=O)NCCC(N)=O
Temperature: 60 °C

Procedure:
To a solution of 200 mg of 3-(1-methyl-4 (1-methyl-4-(1-methyl-3-nitropyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamidine hydrochloride (prepared as described in WO 96/05196) in 10 ml of acetonitrile and 10 ml of water, 2 ml of NaOH 1N were added. The solution was heated at 60° C. for 4 hours then the solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (methylene chloride/methanol: 10/1) affording 175 mg of 3-(1-methyl-4(1-methyl-4-(1-methyl-3-nitropyrazole-5-carboxamido)pyrrole-2-carboxamido)pyrrole-2-carboxamido)propionamide as a light yellow solid.
Reaction SMILES: N1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:16](=[O:19])[CH2:17]Br.C([OH:26])C>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:16](=[O:19])[CH2:17][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:6]1=[O:26]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCO
Reactant: C1=C(N2CCCC2)CCCC1
Product: O=C(CC1CCCCC1=O)c1ccc(Cl)c(Cl)c1

Procedure:
(0.19 mole) of 1-pyrrolidino-1-cyclohexene and 51.2 g. (0.19 mole) of 3,4-dichlorophenacyl bromide by the method described in Example 39a gave 32.6 g. (60%) of crystals, m.p. 78°-79° (from ethanol).
Reaction SMILES: [CH:1](/[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=C\C1C=CC=CC=1.C(Cl)Cl.C[OH:27]>>[CH:1]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)=[O:27]
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2)c2ccccc12
Reactant: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of (E)-methyl 4-styryl-1-naphthoate (Preparation 2, 1.31 g, 2.0 mmol) in 3:1 CH2Cl2/MeOH (40 mL) was cooled to −78° C. Sample was subjected to ozonylysis for 10 minutes until blue color was noted. Reaction was quenched with dimethyl sulfide (400 μL) and allowed to warm to room temperature. The residue was purified by chromatography on silica gel eluting from 100% heptane to 50:50 EtOAc:heptane to afford a solid (0.78 g, 80%). 1H NMR (CDCl3) δ ppm: 10.52 (1H), 9.28 (1H), 8.83 (1H), 8.22 (1H), 8.04 (1H), 7.79-7.70 (2H), 4.08 (3H).
Reaction SMILES: [Li].C[CH:3]1[CH2:9][CH2:8][CH:7]2[C:10](=[O:11])[C:4]1([CH3:12])[CH2:5][CH2:6]2.[CH:13](Br)([CH3:15])[CH3:14].[CH3:17]COCC>>[CH3:17][C:7]12[C:10]([CH:13]([CH3:15])[CH3:14])([OH:11])[C:4]([CH3:12])([CH2:5][CH2:6]1)[CH2:3][CH2:9][CH2:8]2
Reactant: CCOCC
Reactant: CC1CCC2CCC1(C)C2=O
Reactant: CC(C)Br
Agent: [Li]
Product: CC(C)C1(O)C2(C)CCCC1(C)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
10,5 g (1,5 mole) lithium (finelly divided) and 76 g (0,5 mole) dimethylbicyclo[3.2.1]octane-8-one (4) were added to 800 ml ether (absolute). Into this mixture a solution of 92,3 g (9,75 mole) isopropylbromide in 300 ml absolute ether was dropwise added at -10° C. within 4 h. After 1 h of stirring at 40° C. the mixture was hydrolysed and processed for isolation in usual manner. By distillation over a turning band column 46 g (47%) of 10 having a boiling point (1 mm) of 76° C. resulted from the raw product. IR: 3500/3600 cm-1 (O--H).--NMR (CCl4): δ=0,91, s (1-, 5-CH3), 1,15, d, J=7 Hz (CH3 --CH--CH3), 1,55 ppm, br. s (6-, 7-CH2).C13H24O (M=196,32)
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][NH2:25].C(N(CC)CC)C>C(O)C(C)C>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][NH:25][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Reactant: NCc1ccc(-c2ccccc2)c(O)c1
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(O)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Yield: 30.3 %

