Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:7]2[CH2:8][CH2:9][C:4]3[CH:3]=[CH:2][S:1][C:5]=3[C:6]2=[O:10])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: O=C1NCCc2ccsc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1c2sccc2CCN1c1cccnc1
Yield: 39.3 %

Procedure:
Using analogous reaction conditions as described in example 1, 5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (I-5d: 110 mg, 0.718 mmol) was reacted with 3-bromo-pyridine (136 mg, 0.861 mmol), 1,4-dioxane (5 mL), copper iodide (13.5 mg, 0.071 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.033 mL, 0.215 mmol) and potassium phosphate (456 mg, 2.15 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 65 mg of the product (39.3% yield).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C(O)(=O)C(O)=O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 86 %

Procedure:
20.75 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 100 ml of toluene, and 1.00 g of oxalic acid was added thereto. The resulting mixture was refluxed for 1.25 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 17.13 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =3.7 : 1) (purity: 97.8%). The product was further column chromatographed to obtain a purified product having a refractive index (nD20) of 1.5274. The yield was 86.0%.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[S:12][C:11]=2[CH3:16])(O)[CH:7]([C:17]2[CH:21]=[C:20]([CH3:22])[S:19][C:18]=2[CH3:23])[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>>[CH2:1]([N:4]1[C:8]([C:10]2[CH:14]=[C:13]([CH3:15])[S:12][C:11]=2[CH3:16])=[C:7]([C:17]2[CH:21]=[C:20]([CH3:22])[S:19][C:18]=2[CH3:23])[O:6][C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)OC(c2cc(C)sc2C)C1(O)c1cc(C)sc1C
Solvent: O=C(O)C(F)(F)F
Product: C=CCn1c(-c2cc(C)sc2C)c(-c2cc(C)sc2C)oc1=O

Procedure:
A solution of 0.9 g (2.5 mmol) of 1,3-oxazolane-2-one 7 in 25 ml (0.325 mol) of CF3COOH was stirred at ˜25° C. for 3-3.5 hours. The solvent was evaporated under vacuum and the residue was crystallized from ethanol. The yield was 0.63 g of oxazole 8 (73%), Tmelt=103-104° C. The results found (%): C, 62.43; H, 5.62; S, 18.78. C18H19NO2S2. The results calculated (%): C, 62.58; H, 5.54; S, 18.56. 1H NMR spectrum (DMSO-d6, δ, ppm): 1.99 (s, 3H, CH3); 2.12 (s, 3H, CH3); 2.27 (s, 3H, CH3); 2.32 (s, 3H, CH3); 4.03 (d, 2H, CH2, J=6 Hz); 4.93 (d, 1H, CH, J=17 Hz); 5.09 (d, 1H, CH, J=10 Hz); 5.73 (m, 1H, CH); 6.37 (s, 1H, CH); 6.74 (s, 1H, CH).
Reaction SMILES: N1C=CC=CC=1.O(S(C)(=O)=O)S(C)(=O)=O.[CH3:16][O:17][C:18]([C:20]1[CH:24]=[C:23]([Br:25])[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)O)=[O:19].[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[F:46])[NH2:42]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O.[Cl-].[Na+].O>[CH3:16][O:17][C:18]([C:20]1[CH:24]=[C:23]([Br:25])[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[CH:29]([NH:42][C:41]1[CH:43]=[CH:44][C:45]([F:46])=[C:39]([Cl:38])[CH:40]=1)[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:19]
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)n(C(C)C)c1C(Nc1ccc(F)c(Cl)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
Pyridine (5.59 mmol), DMAP (0.486 mmol) and then Ms2O (4.22 mmol) were added to a solution of 5-bromo-2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (step D3) (1.622 mmol) in CH2Cl2 (20 mL) and the reaction mixture was stirred at rt 17.5 h. The reaction mixture was diluted with H2O/brine and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was diluted with CH2Cl2 (20 mL) and 3-chloro-4-fluoroaniline [367-21-5] (1.865 mmol) was added and the mixture was stirred at rt for 20.5 h. The reaction mixture was diluted with H2O/brine and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a yellow foam. tR: 6.29 min (HPLC 1); ESI-MS: tR=1.57 min, [M+H]+ 513/515/517 (LC-MS 1); TLC: Rf=0.45 (1:6 EtOAc/heptanes).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].O.S(=O)(=O)(O)[OH:20]>C([O-])(=O)C>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:14][C:13]2=[O:15])(=[O:20])[CH3:17]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Agent: CC(=O)[O-]
Solvent: O
Product: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetate acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid. CI MASS SPEC 245(MH+).
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.O>[S:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=2[Cl:18])=[CH:7][CH:8]=1)(=[O:10])(=[O:2])[NH2:11]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 2 h

