Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(P([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[H-].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([Br:40])[C:37]=1[CH:38]=O)[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([Br:40])[C:37]=1/[CH:38]=[CH:17]\[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:31]([O:33][CH3:34])=[O:32]
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1cc(Br)c(C=O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(/C=C\C(=O)OC(C)(C)C)c(Br)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (diphenoxyphosphoryl)acetate (267 mg) in THF (7.5 mL) at 0° C. under nitrogen was added sodium hydride and the mixture stirred for 15 min until gas evolution ceased. This anion mixture was then cooled to −78° C. and a solution of methyl 3,5-dibromo-4-formylbenzoate (262 mg) in THF (7.5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for an additional 40 min before being quenched with saturated ammonium chloride solution, extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with 90% hexane:10% ethyl acetate to give the title compound which also contained 20% of the E double-bond isomer. No attempt was made to separate these isomers at this stage. 1H NMR (500 MHz, CDCl3): 88.23 (s, 1H, E isomer); 8.21 (s, 1H, Z isomer); 7.57 (d, J=16.3 Hz, 1H, E isomer); 6.76 (d, J=11.9 Hz, 1H, Z isomer); 6.38 (d, J=16.3 Hz, 1H E isomer); 6.12 (d, J=11.9 Hz, 1H Z isomer); 3.954 (s, 3H, E isomer); 3.948 (s, 3H, Z isomer); 1.28 (s, 9H, both isomers). Mass spectrum: m/z 365 (M+H-t-Bu).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23][CH3:24])[C:16]=1[NH2:17])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:24])=[O:9])[C:16]=1[NH2:17])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc(C(C)C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cccc(CS(C)=O)c1N
Reaction time: 1.5 h
Yield: 70 %

Procedure:
12.9 g (52.3 mmol) of m-chloroperbenzoic acid (70% purity) were added over a period of 15 minutes to a suspension of 10.21 g (52.3 mmol) of 2-isopropyl-6-methylthiomethylaniline [prepared as described in step (i) above] and 5.31 g (50 mmol) of sodium carbonate in 200 ml of methylene chloride, whilst ice-cooling. The reaction mixture was stirred for 1.5 hours at the same temperature, after which it was diluted with methylene chloride, and the diluted mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, with an aqueous solution of sodium sulfite and with water, in that order. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of diethyl ether and diisopropyl ether, to give 7.74 g of the title compound as a first crop. The mother liquor was then concentrated by evaporation under reduced pressure, and the concentrate was repeatedly recrystallized from the same solvent to give a further 0.75 g of the title S-oxide derivative. The total yield was 8.49 g (yield 77%). The title compound melted at 91°-91.5° (after recrystallisation from a mixture of methylene chloride and diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:6]1[C:7](=[O:19])[C:8]2[CH:18]=[CH:17][CH:16]=[N:15][C:9]=2[N:10]([CH2:13][CH3:14])[C:11]2[N:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:20])[C:5]1=2)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)N(C(C)=O)c2c(C)cc(Cl)nc21
Temperature: 140 °C

Procedure:
A suspension of 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (5.1 g) in acetic anhydride (25 mL) was heated at 140° C. for 5 hours. The solvent was evaporated and the residue fractionated over silica gel to give 4.48 g of 5-acetyl-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (5.2 g) and 4-nitrophenol (3.14 g) in 30 mL of carbon tetrachloride and 10 mL of dichloromethane was treated with 1.3-dicyclohexylcarbodiimide (3.8 g). The mixture was stirred at room temperature for 2 days. After the usual work up. the ester was crystallized from ether-hexane to yield 4.14 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester, mP 113°-115° C.
Reaction SMILES: [C:1](O)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[S:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.ClCC(OC(=O)CCl)=O>C1(C)C=CC=CC=1>[C:1]([C:8]1[S:7][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)O
Reactant: c1ccsc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: C/C=C/C(=O)c1cccs1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 56 %

