Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:41])[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH:33]C(OC(C)(C)C)=O)=[CH:15][CH:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C>CO>[C:29]([N:25]1[C:26]2[C:21](=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:9](=[O:41])[O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][CH:15]=3)=[CH:28][CH:27]=2)[C@H:22]([NH2:33])[CH2:23][C@@H:24]1[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of phenylmethyl({4-[(2S,4R)-1-acetyl-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (for a preparation see intermediate 81) (1 g, 1.793 mmol) in methanol (50 mL) was added acetyl chloride (2 mL, 28.1 mmol). The resulting mixture was stirred at room temperature for 3 h then concentrated in vacuovacuo. The residue was loaded on a 50 g SCX column, then eluted with MeOH (3 column volume (CV)) followed by 2N NH3 in methanol (4 CV). The ammonia fractions were combined and evaporated in vacuovacuo. Purification of the residue obtained by flash chromatography on silica gel (40 g column, gradient:0 to 5% (2N NH3 in MeOH) in DCM) gave phenylmethyl ({4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (581 mg, 1.27 mmol, 71%) as a colourless oil which solidified on standing.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(Cl)Cl>[CH2:34]([NH:36][C:37]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
1-(2-Phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2. At four 15 min. increments, 10 μL (0.47 equiv), 5 μL (0.24 equiv), 2.1 μL (0.1 equiv) and 2.1 μL (0.1 equiv) of ethyisocyanate were added dropwise, respectfully. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2; dry loaded with silica gel, eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=1.64), 8.29 (1H, d, J=8.38), 8.20 (2H, dd, J=1-0.52, J=1.10), 7.97 (2H, m), 7.87 (1H, dd, J=1.71, J=1.71), 7.53 (4H, m), 7.24 (1H, d, J=5.26), 7.08 (1H, d, J=5.23), 4.38 (1H, t), 3.97 (2H, d, J=13.44), 3.28 (2H, m), 2.96 (2H, d, J=7.12), 2.79 (2H, t), 2.20 (1H, m), 1.80 (2H, d, J=10.60), 1.36 (2H, m); MS (ES+): m/z 506.07/507.08 (50/25) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH3:14]O>Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1
Reactant: CO
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Agent: Cl
Product: COC(=O)Cc1n[nH]c2ncccc12
Reaction time: 0.17 h

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridin-3-ylacetic acid (92 mg, 0.520 mmol) in methanol (4 mL) was bubbled in HCl gas for 2 minutes and the resulting solution was allowed to stand for a further 10 minutes. After this time, the solution was concentrated in vacuo and the resulting residue was partitioned between aqueous NaHCO3 (10 mL) and ethyl acetate (2×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo to provide the title compound. LRMS (M+1): 192.0.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2ccnn2)C1
Yield: 46 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 6, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (142 mg, 46%). Major isomer: 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.76 (d, 2H), 7.40 (d, 2H), 7.11-6.83 (m, 9H), 5.31 (d, 1H), 5.15 (d, 1H), 4.77 (d, 1H), 3.71 (t, 1H), 3.30 (t, 1H), 3.02-2.91 (m, 1H), 2.82 (dd, 1H), 2.71 (dd, 1H), 2.57 (dd, 1H), 2.33 (s, 3H), 1.78-1.68 (m, 1H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:14]1[C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:19][C:11]=2[S:10][C:9]1=[N:8][C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Yield: 75.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 616 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 880 mg of 3-benzyl-2,3-dihydro-2-[(4-nitrophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (75%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]2[C@:11]3([OH:31])[C@@H:16]([OH:17])[CH2:15][C@@H:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@:12]3([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[O:13][C:9]=2[CH:8]=1)=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:33]=[CH:32][C:10]2[C@:11]3([OH:31])[C@@H:16]([OH:17])[CH2:15][C@@H:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@:12]3([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:13][C:9]=2[CH:8]=1
Reactant: [N-]=[N+]=NCCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O
Agent: [Pd]
Solvent: CCO
Product: NCCOc1ccc2c(c1)O[C@@]1(c3ccc(Cl)cc3)[C@H](c3ccccc3)C[C@H](O)[C@@]21O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
210 mg (0.45 mmol) of (1S*,3S*,3aR*,8bS*)-6-(2-azidoethoxy)-3a-(4-chlorophenyl)-3-phenyl-2,3,3a,8b-tetrahydrocyclopenta[b]benzofuran-1,8b-(1H)-diol (Example 49A) are dissolved in 34 ml of ethanol. Addition of 56 mg of 10% palladium on activated carbon is followed by stirring at RT under hydrogen at atmospheric pressure for 15 minutes. The residue from filtration and concentration is filtered through silica gel 60. Toluene is used for washing, and a 1:1 dichloromethane/ethanol mixture is used for elution. Concentration results in 179 mg (90% of theory) of the product, which is finally purified by Method 23A.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][C:4]2=[C:3]([C:10]#[N:11])[CH:2]=1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:8][CH2:7][CH2:6][N:5]3[N:1]=[CH:2][C:3]([C:10]#[N:11])=[C:4]23)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cnn2c1NCCC2
Solvent: c1ccncc1
Product: N#Cc1cnn2c1N(C(c1ccccc1)(c1ccccc1)c1ccccc1)CCC2
Temperature: 65 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (6.9 g) in pyridine (70 ml) was added triphenylmethyl chloride (15.6 g), and the mixture was stirred at 65° C. for 4 hours. After evaporation of the solvent in vacuo, the residue was dissolved in chloroform, and the solution was washed with 10% aqueous citric acid solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give 4-triphenylmethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (16.2 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH3:22]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][O:19][CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)Sc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)c2ccccc2S1
Temperature: 25 °C

