Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.Cl>CCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][OH:9]
Reactant: CN1CCCCC1CO
Agent: Cl
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CCO
Product: CN1CCCC[C@@H]1CO
Yield: 15.6 %

Procedure:
Following the known procedure of patent EP 0 429 984 A2 (reference example 8). The resolution was identical to the above given procedure except that 4 rounds of crystallization were performed instead of the two as sited above. To a mixture of (±)-1-methyl-2-piperidinemethanol (77 g, 596 mmol) in EtOH (615 mL) was added dibenzoyl-D-tartaric acid (205 g, 573 mmol). The resulting mixture was slowly heated until a solution was obtained at which time the solution was slowly cooled with gentle stirring. After 12 h the crystals were isolated and dried to afford 131.6 g. This process was repeated: (2) EtOH (533 mL) provided 92.5 g. (3) EtOH (225 mL) provided 68 g (4) EtOH (200 mL) provided 49 g. The resulting salt was treated with 3M HCl (200 mL) which was heated to induce it to dissolve. The still warn solution was poured into a separatory funnel and extracted with ethyl acetate. The remaining aqueous layer was adjusted to pH 10 with K2CO3. The solution was extracted with CH2Cl2, dried (MgSO4) and concentrated to give 12 g of the alcohol. This alcohol (12 g, 92.8 mmol) was suspended in CH2Cl2 (200 mL) and SOCl2 added. After stirring for 12 h, the solvent was removed to provide a crude HCl salt. This salt was dissolved in EtOH (100 mL) and treated with NH2NH2 (89 mL, 1.86 mol) and heated to reflux for 12 h. NaOH (74 g) in H2O (30 mL) was added and stirred for 1 h. Half the solvent was removed and the residue extracted with ether to give a crude oil. After distillation under reduced pressure (50–60° C.) the pure hydrazine product (4.87 g) was obtained. This hydrazine (1.6 g, 11.2 mmol) was dissolved in THF (10 mL) and triphenylmethylisocyanate (3.19 g, 11.2 mmol) was added slowly. The solution was then stirred overnight and filtered to provide 650 mg of the desired product in good purity. 1H NMR (DMSO-d6): δ 1.10 (m, 2H), 1.30–1.56 (m, 4H), 1.95 (t, 1H), 2.15 (s, 1H), 2.18 (s, 3H), 2.71(d, 1H), 3.25 (q, 1H), 3.55(q, 1H), 4.80 (s, 2H), 7.12–7.32 (m, 15 H), 8.02 (s, 1H). ESI-MS m/z 429.2 (100, M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17]C([O-])(C)C.[K+].CI>C1COCC1.O>[CH3:17][N:4]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](=[O:16])[O:2][CH3:1]
Reactant: COC(=O)NCCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)N(C)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl[2-(4-nitrophenyl)ethyl]carbamate (224 mg, 1 mmol) in THF (2 mL) was added KOtBu (201 mg, 1.8 mmol) and MeI (256 mg, 1.8 mmol) sequentially. The reaction mixture was stirred for 12 hours at room temperature. The reaction was diluted with water (5 mL), extracted with EtOAc (2×15 mL), washed with water (5 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (60% ethyl acetate/hexane) afforded the title compound as a semi solid (160 mg, 67.2%). MS (ES+): 239 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1([CH3:28])[O:23][C:22](=[O:24])[CH:21]([CH2:25][CH3:26])[C:20](=[O:27])[O:19]1.C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:21]2([CH2:25][CH3:26])[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:23][C:22]2=[O:24])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CCC1C(=O)OC(C)(C)OC1=O
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC1(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)OC1=O
Yield: 87.3 %

Procedure:
(5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.0 g, 3.48 mmol) was added to a solution of 2,2-dimethyl-5-ethyl-1,3-dioxane4,6-dione (600 mg, 3.48 mmol) and triethylamine (0.51 mL, 3.66 mmol) in dimethyl sulfoxide (40 mL) under nitrogen. The reaction mixture was stirred over night and water (100 mL) was added. Filtration of the precipitate gave [5-(5-ethyl-2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (1.15 g, 87%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:16]2[CH:15]=[C:14]([C:17]([OH:19])=O)[S:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>ClCCl.CN(C)C=O.O>[Cl:7][C:8]1[C:16]2[CH:15]=[C:14]([C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])[S:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
Oxalyl chloride (9.2 ml) was added dropwise at 0° C. to a stirred suspension of 4-chlorobenzo[b]thiophene-2-carboxylic acid (17.89 g) in dichloromethane (240 ml), then the mixture was allowed to warm to ambient temperature. Dimethylformamide (8 drops) was added and the mixture was stirred at ambient temperature for 4 hours. The dichloromethane was removed in vacuo and tetrahydrofuran (200 ml) and dichloromethane (50 ml) were added to the residue to give a solution. N,O-Dimethylhydroxylamine hydrochloride (9.03 g) and triethylamine (25 ml) were added and the mixture was stirred at ambient temperature for 18 hours. Water (50 ml) and triethylamine (10 ml) were added then the solution was stirred at ambient temperature for 1 hour and diluted with water (1000 ml). The product was extracted into dichloromethane (3×300 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (19.7 g) as an off-white solid which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:52])[CH2:45][CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:52])[CH2:45][CH:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(CC1CCOCC1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC2CCOCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-ylmethyl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]([N+]([O-])=O)[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].C(O)(=[O:20])C>[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:20])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(=O)O
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]
Agent: [Fe]
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Temperature: 100 °C