Procedure:
In 50 ml of toluene were dissolved 4.31 g (0.05 mole) of crotonic acid, 5.47 g (0.065 mole) of thiophene and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was stirred at 50° C. for 6.5 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure to obtain 4.26 g of 2-crotonylthiophene.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([N:15]1[CH2:16][CH2:17][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22]2)[CH2:19][CH2:20]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Solvent: CCO
Product: CCOC(=O)CCN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 mL (50.8 mmol) ethyl acrylate were added to a solution of 11.7 g (44.9 mmol) 1-benzyl-4-piperidin-4-yl-piperazine in 120 mL dry EtOH and the reaction mixture was refluxed for 1 h and then stirred overnight at RT. The solvent was eliminated i. vac. and the residue was dried for 1 h under an oil pump vacuum. The crude product was reacted further without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([NH:25][CH3:26])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C:38]1[CH:39]=[C:40]([C:48]([CH3:53])([CH3:52])[C:49](Cl)=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([N:25]([CH3:26])[C:49](=[O:50])[C:48]([C:40]3[CH:39]=[C:38]([C:37]([F:55])([F:54])[F:36])[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=3)([CH3:53])[CH3:52])[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnc2c(cnn2Cc2ccccc2)c1-c1ccc(F)cc1C
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc2c1cnn2Cc1ccccc1
Temperature: 40 °C
Yield: 83 %

Procedure:
To a solution of [1-benzyl-4-(4-fluoro-2-methyl-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-methyl-amine (2.125 g, 6.13 mmol) in CH2Cl2 (30 mL) was added iPr2NEt (2.14 mL, 12.3 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 2.93 g, 9.20 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 3.2 g (83%) of the title compound as a white foam. ES-MS m/e: 629.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[CH:37]=[CH:38][C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Yield: 37.2 %

Procedure:
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.7 g, 3.7 mmol) and 5-bromo-1-methylpyridin-2(1H)-one (816 mg, 4.4 mmol), Pd(Ph3P)2Cl2 (200 mg), and aq Cs2CO3 solution (4 mL, 2M) in 1,4-dioxane (30 mL) was stirred and heated to reflux for 2 h. When the reaction was over, the mixture was washed with water and extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (614 mg, 37%). LC-MS Method 2 tR=1.075 min, m/z=447.1; 1H NMR (CDCl3): δ=1.38 (m, 1H),1.47 (d, 3H), 1.73 (m, 2H), 1.98 (m, 2H), 2.20 (m, 1H), 2.31 (m, 2H), 2.94 (m, 1H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1H), 6.67 (m, 1H), 6.87 (m, 2H), 7.05 (m, 2H), 7.31-7.41 (m, 6H), 7.48 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]1[N:25](CCO)[C:24]([N+:29]([O-:31])=[O:30])=[CH:23][N:22]=1.[CH3:32][CH2:33]N=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:20][C:21]1[NH:25][C:24]([N+:29]([O-:31])=[O:30])=[CH:23][N:22]=1.[C:1]1([C:7]2[CH:16]=[C:15]([C:17]([O:19][CH2:32][CH3:33])=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C(O)c1cc(-c2ccccc2)nc2ccccc12
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)nc2ccccc12
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.4 %

Procedure:
The reaction mixture of 2-Phenyl-4-quinolinecarboxylic acid (274 mg, 1.1 mmol), metronidazole (171 mg, 1.0 mmol), EDCI (228 mg, 1.2 mmol), DMAP (20 mg, 0.2 mmol) and THF (5 ml) was stirred at room temperature for 10 h. THF was then removed under reduced pressure. The residue was dissolved in ethyl acetate. The organic layer was washed with H2O, 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed under vacuum. The resulting solid was recrystallized from C2H5OH to give 305 mg (76.62%) 2-methyl-5-nitro-1H-imidazole-1-ethyl 2-phenyl-4-quinolinecarboxylate. m.p.: 122-124° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[O:30]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[OH:30])(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Yield: 98.3 %

