Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[F:22].[F:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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].C(Cl)Cl>[F:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:31](=[O:34])[CH:32]=[C:33]4[C:24]([F:23])=[CH:25][CH:26]=[CH:27][N:28]4[C:29]2=[O:51])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2c(F)cc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 60 °C
Reaction time: 0.01 h
Yield: 63.8 %

Procedure:
A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (0.200 g, 0.548 mmol), 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 37] (0.260 g, 0.657 mmol) and Cs2CO3 (0.357 g, 1.10 mmol) in dioxane (4 mL) and water (1 mL) was bubbled with nitrogen for 2 min, then was treated with PdCl2(dppf) DCM adduct (0.022 g, 0.027 mmol). Bubbling with nitrogen was continued for 30 sec and the reaction vessel was sealed. The mixture was heated at 60° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with DCM, and combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give 3-fluoro-4-(3-(5-fluoro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (0.194 g, 63% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]C)[CH2:5][NH:6][C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:29]([O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:30]([CH:33]=1)[CH:31]=[O:32]>>[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[C:26]([F:25])[CH:33]=[C:30]([CH:31]=[O:32])[C:29]=2[O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[C:16]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=1)=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: COCCOCOc1c(C=O)cc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1Br
Product: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1-c1cc(F)cc(C=O)c1OCOCCOC
Yield: 54.9 %

Procedure:
Proceeding as in Reference 19, but substituting 1-[3-bromo-4-(2-ethoxyethoxymethoxy)benzyl]-3-tert-butylurea (1.0 g, 2.9 mmol) and 5-fluoro-2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (29 mL, 0.1 mM in toluene, 2.9 mmol) gave 1-tert-butyl-3-[5′-fluoro-3′-formyl-6,2′-bis-(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]-urea (0.854 g).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.N#C[Br:21]>CCOCC>[Br:21][CH2:4][C:5]#[C:6][CH:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N#CBr
Reactant: CCCCCC(C#CCN(CC)CC)OC(C)=O
Solvent: CCOCC
Product: CCCCCC(C#CCBr)OC(C)=O
Reaction time: 18 h

Procedure:
A solution of 1-diethylamino-4-acetoxy-2-nonyne (50.6 g., 0.20 mole) and cyanogen bromide (21.2 g., 0.20 mole) in ether (250 ml.) is allowed to stand at 25°-27° for 18 hours. The ether solution is washed with 5% hydrochloric acid solution, water, and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled. After a forerun of diethylcyanamide, there is collected 34.1 g. (65%) of 1-bromo-4-acetoxy-2-nonyne, b.p. 97°-105°/0.2 mm.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: ClCc1nc2ccccc2o1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 59.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (241 mg, yield: 59.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:11]=[CH2:12]
Reactant: COc1ccc(O)cc1
Reactant: C=CCBr
Product: C=CCOc1ccc(OC)cc1
Yield: 98 %

Procedure:
Allyl(4-methoxyphenyl)ether was prepared in the same manner as described in Example 17A, but using 4-methoxyphenol (10 g, 84 mmol) and allyl bromide (9.7 g, 84 mmol), in 98% yield as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](I)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.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:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(I)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)N1c2ccc(-c3ccccc3-c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Suzuki cross-coupling of 1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg), (1,1′-biphenyl-4-yl)boronic acid (28 mg), cesium fluoride (15 mg), triphenylphosphine (5 mg) and tris(dibenzylideneacetone)dipalladium(0) (4.5 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to the method described in example 13.
Reaction SMILES: [CH3:1][N:2]([CH3:53])[C:3](=[O:52])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[C:6]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]([C:27]4[N:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:31](=[O:39])[C:30]5=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]5[N:28]=4)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=3[N:17](COCC[Si](C)(C)C)[CH:16]=2)[CH:5]=1.FC(F)(F)C(O)=O.N>>[CH3:53][N:2]([CH3:1])[C:3](=[O:52])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[C:6]([C:15]2[C:23]3[C:22]([NH:24][C@H:25]([C:27]4[N:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:31](=[O:39])[C:30]5=[C:40]([CH3:43])[CH:41]=[CH:42][N:29]5[N:28]=4)[CH3:26])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][CH:16]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)cc(C(=O)N(C)C)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 82.2 %

