Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=O.[CH2:4]([NH:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[C:10]=1[O:20][CH:21]([CH3:23])[CH3:22])=[O:8])[CH3:5].OO.C([O-])(O)=[O:27].[Na+]>CO.CCOC(C)=O>[CH2:4]([NH:6][C:7]([C:9]1[S:13](=[O:27])[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=2[C:10]=1[O:20][CH:21]([CH3:22])[CH3:23])=[O:8])[CH3:5]
Reactant: CCNC(=O)c1sc2ccc(OC)cc2c1OC(C)C
Reactant: O=C([O-])O
Agent: O=[Se]=O
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNC(=O)C1=C(OC(C)C)c2cc(OC)ccc2S1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Selenium dioxide is added to a room temperature solution of N-ethyl-5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide (195 mg, 0.66 mmol) in 8 mL of MeOH containing 530 μL of hydrogen peroxide (30% aqueous). The reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into EtOAc and saturated NaHCO3. The organic phase is washed with saturated NaHCO3, 1N HCl, then brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid is chromatographed, eluting with a gradient of 1:9 EtOAc:CH2Cl2 to 1:1 EtOAc:CH2Cl2, to provide 96 mg (47%) of N-ethyl-5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide -1-oxide; mp 88°-90° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1.CCN(CC)CC>CC#N>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:12]2[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(CCOc2ccc(O)cc2)CC1

Procedure:
To a stirred suspension of 4-(2-bromo-ethoxy)-phenol (600 mg, 2.77 mmol) and ethyl isonipecotate (470 μL, 3.06 mmol) in CH3CN (12 mL) was added Et3N (768 μL, 5.54 mmol). The resultant mixture was stirred at rt overnight and then concentrated to afford the title compound, which was used immediately in the next step. MS (ESI): mass calcd. for C16H23NO4, 293.16; m/z found, 294.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[B:10](OC)([O:13]C)[O:11]C>C1COCC1>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([B:10]([OH:13])[OH:11])=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1
Temperature: -78 °C

Procedure:
Under nitrogen, a solution of 94.1 g (0.55 mol) of 4-bromotoluene in 400 mL of anhydrous THF was treated with 14.5 g (0.60 mol) of magnesium turnings. The reaction was stirred at reflux for 2 h, cooled to -78° C. treated with a solution of 156 mL (1.38 mol) of trimethyl borate in 475 mL of THF, stirred for 1 h, and allowed to warm to ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between aqueous base and methylene chloride. The pH of the aqueous phase was adjusted to one with hydrochloric acid and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated in vacuo to give 4-tolylboronic acid: NMR (CDCl3) δ2.45 (s, 3H), 7.31 (d, J=8 Hz, 2H), 8.13 (d, J=8 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:18]=[N:19][C:20]4[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:21]=4[N:22]=3)=[N:15][N:14]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:11]2=[N:12][CH:13]=1.[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]2[C:16]([C:17]3[N:18]=[N:19][C:20]4[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[N:23]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:21]=4[N:22]=3)=[N:15][N:14]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:11]2=[N:12][CH:13]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(Cn2nc(-c3nnc4c(n3)NC(=O)C4(C)C)c3cc(F)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(-c3nnc4c(n3)N(COCC[Si](C)(C)C)C(=O)C4(C)C)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.067 g (6.345 mmol) of cesium carbonate in DMF (30 ml) were added to 2.45 g (5.768 mmol) of the compound from Example 34A. 1.221 ml (6.922 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride were then added, and the mixture was stirred at room temperature for 1 h. The solids were then filtered off and washed with DMF, the filtrate was concentrated and the residue was dried under high vacuum. This gave 4.45 g of crude material which were used without further purification for the next step.
Reaction SMILES: [CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([OH:24])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:38]1(=[O:44])[O:43][C:41](=[O:42])[CH:40]=[CH:39]1>C(Cl)(Cl)Cl>[CH:1]1([C@H:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[O:5][CH2:6][C@H:7]([O:24][C:38](=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42])[CH2:8][NH:9][C:10]([CH3:23])([CH3:22])[CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccccc1[C@H](OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)C1CC1
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1[C@H](OC[C@@H](CNC(C)(C)Cc1ccc2ccccc2c1)OC(=O)/C=C\C(=O)O)C1CC1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
(2R)-1-[(1R)-(Cyclopropyl)-(2-methylphenyl)methoxy]-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propan-2-ol (1.25g) was dissolved in chloroform (10 ml) and, under ice-cooling, pyridine (0.485 ml) and maleic anhydride (294 mg) were added and the mixture was stirred for 4 hr. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the obtained residue. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=98:2-95:5) to give the title compound (1.40 g).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[O:8][C:6](=[O:7])[C:3]1([CH3:11])[CH2:4][CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:9]([C:2]2([CH3:1])[CH2:5][CH2:4][C:3]2([CH3:11])[C:6]([OH:8])=[O:7])[OH:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CC12CCC1(C)C(=O)OC2=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: CC1(C(=O)O)CCC1(C)C(O)=Nc1cc(Cl)cc(Cl)c1
Yield: 34 %