Procedure:
10 g (60mmol) of sulfanilamide are suspended in 150 ml of dioxane and 4.6 g (60 mmol) of pyridine are added. 12.2 g (60 mmol) of 2,4-dichloro-benzoyl chloride are then added at 0° C., and stirring is continued for 2 hours at room temperature. The mixture is stirred in 200 ml of water, and the precipitate which separates out is filtered off with suction and dried;
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[ClH:11].O=[C:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19](OC)=[O:20].[OH-].[NH4+]>S(=O)(=O)(O)O>[ClH:11].[CH2:18]1[CH2:17][NH:16][CH2:15][C:14]2[C:19](=[O:20])[O:10][C:5]3[CH:4]=[C:3]4[C:8]([O:9][CH2:1][O:2]4)=[CH:7][C:6]=3[C:13]1=2
Reactant: Oc1ccc2c(c1)OCO2
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=c1oc2cc3c(cc2c2c1CNCC2)OCO3
Temperature: 25 °C
Reaction time: 64 h
Yield: 47.1 %

Procedure:
A mixture of 3,4-methylenedioxyphenol (125 g, 0.91 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (125 g, 0.65 moles) is cooled in ice and treated over one hour with 600 ml of 72% sulfuric acid. The mixture is then stirred at room temperature for 64 hours. Ice/water (1.0 kg) is added, followed by conc. ammonium hydroxide, until the pH of the mixture is 9.0. The crude product is filtered, stirred briefly in 2.5% aqueous sodium hydroxide (1.0 l), and refiltered. Several recrystallizations from dilute aqueous hydrochloric acid yielded the product (86.2 g) as the hydrochloride, mp 258°-259° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[Cl:9][C:10]1[C:15]([NH2:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(CC)CC)C>O>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:15]=1[NH2:16]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1c(Cl)ncnc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A mixture of 3.7 parts of 2-pyridinemethanamine, 4.1 parts of 4,6-dichloropyrimidin-5-amine, 3.03 parts of N,N-diethylethanamine and 150 parts of water was stirred for 8 hours at room temperature. After cooling, the whole was stirred overnight. The product was filtered off, washed with water and dried overnight in vacuo at 80° C., yielding 5.35 parts (90.8%) of 6-chloro-N4 -(2-pyridinylmethyl)-4,5-pyrimidinediamine; mp. 140.3° C. (interm. 1).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([CH:42]=[O:43])[CH:41]=1)[C:37]#[N:38].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:37]([C:36]1[CH:35]=[C:34]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:41]=[C:40]([CH:42]=[O:43])[CH:39]=1)#[N:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: N#Cc1cc(Br)cc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C#N)cc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (46 mg, 0.1 mmol) in dioxane (2.0 mL, 0.7 mL) was added 3-bromo-5-formylbenzonitrile (68 mg, 0.3 mmol) and K2CO3 (83 mg, 0.6 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (11 mg, 0.01 mmol). The reaction was heated in a microwave for 20 min at 160° C. It was then purified by Gilson Preparatory HPLC to give 5-(3-cyano-5-formylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[C:7]=2[CH:24]=1)#[N:2].C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Li+]>CCOCC.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:12][F:13])([CH2:14][F:15])[CH:9]=[C:8]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=CC(CF)(CF)O2
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [Cl-]
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)C(c1ccccn1)=CC(CF)(CF)O2
Yield: 82.5 %

