Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][CH2:15][C:16]([OH:18])=O.[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=1>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:16](=[O:18])[CH2:15][NH:14][C:25](=[O:26])[C:24]3[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:30])=[CH:29][CH:28]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: NCC(=O)O
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Product: CN(C)c1ccc(C(=O)NCC(=O)Nc2ccc(N3CCOCC3)cc2)cc1

Procedure:
Compound 467 was prepared according to the procedure described in Scheme IV from 4-morpholinoaniline, glycine, and 4-dimethylaminobenzoate. 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.74 (s, J=9 Hz, 2H), 6.82 (t, J=5.5 Hz, 1H), 6.68 (d, J=9 Hz, 2H), 4.25 (d, J=5.5 Hz, 2H), 3.85 (m, 4H), 3.11 (m, 4H), 3.04 (s, 6H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]12[O:20][C:17]([CH3:21])([CH:18]=[CH:19]1)[CH2:16][CH:15]([OH:22])[CH2:14]2.Cl>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:22][CH:15]2[CH2:16][C:17]3([CH3:21])[O:20][C:13]([CH3:12])([CH:19]=[CH:18]3)[CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC12C=CC(C)(CC(O)C1)O2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CC3(C)C=CC(C)(C2)O3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
para-Toluenesulfonyl chloride (15.5 g, ) was added portionwise over 20 minutes to an ice-cold stirred solution of 1,5-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-ol (10.0 g, ) in dry pyridine (75 ml). The reaction mixture was stirred at 0° C. for 0.5 hour, allowed to stand in a refrigerator (0° C.) for 72 hours, and poured into a mixture of 80 ml concentrated hydrochloric acid and 100 g of ice. After stirring for 10 minutes, the precipitated solid was filtered. The collected solid dissolved methylene chloride was dried (MgSO4), filtered and concentrated to give 17.6 g (88%) of the desired product, m.p. 75°-77° C., as a 70:30 mixture of epimers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([NH2:14])[CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].[I-].[Na+].[C:34]([N:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>CN(C)C=O>[C:34]([N:37]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:14][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[NH:13][N:12]=2)=[O:30])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: CC(=O)N1CCCNCC1
Reactant: O=C(Cl)CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(NC(=O)CCCCN3CCCN(C(C)=O)CC3)n[nH]2)cc1
Temperature: -5 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 5-(4-methoxyphenyl)-1H-pyrazol-3-ylamine (12 g, 62.8 mmol) and N,N-diisopropylethylamine (10.96 mL, 62.8 mmol) in dry N,N-dimethylformamide (150 mL) at −10° C. was added a solution of 5-bromovaleryl chloride (8.4 mL, 62.8 mmol) in dry N,N-dimethylformamide (50 mL) slowly (˜40 min) and the reaction mixture was allowed to stir at −10 to 0° C. for 8 hrs. Sodium iodide (9.44 g, 62.8 mmol) was added at 0° C. and followed by N-acetylhomopiperazine (8.24 mL, 62.8 mmol) and N,N-diisopropylethylamine (10.96 mL, 62.8 mmol) and the reaction mixture was allowed to stir at 50° C. for 18 hrs. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (500 mL) and saturated aqueous sodium bicarbonate (500 mL) and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, dried over sodium sulfate, and the solvent was removed in vacuo to provide 25.8 g (99%) of 5-(4-acetyl-1,4-diazepan-1-yl)-N-(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)pentanamide as a thick light yellow oil (crude).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(-c2ncc(Br)cc2N)cc1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(4-methoxyphenyl)pyridin-3-amine (0.14 g, 0.52 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.043 g, 1.07 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.18 g, 0.62 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was purified on silica gel (50-100% EtOAc in hexanes) to afford a mostly N-(5-bromo-2-(4-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=533.0 (M+1).
Reaction SMILES: C(N)C=CC#CCC.[S:9]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22]Br)=[CH:10]1.[ClH:27].[CH2:28]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:29].Cl>>[ClH:27].[CH2:28]([N:30]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([CH2:18][O:17][CH2:16]/[CH:15]=[CH:14]/[C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)[CH:20]=1)[CH2:31]/[CH:32]=[CH:33]/[C:34]#[C:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH3:29]
Reactant: CCNC/C=C/C#CC(C)(C)C
Reactant: BrCc1cccc(COC/C=C/c2ccsc2)c1
Agent: CCC#CC=CCN
Agent: Cl
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(COC/C=C/c2ccsc2)c1