Procedure:
7.7 g (0.05 mol) of 1,2-dimethylcyclobutane-1,2-dicarboxylic acid anhydride with 8.1 (0.05 mol) of 3,5-dichloroaniline are heated for 8 hours at 180° C. After cooling, the crude product is recrystallised from ethyl acetate to obtain 5.1 g (34% of theory) of 1,2-dimethylcyclobutane-1,2-dicarboxylic acid-(3,5-dichlorophenyl)-imide, the properties of which are identical to those of the compound produced according to Example 1.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:4][CH2:3][CH:2]([NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH3:5]
Reactant: CC(N)CO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC(C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
19 ml (0.24 mol) of 2-amino-1-propanol were added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 27.12 g (0.17 mol, 71% yield) of a colorless oil.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22]>C(O)CCC>[Cl:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: NN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2F)CC1
Solvent: O
Solvent: CCCCO
Product: Clc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20 %

Procedure:
A solution of 18.0 g of 1-acetyl-4-(4-chloro-2-fluorobenzoyl)piperidine, 130 ml of n-butanol and 51 ml of hydrazine monohydrate was stirred under reflux for 48 hrs. Most of the n-butanol was evaporated in vacuo and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from acetonitrile to yield 3.0 g (20%) of product. This product was combined with a 1.3 g sample from another experiment and the combined samples (4.3 g) were recrystallized from acetonitrile to yield the analytical sample, mp 174°-176° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=1[CH:7]=[O:8].C1(C)C=CC=CC=1.[C:19]1(B(O)O)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:27]1([C:2]2[N:3]=[C:4]([CH2:9][CH2:10][CH3:11])[NH:5][C:6]=2[CH:7]=[O:8])[C:28]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCCc1nc(I)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Reaction time: 0.08 h

