Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.O1CCOCC1>[C:11]1([N:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][CH:1]2[CH2:6][CH2:5]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: O=C1NC2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1C2CCC(CC2)N1c1ccccc1
Temperature: 125 °C
Yield: 62.1 %

Procedure:
A mixture of 2-azabicyclo[2.2.2]octan-3-one (0.6 g, 4.8 mmol), iodo benzene (1.16 g, 5.76 mmol), Cs2CO3 (2.36 g, 7.20 mmol), xantphos (0.22 g, 0.38 mmol) and 1,4-dioxane (30 ml) was charged in a sealed tube and degassed with argon gas for 15 min. Tetrakis(triphenylphosphine)palladium (0) (0.22 g, 0.19 mmol) was added and degassed for another 15 min and heated at 125° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography over neutral alumina using 0.5% MeOH in CHCl3 as eluent to afford 600 mg (62%) of 2-phenyl-2-aza-bicyclo[2.2.2]octan-3-one as pale yellow solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[CH3:16].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:22]=[O:23])=[C:8]1[CH3:16]
Reactant: Cc1cc2ccccc2n1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of POCl3 (7.0 mL, 75 mmole) in DMF (100 mL) was stirred for 5 minutes at 0° C., then 1,2-dimethylindole (10.0 g, 69 mmole) was added in one portion. The reaction was allowed to warm to RT and stirred for 4 h. The thick slurry was poured into ice water (300 mL) and the flask was rinsed with additional water (50 mL). The aqueous mixture was basified with a solution of NaOH (13.2 g, 330 mmole) in H2O (50 mL), and the thick suspension was filtered to collect the solid. This was washed with water and dried under vacuum to give the title compound (11.59 g, 97%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.07 (s,1H), 8.09 (d, J=7.9 Hz,1H), 7.54 (d, J=7.6 Hz, 1H), 7.21 (dt, 2H), 3.73 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](/[CH:12]=[CH:13]/[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:5]=1)(=O)[CH3:2].[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH:1]([C:4]2[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](/[CH:12]=[CH:13]/[CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:5]=2)[CH3:2])[CH2:22][CH2:21]1
Reactant: COC(=O)NC/C=C/c1cc(C(C)=O)cc(OC)n1
Reactant: NC1CC1
Product: COC(=O)NC/C=C/c1cc(C(C)NC2CC2)cc(OC)n1

Procedure:
Methyl [(2E)-3-(4-acetyl-6-methoxypyridin-2-yl)prop-2-en-1-yl]carbamate and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give methyl ((2E)-3-{4-[1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}prop-2-en-1-yl)carbamate [Ex(298-2)] as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:32])([CH3:3])[CH3:2]>Cl.CO>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:32])([CH3:3])[CH3:2]
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Agent: Cl
Solvent: CO
Product: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C

