Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][CH:5]=1.Cl[CH2:18][O:19][CH2:20][CH3:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[CH2:20]([O:19][CH2:18][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:16])[CH2:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][CH:5]=1)[CH3:21]
Reactant: CCOCCl
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOCOc1ccc2c(c1)OC(C)(C)CC2=O
Yield: 83.9 %

Procedure:
A mixture of 40 ml of an 5% sodium hydroxide solution, 60 ml of dichloro methane, 0.5 g (2 millimoles) of triethyl benzyl ammonium chloride and 1.9 g (10 millimoles) of 7-hydroxy-2,2-dimethyl-4-chromanone is intensively stirred at room temperature for 20 minutes, whereupon 2.3 g (2,2 ml, 25 millimoles) of chloromethyl-ethyl-ether are added and the reaction mixture is stirred for an hour. The reaction mixture is worked up according to Example 12. Thus 2.1 g of the desired compound are obtained in the form of a light yellow oil, yield 85%.
Reaction SMILES: C([O-])(O)=O.[Na+].O.[CH3:7][CH:8]([CH2:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14]1)[CH2:9][CH2:10][OH:11].[O-]Cl.[Na+]>[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1.C1(C)C=CC=CC=1>[CH3:7][CH:8]([CH2:12][CH:13]1[CH2:18][CH:17]([CH3:19])[CH2:16][C:15]([CH3:20])([CH3:21])[CH2:14]1)[CH2:9][CH:10]=[O:11]
Reactant: CC(CCO)CC1CC(C)CC(C)(C)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC=O)CC1CC(C)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
KBr (0.6 g, 0.005 mol) and NaHCO3 (6.4 g, 0.076 mol) and 0.8 g (0.00566 mols) 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) were mixed together with water (60 ml), toluene (250 g) and 3-Methyl-4(3,3,5-trimethylcyclohex-1-yl) butan-1-ol (96 g 0.45 mol, purity: 98% sum of the isomers) the reaction temperature maintain 0° C. with continuous stirring. NaOCl (13% w/w aqueous 426.8 g, 0.745 mol) was added to the reaction mass over 2 h. Stirring was continued for another 12 h. The aqueous phase was removed, organic phase was washed with a solution of NaHCO3 and then with water. The organic phase thus obtained was concentrated and crude product purified by fractional distillation to provide 3-Methyl-4(3,3,5-trimethylcyclohexyl) butanal (42.63 g, yield: 45%, GC purity: 96% sum of isomers).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:36]([SH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][S:43][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSCc4ccccc4)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
1-[4′-(3-Methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.26 mmol) and potassium carbonate (0.054 g, 0.39 mmol) were stirred in DMF (5 mL) and then benzyl mercaptan (0.040 mL, 0.31 mmol) was added. After stirring 4 hours at room temperature an additional portion of benzyl mercaptan (0.010 mL) was added. After 1 hour the reaction was submitted to standard aqueous workup and purified on silica gel (0-40% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [OH:1]S(O)(=O)=O.ON=[CH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([CH3:20])[CH3:19])=[O:10]>O>[CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:9](=[O:10])[C:8]2=[O:1])([CH3:20])[CH3:19]
Reactant: O=S(=O)(O)O
Reactant: CC(C)c1ccccc1NC(=O)C=NO
Solvent: O
Product: CC(C)c1cccc2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a stirred solution of concentrated H2SO4 (210 ml) and H2O (50 ml), was added over 20 min (26.7 g, 0.13 mol) of 2-(hydroxyimino)-N-(2-isopropylphenyl)acetamide. The mixture was stirred at 75° C. for 2 hr, cooled and poured onto cracked ice. After standing for 15 min, it was extracted with EtOAc, washed with water, dried over MgSO4, and concentrated. Air drying afforded (23.8 g, 97%) of crude product). 1H NMR (300 MHz, CDCl3) δ 8.15 (b, NH), 7.49 (d, 2H), 7.11 (t, 1H), 2.87 (m, 1H), 1.30 (d, 6H); ESI (+) MS m/e=190 (MH+), ESI (−) MS m/e=188 (MH−).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:16](O)[CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][O:11][C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cl
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Yield: 57.4 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 40 (100 g, 507 mmol) and ethylene glycol (300 ml) was passed dry HCl gas for 1 hr. During HCl gas bubbling the temperature rose to 60° C. The crude reaction mass was poured onto ice (2 Kg). Crude 41 was filtered, dried and purified by column chromatography on silica gel using hexane:ethyl acetate (95:5) to give pure 41 (70 g, 57.4%) as a white powder. M.p: 73.5-75.5° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](=[O:42])[N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][C:30]=2[CH:34]=[O:35])[CH:28]=1)#[N:16].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24](=[O:42])[N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=[C:27]([C:29]2[CH:33]=[CH:32][S:31][C:30]=2[CH2:34][OH:35])[CH:28]=1)#[N:16]
Reactant: N#Cc1ccccc1-c1cc(-c2ccsc2C=O)cn(-c2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(-c2ccsc2CO)cn(-c2ccccc2)c1=O
Reaction time: 1 h
Yield: 79.6 %