Procedure:
Compounds of Examples 2 to 7 were obtained by s performing the same reaction as in Example 1 except that the corresponding bromomethyl or chloromethyl derivatives and/or 2-hepten-4-ynylamine derivatives were used instead of the starting compounds, (E)-3-[3--(3-thienyl)-2-propenyloxymethyl]benzyl bromide and/or (E)- N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride, which were used in the above-mentioned reaction. ( When the reaction product was a free base, the hydrochloride producing step in the after-treatment was not included.)
Reaction SMILES: C(O)=O.[CH3:4][O:5][C:6]1[CH:53]=[CH:52][CH:51]=[CH:50][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][C:35]2[O:36][C:37]3[C:43]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])=[CH:42][CH:41]=[CH:40][C:38]=3[CH:39]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C>CC(C)=O.[Pd]>[CH3:4][O:5][C:6]1[CH:53]=[CH:52][CH:51]=[CH:50][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]2[O:33][CH2:34][CH:35]2[CH2:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[C:37]=3[O:36]2)=[CH:16][CH:15]=1
Reactant: COCCCOc1cccc2cc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)oc12
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCCCOc1cccc2c1OC(COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc3ccccc3OC)cc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.035 ml of formic acid are added to the suspension of 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[7-(3-methoxypropoxy)benzofuran-2-ylmethoxy]piperidine-1-carboxylate (Example 7a) and 0.20 g of 10% Pd/C in 3 ml of acetone. After 15 minutes, 0.16 ml of triethylamine is added in portions. The reaction mixture is stirred at room temperature over 20 hours and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=6.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][C@H:20]([OH:22])[CH2:19][C@H:18]4[CH:23]([CH3:25])[CH3:24])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36]I.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:36])[CH2:19][C@H:18]4[CH:23]([CH3:24])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C#N)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (71.4 mg, 0.145 mmol) in THF (0.483 mL) at 0° C. was added methyl iodide (31.1 μl, 0.498 mmol) followed by sodium hydride (7.65 mg, 0.319 mmol). The mixture was stirred for 3 hours at room temperature, quenched with ice, and diluted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C28H35ClN6O [M+H]+ 507. found 507.
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1>C(O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:1]#[N:2])=[CH:8][CH:9]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)c1ccc(CC#N)cc1
Temperature: 50 °C

Procedure:
A solution of 34.3 g. (0.700 mole) sodium cyanide in 40 ml. of water is warmed to 50°C. and a solution of α-bromo-4-pivaloyl toluene in 85 ml. ethanol is then added dropwise at such a rate as to maintain the temperature at 50°C. After the addition is complete, the mixture is refluxed for four hours. The excess ethanol is removed in vacuo and the resulting residue is treated with ether/water. The layers are separated and the ether is washed with cold 50% sulfuric acid, water and sodium bicarbonate; then the ether layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is distilled in vacuo to give 4-pivaloylphenyl acetonitrile (b.p. 143°-148°C/0.75 mm n22 =1.5244.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.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>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33,576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)palladium (0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:16][C:15](=[O:31])[C:14]=2[C:32]=1[CH3:33])=[O:8].N1(C(N)=O)CCC[CH2:35]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([C:28]([O:30][CH3:35])=[O:29])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:16][C:15](=[O:31])[C:14]=2[C:32]=1[CH3:33])=[O:8]
Reactant: Cc1c(NC(=O)Cc2cccs2)ccc2nc(N[C@@H](Cc3ccccc3)C(=O)O)oc(=O)c12
Reactant: NC(=O)N1CCCC1
Product: COC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(NC(=O)Cc3cccs3)c(C)c2c(=O)o1

Procedure:
N-[6-[[(2-thienylmethyl)carbonyl]amino]-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl]-L-phenylalanine, pyrrolidineamide;
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.Cl.CCCCCC.C(OCC)C.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:38]([C:37]([F:42])([F:36])[CH3:41])=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)c1oc2c(ccc3[nH]c(C(C)(F)F)nc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (168 mg, 0.511 mmol) is dissolved in 2,2-difluoropropionic acid (562 mg), dilute hydrochloric acid (2M, 0.1 ml) is added, and the mixture is heated at 110° C. for 4 h. The reaction mixture is cooled to room temperature, diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The ethyl acetate extracts are combined and washed with saturated sodium bicarbonate solution (2×40 ml) and saturated brine (40 ml). The organic layer is dried (MgSO4), treated with decolourising charcoal (50 mg), filtered and evaporated to give a colourless solid. This is sonicated with n-hexane/diethyl ether and filtered to give a cream-coloured powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9].[CH3:20][NH:21][CH3:22]>O1CCCC1.C(OCC)(=O)C.C(OCC)C>[CH3:20][N:21]([CH2:2][C:3]1[CH:4]=[C:5]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[F:9])[CH3:22]
Reactant: CNC
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(CCl)c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 70 °C
Yield: 58 %

