Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C@@H:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=1[NH:28][C@@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Yield: 100.2 %

Procedure:
In a dry flask equipped with a Dean-Stark trap and reflux condenser, ethyl 1-(t-butoxycarbonyl)-3-oxo-4-piperidinecarboxylate (4.19 g, 15.4 mmol) was dissolved in toluene (50 mL). (R)-(+)-a-Methylbenzylamine (1.91 g, 15.8 mmol) and p-toluenesulfonic acid monohydrate (0.019 g, 0.1 mmol) were added and the mixture heated to reflux for 6 hours. The crude reaction mixture was concentrated in vacuo to give the desired amine (5.78 g, 100%) as a thick orange oil. 1H NMR (300 MHz, CDCl3), δ: 7.36 (t, J=3, 2H), 7.33 (t, J=4, 1H), 7.31 (dd, J=3, J′=4, 2H), 4.59 (m, 1H), 4.16 (q, J=7, 2H), 3.59 (m, 2H), 2.34 (m, 2H), 1.58 (bs, 2H), 1.52 (d, J=3, 3H), 1.29 (s, 9H), 1.26 (t, 3H, J=7). MS (ESI), m+/z: (M+H)+=375.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(3-fluoro-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6 Hz), 7.42 (dd, 1H, J=3.5 Hz, 1.17 Hz), 7.36 (dd, 1H, J=5.1 Hz, 1.17 Hz), 7.18–7.10 (m, 4H), 6.82 (d, 2H, J=8.6 Hz), 6.76–6.60 (m, 3H), 4.21 (t, 2H, J=6.3 Hz), 3.26 (d, 1H, J=14.1 Hz), 3.12 (d, 1H, J=14.1 Hz), 3.07 (t, 2H, J=6.3 Hz), 2.73 (s, 3H), 1.45 (s, 3H). HRMS (ES+) m/z exact mass calcd for C32H28FNO5S 558.1750, found 558.1743.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[C:21]=1[CH3:22]
Reactant: COC[C@H](N)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of (R)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (270 mg, 0.9 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (258 mg, 1.08 mmol) and DIPEA (308 μL, 1.8 mmol) in n-butanol (5 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford [(R)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine: LCMS (Method C): RT 3.38 min [M+H]+ 502.2.
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH:12]C1C(C(F)(F)F)=CC([N+]([O-])=O)=CC=1[N+]([O-])=O.[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38]Cl.[H-].[Na+]>C1COCC1.C(Cl)(Cl)(Cl)Cl>[S:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[S:38][NH2:12]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Reactant: ClSc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: NSc1nc2ccccc2s1
Reaction time: 3 h

Procedure:
The sulfenylated diphenylamine was prepared from N-[2-chloro-5-(trifluoromethyl)phenyl]-2,4-dinitro-6-(trifluoromethyl)benzenamine (4.3 g, 0.010 mol) in dry THF (20 ml), 2-benzothiazolesulfenyl chloride [2.0 g, 0.010 mol, Zh. Obshch. Khim. 45, 1127 (1975)] in carbon tetrachloride (45 ml) and 50% NaH (0.53 g, 0.011 mol) as outlined in Example 1 with the following exception: the reaction mixture was stirred at 0° for 3 hours and then at room temperature for 16 hours. Purification by dry column chromatography (silica gel, hexane/ethyl acetate, 8.5/1.5) gave N-[2-chloro-5-(trifluoromethyl)-phenyl]-N-[2,4-dinitro-6-trifluoromethyl)phenyl]-2-benzothiazolesulfenamide as a red-orange glass: mp 46°-53°; NMR (CDCl3) δ 7.20-8.25 (m, 7H, Ar-H), 8.8-9.05 (AB quartet, 1.6H, Ar-H); IR(KBr) 1600, 1540, 1500, 1330, 1270, 1170, 1150, 1130 and 1070 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:27](/B(O)O)=[CH:28]\[CH3:29].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2/[CH:27]=[CH:28]/[CH3:29])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Reactant: C/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: C/C=C/c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccc(F)cc2C1
Yield: 50.9 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and trans-1-propen-1-ylboronic acid (294 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (153) as white solid (165 mg, 51%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][C:21]1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38](N)[CH2:39][CH2:40][CH2:41][CH2:42]C>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[NH:13][S:14]([CH2:17][C:18]([NH:20][CH2:21][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:19])(=[O:16])=[O:15])([CH3:11])[CH3:12]
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with N-hexylamine, mp 125°-127° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH3:19][OH:20].[H-].[Na+]>CS(C)=O>[CH3:19][O:20][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCC(Oc1ccc(Cl)nc1C)[C@H]1CCNC1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC(Oc1ccc(OC)nc1C)[C@H]1CCNC1
Temperature: 100 °C
Yield: 65.1 %