Procedure:
Freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 68b) (20 g, 77 mmol) in glacial acetic acid (150 ml) is added slowly in 15×10 ml portions to a stirred slurry of iron powder (46 g, 833 mmol) in glacial acetic acid (150 ml) at 60° C. The reaction mixture is heated at 100° C. for an additional 2 hours, allowed to cool to room temperature and poured on to ice water (600 ml). The mixture is filtered through celite to remove iron residues, washing with dichloromethane (300 ml). The organic layer is removed and the aqueous solution is extracted with more DCM (3×200 ml). The combined organic extracts are dried (MgSO4), filtered and concentrated to a red solution. The titled product crystallises from this solution on standing.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(O[N:42]1N=[N:49][C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NCC#N>CN(C=O)C.CCOC(C)=O>[C:43]([CH2:44][NH:49][C:20]([CH:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:12]=[N:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:9]([CH3:24])[C:10]=2[CH3:23])[CH2:19][CH2:18]1)=[O:22])#[N:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)NCC#N)CC2)c1C
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (350 mg, 1.08 mmol) in DMF (10 mL) is added DIPEA (0.94 mL, 5.4 mmol) and HATU (490 mg, 1.29 mmol). After being stirred at 25° C., aminoacetonitrile hydrochloride (119 mg, 1.29 mmol) is added. The mixture is stirred for 2 h, and diluted with EtOAc (20 mL) and washed with H2O (3×10 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography (CH2Cl2/MeOH: 97%/3%) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid cyanomethyl-amide (280 mg, 72%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([C:21]([C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:22])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccccc1OC
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
Aluminum chloride (2.15 g, 16.12 mmol) was added to a stirred mixture of 1,2-dimethoxybenzene (2.03 g, 14.65 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 4-methoxybenzoyl chloride (2.50 g, 14.65 mmol) in anhydrous methylene chloride (50 ml) was added. The mixture was allowed to warm up to rt. then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,4-dimethoxy-phenyl)-(4-methoxy-phenyl)methanone as an off-white solid (3.66 g, 92%); 1HNMR (CDCl3) δ 7.80 (d, J=8 Hz, 2H, Ar), 7.44 (d, J=1 Hz, 12H, Ar), 7.37 (dd, J=1 Hz and 8 Hz, 1H, Ar), 6.97 (d, J=8 Hz, 2H, Ar), 6.90 (d, J=8 Hz, 1H), 3.96 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.89 (s, 3H, OCH3). The product was carried over to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[OH-].[Na+].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)=CC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a biphasic mixture of 3-bromo-4-methylaniline (50 g, 0.269 mol, Example e), 10% NaOH (270 mL) and dichloromethane (160 mL) was added dropwise over a period of 2 hours 3,3-dimethylacryloyl chloride (36 mL, 0.322 mol) in dichloromethane (95 mL). The solution was stirred at room temperature for 48 hours then diluted with water (100 mL). The aqueous layer was further extracted with dichloromethane. The organic layers were combined and washed with water and brine, dried (Mg2SO4), filtered and evaporated. The white solid was triturated with hexane and collected to give 70 g (97%) of 3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-amide. 1H NMR (300 MHz; CDCl3): 1.89 (s, 3 H), 2.21 (s, 3 H), 2.33 (s, 3 H), 5.68 (s, 1 H), 7.14 (d, J=8.0 Hz, 1 H), 7.17 (br s, 1 H), 7.33 (d, J=8.0 Hz, 1 H), 7.79 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]=1B(O)O.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:27]3[CH:28]=[CH:29][C:30]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:31][C:26]=3[F:25])[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (380 mg, 0.86 mmol, 1.00 equiv), (2-fluoro-4-phenoxyphenyl)boronic acid (240 mg, 1.03 mmol, 1.20 equiv), tetrakis-(triphenylphosphane) palladium (60 mg, 0.05 mmol, 0.06 equiv), dioxane (50 mL), sodium carbonate (228 mg, 2.15 mmol, 2.50 equiv) and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and the resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.347 g (80%) of tert-butyl (2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[CH:6][C:5]=1[S:12](Cl)(=[O:14])=[O:13].O>O1CCCC1>[Br:10][C:8]1[C:7]([F:11])=[CH:6][C:5]([S:12]([NH2:2])(=[O:14])=[O:13])=[C:4]([F:3])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc(F)c(Br)cc1F
Reaction time: 0.17 h