Procedure:
Sodium triacetoxyborohydride (10 mg) was added to a solution of 10 mg of 3-(2-cyanophenyl)-5-(2-formylthiophen-3-yl)-1-phenyl-1,2-dihydropyridin-2-one in 2 ml of tetrahydrofuran and the mixture was stirred for 1 hour. A 10% aqueous solution of sodium carbonate was added thereto, the mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by an NH silica gel column chromatography to give 8 mg of the title compound as white powder.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: NCc1cccc(C(F)(F)F)c1
Product: Nc1cc2ncnc(NCc3cccc(C(F)(F)F)c3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (225 mg, 1.17 mmole) and 3-(trifluoromethyl)benzylamine (0.63 mL, 4.40 mmole) is stirred under N2 at 140° C. for 1 h. The resulting product is chromatographed on silica gel (3-5% EtOH/EtOAc) to give 7-amino-4-[(3-trifluoromethylphenyl)methylamino]pyrido[4,3-d]pyrimidine (0.24 g, 63%) as a light brown solid. 1H NMR (DMSO) δ 9.10 (1H, s), 8.92 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.71 (1H, s), 7.66 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=7.8 Hz), 7.57 (1H, t, J=7.6 Hz), 6.49 (2H, brs), 6.38 (1H, s), 4.82 (2H, d, J=5.8 Hz).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=2[S:26][CH:25]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[C:32]2[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]3[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]4[N:85]=[CH:86][NH:82][N:83]=4)[CH:92]=3)=[O:36])=[N:28][C:27]=2[S:26][CH:25]=1
Reactant: CCOC(=O)c1nc2scc(-c3ccccc3F)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccccc3F)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22r and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(2-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 69 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (59.0 mg, 46%).
Reaction SMILES: [CH3:1][N:2]([CH:14]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[C:18]1=[O:31])[CH2:15][CH3:16])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[ClH:32].O1CCC[CH2:34]1>>[ClH:32].[CH3:1][N:2]([CH:14]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[CH:23]=2)[C:18]1=[O:31])[CH2:15][CH3:16])[CH2:3][C:12]1[C:7]2[C:8](=[CH:13][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][C:11]=1[CH3:34]
Reactant: CCC(N1CCc2cc(OC)c(OC)cc2C1=O)N(C)c1c(C)ccc2ccccc12
Reactant: C1CCOC1
Agent: Cl
Product: CCC(N(C)Cc1c(C)ccc2ccccc12)N1CCc2cc(OC)c(OC)cc2C1=O
Temperature: 25 °C