Procedure:
1.9 g of 4-tert-butoxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H1,4-benzothiazine are dissolved in 20 ml of tetrahydrofuran, and 1.5 g of a 20% potassium hydride suspension in oil are added at 0° C. 1.3 ml of methyl iodide are then added dropwise. The mixture is allowed to warm to room temperature and, when the reaction has ended, the mixture is poured onto water. After customary working up, the crude product is purified over 250 g of silica gel by means of FC (methylene chloride as the mobile phase): Rf (D)=0.45.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C@H:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:18][CH2:17][CH2:16][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([S:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:14]=1)[OH:19]
Reactant: N#CC[C@@H](O)c1cccc(SCC2CCCCC2)n1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCC[C@@H](O)c1cccc(SCC2CCCCC2)n1

Procedure:
Reduction of (R)-3-(6-((cyclohexylmethyl)thio)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 6 gave after flash chromatography purification (15%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 25 as a colorless oil. Yield (0.3 g, 43%); 1H NMR (400 MHz, CD3OD) δ 7.56 (t, J=7.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.75-4.72 (m, 1H), 3.04 (d, J=7.2 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.03-1.98 (m, 1H), 1.94-1.54 (m, 7H), 1.30-0.99 (m, 5H); RP-HPLC tR=9.63 min; ESI-MS m/z 281.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:19](=[O:20])[C:18]1[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=1[C:16]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:25]
Reactant: COCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Product: COCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.500 g, 1.37 mmol), 2-methoxyethylamine (0.118 g, 1.57 mmol), and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-methoxyethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.232 g, 38.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH3:13][NH2:14]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH3:13])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)Cl
Reactant: CN
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C(=O)NC
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-2-ethyl-benzoyl chloride (1.00 g, 4.04 mmol) in CH2Cl2 (20 mL) was added methylamine (0.70 mL, 40% solution in water, 8.08 mmol). The mixture was stirred for 3 hours, at which time the volatiles were removed in vacuo. The residue was dissolved in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a brown oil (0.857 g, 88%). 1H NMR (300 MHz, CDCl3): δ 1.21 (t, J=7.4 Hz, 3 H), 2.75 (q, J=7.5 Hz, 2 H), 2.97 (d, J=4.9 Hz, 3 H), 5.74 (s, 1 H), 7.17 (d, J=8.1 Hz, 1 H), 7.32 (d, J=8.1 Hz, 1 H), 7.39 (s, 1 H).
Reaction SMILES: [C:1]([CH:4]([S:9][CH2:10][C@@H:11]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2].C(=O)([O-])[O-].[Mg+2:33].[Ca]>>[Mg:33].[C:1]([CH:4]([S:9][CH2:10][C@@H:11]([C:22]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])[NH:12][C:13](=[O:21])[CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])[CH2:5][C:6]([OH:8])=[O:7])([OH:3])=[O:2]
Reactant: [Mg+2]
Agent: N[C@@H](CCC(=O)N[C@@H](CSC(CC(=O)O)C(=O)O)C(=O)NCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca]
Product: [Mg]

