Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([NH:25]C(=O)OCC4C=CC=CC=4)[C:22](=[O:36])[NH:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:6][C:5]=1[CH3:37])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:25][C:23]1[C:22](=[O:36])[NH:21][CH:20]=[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([CH3:37])[CH:6]=3)=[O:12])[CH:18]=2)[CH:24]=1
Reactant: Cc1cc(NC(=O)c2cc(-c3c[nH]c(=O)c(NC(=O)OCc4ccccc4)c3)ccn2)ccc1C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(-c3c[nH]c(=O)c(N)c3)ccn2)ccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of benzyl (2′-((4-isopropyl-3-methylphenyl)carbamoyl)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-5-yl)carbamate (210 mg, 0.420 mmol) in MeOH (100 mL) was added Pd(OH)2/C (21 mg) and the mixture stirred overnight at RT under hydrogen. The Pd(OH)2/C was removed by filtration and the solvent evaporated to afford 5-amino-N-(4-isopropyl-3-methylphenyl)-6-oxo-1,6-dihydro-[3,4′-bipyridine]-2′-carboxamide (120 mg, 80% yield) as a grey solid: 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.48 (s, 2H), 7.45 (s, 1H), 7.00 (d, J=2.8 Hz, 1H), 6.85 (s, 1H), 4.40 (s, 1H), 2.87-2.92 (m, 1H), 2.37 (s, 3H), 1.27 (d, J=6.8 Hz, 6H); MS (ES) m/z 363 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:32]1([NH:35][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:13]4([C:10]5[N:6]6[CH2:7][CH2:8][S:9][C:3]([CH2:2][OH:1])([CH3:31])[CH2:4][C:5]6=[N:12][N:11]=5)[CH2:14][CH2:15]4)=[CH:21][CH:20]=3)=[N:23][CH:24]=2)[CH2:34][CH2:33]1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)NC6CC6)cn5)cc4)CC3)n2CCS1
Yield: 17.7 %

Procedure:
A solution of the compound (150 mg, 0.344 mmol) obtained in Example 66, cyclopropylamine (119 μL, 1.72 mmol), N,N-dimethylaminopyridine (4 mg, 34 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) in N,N-dimethylformamide (3.00 mL) was stirred at room temperature for 5 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and purified by silica gel column chromatography (ethyl acetate:methanol=1:4) to obtain the title compound (29 mg, 18%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH:17]=O.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[O:12][CH2:13][CH2:14][O:15][C:5]=3[C:4]=2[N:3]1[CH2:16][CH2:17][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]1
Reactant: O=CCn1c(=O)ccc2ccc3c(c21)OCCO3
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc4c(c32)OCCO4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
(9-oxo-2,3-dihydro[1,4]dioxino[2,3-h]quinolin-10(9H)-yl)acetaldehyde (1.5 g; 6.12 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (1.84 g; 9.18 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (50 ml:50 ml) and stirred at rt for 30 mins. NaBH(OAc)3 (5.81 g; 27.54 mmol) was added and the reaction left overnight. The solvents were then removed and the residues purified by column chromatography on silica gel using a 0-12% MeOH/DCM gradient to give the desired product (1 g; 38%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O>[CH2:8]([NH:12][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1OCCO1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and n-butylamine (120 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-n-butyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[CH:14][N:13]=1>CN(C)C=O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:13][CH:14]=1)=[O:29]
Reactant: CNc1ccccc1
Reactant: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
In dimethylformamide (30 ml) was dissolved N-methylaniline (1.2 g). To the solution was added 60% sodium hydride (dispersion in praraffin) (150 mg), and the mixture was stirred for 30 minutes. Then there was added 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine (500 mg). The mixture was stirred for 4 hours at 90° C. The reaction mixture was poured into ice-water, which was subjected to extraction with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (eluent: n-hexane +ethyl acetate=2:1) to obtain 5-(3,4-dimethoxybenzo-yl)-2-(N-methylanilino)pyridine (200 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: CCCCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 355.6 %