Procedure:
To a solution of 1.3 g (3 mmol) of 2-[N-methyl-N-(2-methyl-naphth-1-yl)-amino-prop-3-yl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolin-1-one in 50 ml of tetrahydrofuran, 4.5 ml of a 1 molar borane-tetrahydrofuran complex in tetrahydrofuran are added and 0.55 ml (4.5 mmol) of boron trifluoride-diethyl etherate complex are added dropwise with stirring at ambient temperature. After 3 hours' reaction time, 5 ml of 6 molar hydrochloric acid are added dropwise, the mixture is refluxed for 0.5 hours and then the solvent is evaporated off in vacuo. The aqueous portion remaining is made alkaline with 2 molar sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, evaporated down in vacuo and purified over a silica gel column (0.063-0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%). The hydrochloride is precipitated from a solution in acetone with ethereal hydrochloric acid and is then recrystallised from acetone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][CH2:11][CH3:12])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(NC(=O)c2cnc(C)cn2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-methylpyrazine-5-carboxylic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 12.82 (s, 1H), 9.36 (s, 1H), 8.90 (d, J=9.6, 1H), 8.56 (d, J=1.0. 1H), 7.74 (d, J=2.7, 1H), 7.32-7.29 (m, 1H), 4.11 (q, J=6.9, 2H), 2.71 (s, 3H), 1.46 (t, J=6.9, 3H).
Reaction SMILES: O[C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.P(Cl)(Cl)([Cl:16])=O.C(#N)C>CN(C)C=O>[Cl:16][C:2]1[C:3]2[N:13]=[CH:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: CSc1nc(O)c2ncccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: CSc1nc(Cl)c2ncccc2n1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
A mixture of 19.0 g (98 mmol) of 4-hydroxy-2-methylthiopyrido[3,2-d]pyrimidine, 36.5 mL (60 g, 390 mmol) of phosphorus oxychloride and 200 mL of acetonitrile was prepared and heated to reflux with stirring. Since not much appeared to happen, about 1 mL of N,N-dimethylformamide was added. The solids then all went into solution in about 10 min. After about 2 hours, the volatiles were removed by evaporation under reduced pressure and the residue was diluted with dichloromethane. The resulting mixture was carefully washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with hexane and the solids were recovered by filtration and dried to obtain 17.8 g of the title compound melting at 120°-121° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[N:9]1([C:15]2[N:16]=[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:18][C:19](=[O:21])[CH:20]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O1CCOCC1>[CH3:1][N:18]1[C:19](=[O:21])[CH:20]=[C:15]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:16]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Temperature: 40 °C
Yield: 38 %

Procedure:
330 mg of potassium carbonate and 0.15 ml of methyl iodide are added to a solution of 500 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (prepared in step 1d of example 1d) in 1.5 ml of dioxane. The reaction mixture is heated at 40° C. for 16 hours and then cooled to ambient temperature. The suspension is filtered through sintered glass and then rinsed with dioxane, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column, elution being carried out with a mixture of dichloromethane, acetonitrile and methanol (98/01/01, 96/02/02, then 90/05/05 V/V/V). 200 mg of ethyl [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[Cl:19][CH2:20][CH2:21][O:22][CH2:23][C:24](Cl)=[O:25]>C1(C)C=CC=CC=1>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([NH2:18])=[O:17])[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH2:21][CH2:20][Cl:19])[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Reactant: O=C(Cl)COCCCl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(Br)nc2c1[nH]c1cc(NC(=O)COCCCl)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
A mixture of 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.655 mmol) and 2-(2-chloroethoxy)acetyl chloride (113 mg, 0.721 mmol) in toluene (1.5 mL) was stirred at 100° C. for 12 hr. The solvent was removed and preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10-60% B at 42 mL/min over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH left 2-bromo-7-(2-(2-chloroethoxy)acetamido)-5H-pyrido[3,2-b]indole-4-carboxamide (80 mg, 0.19 mmol, 29% yield) as a yellow solid. MS (ESI) m/z 426.97 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 9.99 (1H, s), 8.44 (1H, br. s.), 8.24 (1H, s),8.09 (1H, d, J=8.55 Hz), 7.98 (1H, s), 7.91 (1H, br. s.), 7.49 (1H, d, J=9.46 Hz), 4.21 (2H, s), 3.86 (4H, s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 178 (80 mg, 0.15 mmol) is treated with acid chloride 8 (57 mg, 0.21 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:30]([O:32]CC)=[O:31])=[C:21]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])[N:22]=3)[CH2:14][C@H:13]2[O:35][CH:36]([CH3:38])[CH3:37])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].O.[OH-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:30]([OH:32])=[O:31])=[C:21]([C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][CH3:28])[N:22]=3)[CH2:14][C@H:13]2[O:35][CH:36]([CH3:37])[CH3:38])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC(C)C)C2)nc1C(=O)NCCOC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C(=O)NCCOC)c(C(=O)O)s3)C[C@H]2OC(C)C)nc1Cl
Yield: 97.6 %