Procedure:
Using 2 g of S-(α,β-dicarboxyethyl)glutathione and 1 g of basic magnesium carbonate, 2.2 g of the magnesium salt is prepared in a similar manner to the above production of the calcium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[NH:8][CH2:7][CH2:6]2.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:9]1([CH2:10][CH2:11][N:12]([C:24](=[O:25])/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[C:19]([F:31])([F:32])[F:18])[CH2:13][CH2:14]1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC21CCNCC1
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCNC21CCN(C(=O)/C=C/c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (570 mg, 2.45 mmol) in CH2Cl2 (20 mL) were added ortho-(trifluoromethyl)cinnamic acid (132 mg, 0.61 mmol), i-Pr2NEt (0.43 mL, 2.45 mmol), HOBt (99 mg, 0.73 mmol) and EDC.HCl (141 mg, 0.73 mmol). The mixture was stirred at rt for 3 d. The mixture was diluted with EtOAc (80 mL), washed with water (30 mL) and satd aq NaHCO3 (30 mL), and dried over Na2SO4. Removal of the solvent left an orange oil (378 mg). A portion of the oil was purified by preparative HPLC to afford (E)-1-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one. LC-MS Method 1 tR=1.37, min, m/z=431; 1H NMR (CDCl3) 2.25 (m, 4H), 3.16 (br s, 2H), 3.39 (m, 1H), 3.45 (br s, 2H), 3.78 (s, 3H), 3.84 (m, 1H), 4.11 (m, 1H), 4.78 (m, 1H), 4.9 (1H), 6.65 (s, 1H), 6.83 (m, 2H), 7.12 (d, 1H), 7.4-7.75 (4H), 7.98 (d, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:52]([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:5][C:4]1=[O:65])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:75]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][C:79]=1[S:84](Cl)(=[O:86])=[O:85])([O-:77])=[O:76]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:84]([C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][C:78]=3[N+:75]([O-:77])=[O:76])(=[O:85])=[O:86])[CH:46]([O:51][CH:52]([CH3:53])[CH3:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([O:57][Si:58]([C:61]([CH3:62])([CH3:63])[CH3:64])([CH3:59])[CH3:60])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C(OC(C)C)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80 mg) in dry methylene chloride (1 ml) was added an excess of diisopropylethyl amine (36 μl) and o-nitrophenylsulfonyl chloride (39 mg) followed by addition of 4-dimethylaminopyridine (22 mg). The mixture was stirred at room temperature for 5 hours at which time it was diluted with ethyl acetate, extracted from half saturated sodium bicarbonate solution and washed with brine. The combined organics were dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol to give the title compound (87 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][CH:29]=[C:30]4[C:25]=3[CH:24]=[CH:23][CH:22]=[N:21]4)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc2ncccc12
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3cccc4ncccc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 5-quinolineboronic acid using General Procedure A. Purification on silica yielded 116. NMR: (CDCl3): 3.80 (s, CH3), 4.13 (s, CH3), 6.88 (dd, H, ArH, J=2.3, 8.3), 7.07 (d, H, ArH, J=6.18), 7.22 (s, H, NH), 7.35 (t, H, ArH, J=8.1), 7.44-7.51 (m, 3H, 3×ArH), 7.85 (t, H, ArH, J=8.4), 8.25 (d, H, ArH, J=8.4), 8.29 (dd, H, ArH, J=1.1, 8.3), 8.98 (dd, H, ArH, J=1.7, 4.1), 9.26 (d, H, ArH, J=8.6). MS: (ESI+) MH+=383.21
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Brc1cccc(CN2CCOCC2)n1
Reaction time: 14 h

Procedure:
A solution of 6-bromopyridine-2-carbaldehyde (3 g, 16.13 mmol) and morpholine (1.405 ml, 16.13 mmol) in 1,2-dichloroethane (22 ml) under argon was charged with sodium triacetoxyborohydride (4.79 g, 22.58 mmol) and allowed to stir for 14 hours. The reaction mixture was then diluted with ethyl acetate (100 mL), saturated aqueous sodium bicarbonate (60 mL), and saturated aqueous sodium carbonate (90 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (30-100% ethyl acetate/hexanes) which afforded the title compound. LRMS (APCI) calc'd for C10H13BrN2O [M+1]+: 257, Found: 257.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1O)[C:11]#[N:12]>CN(C=O)C>[Cl:4][C:15]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[F:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(F)c(O)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)c([N+](=O)[O-])c1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (5.44 g; 42.8 mmol) was added dropwise to a solution of 3-fluoro-4-hydroxy-5-nitrobenzonitrile (3.9 g; 21 mmol) in DMF (40 mL) at −25° C. The mixture was stirred at −25° C. for 15 min and thereafter at 80° C. for 2.5 h. The mixture was slowly poured into ice, the precipitate was filtered off and the filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was combined with the precipitate and filtered through a plug of silica gel to give the sub-title compound.