Procedure:
A solution of tert-butyl 4-({[(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate (15.0 g, 32.6 mmol, step 3) in 10% hydrogen chloride in methanol was stirred at room temperature for 12 h. Then, the solvent was removed in vacuo to give the title compound as hydrochloride salt. This salt was poured onto saturated aqueous sodium hydrogen carbonate solution (500 mL), and the aqueous layer was extracted with dichloromethane (500 mL×5). The combined organic layer was dried over magnesium sulfate and sodium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl silica gel eluting with methanol/dichloromethane (1:10) to give 10.3 g (92%) of the title compound as a pale yellow amorphous.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][N:4]([CH2:3][CH2:2][O:1][C:27]1[CH:28]=[CH:29][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-(trifluoromethyl)phenol: MS (El) m/z 456 (M+, 4%), 295 ([M-C7H4F3O]+, 9%), 281 (100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:20]C)[CH2:4][C:5]([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)[CH2:6][NH2:7])C.CNCCO>>[CH3:20][N:3]([CH3:1])[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][NH2:7]
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Agent: CNCCO
Product: CN(C)CC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using 2-(methylamino)ethanol. LC/MS (M+H)+: 255. HPLC ret. time (Condition B): 1.300 min. 1H NMR (400 MHz, CDCl3) δ ppm: 1.98 (6H, s), 3.12 (2H, s), 3.54 (2H, s), 7.19-7.22 (6H, m), 7.28-7.31 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[OH:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 3,4-dihydroxybenzoate (10.0 g, 59.4 mmol) in acetone (400 mL) was added potassium carbonate (8.21 g, 59.5 mmol). The mixture was stirred at room temperature (rt) for 30 minutes (min). To the resulting mixture was added benzyl bromide (7 mL, 59.4 mmol) in acetone (200 mL) dropwise over 2 hours (h) and stirring was continued for 48 h. Acetone was removed under vacuum and the resulting residue was partitioned between water (100 mL) and ethyl acetate (3×25 mL). The organic layer was dried over NaSO4, concentrated under vacuum and the resulting crude material purified via column chromatography to afford the product 30 (8.00 g, 52%). 1H NMR (300 MHz, CDCl3): δ 7.70 (m, 2H), 7.50 (m, 5H), 6.95 (m, 1H), 5.70 (s, 1H), 5.10 (s, 2H), 3.93 (s, 3H). MS (M+H): 259.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.C(Cl)Cl>[O:18]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C@H:8]3[CH2:9][C@H:7]3[CH2:6][N:19]=[N+:20]=[N-:21])[C:15]=2[CH2:16][CH2:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A solution of (cis)-[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl methane sulfonate (5.0 mmol) and sodium azide (10.0 mmol) in 100 mL of dimethylformamide was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and stirred overnight. The crude reaction mixture was then diluted with CH2Cl2 (100×mL) and washed sequentially with water (3×100 mL) and then brine (1×100 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.1 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1cccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cccc(CO)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
25.66 g (166.47 mmol) of 2-fluoro-3-methoxybenzaldehyde is dissolved in 140 ml of ethanol and mixed in portions at 0° C. with 3.15 g (83.35 mmol) of sodium borohydride. After one hour of stirring at room temperature, the reaction mixture is mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts are shaken with water and brine, dried, the desiccant is suctioned off, and the solvent is spun off. The remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 24.79 g (95.3%) of the desired compound is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:23])[C:8]3([CH2:22]C[CH2:20][CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:25][C:26]1[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:42][CH3:43].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:22][CH2:20][CH2:19][CH2:18]3)[C:7](=[O:23])[N:6]([CH3:24])[C:5]3[CH:4]=[N:3][C:2]([NH:25][C:26]4[CH:41]=[CH:40][C:29]([C:30]([NH:32][CH:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)=[O:31])=[CH:28][C:27]=4[O:42][CH3:43])=[N:12][C:11]2=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN1C(=O)C2(CCCCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCCC1)C(=O)N2C

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclohexane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 255; 80 mg, 0.24 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 63 mg, 0.24 mmol) and p-toluenesulphonic acid monohydrate (114 mg, 0.60 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were evaporated and the residue purified on a silica column (2% 7N ammonia in methanol/DCM) to give the title compound as a white solid. (70 mg, 52%)
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:25])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:25])=[O:5]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)Oc1cccc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (278 mg, 1.16 mmol) produced in Example C70(iii) in tetrahydrofuran (2.5 mL) were added N,N-dimethylformamide (25 μL) and oxalyl chloride (125 μL, 1.46 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethoxy)benzoyl chloride as a pale-yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.O.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[OH-].[Na+]>C(OCC)(=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCC(O)C1

