Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.[Cl-].[Li+]>C(#N)C.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>[C:31]([C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1)(=[O:33])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (0.1 g, 0.27 mmol), tributyl-(1-ethoxy-vinyl)-stannane (0.091 ml, 0.27 mmol, 1 equiv), lithium chloride (0.034 g, 0.81 mmol, 3 equiv) in acetonitrile (4 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.031 g, 27.2 μmol, 0.1 equiv). The reaction mixture was degassed by bubbling through N2, heated in the microwave at 150° C. for 20 min and filtered through a glass microfibre filter. To the filtrate was added 2N HCl (3 ml) and the mixture stirred vigorously for 2 h at room temperature, neutralised with saturated aqueous NaHCO3, extracted with CH2Cl2, the organics combined dried (MgSO4) and the solvent removed in vacuo. The residue was purified by preparative LC-MS to give the desired product as a yellow solid. MS: [M+H]+ 377
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH2:30]([N:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([N:32]([CH2:36][CH3:37])[C:33]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:34])[CH3:31]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 470.6 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC([O-])(C)C.[K+].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>CS(C)=O.O>[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of (3-carboxypropy)triphenylphosphonium bromide (25 g, 58.3 mmol) in DMSO (53 mL) was added t-BuOK (12.4 g, 110.7 mmol). The mixture was stirred at rt for 20 min. Then a solution of 3-Bromo-benzaldehyde (9.3 g, 50.3 mmol) in DMSO (15 mL) was added dropwise. The reaction mixture was stirred at rt for 4 h. The mixture was poured in water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a solvent system of 5:1 petroleum ether/EtOAc to give 5-(3-Bromo-phenyl)-pent-4-enoic acid (4.8 g, 38%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.45 (s, 1H), 7.2-7.25 (m, 1H), 7.1-7.15 (m, 2H), 6.4-6.45 (m, 1H), 6.23-6.3 (m, 1H), 2.4-2.6 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:19][C:20]1([CH3:25])OCC[O:21]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH3:18].Cl>>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH3:18])[N:4]([CH2:3][C:2]([CH3:26])([CH3:1])[CH2:19][C:20](=[O:21])[CH3:25])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Agent: Cl
Product: CC(=O)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method of Example 11, 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine was hydrolyzed with aqueous hydrochloric acid to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one as a light brown solid after recrystallization from aqueous acetonitrile, mp 223-225° C.
Reaction SMILES: [F:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:15](Br)([CH3:17])[CH3:16].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>C1C=CC=CC=1>[F:1][C:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(C)Br
Reactant: CCOC(=O)C(F)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(F)(c1ccc(Cl)cc1)C(C)C
Temperature: 35 °C
Reaction time: 22 h
Yield: 61.4 %