Procedure:
(S)—N,N-Dimethyl-3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-(methylsulfonamido)benzamide (215 mg, 0.28 mmol) was treated with trifluoroacetic acid (3.0 ml, 39 mmol) and a solution of ammonia (7N in methanol, 3.0 ml, 21 mmol) according to the method described in Example 27 to give 144 mg (81% yield) of the title compound. Purity 99%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:29]([O-:31])=[O:30])=[CH:19][CH:18]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](Cl)Cl>>[CH:6]1[C:7]2[C:15]([C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]([C:29]([O:31][CH3:32])=[O:30])=[CH:19][CH:18]=3)=[N:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]=2[CH:3]=[CH:4][CH:5]=1
Reactant: ClCCl
Reactant: O=C(Nc1ccccc1Oc1ccccc1)c1ccc(C(=O)[O-])c(-c2ccccc2)c1
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1-c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirring solution of methyl 5-(2-phenoxyphenylcarbamoyl)biphenyl-2-carboxylate 102 (0.723 g, 1.7 mmol) in DCM (3 mL) was added PPA (40 g, 1.7 mmol). The reaction was heated to slowly distill off the DCM then stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, poured into ice water then extracted with DCM. The combined organic layers were washed with water, dried over Na2SO4, filtered and solvent evaporated to provide 103 as a yellow solid (0.537 g, 78% yield) after purification by ISCO (5 to 30% ethyl acetate in hexane).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1(C)C=CC=CC=1.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>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[CH2:13]
Reactant: Clc1ccc2c(n1)CCCC2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(n1)CCCC2

Procedure:
A solution of 2-chloro-5,6,7,8-tetrahydroquinoline (3.69 g, 22 mmol) and vinyl tributyl tin (7.7 mL, 33 mmol) in toluene (60 mL) was treated with Pd(PPh3)4 (2.5 g, 2.2 mmol) and heated to reflux overnight. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the title compound as a colorless oil. LRMS m/z (M+H) 160.2 found, 160.1 required.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[N:3]=1
Reactant: NCCCn1ccnc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCn2ccnc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3-(1-imidazolyl)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 1-(3-aminopropyl)imidazole, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:24])[F:23])[N:6]2S(C1C=CC=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:22]([F:23])[F:24])[NH:6]2
Reactant: N#Cc1ccc2c(cc(C(F)F)n2S(=O)(=O)c2ccccc2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Temperature: 75 °C
Yield: 92.1 %

Procedure:
To a solution of 4-chloro-2-(difluoromethyl)-1-(phenylsulfonyl)-1H-indole-5-carbonitrile (1.05 g, 2.85 mmol) in anhydrous THF (12 mL) under N2, was added TBAF (1M in THF, 8.6 mL) and the mixture was heated at 75° C. for 2 h. Upon cooling, the mixture was partitioned between EtOAc and 0.2N HCl. The organic phase was washed with 0.2N HCl and sat'd brine. The combined aqueous phases were reextracted with EtOAc. The second EtOAc phase was washed with 0.2N HCl and sat'd brine. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) to afford the title compound as a light yellow solid (0.595 g, 92% yield): 1H NMR (400 MHz, CD3OD) δ 7.53 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.03 (t, J=54.2 Hz, 1H), 6.95 (bt, J=2 Hz, 1H); MS (ES) m/z 227 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13]#[N:14])=[O:4].[OH:15]O>C(O)(=O)C>[CH3:1][NH:2][C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:15])[C:7]=1[C:13]#[N:14])=[O:4]
Reactant: CNC(=O)Nc1snc(SC)c1C#N
Reactant: OO
Solvent: CC(=O)O
Product: CNC(=O)Nc1snc(S(C)=O)c1C#N

Procedure:
The reaction was repeated using 24.2 of 1-methyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea and 12 ml of 30% hydrogen peroxide in 175 ml of acetic acid to give 7.9 g of 1-methyl-3-(4-cyano-3-(methylsulfinyl)-5-isothiazolyl)urea, m.p. 241° (decomposes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]2[C:5]=1[CH2:6][O:7][C:8]2=[O:11]
Reactant: O=C1OCc2c1cc(Cl)cc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc2c1COC2=O
Yield: 89.7 %

Procedure:
A suspension of 6-chloro-4-nitroisobenzofuran-1(3H)-one (5 g, 23.5 mmol) and Pd/C (10%, 500 mg) in EtOAc (250 mL) was stirred at 25° C. under 1 atm of hydrogen for 12 hr. The mixture was filtered, and the cake was washed with EtOAc (100 mL×3). The filtrate was concentrated to give the title compound (3.87 g, yield 90%) as a white solid. LC-MS (ESI) m/z: 184 (M+1)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=O)[CH2:4][CH2:3]1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:2](=[O:1])(=[O:15])[CH2:3][CH2:4]2)=[O:14])=[CH:22][CH:23]=1
Reactant: O=C(O)C1CCS(=O)(=O)c2ccccc21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCS(=O)(=O)c3ccccc32)cc1
Yield: 12.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,1-dioxothiochroman-4-carboxylic acid (0.26 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.31 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-isopropylphenyl)-1,1-dioxothiochroman-4-carboxamide (0.07 g) was obtained. melting point: 185-187° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:42][CH:43]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate (660 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid (580 mg, yield 92%) as colorless crystals. m.p. 116-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12]O>>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: COC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 3,4-dihydroxybenzoic acid (5.0 g, 32 mmol) in methanol (80 mL) containing c-H2SO4 (3 mL) was heated at reflux for 4 hrs and cooled to room temperature. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with water, saturated NaHCO3, and brine. The organic fraction was dried over MgSO4 and concentrated to give 3,4-dihydroxybenzoic acid methyl ester (5.2 g, 96%). 1H NMR (DMSO-d6, 600 MHz) δ 9.77 (s, 1H), 9.35 (s, 1H), 7.35 (s, 1H), 7.30 (d, 1H, J=7.8 Hz), 6.79 (d, 1H, J=7.8 Hz), 3.78 (s, 3H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]3=[O:20])[CH2:7][CH2:6]2)[O:4]CC1.CC(C)=O.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1
Reactant: O=c1[nH]c2ccccc2n1C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 74.1 %