Procedure:
11.4 g (20.7 mmol) (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 1 g 20% Pd/C, and 100 mL tetrahydrofuran was shaken under a 50 psi hydrogen atmosphere for 19 h. TLC analysis indicated incomplete reaction, so an additional 1 g 20% Pd/C was added and the reaction shaken an additional 20 h under a 50 psig hydrogen atmosphere. TLC showed complete reaction. The catalyst was filtered and the resulting solution was concentrated to give an oil. The product was purified over silica eluting with ethyl acetate to yield 9.37 g (20.34 mmol, 98.3%) of (S)-3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as an ivory-yellow solid. MS (APCI) m/z 459.1 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]CC)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1>ClCCCl>[NH3:13].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][C:19]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:23])=[N:18][N:17]=2)(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)c(C)c1
Product: N
Temperature: 0 °C

Procedure:
Ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (1.0 g, 2.6 mmol) and 1-[(1-methylpiperidin-4-yl)methyl]piperazine (1.03 g, 5.2 mmol) were dissolved in DCE (5 mL) and stirred at 0° C. prior to degassing with N2. Trimethylaluminium (2M in toluene, 2.6 mL) was added dropwise to this solution. Upon complete addition, the reaction was stirred for 1 h at 80° C. The reaction was cooled, diluted with DCM (30 mL) and washed with saturated aqueous NaHCO3 (30 mL). The aqueous layer was extracted with DCM (2×30 mL) and the combined organic extracts dried over MgSO4 and concentrated in vacuo. The resulting brown oil was purified by FCC, eluting with 98:2 DCM:7N NH3 in MeOH to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C[O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[N:35][CH:34]=[C:33]([OH:32])[CH:38]=3)[C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)c1
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was made in a similar way as that of the compound of example 89 from of 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 804 mg, 1.579 mmol) and 3-methoxy-5-(tributylstannyl)pyridine (1257 mg, 3.16 mmol) at 120° C. overnight. Solvent was removed, and product was purified by Biotage Si 25 g with a gradient of DCM and EtOH affording a as yellow pale solid (500 mg). This material was dissolved in dry DCM (10 mL), 1M BBr3 in DCM (24 ml) was added and the solution was stirred at room temperature for 48 hrs. Then, solution was cooled to 0° C. and dry ethanol (10 ml) was added. Solvent was evaporate and product was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); (Phase B ACN 95%, water 5%, formic acid 0.1%) affording the title compound as white solid. Then, product was dissolved in a mixture of DCM (100 ml) and EtOH (5 ml) and the solution was washed with saturated solution of aqueous NaHCO3. aqueous phase was extracted with DCM (5×50 ml). Organic phases were collected, dried and solvent evaporated to dryness affording desired product affording the title compound (331 mg, 0.695 mmol, 68.4% yield) as a white solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:21][CH:22]([C:24]1[N:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=1[Cl:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:31][C:25]1[C:26]([NH:12][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:13])[F:1])=[CH:9][CH:8]=2)[CH3:11])=[N:27][CH:28]=[N:29][C:24]=1[CH:22]([Cl:21])[CH3:23]
Reactant: CC(N)c1ccc(OC(F)F)cc1
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)c1ncnc(NC(C)c2ccc(OC(F)F)cc2)c1Cl

