Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClI
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a thermometer, and a condenser were added 10.0 g of methyl 4-hydroxybenzoate (Aldrich) and 30 mL of glacial acetic acid. To this suspension was added a solution of 11.74 g of iodine monochloride in 30 mL of glacial acetic acid via addition funnel. The solution was heated at 80° C. for 1 h, 45° C. for 18 h, and 90° C. for an additional 4 h. Cooling to RT afforded a thick red-orange suspension which was transferred to a 1 L separatory funnel and dissolved in 500 mL of CHCl3 by shaking vigorously. The dark purple solution was washed with water (2×100 mL), saturated aqueous sodium thiosulfate (2×100 mL), and 5% aqueous NaHCO3 (2×100 mL). A light yellow solution resulted which was dried over MgSO4, and concentrated in vacuo to give a white solid. This material was recrystallized from water-MeOH to afford 14.92 g (82%) of methyl 4-hydroxy-3-iodobenzoate as a white crystalline solid, m.p. 145-146° C.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:6][C:7]4[CH:8]=[C:9]5[C:13](=[CH:14][CH:15]=4)[NH:12][CH:11]=[CH:10]5)[C:38]=3[CH:37]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Temperature: 137.5 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
After adding 1.9 ml of dimethylformamide, 180 mg of 5-hydroxyindole and 112 mg of potassium carbonate to 190 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 135-140° C. for 4 hours. After returning it to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 90 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([CH2:13][CH2:12][CH2:11][CH:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH3:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCc1ccccc1
Reactant: CCc1ccncc1C
Product: Cc1cnccc1C(C)CCCc1ccccc1
Yield: 38.7 %

Procedure:
1.83 g (15.1 mmol) of 3-methyl 4-ethylpyridine and 3.0 g (15.1 mmol) of 1-bromo-3-phenylpropane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 1.40 g of the desired compound (yield: 38.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([OH:28])([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)[C:17]([F:20])([F:19])[F:18])[O:5][CH2:6][CH2:7][O:8]C(=O)C.[OH-].[K+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:5][CH2:6][CH2:7][OH:8])[CH:12]=[CH:13][C:14]=1[CH:15]([CH3:29])[C:16]([C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][N:22]=1)([OH:28])[C:17]([F:19])([F:20])[F:18]
Reactant: CC(=O)OCCOc1ccc(C(C)C(O)(c2cnc(C)cn2)C(F)(F)F)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cnc(C(O)(C(C)c2ccc(OCCO)cc2Cl)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of acetic acid 2-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenoxy}-ethyl ester in ethanol was added to a solution of KOH in ethanol. The reaction mixture was stirred for 3 h at r.t., before it was taken up in ethyl acetate, washed with water and brine, and the solvent was evaporated. Flash chromatography provided the title compound. MS (m/e)=391.0 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[CH2:2][Br:1])[C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])O
Product: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 85 %

Procedure:
The bromoacid 3 (11.8 g) was added in portions over 0.5 hour to 100 ml of 90% HNO3 (white fumming) at -10° C. The suspension was stirred at -10° for an additional 2 hours when the solution became clear orange. This solution was poured onto crushed ice. The product was collected by filtration, washed with ice cold H2O (3 × 50 ml) until the washings were neutral. Drying in vacuo followed by crystallization twice from CH2Cl2 /hexane gave pure nitro acid 4 (11.02 g, 85%): m.p. 125-126, i.r. (Nujol) 2800-2300, 1690, 1610 (COOH), 1600 (Aromatic), 1540, 1300 cm-1 (NO2); nmr (CDCl3, DMSO-d6) 4.9 (S,2), 7.8 (d,1), 8.2 (dd,1), 8.6 (d,1) 10.8 (s,1); Rf(5) 0.55; Rf (1) 0.82; UVmax (CH3OH) 227 mμ (t = 2.13 104) 305 mμ (t 4.1 × 103).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:27]=[CH:26][C:10]([CH2:11][C:12]2[O:13][C:14]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=3[C:16]=2[CH3:17])=[CH:9][CH:8]=1.Cl[CH:29]([O:31]C)Cl.O>ClCCl>[CH:29]([C:27]1[CH:26]=[C:10]([CH:9]=[CH:8][C:7]=1[O:6][CH3:5])[CH2:11][C:12]1[O:13][C:14]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:25])[C:15]=2[C:16]=1[CH3:17])=[O:31]
Reactant: COC(Cl)Cl
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc2oc(Cc3ccc(OC)c(C=O)c3)c(C)c2c1O
Temperature: 0 °C
Yield: 37 %