Procedure:
To a 1-liter 3-necked round bottom flask, equipped with mechanical stirrer and two addition funnels, is added 30 g (0.2966 mole) of 3-hydroxypiperidine and 300 ml of water. The resulting solution is stirred and is cooled to ~0° C. with ice-salt bath. At this point benzyl chloroformate (51 ml, 0.356 mole) is added dropwise from one funnel and the 2N NaOH (178 ml) from the other funnel (at a slightly faster rate) during which time the temp. is maintained at ~0° C. After addition is complete, stir cold for 2 hr, then overnight at ambient temp. After this time an oily residue separates from the reaction solution, ethyl acetate is added (250 ml) to the reaction and is stirred for 1/2 hr. The phases are separated and the aqueous phase is extracted once more with EtOAc (250 ml). All organic phases are combined, washed with 1×150 ml saturated NaHCO3, 1×150 ml H20, 1×150 ml 10% HCl, 1×150 ml H20 and dried over MgSO4. The mixture is filtered and concentrated on roto-evap under reduced pressure to yield a viscous oil which is stored under vacuum to remove any residual solvents as 3-Hydroxy-1-piperidine-carboxylic Acid, Phenylmethyl Ester, a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]2[C:10]3[N:11]([CH:17]=[CH:18][N:19]=3)[N:12]=[C:13]([C:15]#[N:16])[CH:14]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(OCC)(=O)C>[NH2:16][CH2:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]2[N:11]([CH:17]=[CH:18][N:19]=2)[N:12]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(C#N)nn3ccnc23)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(CN)nn3ccnc23)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a 25 ml round bottom flask was added 8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-6-carbonitrile (0.62 g, 1.7 mmol) from (1a) and toluene (3.4 ml, 0.5 M) and the solution cooled to −5° C. To this was added dropwise, a 1.0 M solution of diisobutylaluminum hydride [DIBAL] in toluene (3.5 ml, 3.5 mmol) over a period of 10 minutes. The reaction was stirred at −5° C. for 1 hour and then warmed to room temperature and allowed to stir for an additional 2 hours. Dilute 1N HCl and ethyl acetate were added and the layers separated. The acidic aqueous layer was extracted 1 additional time with ethyl acetate and then basified with a 50% NaOH solution. The aqueous layer was extracted 2× with ethyl acetate and the combined organics were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo to provide crude 6-(aminomethyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.44 g) which was used as such in the subsequent step. m/z=(360, M+1).
Reaction SMILES: [N:1]1(C2CCCCCCC2)[CH2:8]CCCCCN1.Cl[C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.[C-]#N.[Na+]>CS(C)=O.O>[CH:24]1([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:8]#[N:1])[N:23]=2)[CH2:26][CH2:25]1
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Reactant: Clc1nccc(C2CC2)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 803.7 %

Procedure:
To a solution of diazabicyclooctane (0.013 g, 0.12 mmol) in dimethylsulfoxide and water was added a solution of 2-chloro-4-cyclopropylpyrimidine (0.2 g, 1.2 mmol) in dimethylsulfoxide followed by sodium cyanide (0.066 g, 1.3 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was then poured into water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified via flash chromatography (10% ethyl acetate in petroleum ether) to afford 4-cyclopropylpyrimidine-2-carbonitrile (0.14 g, 77%). MS (ES+APCI) (M+H) 146.1; LCMS retention time 3.054 min (Method J).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N#N.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2cc[nH]c2c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
A 500 mL 3-neck round-bottom flask was charged with 6-bromo-1H-indole (5.95 g, 30.4 mmol) and THF (60 ml) to give a deep red solution. The flask was fitted with a N2 sweep, then cooled in an ice bath until an internal temperature of 2 to 5° C. was reached. At this time, sodium hydride (1.457 g, 36.4 mmol) was added portion-wise over 2 to 3 minutes such that the internal temperature was maintained below 10° C. The resulting mixture was stirred at this temperature for 20 minutes before triisopropylsilyl chloride (8.12 ml, 37.9 mmol) was added over 1 min. The cooling bath was removed, and the mixture was stirred for 15 min at room temperature. The volatiles were evaporated in vacuo, and the residue was taken up in saturated aq. sodium bicarbonate solution (150 mL). The mixture was extracted with DCM (2×250 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 10% EtOAc/Heptane) to give 6-bromo-1-(triisopropylsilyl)-1H-indole (7.33 g, 20.80 mmol, 68.5% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ=8.22 (td, J=0.8, 1.5 Hz, 1 H), 7.85-7.70 (m, 2 H), 7.58 (d, J=3.1 Hz, 1 H), 6.78 (dd, J=1.0, 3.1 Hz, 1 H), 1.84-1.65 (m, 3 H), 1.17 (d, J=7.5 Hz, 18 H).
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:36])C(=O)C1>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:36][C:9]1[N:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:11]2[C:12]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[C:13]=3[N:14]=[CH:15][C:10]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CCCCC4)n23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C4CCCCC4)n23)cc1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g, 0.672 mmol) in THF (10 mL) at about 0° C. was added a solution of NBS (0.12 g, 0.672 mmol) in THF (2 mL). After about 30 min, the mixture was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was separated, concentrated in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc:DCM:heptane (1:1:2) to provide 3-Bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.27 g, 83%). LC/MS (Table 2, Method a) Rt=3.12 min; MS m/z 473 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19])[N:10]=[C:9]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:8]=2[C:7]1=[O:32]>C(O)(C(F)(F)F)=O>[F:15][C:12]1[C:13]2[CH2:14][NH:6][C:7](=[O:32])[C:8]=2[C:9]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)=[N:10][C:11]=1[NH:16][C@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([NH:20][CH3:21])=[O:19]
Reactant: CNC(=O)[C@@H](CC(C)C)Nc1nc(-c2cnn(C)c2)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](CC(C)C)Nc1nc(-c2cnn(C)c2)c2c(c1F)CNC2=O