Procedure:
Beginning with 0.15 gm (0.55 mMol) 5-amino-3-(1-butyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.079 mL (0.067 mMol) 4-fluorobenzoyl chloride, 0.094 gm (43%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[CH:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:6]1[CH:5]=[N:4][N:3]2[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:11][CH:10]=[N:1][C:2]=12
Reactant: Cc1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1cccnc1
Solvent: CC(=O)O
Product: Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 3-amino-4-methylpyrazole is heated at reflux temperature for 6 hours with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in glacial acetic acid to give the product of the example.
Reaction SMILES: [C:1]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)(=[O:4])[CH:2]=[CH2:3].[C:18]([O:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([OH:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1)(=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]1[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31]1)=[O:28]>>[C:18]([O:42][CH:43]1[CH2:44][C:45]([CH3:53])([CH3:52])[N:46]([O:51][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:16])([CH3:17])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:47]([CH3:50])([CH3:49])[CH2:48]1)(=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]1[CH2:31][C:32]([CH3:39])([CH3:40])[N:33]([O:38][CH2:3][CH2:2][C:1]([O:5][CH:6]2[CH2:7][C:8]([CH3:17])([CH3:16])[N:9]([O:14][CH3:15])[C:10]([CH3:12])([CH3:13])[CH2:11]2)=[O:4])[C:34]([CH3:36])([CH3:37])[CH2:35]1)=[O:28]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: C=CC(=O)OC1CC(C)(C)N(OC)C(C)(C)C1
Product: CON1C(C)(C)CC(OC(=O)CCON2C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC3CC(C)(C)N(OCCC(=O)OC4CC(C)(C)N(OC)C(C)(C)C4)C(C)(C)C3)CC2(C)C)CC1(C)C

Procedure:
The title compound is prepared from 1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl acrylate and bis(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate according to the general procedure of Example 2.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([CH3:40])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][C:35]=3[CH3:40])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 86.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.07 g, 0.16 mmol) obtained in Example 108, step 2 and 4-fluoro-2-methylaniline (0.03 g, 0.24 mmol), the title compound (0.073 g, 88%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:24]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH2:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1

Procedure:
(S)-2-Tert-butoxycarbonylamino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester (290 mg, 0.66 mmol) was treated with 4 mL of 4N HCl in dioxane for 1 h at room temperature. The solvent was evaporated and the remaining solid triturated with diethyl ether to give (S)-2-amino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester-hydrochloride (214 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:29][C:28]4[NH:27][CH:26]=[C:25]5[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=45)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc3c2CCOC3=O)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].O>CS(C)=O>[CH2:25]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
1-(8,9-Oxidononyl)-3,7-dimethylxanthine was synthesized as follows: A mixture of theobromine (17.64 g, 98 mmol) and sodium hydride (2.35 g, 98 mmol) in dimethylsulfoxide (250 ml) was stirred for 15 minutes. 9-Bromo-1-nonene (20.0 g, 98 mmol) was added, and stirring was continued for 3 days. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (4×200 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×150 ml), dried over sodium sulfate, and the solvents were evaporated under vacuum. The residue was crystallized (dichloromethane-ether) to give 1-(8-nonenyl)-3,7-dimethylxanthine (24.34 g, 99% yield) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]2[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][N:20]=[CH:21][C:16]2=[N:15][N:14]=1.[BH4-].[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]2[CH:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][NH:20][CH2:21][C:16]2=[N:15][N:14]=1
Reactant: COc1cc(Br)c(Nc2nnc3cncc(-c4ccccc4)n23)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Br)c(Nc2nnc3n2C(c2ccccc2)CNC3)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.3 %

Procedure:
To a stirring suspension of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine (0.2 g, 3.7 mmol) in a mixture of THF (20 mL) and TFA (1 mL) at 0° C. was added sodium borohydride (20 mg, 4.0 mmol). The reaction mixture was stirred 15 minutes at room temperature, thane quenched by addition of 10% aqueous HCl. The resulting mixture was heated to reflux for 10 minutes, then cooled and made basic by addition of 1M aqueous NaOH. The mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 0.18 g of (2-bromo-4,5-dimethoxy-phenyl)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine, MS (M+H)=431.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2[C:7]([C:16]#[CH:17])=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:19])[CH2:3]1.I[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][C:2]1([CH3:20])[CH2:18][C:6]2[C:7]([C:16]#[C:17][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:19])[CH2:3]1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1c(N2CCOCC2)sc2c1CC(C)(C)CC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC1(C)CC(=O)c2sc(N3CCOCC3)c(C#Cc3ccc(O)cc3)c2C1
Reaction time: 0.83 h
Yield: 82.4 %