Procedure:
A solution of 2.64 g (0.01 mol) of 4-iodo-2-n-propylimidazole-5-carboxaldehyde, toluene (40 mL), and 0.33 g (0.00029 mol) of tetrakistriphenylphosphine palladium (0) was stirred at room temperature under nitrogen, while a solution of 3.44 g (0.022 mol) of 1-naphthylboronic acid in 50 mL of ethanol was slowly added. The reaction was stirred for 5 minutes, after which 12 mL of 2M sodium carbonate was slowly added. After the addition was completed, the reaction was refluxed for 48 h and cooled. The reaction was filtered, the filtrate was evaporated under reduced pressure, and the resulting residue was dissolved in 300 mL of methylene chloride, washed twice with 100 mL of saturated sodium chloride solution, washed twice with 100 mL of distilled water, and washed twice with 300 mL of 10% HCl. The HCl layer was made basic with 50% sodium hydroxide until the pH=10. At this point, the basic water layer was extracted three times with 300 mL of methylene chloride, the methylene chloride layer was dried over sodium sulfate and evaporated under reduced pressure. Yield: 0.90 g (0.0034 mol, 34%) of product. NMR (CDCl3) δ 11.45 (m, 1H); 9.42 (s, 1H); 7.28 (m, 7H); 2.82 (t, 2H); 1.85 (m, 2H); 1.01 (t, 3H). ##STR75##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[OH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[OH:33])=[N:3][CH:4]=[C:5]2[F:32])(=[O:13])=[O:14]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: OB(O)c1ccccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.075 g, 0.152 mmol), (2-hydroxyphenyl)boronic acid (0.031 g, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol), and potassium carbonate (0.105 g, 0.759 mmol). Dioxane (0.759 mL) and Water (0.253 mL) were added; the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 522.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][CH:3]=1.C([O:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])(C)C.C[O-].[Na+].Cl>O.C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[C:15](=[O:14])[CH2:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CC(C)OC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
A mixture of 4-methylacetophenone (0.85 g), isopropyltrifluoroacetate (1.0 g) and toluene (2 ml) was added to a mixture of sodium methoxide (0.4 g) and toluene (2 ml) at 35-40° C. The reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to 25-30° C. Water (2 ml) and aqueous HCl (3 ml, 20%) were added and the reaction mixture was stirred at 25-30° C. for 30 minutes. The layers were separated. Aqueous layer was extracted with toluene (2×2 ml). The organic layers were combined and the solvent was removed by distillation at 55° C. under vacuum to obtain the title compound (Yield: 1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=O)[CH:15]=[C:14]([CH3:21])[CH:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[CH:9]=[CH:20][C:18]([C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[C:14]([CH3:21])[CH:15]=1)=[N:1]2
Reactant: Nc1cccc(Cl)c1CO
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(Cl)cccc3n2)c1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
(2-Amino-6-chlorophenyl)methanol (16 g, 102 mmol), 3,5-dimethylacetophenone (22.6 g, 152 mmol), RuCl2(PPh3)3 (0.973 g, 1.015 mmol), and KOH (10.25 g, 183 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature, filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation to give 23.5 g of crude product, which was crystallized from 60 mL of MeOH to give 8.6 g (32% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Br)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[O:16]>CN(C)C=O>[NH2:17][C:15]1[O:16][CH:12]=[C:10]([C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:14]=1
Reactant: CCOC(=O)C(=NOC)C(=O)CBr
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1coc(N)n1
Yield: 26 %

Procedure:
A solution of 50.4 g (0.2 mol) of ethyl 2-methoxyimino-4-bromoacetoacetate [M. Ochiai et al., Chem. Pharm. Bull. 25, 3115 (1977)] and 60.1 g (1 mol) of urea in 200 ml of dimethylformamide is heated to 100° C. for 30 minutes. Thereafter, the mixture is evaporated, the residue is taken up in 800 ml of water, neutralized with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extract is chromatographed on silica gel with acetonitrile/methylene chloride (1:1). There is obtained ethyl 2-(2-amino-4-oxazolyl)-2-methoxyimino-acetate in a yield of 26%; melting point 120° C. (decomposition).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([F:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:9]1[CH:8]=[C:7]([C:26](=[O:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc(-c2cscn2)c(F)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2cscn2)c(F)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(1,3-thiazol-4-yl)phenyl trifluoromethanesulfonate (1.45 g, 4.43 mmol) in dioxane (42 ml) was added tributyl(1-ethoxyvinyl)tin (1.92 g, 5.32 mmol), tetrakis(triphenylphosphine)palladium (512 mg, 0.44 mmol), lithium chloride (466 mg, 11.0 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was concentrated in vacuo. To the residue was added THF (20 ml), 2N HCl aqueous solution (20 ml), and the mixture was heated at reflux temperature for 8 hours. The reaction mixture was cooled down to room temperature, made neutral by addition of NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (666 mg, 68% yield).
Reaction SMILES: FC1N(C)C(O)CN(C2C=CC(N[C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=4)[C:20]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)=[CH:19][N:18]=3)=CC=2)C1.[Cl:42]C1N=C(Cl)C(NC2C=CC=C(F)C=2)=CN=1.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>[Pd]>[Cl:42][C:17]1[N:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)[C:20]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[CH:19][N:18]=1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CC(O)N(C)C(F)C4)cc3)ncc2Nc2cccc(F)c2)c1
Reactant: Fc1cccc(Nc2cnc(Cl)nc2Cl)c1
Agent: [Pd]
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1