Procedure:
In 50 ml of toluene were dissolved 3.8 g of 1-(4-difluoromethoxyphenyl)ethylamine and 2.3 g of triethylamine, and to the mixture was added 3.5 g of 6-(1-chloroethyl)-4,5-dichloropyrimidine. The mixture was refluxed under heating for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13]Cl)[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:12][CH2:13][N:17]=[N+:18]=[N-:19])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)ncn2CCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)ncn2CCN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To a solution of 1-(2-chloroethyl)-1H-benzimidazole-5-carboxylic acid methyl ester (9.9 g, 0.0416 mol) in dry DMSO (90 mL) was added with stirring NaN3 (5.4 g, 0.0832 mol) and the mixture was stirred for 15 h at 75° C. The reaction mixture was cooled to ambient temperature and diluted with ice water (500 mL) and the solid precipitated was filtered, washed with water and dried under vacuum affording 9.3 g (91%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid methyl ester as a solid. MS-ESI m/z 246 (M+1); 1H NMR (300 MHz, DMSO-d6) δ 3.8 (t, 2H), 3.9 (s, 3H), 4.5 (t, 2H), 7.8 (d, 1H), 7.9 (dd, 1H), 8.25 (s, 1H), 8.4 (s, 1H).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=O)[CH3:2].[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[NH2:12].[N+:18]([O-])([OH:20])=[O:19]>O>[F:8][C:9]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:11]([NH:12][C:1](=[O:4])[CH3:2])[CH:10]=1
Reactant: COc1ccc(N)cc1F
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Acetic anhydride (5 ml) was added to 3-fluoro-4-methoxyaniline (5.0 g), and the mixture was stirred for 30 minutes. The reaction mixture was cooled to room temperature, and nitric acid (2.3 ml) was added dropwise thereto. The mixture was stirred for 30 minutes, and water was added thereto. The resulting precipitate was collected and washed with water to obtain the title compound as crystals (5.7 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.Cl[Si:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CN(C)C=O.[Cl-].[Na+]>[CH3:25][Si:16]([O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCCCCCCC[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCC[Si](C)(C)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3.75 g (0.023 mole) 2,5-dichlorophenol in 30 ml N,N-dimethylformamide are added 5.58 g (0.082 mole) imidazole and 16.6 ml (0.070 mole) chlorodimethyloctyl silane under argon. After stirring at room temperature for two hours, the mixture is diluted with an aqueous saturated sodium chloride solution and extracted with ether. The combined organic extracts are dried and condensed. The product is purified by column chromatography.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.[C:16]([Cl:19])(=[O:18])C>CCOCC>[ClH:19].[CH3:16][O:18][C:12](=[NH:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: N#CCc1cccc2ccccc12
Solvent: CCOCC
Solvent: CO
Product: COC(=N)Cc1cccc2ccccc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a cooled (0° C.), stirred mixture of 1-naphthylacetonitrile (9.2 g, 0.055 mol), methanol (5.0 mL, 0.124 mol), and ether (5 mL) was added acetyl chloride (5.2 g, 0.066 mol) dropwise. Stirring was continued for 30 minutes and the mixture was allowed to stand at room temperature for 60 hours. The resulting precipitate was collected by filtration, washed with ether, crushed with a mortar and pestle, and again washed with ether. The product was dried in vacuo to give a white crystalline solid (11.7 g, 91%), which was used without further purification.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][CH2:7][CH2:8][OH:9].[I:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(OCC)(=O)C.O>[OH:9][CH2:8][CH2:7][NH:6][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=1[I:10]
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCO)c1ccccc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of sodium hydrogen carbonate (3.30 g, 39.7 mmol) and 2-aminoethanol (1.80 ml, 29.8 mmol) in ethyl acetate (25 ml) and water (15 ml) was added dropwise the solution of 2-iodobenzoyl chloride in ethyl acetate prepared above under ice-cooling, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give N-(2-hydroxyethyl)-2-iodobenzamide (5.12 g, yield 87.6%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N:10]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:11]=1[CH3:12].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:12][C:11]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:23])[CH3:22]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc2ccccc2n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(C=Cc2ccc3ccccc3n2)c1

Procedure:
A solution of 3-hydroxybenzaldehyde (25 g) and quinaldine (28 ml) in acetic anhydride (150 ml) was heated overnight at 130° cooled and evaporated in vacuo. Purification of the residue by flash chromatography using 35% ether in hexane to 45% ether in hexane afforded the title quinoline compound after recrystallization from ether/hexane, m.p. 86-87°.