Procedure:
Add (3S)-3-(1-(6-chloro-2-methyl-3-pyridyloxy)-butyl)-pyrrolidine (S-2) (0.65 g, 2.44 mmol), DMSO (9.75 mL), methanol (0.493 mL, 12.18 mmol), and sodium hydride (0.390 g, 9.75 mmol) to a reaction vial. Evacuate the vial and purge with nitrogen. Heat the mixture at 100° C. over night. Pour the reaction mixture onto an SCX column and rinse with methanol. Attach the SCX column on top of a silica gel column and elute with 5-30% of NH3OH/ethanol (1:9) in chloroform to obtain 0.420 g (65%) of (3S)-3-(1-(6-methoxy-2-methyl-3-pyridyloxy)-butyl)-pyrrolidine
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: C#C[C@@H](C)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-but-3-yn-2-ol (37 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and CuI (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after a silica gel column with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 21 mg, 48%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])O.[NH4+].O>C(#N)C>[C:1]([NH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@@H](Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A mixture of 2.8 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate in 17 cm3 of acetonitrile [lacuna] to which is added 3.95 g of ammonium hydrogen carbonate and 35 cm3 of water at a pH in the region of 8. 0.017 g of type-II α-chymotrypsin is then introduced and the mixture is left stirring at room temperature for 1 hour 15 min, while measuring the GpH regularly. After this reaction time, the pH is less than 8, a further 0.017 g of type-II α-chymotrypsin is added and stirring of the reaction medium is continued for 2 hours 45 min. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate; the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.4 g of ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the form of white crystals melting at 110° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 35.5 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-bromobenzaldehyde 1.37 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 250 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.72 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21]Cl.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][O:16][CH2:19][O:20][CH3:21])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CC(C)(CO)c1ccc(-c2ccc(Br)cc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC(C)(C)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
2-(4′-Bromobiphenyl-4-yl)-2-methylpropan-1-ol (5.0 g, 16 mmol) was dissolved in toluene (40 mL), and chloromethyl methyl ether (2.5 mL, 33 mmol) and N,N-diisopropylethylamine (3.6 mL, 21 mmol) were added, followed by stirring at room temperature for 17 hours. After the reaction solution was diluted with ethyl acetate, the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.45 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (5.8 g, 16 mmol) as a white solid (yield 100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]1([C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)[OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[C:2]12([O:14][C:13]3[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=3[O:1]1)[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)Oc1ccccc1O2

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (22.75 g) and pyrocatechol (14.75 g) in toluene (200 mL) was added catalytic amount of para-toluenesulfonic acid monohydrate and the mixture was stirred under reflux and a Dean-Stark trap overnight. The mixture was diluted with diethyl ether (600 mL) and washed with aqueous NaHCO3, water and brine. After drying over Na2SO4, the mixture was filtered and the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.06 g, 0.16 mmol) was suspended in dry CH2Cl2 (1.5 mL) under an argon atmosphere in a screw cap vessel. K2CO3 (0.044 g, 0.32 mmol) was added followed by benzyl chloroformate (0.046 mL, 0.032 mmol). The suspension was stirred for 18 h at room temperature. H2O and CH2Cl2 were added and the phases were separated. The water phase was washed with CH2Cl2 (×2) and the combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:4 as the eluent. This afforded the title compound as yellow oil. 13C NMR (CD3OD) δ 198.3, 161.0 (dd), 157.8 (dd), 155.8, 151.1, 141.1, 138.0, 136.2, 135.0, 132.8, 132.7, 129.5, 129.1, 129.0, 128.7, 127.3 (dd), 126.0 (dd), 122.3, 120.6, 116.7, 112.9, 112.6 (dd), 105.7 (dd), 67.6, 19.7
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:10]1[NH:11][C:12](=O)[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]>C(#N)C>[CH2:6]([C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc2cc(C)[nH]c2c(=O)[nH]1
Solvent: CC#N
Product: CCCCc1nc(Cl)c2[nH]c(C)cc2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 37.9 %