Procedure:
Treat 5-(3-chloromethyl-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in PREPARATION 32), (100 mg, 0.37 mmol) with a 2.0 M solution of dimethylamine in tetrahydrofuran (3 mL) and heat at 70° C. in a sealed tube for 2 h. Cool to room temperature, dilute with ethyl acetate, and wash with an aqueous saturated solution of sodium bicarbonate and an aqueous saturated solution of sodium chloride. Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with a gradient from 50:50 hexanes:dichloromethane to 90:10 (50:50 hexanes:dichloromethane):methanol, to give a yellow oil. Dissolve the oil in diethyl ether and extract twice with 1 N hydrochloric acid. Combine the aqueous layers and make basic with a 1 N sodium hydroxide. Extract the resultant purple aqueous layer three times with ethyl acetate. Combine the organic extracts, wash with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate to an oil. Concentration of the oil from diethyl ether provides the title compound as a crystalline solid (60 mg, 58%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:26])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23](O)=[O:24])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>C(Cl)Cl>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:26])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[O:24])[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCc2cc(C(=O)N3CCCC3)ccc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[2-(4-cyclobutyl-piperazin-1-yl)-2-oxo-ethyl]-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid (179 mg, 0.5 mmol) and pyrrolidine (71 mg, 1.0 mmol, 2.0 eq.) in DCM (5.0 ml) are added BOP (265 mg, 0.6 mmol, 1.2 eq.) and TEA (101 mg, 1 mmol, 2.0 eq.). The mixture is stirred at rt for 2 hr. Water (5.0 ml) is added to quench the reaction, and the organic layer is collected, dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.23-7.30 (2H, m), 7.01 (1H, d), 3.69 (2H, s), 3.55-3.66 (6H, m), 3.40 (2H, t), 3.35 (2H, s), 2.90 (2H, t), 2.78 (2H, t), 2.66 (1H, m), 2.26 (4H, m), 1.60-2.05 (10H, m); MS (+VE) m/z 411.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:9]=1)=[O:4].[ClH:24]>CCOC(C)=O.CO>[ClH:24].[ClH:24].[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn([C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cn([C@H]2CC[C@@H](N)CC2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(cis-4-tert-butoxycarbonylamino-cyclohexyl)-1H-[1,2,3]triazole-4-carboxylic acid methyl ester (2.53 g) in a mixture of 4.6 M HCl in EtOAc (25 ml) and MeOH (7.6 ml) was stirred 1 h at RT. The product precipitated and was collected by filtration. Yield: 1.36 g (58%). White powder. MS 225.0 (100, [M+H]+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([I:13])[C:4]=1[OH:14].[S:15]([CH2:19][CH2:20][OH:21])([OH:18])(=[O:17])=[O:16]>CC(O)C.CCOCC>[OH2:14].[S:15]([O:18][C:4]1[C:5]([I:13])=[CH:6][C:7]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:8][C:3]=1[CH2:2][NH2:1])([CH2:19][CH2:20][OH:21])(=[O:17])=[O:16].[NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:6]=[C:5]([I:13])[C:4]=1[O:14][S:15]([CH2:19][CH2:20][OH:21])(=[O:17])=[O:16]
Reactant: CC(C)(C)c1cc(I)c(O)c(CN)c1
Reactant: O=S(=O)(O)CCO
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)c1cc(I)c(OS(=O)(=O)CCO)c(CN)c1
Product: O

Procedure:
To a freshly-prepared solution of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (1.95 g., 6.5 millimole) in 2-propanol (20 ml.) is added 6.5N isethionic acid (1 ml., 6.5 milliequivalents) at room temperature. Upon diluting the resulting solution with ether (100 ml.), a white solid precipitates and is collected to 2.4 g., m.p. 160°-163° C. (dec.). Crystallization (twice) of this solid from 2-propanol-ether (2:5; 70 ml.) affords 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol isethionate-hemihydrate as colorless crystals (1.93 g.), m.p. 166°-167.5° C.(dec.).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[CH:19]=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([Mg]Br)([CH3:23])=[CH2:22]>C1COCC1>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:20])[C:21]([CH3:23])=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=Cc1nc2ccccn2c(=O)c1Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C(O)c1nc2ccccn2c(=O)c1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
A mixture of 500 mg (1.9 mmol) of the product from Step 6 (16) in 15 ml THF was cooled to −78° C. To the resulting solution was added dropwise 7.6 ml (3.8 mmol) of isopropenylmagnesium bromide and stirred at −78° C. for 2 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo yielding 613 mg (2.0 mmol, 106%) of 3-benzyl-2-(1-hydroxy-2-methylprop-2-enyl)-4H-pyrido [1,2-a]pyrimidin-4-one (17) as a pale yellow solid. This was purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(C)=O.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.CCO>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1cc(-c2ccccc2)nc(Cl)n1
Yield: 110.1 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine 8 (1 g, 5.45 mmol), phenylboronic acid (665 mg, 5.45 mmol), Pd(PPh3)4 (100 mg) and 2N aqueous Na2CO3 (4.1 mL) in 1:1 toluene:EtOH (15 mL) was heated in a microwave at 120° C. for 20 min. The reaction mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 2,4-dichloro-6-phenylpyrimidine as a solid (1.35 g), which was used without further purification in the next step.