Procedure:
A mixture of ethyl α-fluoro-4-chlorophenylacetate (2.3 g), isopropyl bromide (1.10 g), sodium hydride (0.56 g of a 50% mixture in oil), dry hexamethylphosphoramide (6 ml) and dry benzene (6 ml) was heated with stirring at a temperature of 35° C. under nitrogen for a period of 22 hours. The reaction mixture was poured into ice-water and the aqueous mixture extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and solvent removed by distillation under reduced pressure. The product was chromatographed over silica gel using 15% ethylene dichloride in petroleum ether as eluant to give ethyl α-fluoro-α-isopropyl-4-chlorophenylacetate (1.42 g; 62%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:42])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26]([CH2:28][C:29]4([OH:42])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CN(CC2(O)CCNCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate (0.090 g, 0.00016 mol) in dichloromethane (2 mL) was slowly added a 20% solution of trifluoroacetic acid in dichloromethane (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature and stirred for four hours. The solvent was removed under reduced pressure. An aqueous solution of 5 N sodium hydroxide was added to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-piperidinol (0.045 g, 0.000096 mol).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](CO)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]>O1CCCC1>[CH3:25][S:26]([C:29]1[CH:34]=[C:33]([CH:32]=[CH:31][CH:30]=1)[CH2:20][Cl:24])(=[O:28])=[O:27]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Triphenylphosphine (7.5 g, 29 mmol), carbon tetrachloride (11.0 mL, 114 mmol) and tetrahydrofuran (18 mL) were combined and stirred at room temperature for 10 minutes. A suspension of (3-methanesulfonyl-phenyl)-methanol (2.68 g, 14.3 mmol) in 18 mL tetrahydrofuran was added, then the reaction mixture was heated at 75° C. for 3 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (15%-35% ethyl acetate in hexanes) afforded 2.26 g (77%) of 3-(methanesulfonyl)benzyl chloride as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.01 (s, 1 H), 7.91 (d, J=7.8 Hz, 1 H), 7.81 (d, J=7.8 Hz, 1 H), 7.68 (t, J=7.8 Hz, 1 H), 4.90 (s, 2 H), 3.24 (s, 3 H). HRMS (EI+) cald. for C8H9ClO2S [M+] 204.0012, obsd. 204.0012.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]1[C:9](=[O:10])[NH:8][CH2:7][CH2:6][NH:5]1.[Cl:11][CH:12]([Cl:16])[C:13](Cl)=[O:14]>O.C(Cl)Cl>[Cl:11][CH:12]([Cl:16])[C:13]([N:5]1[CH2:6][CH2:7][NH:8][C:9](=[O:10])[CH:4]1[CH3:3])=[O:14]
Reactant: CC1NCCNC1=O
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1C(=O)NCCN1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
A solution of 8 g (0.2 mole) of sodium hydroxide in 15 ml of water was added to a solution of 20 g (0.18 mole) of 2-methyl-piperazin-3-one in 150 ml of methylene chloride. 26.6 g (0.18 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred at 25° C. for 10 hours and the precipitated crude product was filtered off with suction, washed with water and recrystallized from a 2:1 mixture of isopropanol and H2O to give 14.4 g (36% of theory) of 1-dichloroacetyl-2-methyl-3-oxo-piperazine of melting point 167°-168° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:4]([O:6][CH3:7])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:8]1([C@H:3]([N:2]=[C:14]=[O:16])[C:4]([O:6][CH3:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@@H](N)C1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 215.8 %

Procedure:
A suspension of methyl (25)-amino(cyclopentyl)acetate hydrochloride (3.21 g, 16.57 mmol) in DCM (69 mL) and saturated NaHCO3(aq.) (132 mL) was cooled to 0° C. and treated with triphosgene (2.21 g, 7.46 mmol). The mixture was stirred at 0° C. for 3 hours, then warmed to 20° C. and diluted with DCM. The layers were separated, and the aqueous phase was re-extracted with DCM. The combined organic phases were washed with brine and dried over Na2SO4. Filtration and removal of the volatiles afforded the title compound (2.95 g, 97%) as an oily solid that was used directly in subsequent steps. 1H NMR (400 MHz, DMSO-d6) δ 4.36 (d, J=4.8 Hz, 1H), 3.73 (s, 1H), 2.35-2.24 (m, 1H), 1.76-1.24 (m, 8H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([NH:22][NH2:23])=[N:19][C:18]=3[CH3:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:25][C:26](=O)[CH2:27][C:28](=O)[CH3:29]>CC(O)=O>[CH3:25][C:26]1[CH:27]=[C:28]([CH3:29])[N:22]([C:20]2[S:21][C:17]([C:13]3[N:8]4[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]4=[N:15][C:14]=3[CH3:16])=[C:18]([CH3:24])[N:19]=2)[N:23]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(NN)nc3C)c(C)nc12
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-n4nc(C)cc4C)nc3C)c(C)nc12
Temperature: 100 °C
Yield: 70.4 %