Procedure:
Ammonium hydroxide (5 ml) was added to a solution of 2,5-difluoro-4-bromophenylsulfonyl chloride (4.3 g) in tetrahydrofuran (20 ml) at room temperature (CARE:exotherm) and stirred for 10 min. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and the residue triturated with 20% diethyl ether in isohexane to give the sub-title compound as a solid (4.3 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C1(C)C=CC=CC=1>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a mixture of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (8.30 g, 15.0 mmol), 2-(di-t-butylphosphino)biphenyl (223 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (344 mg, 0.38 mmol), sodium tert-butoxide (2.17 g, 22.5 mmol) and 1-methyl-piperazine (2.16 mL, 19.5 mmol) under a N2 atmosphere was added anhydrous toluene (100 mL). The mixture was taken to 80° C. and heated at this temperature for 16 h. The mixture was allowed to cool to ambient temperature, diluted with ether (150 mL) and filtered through a plug of Celite, washing with ether. The filtrate was reduced in vacuo and the residue purified by column chromatography using an eluant of CH2Cl2-DMAW120 (1:0-0:1) to give the title compound (9.39 g) as a red gum.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[O:14])=[C:11]([CH3:31])[N:10]=1>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:29]=[CH:30][C:9]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[N:10][C:11]=2[CH3:31])=[CH:17][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cncn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 41 mg of 1,2,4-triazol and 14 mg of sodium hydride in 2 mL of DMF was stirred for 10 min. 70 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 6 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-1,2,4-triazol-1-yl)nicotinamide. MS (Q1) 391.4 (M)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([OH:29])[C:27]=1[Br:28])[C:21]([O:23]C)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.O1CCCC1.CO>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([O:29][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])[C:27]=1[Br:28])[C:21]([OH:23])=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1cc(C(=O)O)cc(OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.2 %

Procedure:
(2-(Trimethylsilyl)ethoxymethyl chloride (SEM-Cl, 3.10 mL, 17.5 mmol) was added to a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (Example 22-1 Step 1, 5.36 g, 15.9 mmol) and potassium carbonate (5.49 g, 39.7 mmol) in DMF (53.0 mL), and the mixture was allowed to stir at room temperature for two days. An additional portion of SEM-Cl (3.10 mL, 17.5 mmol) was added and the mixture stirred an additional 4 hours. The reaction mixture was partitioned between saturated sodium bicarbonate and 1:1 ethyl acetate/diethyl ether. The organic phase was washed with water (5×), brine, dried over MgSO4, and concentrated to a light orange oil. The crude product was dissolved into 2:1 tetrahydrofuran/methanol (100 mL) and aqueous sodium hydroxide solution (2.0 M, 63.6 mL, 127 mmol) was added. The solution was stirred for 1 hour after which time volatiles were removed via rotary evaporation. The remaining solution was acidified to pH 3 by slow addition of concentrated hydrochloric acid, extracted with dichloromethane (1×), then with 1:1 ether/ethyl acetate (4×). The combined extracts were washed with brine, dried over MgSO4 and concentrated to a solid. The crude product was triturated with heptane and dried under vacuum to provide 3-(benzyloxy)-4-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)benzoic acid (6.36 g) as a white solid. MS (M+1)=453.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.59 (m, 7H) 5.36 (s, 2H) 5.18-5.28 (m, 2H) 3.75-3.90 (m, 2H) 0.92-1.03 (m, 2H) 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][C:7]([CH3:10])([CH3:9])[O:8][C:4]=2[C:3]=1[C:13]#[N:14].[OH-:15].[K+].O>CC(O)(C)C>[NH2:14][C:13]([C:3]1[C:4]2[O:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]=2[CH:11]=[CH:12][C:2]=1[Cl:1])=[O:15]
Reactant: CC1(C)Cc2ccc(Cl)c(C#N)c2O1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1(C)Cc2ccc(Cl)c(C(N)=O)c2O1
Yield: 75.7 %

Procedure:
A stirred solution of 10.0 grams (0.048 mole) of 6-chloro-7-cyano-2,3-dihydro-2,2-dimethylbenzofuran in 200 mL of 2-methyl-2-propanol was warmed to reflux, and 9.5 grams (0.17 mole) of 85% potassium hydroxide was added in one portion. Upon completion of addition, the reaction mixture was heated at reflux for about 75 minutes. The reaction mixture was then cooled and poured into 400 mL of water that was cooled in an ice bath. The resultant solid was collected by filtration and dried under vacuum, yielding 8.2 grams of 7-aminocarbonyl-6-chloro-2,3-dihydro-2,2-dimethylbenzofuran. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH3:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[CH2:2][O:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(C(=O)CBr)oc2ccccc12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)COc2ccccc2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a mixture of 2-bromo-1-(3-methyl-1-benzofuran-2-yl)ethanone (1.00 g), phenol (446 mg) and N,N-dimethylformamide (20 mL) was added potassium carbonate (655 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give the title object compound (697 mg, 66%) as a yellow solid.