Procedure:
A mixture of 120 mg of 6-cyano-4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-2H-1-benzopyran, 87 mg of 2-trimethylstannylpyridine, 25.4 mg of tris-dibenzylidene acetone chloroform dipalladium (O), 12.8 mg of triphenylphosphine, 110 mg of lithium chloride and 6 ml of dry tetrahydrofuran was refluxed for 6.5 hours. After cooling, ether was added and the mixture was filtered using Celite. After the organic layer of the mother liquor was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, CH2Cl2) to obtain 80 mg of oily 6-cyano-2,2-bisfluoromethyl-4-(2-pyridyl)-2H-1-benzopyran represented by the following formula.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[S:5][C:6]=1[CH2:7][CH3:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:39][C@H:40]1[C:45]([F:47])([F:46])[CH2:44][CH2:43][CH2:42][C@H:41]1[NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:51]([O:50][C:49](=[O:55])[NH:48][C@@H:41]1[CH2:42][CH2:43][CH2:44][C:45]([F:47])([F:46])[C@@H:40]1[NH:39][C:9]([C:4]1[S:5][C:6]([CH2:7][CH3:8])=[C:2]([Br:1])[CH:3]=1)=[O:11])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
4-Bromo-5-ethylthiophene-2-carboxylic acid (1.00 g, 4.25 mmol) and BOP (5.64 g, 12.8 mmol) were dissolved in DMF (42.5 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (1.07 g, 4.25 mmol) and diisopropylethyl amine (1.11 mL, 6.38 mmol) and the reaction stirred at room temperature for 64 h. The reaction mixture was diluted with ethyl acetate and washed with water 3×. The organic layer was collected, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-50% EtOAc/Hex) to give the title compound (1.56 g, 3.34 mmol). LRMS (APCI) calc'd for (C18H25BrF2N2O3S) [M+H]+, 467.1; found 466.9. 1H NMR (CDCl3, 500 MHz) δ 7.32 (s, 1H), 6.28 (s, 1H), 4.90 (s, 1H), 4.54 (s, 1H), 4.29 (s, 1H), 2.81 (q, J=7.5, 2H), 2.22 (m, 1H), 1.88 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H), 1.46 (s, 9H), 1.41 (m, 1H), 1.28 (t, J=7.3, 3H)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.O>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: BrCCCOC1CCCCO1
Reactant: Fc1ccc(S)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (120 mg, 3.01 mmol) was added to a solution of 2,4-difluorothiophenol (0.4 g, 2.74 mmol) in THF (10 mL) at 0° C., under argon. The reaction was allowed to warm to RT and 2-(3-bromopropoxy)tetrahydro-2H-pyran (672 mg, 3.01 mmol) added. The reaction was stirred at RT for 4 hours then poured into iced water (50 mL) and extracted into ethyl acetate (50 mL). The organics were washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane, to give the desired compound as a colourless oil (610 mg). 1H NMR δ (CDCl3): 1.49-1.61 (m, 4H), 1.65-1.73 (m, 1H), 1.75-1.90 (m, 3H), 2.96 (t, 2H), 3.46-3.52 (m, 2H), 3.79-3.87 (m, 2H), 4.55-4.56 (m, 1H), 6.80-6.86 (m, 2H), 7.38-7.44 (m, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[C:8](=[O:20])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: COC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2c(s1)C(=O)COc1ccc(C#CC(C)(C)O)cc1-2
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
A mixture of 9-Bromo-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (200 mg, 0.565 mmol), 2-methyl-3-butyn-2-ol (237 mg, 2.825 mmol), Pd(OAc)2 (13 mg, 0.0565 mmol), CuI (21 mg, 0.113 mmol) and PPh3 (45 mg, 0.17 mmol) in Et3N (10 mL) was degassed with N2, and the mixture was stirred at 80° C. overnight. The reaction was cooled to room temperature, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 30%) to give 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester as an off-white solid (81 mg, 40%). LC-MS (ESI & APCI): 358.2 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:17][CH:16]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-hydroxyphthalimide (11.1 g) and p-methoxybenzyl bromide (13.7 ml) in N,N-dimethylformamide (100 ml) is added triethylamine (6.8 g), and the mixture is stirred at room temperature for 1 hour and at 60° to 70° C. for 1 hour. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract solution is washed with diluted hydrochloric acid and water, dried and concentrated under reduced pressure. The residue is crystallized from methanol to give N-p-methoxybenzyloxyphthalimide (17 g). mp. 139°-141° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:26]([CH3:25])(=[O:28])=[O:27])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(C)(=O)=O)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-(3{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and methanesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2H), 7.14 (m, 3H), 6.98 (d, 1H), 6.73 (d, 1H), 4.57 (t, 2H), 4.29 (s, 4H), 4.24 (s, 2H), 3.66 (s, 3H), 3.19 (t, 2H), 2.94 (t, 2H), 2.75 (s, 3H), 2.61 (t, 2H).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:24]=[CH:23][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[N+:20]([O-:22])=[O:21])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.C(O)(=O)C.[BH4-].[Na+]>O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=[O:21])=[CH:14][N:13]=2)=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccc(F)cc2)nc1
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a dimethyl sulfoxide (20.0 mL) solution of 2-(4-fluoro-benzyloxy)-5-((E)-2-nitro-vinyl)-pyridine (2.60 g, 9.48 mmol) described in Manufacturing Example 58-1-3 and acetic acid (3.00 mL) was added sodium borohydride (574 mg, 15.2 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 20 minutes. Water was then added dropwise at room temperature while cooling appropriately to quench sodium borohydride. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (785 mg, 30.0%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C=O)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)c1ccccc1NC(=O)CBr
Reactant: Nc1ccccc1Br
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)CNc1ccccc1Br
Temperature: 0 °C
Yield: 30.3 %