Procedure:
To a flask charged with 1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-benzo[d]imidazol-2(3H)-one (1.100 g, 4.01 mmol) were added acetone (7.29 mL) and water (0.729 mL) followed by PPTS (1.310 g, 5.21 mmol). The resulting light brown solution was heated at reflux overnight. Water was then added to the mixture leading to an oiling out of the organics. The mixture was transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The oil thus obtained was purified with a 50 g SNAP column (Biotage) ramping DCM:MeOH:NH4OH (90:10:1) in DCM from 0-35% leading to coelution of product and starting material. The mixture was used in the next step without further purification. The mixture containing 1-(4-oxocyclohexyl)-1H-benzo[d]imidazol-2(3H)-one (0.685 g, 2.97 mmol, 74.2% yield) was obtained as a brown foam. m/z (ESI) 231.2 (M+H)+.
Reaction SMILES: [OH-].[Ca+2].[OH-].[C:4]([O:10][CH3:11])(=[O:9])[CH2:5][C:6]([CH3:8])=[O:7].[C:12](Cl)(=O)[CH2:13]CC.[Cl-].[NH4+].N.Cl>C(Cl)Cl.O>[C:6]([CH2:5][C:4]([O:10][CH3:11])=[O:9])(=[O:7])[CH2:8][CH2:12][CH3:13]
Reactant: COC(=O)CC(C)=O
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: N
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)CC(=O)OC
Reaction time: 2 h
Yield: 92.9 %

Procedure:
77.8 g (1.05 mol) of calcium hydroxide were placed in 550 ml of methylene chloride, and 116 g (1.0 mol) of methyl acetoacetate were added dropwise at 20° to 30° C. over 20 minutes, with vigorous stirring. Stirring was then continued for half an hour. 122.6 g (1.15 mol) of butyryl chloride were then metered into the thick suspension at a temperature of 30° to 35° C. over 1.5 hours. Stirring was then continued for 2 hours at 40° C. 56.2 g (1.05 mol) of ammonium chloride in 350 ml of water were then added to the reaction mixture at 30° C. and the resulting mixture was stirred for half an hour. After the pH had been adjusted to 8.9-9.0 by the addition of aqueous ammonia, the mixture was stirred for a further 3 hours at 30° to 35° C. The reaction mixture was then acidified with concentrated hydrochloric acid (pH 0.5-1.0) and washed with sodium bicarbonate solution and water. After separation of the aqueous phase, the methylene chloride was distilled off on an evaporator. This gave 134 g (GC purity 84%) of methyl butyrylacetate as a yellowish liquid (yield 78%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Reactant: CC(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Temperature: 70 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 1-bromo-3,3-dimethylbutane (0.183 g, 1.11 mmol) in DMF (5.3 mL). Heat at 70° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1×30 mL) and brine (1×30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 368.2 (M+H)+, HRMS calcd for C22H30N3O2 368.2338 (M+H)+, found 368.2321, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=11.1 min, 96.8% purity.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[CH:30]=[CH:25][N:26]=[C:27]([C:14]2[C:9]3[O:8][C:6]4[C:5]([C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:28]=1
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Fc1ccccc1-c1ccnc(Cl)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4F)ccn3)cccc12
Temperature: 25 °C
Yield: 70 %

Procedure:
2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (2.8 g, 9.06 mmol), 2-chloro-4-(2-fluorophenyl)pyridine (2.25 g, 10.84 mmol), tris(dibenzylideneacetone) palladium(0) (0.166 g, 0.181 mmol) and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.297 g, 0.725 mmol) were charged into the reaction vessel with 200 mL of toluene. Potassium phosphate tribasic (6 g, 28.3 mmol) was then dissolved in 25 mL of water and was added to the reaction mixture. The reaction mixture was degassed with nitrogen then was heated to reflux overnight. The reaction mixture was cooled to room temperature. The toluene layer was separated and was dried over magnesium sulfate. This mixture was filtered and concentrated under vacuum. The crude residue was passed through a silica gel column using 15-22.5% ethyl acetate/heptanes. The clean product fractions were evaporated under reduced pressure yielding 8-(4-(2-fluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.247 g, 6.34 mmol, 70% yield) as a white solid.