Procedure:
To a stirred solution of Example 38 (0.10 g, 0.35 mmol) and 4-iodophenol (0.11 g, 0.52 mmol) in diisopropylamine (7 mL) at 60° C. was added Pd(PPh3)2Cl2 (0.02 g, 0.03 mmol) followed by CuI (0.01 g, 0.05 mmol). After stirring for 50 minutes, the reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc (25 mL). The organics were then washed with sat. aqueous NaHCO3 (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 EtOAc/hexanes) gave the title compound (0.11 g, 85%) as an off-white powder. δH (DMSO-d6) 9.89 (1H, br. s), 7.31 (2H, d, J 8.2 Hz), 6.79 (2H, d, J 8.2 Hz), 3.78 (4H, m), 3.68 (4H, m), 2.67 (2H, s), 2.35 (2H, s), 1.06 (6H, s). LCMS (ES−) 380.4 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>O>[CH3:1][O:2][C:3]1[CH:10]=[C:7]2[C:6](=[CH:5][CH:4]=1)[O:11][C:18](=[O:19])[C:17]([C:15]([OH:16])=[O:14])=[CH:8]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(O)c(C=O)c1
Solvent: O
Product: COc1ccc2oc(=O)c(C(=O)O)cc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
5-methoxy-salicylaldehyde (211.1 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 241.1 mg of 6-methoxy-3-carboxy-coumarin in a 79% yield.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:14]([N:21]1[CH2:22][CH2:23][C:18]([OH:17])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:20]1)=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: OC1(c2ccccc2)CCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(O)(c2ccccc2)CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A round-bottomed flask was charged with Boc-D-tert-leucine (0.30 g, 1.3 mmol, 4-hydroxy-4-phenylpiperidine (345 mg, 1.95 mmol), HOBT (218 mg, 1.43 mmol) and EDC (274 mg, 1.43 mmol). Then added DMF (6 mL) followed by N,N-diisopropylethylamine (0.34 mL, 1.95 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The organic layers were combined and washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over 24 g SiO2 with 0-40% EtOAc/heptane to give 0.48 g (95%) of [(R)-1-(4-hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester as an off-white foam.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].O=[C:10]([CH:12]=[C:13]([CH3:15])[CH3:14])C.C(Cl)C=C(C)C>CC(C)=O>[CH2:10]([CH2:1][C:2]([CH:3]=[C:4]([CH3:7])[CH3:5])=[O:8])[CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: CC(=O)C=C(C)C
Reactant: CC(=O)CC(C)(C)O
Agent: CC(C)=CCCl
Solvent: CC(C)=O
Product: CC(C)=CCCC(=O)C=C(C)C

Procedure:
Acetone under the reaction conditions forms also some diacetone alcohol and mesityl oxide, and these then react with the prenyl chloride to produce the above isomers of prenyl mesityl oxide, also called prenyl-substituted methyl pentenones, in the same manner as acetone reacts with prenyl chloride to produce methyl heptenone. It is also possible that prenyl chloride reacts with the diacetone alcohol in the same manner to give the corresponding hydroxy derivatives that subsequently dehydrate. The presence of such hydroxy ketones is observed in the residues of the methyl heptenone production by the process of U.S. Pat. No. 3,668,255.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([NH2:22])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1>[Pd].CO.CCOC(C)=O>[O:18]1[CH2:19][CH2:20][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[CH:2][CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([NH2:22])=[CH:11][CH:10]=3)[N:16]=[C:17]1[NH2:21]
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A 15-mL flask was charged with (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.015 g, 0.042 mmol) and 10% palladium on carbon (0.075 g, 0.706 mmol). The material was suspended in MeOH (1.5 mL) and EtOAc (0.5 mL). The reaction was stirred for 2 h at rt under an atmosphere of hydrogen. The mixture was filtered through Celite, rinsing with 10% MeOH-dcm, and the filtrate was concentrated to afford crude (S)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (8 mg, 0.028 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:33])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2cc(Oc3c(F)cccc3F)ccc2c1O
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2cc(Oc3c(F)cccc3F)ccc2c1O
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 7-(2,6-difluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (210 mg) and NBS (133 mg) in MeCN (5 mL) was stirred in an ice/water bath for 2 h; then concentrated, the residue was column purified to give the desired product (156 mg). LC MS ESI: 424 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(C(F)(F)F)ccc1Br)N1CCOCC1
Reaction time: 0.17 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzoic acid (200 mg, 0.74 mmol) was dissolved in DMF (4.65 mL) and HATU (424 mg, 1.12 mmol) added to the resultant mixture at rt. The solution was stirred for 10 min then treated with N,N-diisopropylethylamine (0.51 mL, 3.0 mmol) and morpholine (0.096 mL, 1.1 mmol). The reaction was stirred for 15 hours then quenched by the addition of saturated NH4Cl (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by FCC to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.55-7.49 (m, 2H), 3.92-3.86 (m, 1H), 3.83-3.69 (m, 4H), 3.66-3.58 (m, 1H), 3.32-3.24 (m, 1H), 3.25-3.17 (m, 1H).