Procedure:
As an example, N-(3-(2-((4-(3-fluoro-5-hydroxy-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route I. Beginning with 2,4-dichloro-N-(3-fluorophenyl)pyrimidin-5-amine, a palladium catalyzed coupling reaction with (3-acrylamidophenyl)boronic acid provides N-(3-(2-chloro-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide under mild conditions. Reaction of this product with 4-(4-aminophenyl)-6-fluoro-1-methylpiperazin-2-ol under palladium catalyzed aminolysis conditions can yield the desired product.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][C:15]=2[NH2:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](OCC)(OCC)OCC.Cl.N1C=CC=CC=1>>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:14]3[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=[CH:16][C:15]=3[N:24]=[CH:25]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cnc2ccccc2c1NCCCCCSc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(SCCCCCn2cnc3cnc4ccccc4c32)cc1

Procedure:
Using the general method of Example 1 Part D, N4-[5-(phenylthio)pentyl]quinoline-3,4-diamine (5.1 g, 15.1 mmol) was cyclized using triethyl orthoformate (2.46 g, 16.6 mmol) in the presence of a catalytic amount of pyridine hydrochloride to provide 1-[5-(phenylthio)pentyl]-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[C:8]#[N:9])=[CH:3][CH:2]=1.N1C=C(C)C=C(C)C=1.[CH3:19][O:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:30][C:29]1[C:21]([O:20][CH3:19])=[C:22]([C:26]([Cl:31])=[CH:27][CH:28]=1)[C:23]([O:10][CH:7]([C:8]#[N:9])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:24]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: N#CC(O)c1ccccc1
Agent: Cc1cncc(C)c1
Solvent: ClCCl
Product: COc1c(Cl)ccc(Cl)c1C(=O)OC(C#N)c1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
Benzaldehyde cyanohydrin (13.3 grams; 0.100 moles), 3,5-lutidine (11 grams) and methylene chloride (100 ml) were placed in a 500 ml. 3-necked glass reaction flask equipped with a mechanical stirrer, thermometer, condenser and addition funnel. This mixture was cooled to 10° C. by means of an ice bath and 2-methoxy-3,6-dichlorobenzoic acid chloride (23.9 grams; 0.10 moles) was added dropwise with the temperature of the mixture maintained at 5°-10° C. After the addition of the acid chloride was completed, the reaction mixture was stirred for an additional three hours at room temperature. After the reaction was completed, the mixture was washed three times with water, dried over anhydrous magnesium sulfate, filtered and concentrated by distillation. The residue was heated to a temperature of 150° C. under vacuum from a vacuum pump. Then the residue was dissolved in cyclohexane, treated with nuchar, filtered and stripped dry to give an oil.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCC1
Yield: 70.6 %

Procedure:
To a solution of 4.6 g (0.2 mol) sodium in 80 mL absolute ethanol was added 30.4 mL (0.2 mol) diethyl malonate. After briefly stirring, 21.4 mL (0.2 mol) cyclopentyl bromide was added, and the resulting solution refluxed for 12 hrs. Most of the ethanol was then removed by rotary evaporation, and the reaction was quenched with 250 mL of water and extracted 3×, each with 100 mL ether. The extracts were dried over MgSO4, filtered, and concentrated. Distillation through a 6" Vigreaux at 6 mm Hg provided 32.232 g of a clear colorless oil at bp 122-125 C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:13])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2.[CH3:27]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8]2)=[CH:3][C:2]=1[CH3:27])[CH:15]([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1=Cc2cc(C)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 45 %

Procedure:
A mixture of ethyl 6-chloro-7-[isobutyl(methyl)amino]-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 8c (0.50 g, 1.28 mmole), trimethylboroxine (0.38 g, 2.75 mmole), [(tBu3P)PdBr]2 (0.01 g), and Cs2CO3 (0.75 g, 2.31 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to HPLC (reverse phase) and eluted with 50-85% ACN/water with 0.05% TFA to give yellow solid (0.21 g, 45%). No further purification was performed. GCMS m/z 371.0 (M+). LCMS m/z 372.0 (M+H).