Procedure:
Phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise to a solution of 2-butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (37.5 g, 0.183 mol) in acetonitrile (750 mL) under an atmosphere of nitrogen. The reaction mixture was heated at reflux overnight. After cooling to room temperature an additional portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for a further 3.5 hours. The reaction was cooled to room temperature again and a further portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for 3 hours. The reaction mixture was allowed to stand at room temperature overnight then heated at reflux for 3.5 hours. The reaction mixture was cooled then concentrated. The residue was cooled in an ice-bath and ice-cold water (650 mL) was added carefully. The pH was adjusted to 8 using aqueous potassium hydroxide solution and then mixture stirred for 45 minutes. The mixture was partitioned between dichloromethane (1000 mL) and water (1000 mL). The aqueous layer and solid material was re-extracted with dichloromethane (2×500 mL). The combined organic layers were dried (Na2SO4) and filtered through a plug of neutral alumina. The filtrate was concentrated to a yellow oil, a seed crystal and hexane were added. The solid material was filtered, washed with hexane and dried to give the title compound as an off-white solid (15.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH2:20][CH3:21])[C:18](=[O:22])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[NH:34]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH2:20][CH3:21])[C:18](=[O:22])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:36]=[N:35]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCn1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Product: CCn1c(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 269. MS: (ESI+) 380.2
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[O:27][CH3:28])=[O:7])=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:11]1[C:10]([O:27][CH3:28])=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:14]=[C:13]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
step 5—To a solution of 104 (0.10 g, 0.25 mmol) in pyridine (2 mL) at 0° C. was added methanesulfonyl chloride (0.034 g, 0.30 mmol). Stirring was continued at 0° C. for two h, then at RT for an additional two h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography (EtOAc/hexane) to afford 0.12 g of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylaminobenzamide (106) as a colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1(O)[CH2:14][CH2:13]1)=[O:10].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.CCN(CC)CC>C(Cl)(Cl)Cl.C1COCC1>[Br:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: c1c[nH]cn1
Reactant: O=C(CCCBr)NC1(O)CC1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CCCBr)NC1(n2ccnc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, thionyl chloride (2.72 g, 0.023 mmol) is added to the crude 4-bromo-N-(1-hydroxy-cyclopropyl)-butyramide a16 (2.3 g, 9.13 mmol) in CHCl3 (20 ml). After 3 h at room temperature, the light orange reaction mixture is evaporated, diluted in THF (5 ml) and added into another 50 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, containing a solution of imidazole (0.622 g, 9.1 mmol) and Et3N (2.8 g) in THF (20 ml) at room temperature. After 6 h, the reaction mixture is cooled down to 0° C., filtrated and concentrated in vacuo to give the crude 4-bromo-N-(1-imidazol-1-yl-cyclopropyl)-butyramide a18 (2.76 g) which is used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.S(Cl)(Cl)=O.[CH3:26]O>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[C:14]([O:16][CH3:26])=[O:15])=[C:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1C1CC1
Yield: 31 %

Procedure:
To a solution of Example 26 (15 mg, 0.05 mmol) in MeOH (10 mL) was added thionyl chloride (1 mL) at rt. The reaction was stirred at reflux for 2 days. The solution was concentrated and purified by prep-HPLC to give 5 mg (31%) of the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 0.70-0.73 (2H, m), 1.0-1.04 (2H, m), 2.0-2.04 (1H, m), 3.96 (2H, s), 4.74 (3H, s), 7.08 (1H, d, J=1.6 Hz), 7.14 (1H, dd, J=2.0, 8.4 Hz), 7.25 (1H, d, J=8.0 Hz), 7.91 (1H, d, J=4.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.13 (1H, s). [M+H] Calc'd for C17H17ClN2O2, 317. found, 317.