Procedure:
To a suspension of aluminium chloride (214 mg; 1.6mmole) in dichloromethane (5 mL) cooled at 0° C. was added 2-(p-methoxy benzyl)-3-methyl-4-hydroxy-5-propyl benzofuran (100 mg; 0.32mmoles). A red solution resulted. To this solution was added dropwise dichloromethylmethylether (87 (1; 0.96 mmole). There was a vigorous reaction and a color change from red to green was observed. Ice and water was then added and the mixture was extracted with ethylacetate. The organic phase was dried (Na2SO4), and concentrated in vacuo and the residue was chromatographed on silica gel. Elution with 10% ethylacetate in hexane yielded 40 mg (37%) of 2-(3 formyl-4-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:24]1([N:30]=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1.Cl.CN.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:30][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 10 h
Yield: 58.6 %

Procedure:
Boc-Asp(OBzl) (6.4 g) was dissolved in tetrahydrofuran (30 ml), added with dicyclohexylcarbodiimide (4.1 g), hydroxybenzotriazole (3.0 g), methylamine hydrochloride (2.0 g) and diisopropylethylamine (3.9 g) under ice cooling and stirred for 10 hours. Insolubles were removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was washed with 10% aqueous solution of citric acid and saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate. Then the ethyl acetate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give Boc-Asp(OBzl)-NHMe (3.9 g).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:54])([C:50]([F:53])([F:52])[F:51])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[C:38]([O:40]CC)=[O:39]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH:37]([CH2:36][CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:54])[C:50]([F:51])([F:52])[F:53])[C:38]([OH:40])=[O:39])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:16])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Se](=O)=[O:18]>O1CCOCC1.O>[CH:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH:16]=[O:18])=[N:12]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(OC(C)C)c(C)c2n1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(OC(C)C)ccc2ccc(C=O)nc12
Yield: 35.2 %

Procedure:
To 7-isopropoxy-2,8-dimethylquinoline (120 mg, 0.557 mmol) in dioxane/water (5 mL/0.5 mL) at ambient temperature was added selenium dioxide (74.2 mg, 0.669 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-isopropoxy-8-methylquinoline-2-carbaldehyde (45 mg, 35.2% yield) as a tan solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[CH:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)=[O:24].S([O-])([O-])(=O)=[O:43].[Na+].[Na+].CCOCC>N1C=CC=CC=1>[C:23]([C:25]1[C:33]2[C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[O:30][C:29]=2[CH:28]=[C:27]([Sn:38]([CH3:41])([CH3:40])[CH3:39])[CH:26]=1)([OH:43])=[O:24]
Reactant: O=S(=O)([O-])[O-]
Reactant: C[Sn](C)(C)c1cc(C=O)c2c(c1)oc1ccccc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C[Sn](C)(C)c1cc(C(=O)O)c2c(c1)oc1ccccc12
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of tetra-n-butylammonium permanganate (5.1 g, 14.0 mmol) in anhydrous pyridine (35 mL) was transferred via cannula needle into a solution of the stannane 305 (5.0 g, 14.0 mmol) in anhydrous pyridine (35 mL) at 0° C. under a nitrogen atmosphere. The reaction was stirred for 30 min., then saturated aqueous sodium sulfate (50 mL) was added to quench the reaction. The mixture was then poured into ether and the layers separated. The organic layer was washed with 2N aqueous HCl (6 times with 100 mL), water (2 times) and then brine (2 times). The solution was dried with magnesium sulfate, then filtered and concentrated under vacuum to provide 4.8 g (92% yield) of the stannane 306 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:21]2[CH2:22][CH2:23][CH:18]([CH2:24][CH2:3][CH2:2][CH2:7][CH3:6])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCC1CCC(c2ccc(-c3cccc(F)c3)c(F)c2)CC1
Temperature: 25 °C