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-N,4-dimethylpentanamide (38 mg, 0.072 mmol) in TFA (5 mL) was heated to 65° C. for 4 h. After removal of the solvent, the residue was diluted in MeOH (2 mL) and was purified by preparative HPLC eluting with water (0.05% TFA) and ACN (25-30%, gradient, 0.035% TFA). The collected fractions were stripped to dryness to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.84-0.93 (m, 6 H), 1.63-1.81 (m, 2 H), 2.57 (d, J=4.39 Hz, 3 H), 3.88 (s, 3 H), 4.04-4.19 (m, 2 H), 4.36 (s, 2 H), 6.99 (d, J=7.32 Hz, 1 H), 7.61-7.76 (m, 1 H), 7.93 (d, J=4.39 Hz, 1 H), 8.30 (s, 1 H), 8.83 (s, 1 H). [M+H] calc'd for C18H23FN6O2, 375; found, 375.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])([CH3:4])(C)[CH3:2].Br[CH:31]1CCC[CH2:32]1>C(O)(C(F)(F)F)=O>[CH:1]1([N:5]2[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:6]2(=[O:29])=[O:28])[CH2:2][CH2:32][CH2:31][CH2:4]1
Reactant: BrC1CCCC1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1C1CCCC1
Temperature: 120 °C
Yield: 35.6 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.364 mmol) was dissolved in TFA (3 mL) and heated in a microwave reactor at 120° C. for 20 mins. TFA was removed in vacuo and the residue was coevaporated with DCM two times. The residue was dissolved in MeCN (3 mL) and it was mixed with bromocyclopentan (0.162 g, 1.09 mmol) and TEA (0.110 g, 1.09 mmol) and the mixture was heated in a microwave reactor at 120° C. for 20 mins, at 160° C. for 85 mins and at 170° C. for 20 mins. The residue was purified by column chromatography (Horizons Biotage) using a 90:10 mixture of hexane and EtOAc as eluant, to give the title compound (0.055 g, 36%); 1H NMR (500 MHz, CDCl3): δ 7.53-7.48 (m, 2H), 7.46-7.41 (m, 3H), 7.31-7.25 (m 2H), 7.22-7.18 (m, 1H), 7.10-7.06 (m, 2H), 5.30-5.24 (br m, 1H), 4.41-4.35 (m, 1H), 2.90-2.83 (m 2H), 2.49-2.43 (m 2H), 2.25-2.17 (m 2H), 2.18-2.09 (m 2H), 1.97-1.87 (m 2H), 1.69-1.60 (m 2H), 1.44-1.36 (m 4H); 13C NMR (125 MHz, CDCl3): δ 159.0, 141.8, 135.6, 131.8, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 106.7, 55.2, 44.2, 35.4, 29.5, 29.2, 28.3, 24.3.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:9]=2)[N:4]([CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1>>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:9]=3)[N:4]([CH3:16])[N:3]=2)=[CH:26][CH:27]=1
Reactant: COCCNc1ncc2c(Cl)nn(C)c2n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: COCCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-methoxy-ethyl)-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound [3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-methoxy-ethyl)-amine; LC/MS (m/e)=299.0 (MH+), Rt=1.42 min.