Procedure:
A solution of methyl 2-((bromoacetyl)amino)benzoate (2.0 g, 7.35 mmol) and 2-bromoaniline (3.16 g, 18.4 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with 3×50 mL of ethyl acetate. The layers were separated and the organic layer was dried (MgSO4), filtered, and then concentrated. Purification by chromatography, eluting with hexane-ethyl acetate (3:1), afforded 0.81 g (30%) of the title compound, mp 89°-91° C.: 1H NMR (DMSO-d6) δ11.19 (s, 1H), 8.52 (dd, J=8.4, J=0.8, 1H), 7.90 (dd, J=8.0, J=1.6, 1H), 7.62 (ddd, J=8.8, J=7.6, J=1.6, 1H), 7.47 (dd, J=8.0, J=1.6, 1H), 7.20-7.14 (m, 2H), 6.60 (ddd, J=8.4, J=8.0, J=1.2, 1H), 6.53 (dd, J=8.4, J=1.6, 1H), 6.06 (bt, J=5.6, 1H), 4.00 (d, J=5.6, 2H), 3.73 (s, 3H); 13C NMR (DMSO-d6) δ169.70, 167.01, 144.53, 139.32, 134.16, 132.36, 130.68, 128.67, 123.21, 120.40, 118.35, 116.66, 111.51, 109.04, 52.26, 48.47; MS (El, m/z) 363 (M+). Anal. Calcd for C16H15N2O3Br: C, 52.91; H, 4.16; N, 7.71. Found: C, 52.22; H, 4.05; N, 7.40.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]1([O-:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]1([O-])[CH:30]=CC=C[CH:26]=1.[Na+].[Na+]>>[OH:24][C:18]1[CH:23]=[CH:22][C:21]([C:25]([C:13]2[CH:12]=[C:11]([C:8]([CH3:10])([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH3:9])[CH:16]=[CH:15][C:14]=2[OH:17])([CH3:30])[CH3:26])=[CH:20][CH:19]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)c(C(C)(C)c2ccc(O)cc2)c1

Procedure:
1712 g (5.00 mol) of bisphenol A (BPA, Bayer AG) are melted at 190° C. under a nitrogen atmosphere. 20.4 g (0.05 mol) of solid sodium bisphenolate (Na2BPA) are then added. The phenol formed is removed from the resultant melt at a bottoms temperature of 180-190° C. by distillation under a water-jet vacuum (15-20 mbar). The batch preparation is repeated five times and the crude material, from which the phenol has been removed (after separation of a total of 353 g; 3.75 mol of phenol), is combined.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Clc1ccc2ccccc2n1
Product: Cn1ccc2cc(-c3ccc4ccccc4n3)ccc21

Procedure:
2-(1-Methyl-1H-indol-5-yl)quinoline T453 was prepared using general procedure A from 2-chloroquinoline (32 mg, 0.2 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (51 mg, 0.2 mmol). The product was obtained as off-white solid (22 mg, 42%). 1H NMR (400 MHz, CDCl3): δ 8.43 (dd, J=2.0, 0.8 Hz, 1H), 8.17 (d, J=8.8 Hz, 2H), 8.12 (dd, J=8.8, 2.0 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.80 (dd, J=8.4, 1.6 Hz, 1H), 7.70 (m, 1H), 7.48 (m, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.09 (d, J=3.2 Hz, 1H), 6.60 (dd, J=3.2, 0.8 Hz, 1H), 3.82 (s, 3H); MS (ESI): 259 (M+H+).