Procedure:
The compound (T-31; 20.0 g), 3-fluorophenyl boronic acid (8.20 g), potassium carbonate (22.1 g), Pd/C (NX type; 0.114 g), toluene (100 ml), Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 5 hours. The reaction mixture was cooled to 25° C., and then poured into water (300 ml) and toluene (300 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, whereby 14.2 g of 2,3′-difluoro-4-(4-pentylcyclohexyl)-1,1′-biphenyl (T-32) was obtained. The yield based on the compound (T-31) was 78%.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:26]#[N:27])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:28])=O.CS(C)=O.[Cl-].[Na+]>O>[O:28]=[C:6]1[CH2:5][CH2:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)([C:26]#[N:27])[CH2:8][CH2:7]1
Reactant: COC(=O)C1CC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCC(=O)CC1
Temperature: 144 °C
Reaction time: 5 h
Yield: 39.6 %

Procedure:
To a solution of 5-cyano-2-oxo-5-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarboxylic acid methyl ester (6.6 g, 17 mmol) and dimethylsulfoxide (128 mL) was added water (8.0 mL) and sodium chloride (6.4 g, 109 mmol). The reaction mixture was heated to 142-146° C. After 5 hr, the mixture was concentrated and the residue was dissolved in DCM (120 mL), washed with water (100 mL), and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (70 g silica gel, eluant:gradient of DCM/MeOH 95/5 to 90/10) providing 4-oxo-1-[4-(3-pyrrolidin-1-ylpropoxy)-phenyl]-cyclohexanecarbonitrile as a crystallizing oil (2.2 g, 45.5%). After crystallization in ether, 0.2 g of analytical sample were obtained. 1H NMR (400 MHz, CDCl3) δ7.32 (d, 2H), 6.88 (d, 2H), 4.1 (t, 2H), 2.95-2.8 (m, 2H), 2.65-2.38 (m, 10H), 2.3-2.15 (m, 2H), 2.0-1.9 (m, 2H), 1.8-1.7 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[NH2:16][C:12]1[CH:11]=[C:10]([NH:17][C:7]2[C:2]([Cl:1])=[C:3]([NH2:9])[N:4]=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(N)c1
Reactant: Nc1ncnc(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Nc1cccc(Nc2ncnc(N)c2Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Into a 20 mL was placed 5,6-dichloropyrimidin-4-amine (500 mg, 3.05 mmol), benzene-1,3-diamine (329.72 mg, 3.05 mmol) and a pre-made mixture of TFA:TEA (1:1 mol) (347.64 mg: 308.52 mg) dissolved in DMSO (6 mL). The mixture was heated at 90° C. overnight. The reaction mixture was then cooled to rt and the crude mixture was purified using column chromatography eluting 0-40% MeOH in EtOAc. The fractions containing the desired product was concentrated and lyophilized overnight to afford the desired product N4-(3-aminophenyl)-5-chloropyrimidine-4,6-diamine (82% yield) as a brown syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH2:9][CH:10]=[CH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)c1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of 1-(3-bromophenyl)but-3-en-1-ol (17.0 g, 74.9 mmol), 1H-imidazole (11.8 g, 172.2 mmol) and tert-butyldimethylchlorosilane (13.9 g, 89.8 mmol) in DMF (40 mL) is stirred at room temperature for 2 hours. The mixture is diluted with dichloromethane and is washed sequentially with water and saturated ammonium chloride aqueous solution. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product is purified by silica gel chromatography eluting with 5% ethyl acetate in hexanes to give the title compound as racemic mixture (23.9 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.24-7.14 (m, 2H), 5.78-5.70 (m, 1H), 5.02-4.97 (m, 2H), 4.65-4.62 (m, 1H), 2.45-2.31 (m, 2H), 0.87 (s, 9H), 0.02 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:48]4[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][N:47]=4)[N:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[N:23][N:22]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:50][O:49][C:45]1[CH:44]=[C:43]2[C:48]([C:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]([NH:31][C:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:21]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[N:22][N:23]=4)=[CH:33][CH:34]=3)=[CH:40][CH:41]=[N:42]2)=[N:47][CH:46]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5nccn5C)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