Procedure:
2-Chloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.21 g) and 3-hydroxy-4-phenylbenzylamine (0.19 g) were suspended in isobutanol (5 mL). To the mixture was added triethylamine (0.36 mL), and the mixture was stirred for reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: methanol/ethyl acetate=1/20) to give the title compound (0.1 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1[C:22]2[CH:21]=[CH:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH:17]([C:27]3[C:28](=[O:48])[NH:29][C:30](=[O:47])[N:31]([CH2:33][C:34]4[CH:35]=[C:36]([CH2:40][NH:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH:23]1[C:19]2[CH:20]=[CH:21][C:22]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]([C:27]3[C:28](=[O:48])[NH:29][C:30](=[O:47])[N:31]([CH2:33][C:34]4[CH:35]=[C:36]([CH2:40][N:41]([C:2]([O:4][CH2:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:3])[CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:37]=[CH:38][CH:39]=4)[CH:32]=3)[C:18]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)CNCc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl chloroformate (0.145 ml) was added to a solution of the product of step (iv) (0.44 g) and triethylamine (0.17 ml) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours. Further aliquots of benzyl chloroformate (0.1 ml) and triethylamine (0.3 ml) were added after 2 and 4 hours. The mixture was stirred overnight and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and purified by chromatography eluting with 60% ethyl acetate in isohexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[B-](F)(F)(F)[F:12].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.CC(O)=O>[Cl:1][C:2]1[C:3]2[C:10]([F:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1ncnc2[nH]ccc12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (F-1) (5.01 g, 32.6 mmol, 1 eq) and selectfluor (17.32 g, 48.9 mmol, 1.5 eq) are dissolved in a mixture of anhydrous acetonitrile (250 mL) and AcOH (50 mL). The resulting mixture is stirred at 70° C. under argon for 16 h. The mixture is concentrated in vacuo. The residue is dissolved in a mixture of DCM-ethyl acetate (v/v=1/1, 50 mL) and filtered through celite. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-0.7% MeOH-DCM) to afford the product, 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (F-2).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:14]([CH:15]([CH3:17])[CH3:16])[C:9]3=[N:8][C:7]=2[CH:25]=1.CCN(CC)CC.[C:37](Cl)([CH3:39])=[O:38].CCOC(C)=O>C(Cl)Cl>[C:37]([O:1][CH2:2][C:3]1[C:4]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:25]=1)(=[O:38])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a 50 mL round-bottomed flask containing (R)-tert-butyl 8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (236 mg, 0.558 mmol) in CH2Cl2 (5 mL) was added Et3N (169 mg, 1.67 mmol) and AcCl (87 mg, 1.12 mmol) under N2. The mixture was stirred at rt for 10 min. The reaction was quenched with water (20 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with water (25 mL) and brine, and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE: EtOAc 8:1-4:1 to give (R)-tert-butyl 8-(acetoxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (210 mg, 81.1% yield) as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][O:19][CH2:20][C:21]1([C:26]#[N:27])[CH2:24][C:23](=O)[CH2:22]1>O1CCCC1>[C:7]([CH:9]=[C:23]1[CH2:24][C:21]([CH2:20][O:19][CH3:18])([C:26]#[N:27])[CH2:22]1)#[N:8]
Reactant: COCC1(C#N)CC(=O)C1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1(C#N)CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (2.25 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (0.381 mL, 0.00236 mol) in tetrahydrofuran (4 mL, 0.05 mol). The reaction was warmed to rt and then cooled to 0° C. again. To the reaction mixture was added a solution of 1-(methoxymethyl)-3-oxocyclobutanecarbonitrile (0.298 g, 0.00214 mol) in tetrahydrofuran (2 mL, 0.02 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was used directly in next step. LCMS calculated for C9H11N2O(M+H)+:163.1; Found: 163.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]([OH:13])=O)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:39]1([CH2:45][C:46]2[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=2)[O:49][CH2:50][CH2:51][CH2:52][NH2:53])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[N:39]1([CH2:45][C:46]2[CH:47]=[C:48]([CH:54]=[CH:55][CH:56]=2)[O:49][CH2:50][CH2:51][CH2:52][NH:53][C:11](=[O:13])[CH2:10][S:9][CH2:8][CH2:7][NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CCOC(=O)NCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)NCCSCC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
There was dissolved 2.5 g (0.012 mol) of 2-[2-(ethoxycarbonylamino)ethylthio]acetic acid in 60 ml of dichloromethane and added 1. 8 5 g (0. 0 12 mol) of HOBt and 2.5 g (0.012 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 3.0 g (0.012 mol) of 3-[3-(piperidinomethyl)phenoxy]propylamine and the mixture was stirred for 18 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 5% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform: methanol =5 : 1) to give 4.23 g of the titled compound as oily matter.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>>[ClH:24].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[N:4]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Product: Cl
Yield: 89.6 %

Procedure:
Prepare according to Example 69 starting with N-Methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.91 mmol) and 4-fluorobenzoyl chloride (160 μL, 1.36 mmol) to yield 309 mg (90%) of the title compound: mass spectrum (ion spray): m/z=343.3 (M+1); Analysis calc'd for C19H24N4OFCl.0.6H2O: C, 58.56; H, 6.52; N, 14.38. Found: C, 58.31; H, 6.37; N, 14.39; mp 250–2° C.