Procedure:
28 mg of {5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-hydrazine (0.08 mmol) and 80 mg of 2,4-pentanedione (0.8 mmol) are dissolved in 1.0 ml of AcOH and heated at 100° C. for 2 h. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 23 mg of the title compound. Yield 70%: mass spectrum (m/e): 409 (M+1). 6.72 (s, 1H), 6.03 (s, 1H), 3.36 (m, J=7.1, 14.1 Hz, 1H), 2.75 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 1.87 (m, 4H), 0.91 (t, J=7.5 Hz, 6H).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].C(=O)(O)[O-].[Na+].Cl.[C:30]1([NH:36][C:37](=[O:40])[NH:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:39][NH:38][C:37]([NH:36][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:40])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: NNC(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(C=NNC(=O)Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) in methanol (5 ml) were added sodium bicarbonate (27 mg) and 4-phenylsemicarbazide hydrochloride (59 mg). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (3:1, v/v) to afford 6,9-dihydroxy-4-(4-phenylsemicarbazonomethyl)-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (64 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2([C:35](O)=[O:36])[CH2:34][CH2:33]2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:35]([C:32]2([N:29]3[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]3)[CH2:33][CH2:34]2)=[O:36])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC1CCN(C2(C(=O)O)CC2)CC1
Agent: Cl
Product: CC1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Yield: 39 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-(4-methylpiperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16I carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(4-methylpiperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as an off-white solid (39%). MS ISP (m/e): 519.2 (100) [(M+H)]+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41](C=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56](OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:56][N:50]6[CH2:51][CH2:52][NH:53][CH2:54][CH2:55]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 19 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL), 1,1-dimethylethyl 1-piperazinecarboxylate (44.6 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a beige colored solid [21 mg (19%)]. LC-MS m/z 729.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-fluorobenzeneboronic acid. The title compound was obtained in 93% yield as yellow foam. MS (m/e): 500.2 (MH+, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][NH2:6].[CH:7]1[N:12]=[C:11](Cl)[C:10]2[N:14]=[CH:15][N:16]([C@@H:17]3[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]3[OH:25])[C:9]=2[N:8]=1.C(N(CC)CC)C>O1CCOCC1>[CH3:2][O:3][CH2:4][CH2:5][NH:6][C:11]1[C:10]2[N:14]=[CH:15][N:16]([C:9]=2[N:8]=[CH:7][N:12]=1)[C@@H:17]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@H:18]1[OH:25]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 70.3 %

Procedure:
The title compound was prepared by the procedure described in example 7 by reacting 2-methoxyethylamine hydrochloride (0.27 g, 3.6 mmol) with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-6-chloro-9H-purine)(1.0 g, 3.5 mmol) in dioxan (30 ml) at room temperature for 72 h with triethylamine (1.04 ml, 7.5 mmol) present. The reaction mixture was filtered and evaporated and the resultant residue was recrystallised from methanol (100 ml) to provide the title compound (0.80 g, 82%) as a solid, mp 151°-152° C., 1H NMR (DMSO-d6)δ 3.26 (3H, s, --CH3), 3.50-3.58 (3H, m, H-5'a and --CH2 --), 3.60-3.70 (3H, m, H-5'b, and --CH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, dd, H-3'), 4.60 (1H, dd, H-2') 5.20, 5.45 (2H, 2d, 2'- and 3'-OH), 5.42 (1H, t, 5'-OH) 5.87 (1H, d, H-1'), 7.80 (1H, br s, --NH) 8.22, 8.35 (2H, 2s, H-2 and H-8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH:30][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)N[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 16 h
Yield: 38.3 %

Procedure:
In a dry flask (3R,4S)-3-amino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (77 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2.5 mL) and triethylamine (20 μL, 0.143 mmol) and 3-acetylphenylisocyanate (50 μL, 0.36 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse-phase HPLC (10-90% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (40 mg, 38%). 1H NMR (300 MHz, CDCl3), δ: 7.98 (d, J=8, 1H), 7.83 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 7.56 (m, 1H), 7.46 (m, 1H), 7.01 (m, 2H), 6.87 (m, 1H), 3.09 (m, 1H), 2.51-2.77 (m, 7H), 2.42 (m, 1H), 1.23-1.78 (m, 11H), 1.42 (s, 9H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3142.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30])=O)C1C=CC=CC=1.Br>C(OCC)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Agent: Br
Solvent: CCOCC
Product: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0 g) and hydrobromic acid (45% in acetic acid; 6.2 ml) was stirred for 1 hour at room temperature under a nitrogen atmosphere. The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and it was stirred at 0° C. for 45 minutes. The white precipitate was collected by filtration, washed with cold diethyl ether (4×30 ml) and then dissolved in a mixture of water (30 ml) and 2N sodium hydroxide (15 ml). The basic aqueous phase was extracted with ethyl acetate (3×70 ml) and the combined organic solutions were washed with brine (1×30 ml), dried (Na2SO4) and concentrated. Flash chromatography of the remaining pale red oil (silica gel, dichloromethane-methanol, 94:6) gave the title compound (1.6 g) as a waxy solid; δH (250 MHz, CDCl3) 7.53-7.45 (2H, m), 7.28-7.20 (2H, m), 4.30 (1H, s), 3.39 (3H, s), 2.75 (1H, m), 2.04-1.03 (10H, m); m/z (CI) 272 (M+ +1).