Procedure:
Ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-isopropoxypiperidin-1-yl)-4-(2-methoxyethylcarbamoyl)-1,3-thiazole-5-carboxylate obtained in Example (149b) (0.180 g, 0.315 mmol) was dissolved in tetrahydrofuran (5 mL). The solution was subjected to the same operation as in Example (1i) using lithium hydroxide monohydrate (52.9 g, 1.26 mmol) and water (5 mL), to obtain 0.167 g of the title compound as a white solid (98%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].C1COCC1>>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Brc1ccccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 15.7 mL of 1.6 M n-butyllithium (25.1 mmol) in anhydrous other (25 mL) was stirred under Ar at −78° C. and to this was added a solution of 2-bromopyridine (3.97 g, 25.1 mmol) in anhydrous other (12.5 mL). The resulting orange solution was stirred for 2 h, and trimethyltin chloride in THF (26.0 mmol, 26 and, 1.0 M) added over 30 min. The reaction was stirred for 1 h at −78° C. then warmed to room temperature over 1 h, filtered and the filtrate evaporated. Distillation afforded 3.1 g (51%) of the title compound as a colorless liquid which solidified in the receiver flask. B.p. 65° C./2 mm Hg; Literature B.p. 75° C./4 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][C:7]#N)[O:3]1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:31]>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:19])[O:18][CH:15]([CH:16]=[CH2:17])[CH:4]([CH:5]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:6][CH:7]=[O:31])[O:3]1
Reactant: C=CC1OC(C)(C)OC1C(CC#N)OC(C)OCC
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CC1OC(C)(C)OC1C(CC=O)OC(C)OCC
Temperature: -78 °C
Reaction time: 1.67 h

Procedure:
4,5-(Dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenenitrile (1.40 g) was dissolved in 13 ml of dry toluene, and 2.0 ml of 2N diisobutyl aluminum hydride was added dropwise at -78° C. After stirring at -78° C. for 100 minutes, the temperature was then elevated to 0° C., and 10% dilute sulfuric acid was then gradually added. The reaction mixture was diluted with ether, and the organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.61 g of 4,5-(dimethylmethylenedioxy)-3-(1-ethoxyethoxy)-6-heptenal.
Reaction SMILES: Br[CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]>CN(C=O)C.O>[CH2:6]([CH:2]1[O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:3]1=[O:4])[CH3:7]
Reactant: Nc1ccccc1O
Reactant: CCC(Br)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCC1Oc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromobutanoic acid (11 mmol, 2145 mg) in DMF (10 ml) was added EDC (12 mmol, 2.3 g) and HOBt (5 mmol, 675 mg) followed by the addition of 2-aminophenol (10 mmol, 1091 mg). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. To the crude product in DMF (5 ml) was added K2CO3 (1.6 g) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. Purification by column chromatography gave the desired product as a white solid. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=178; tR=2.36.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Br)ccc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Yield: 87.2 %

Procedure:
A RBF, fitted with a reflux condenser, was charged with (E)-ethyl 3-(5-(benzylthio)-2-((5-bromo-2-methoxyphenyl)amino)phenyl)acrylate (6.92 g, 13.88 mmol) and MeOH (69.4 ml) to give a yellow suspension. Sodium methoxide (0.5N solution in methanol) (11.11 ml, 5.55 mmol) was added and the reaction was heated at 70° C. overnight. The reaction was cooled to RT and the solids were filtered over a fit and washed well with MeOH to yield 6-(benzylthio)-1-(5-bromo-2-methoxyphenyl)quinolin-2(1H)-one (5.48 g, 12.11 mmol, 87 Yo yield) as a tan solid. MS (ESI, pos. ion) m/z: [M+1] 452.0
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
To a solution of 2-bromo-N-(2-(phenylamino)phenyl)benzamide (10.7 g, 29 mmol) in anhydrous 1,4-dioxane (˜100 mL), was added POCl3 (6.92 g, 45 mmol) slowly. The whole was heated to about 100° C. under argon overnight. After cooling the mixture to room temperature, the mixture was poured into ice (˜150 g), and then neutralized with NaHCO3. After filtration, the solid was collected then dissolved in dichloromethane (˜250 mL), which was washed with water (˜250 mL). The aqueous solution was extracted with dichloromethane (˜100 mL×2). The organic phase was combined and dried over Na2SO4, concentrated, and recrystallized in dichloromethane/hexanes to give a light grey solid (6.68 g, 66% yield).