In a nitrogen purged sealed tube was added 1,4-dioxane (1.35 mL), and the solution was purged with nitrogen for 5 minutes, then sealed. 1-Methyl-2-(tributylstannyl)-1H-imidazole (0.311 g, 0.837 mmol), 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.120 g, 0.279 mmol) were added to the tube, which was then purged with nitrogen and sealed. To the tube was added 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.102 mg, 0.140 mmol), and the tube was purged with nitrogen, sealed, and heated to 100° C., while stirring the reaction for 17 hours. The reaction was cooled to RT, and concentrated. The concentrate was purified using reverse phase chromatography, the product fractions were concentrated, extracted into DCM, washed once with sodium carbonate and once with water, upon which the title compound precipitated. The solids were filtered, washed with water, air dried to yield N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine (0.039 g) as light yellow solid. MS [M+H]=476.0; Calc'd 475.5 for C27H21N7O2.
Reaction SMILES: [C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])([OH:3])=O.C[N:30]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>COCCOC>[NH2:30][C:1]([C:4]1[CH2:9][C:8]([C:23]#[N:24])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:11]=2)[CH2:7][CH2:6][C:5]=1[O:25][CH2:26][O:27][CH3:28])=[O:3]
Reactant: COCOC1=C(C(=O)O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: COCOC1=C(C(N)=O)CC(C#N)(c2ccc(OC)c(OCC3CC3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture of 2-carboxy-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-(methoxymethyloxy)cyclohex-1-ene (0.26 g, 0.67 mmol), N-methyl morpholine (0.09 ml, 0.8 mmol) and isobutyl chloroformate (0.1 mL, 0.77 mmol) in dry 1,2-dimethoxyethane (7 mL) was stirred under an argon atmosphere at room temperature for 10 min. Ammonium hydroxide (0.07 mL, 1.0 mmol) was added and stirring was continued for 0.5 h. The mixture was partitioned between methylene chloride and 5% aqueous sodium carbonate, was extracted three times, the organic layer was dried (potassium carbonate) and the solvent was removed in vacuo to provide a white solid (0.22 g, 85%): m.p. 120°-122° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].CCN(CC)CC.[NH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:52]=[CH:53][CH:54]=1)[CH2:25][N:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:31]=1[OH:38])(=[O:29])=[O:28]>C(Cl)Cl>[C:43]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:45][C:40]([CH2:39][N:26]([CH2:25][C:24]2[CH:52]=[CH:53][CH:54]=[C:22]([CH2:21][NH:20][S:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH:23]=2)[S:27]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:31]=2[OH:38])(=[O:29])=[O:28])=[CH:41][CH:42]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)NCc2cccc(CN(Cc3ccc(-c4ccccc4)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
To a solution of 4-cyanobenzene-1-sulfonyl chloride (26 mg, 0.13 mmol) in CH2Cl2 (3 ml) was added Et3N (0.07 ml, 0.49 mmol) followed by N-(3-(aminomethyl)benzyl)-N-(biphenyl-4-ylmethyl)-3,5-dichloro-2-hydroxybenzenesulfonamide (65 mg, 0.12 mmol) at rt under nitrogen. The reaction mixture was stirred at 25° C. for 2 h. It was concentrated and the residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the product as a white solid (50 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C.C([OH:16])C>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:16])[CH2:6]2
Reactant: COc1ccc2c(c1)C(C)C(=S)N2
Reactant: CCO
Agent: [Ni]
Product: COc1ccc2c(c1)CC(=O)N2
Yield: 71 %

Procedure:
Desulfurization of 1.5 g (7.17 mmol) of 5-methoxy-3-methylthio-2-oxindole dissolved in 100 ml of absolute ethanol with W-2 Raney-Ni gave in 71% yield 5-methoxy-2-oxindole, mp. 148.5°-150.5° (lit. mp. 152°-154°).*