Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.Cl.N[OH:27].C(N(CC)CC)C.C1N=CN([C:40]([N:42]2C=NC=C2)=[O:41])C=1>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[C:7]([C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:42][C:40](=[O:27])[O:41][N:21]=4)=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(-c3c(C(F)(F)F)oc4cc(O)ccc4c3=O)cc2)no1

Procedure:
Synthesis: To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzonitrile (see Example 1, step 1 for synthesis) (200 mg, 0.60 mmol) and hydroxylamine hydrochloride (218 mg, 3.13 mmol) in absolute ethanol (2 ml) was added dropwise triethylamine (0.7 ml). The resulting mixture was heated to reflux for 5 hours. The volatiles were evaporated and the residue was dissolved in anhydrous THF (2 ml). CDI (296 mg, 1.83 mmol) was added and the suspension was heated to reflux overnight. The volatiles were evaporated and the residue was purified by prep-TLC (pure EtOAc) and prep-HPLC to afford desired product in Example 9 (35 mg, 15%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Cl:11])[CH3:2]
Reactant: O=C(Cl)CCCCCCl
Reactant: CCOC(CCN)OCC
Product: CCOC(CCNC(=O)CCCCCCl)OCC

Procedure:
This compound was prepared from [3,3-bis(ethyloxy)propyl]amine and 6-chlorohexanoyl chloride using methods similar to Example 669: step 1 to provide a yellow viscous oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.09 Hz, 6 H), 1.28-1.40 (m, 2 H), 1.44-1.56 (m, 2 H), 1.59-1.75 (m, 4 H), 2.04 (t, J=7.23 Hz, 2 H), 3.01-3.09 (m, 2 H), 3.41 (dq, J=9.55, 7.07 Hz, 2 H), 3.50-3.64 (m, 4 H), 4.48 (t, J=5.69 Hz, 1 H), 7.74 (t, J=5.33 Hz, 1 H); ES+ MS: 302 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:33][C:34](Br)=[O:35].[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:33][C:34]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OCc4ccccc4)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OCc4ccccc4)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-7-benzyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[C:2]=[O:3].[OH:24][CH2:25][CH2:26][NH2:27]>C1COCC1>[OH:24][CH2:25][CH2:26][NH:27][C:2]([NH:1][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[O:6]1)=[O:3]
Reactant: O=C=NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)NCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 60 °C
Yield: 20.5 %

Procedure:
A solution of 3-(3-isocyanatomethyl-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (75 mg, 0.24 mmol) and 2-hydroxyethylamine (44.4 μl, 0.74 mmol) in THF (2.0 ml) was stirred at room temperature for 25 minutes and then heated at 60° C. for 5 minutes. The reaction was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to result in a brown-yellow solid. The brown-yellow solid was chromatographed through silica gel column (CHCl3 to 5% MeOH/CHCl3 gradient) to give 1-(2-hydroxy-ethyl)-3-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-ylmethyl]-urea as a yellow solid (18 mg, 20%).
Reaction SMILES: [H-].[Na+].C(OC(=O)[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])C.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.[OH2:22]>CN(C)C=O>[O:21]1[CH2:20][CH:19]1[CH2:17][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:7][CH2:8][C:20]([O:21][CH2:19][CH3:17])=[O:22])=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: O
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.56 g (148.5 mmol) of sodium hydride is added to 24.03 g (123.74 mmol) of 2-(4-hydroxyphenyl)-propanoic acid ethyl ester in 400 ml of dimethylformamide and stirred for 1 hour at room temperature (under nitrogen). 34.35 g (371.22 mmol) of epichlorohydrin is added and then heated for 24 hours at 70° C. It is cooled in an ice bath to 0° C. and 800 ml of water is carefully added. Then, it is extracted twice with 350 ml of ether each. The combined ether phases are washed once with 300 ml of water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/ethyl acetate=20:1)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[O:7])[CH:10]=[CH:11][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-chloroacetophenone, 1,3-bis(4-chlorophenyl)-prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)([Cl:22])=[O:21]>C1C=CC=CC=1>[Cl:22][C:20]([N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:19])[CH2:9]1)=[O:21]
Reactant: O=C1CNC(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: O=C1CN(C(=O)Cl)C(c2ccccc2)c2cc(Cl)ccc2N1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
0.84 g. of dry, solid sodium hydrocarbonate are added to a suspension of 1.36 g. (5 mmoles) of 5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 60 ml. of absolute benzene, and 15 ml. of a 10% phosgene solution in benzene are added dropwise to the mixture at 10°-15° C. The mixture is stirred at 10°-15° C. for one hour and then at room temperature overnight. The inorganic salts are filtered off and washed with 50 ml. of acetone. The organic phase is evaporated, and the dry residue is recrystallized from benzene. 1.08 g. (64.5 %) of 4-chlorocarbonyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 181°-184° C., Rf2 = 0.82.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH2:10][Br:13])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: COC(=O)c1c(C)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)cccc1CBr
Temperature: 80 °C

Procedure:
2-Bromo-6-methyl-benzoic acid methyl ester (21.8 mmol), and N-bromosuccinimide (21.8 mmol), benzoyl peroxide (1.1 mmol) were combined in 50 mL carbontetrachloride and heated to 80° C. overnight. The resulting precipitate was filtered off, and filtrate concentrated to an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.CCOCC.O1CCCC1.N[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[C:26]1([NH:10][C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cccnc1C(N)=O
Reactant: Nc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)Nc1ccccc1
Reaction time: 0.08 h
Yield: 354.5 %

Procedure:
To 3-methyl-2-pyridinecarboxamide (15.0 o, 0.11 mole) are added BF3.OEt2 (14.0 mL, 0.11 mole) and tetrahydrofuran (75 mL). After about 5 minutes, aniline (10.3 g, 0.11 mole) is slowly added and the solution is heated at reflux for 5 hours. The reaction is cooled and diluted with water and the oroduct is extracted into ethyl acetate. The solvent is removed and the residue is purified by silica gel chromatography to give 8.32 g (0.39 mole, 35%) of N-phenyl-3-methyl-2-pyridinecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23]([NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc2ccccc2n(CC(=O)O)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(O)Cn1c(=O)c(NS(=O)(=O)c2ccccc2)cc2ccccc21

Procedure:
2-[3-Amino-2-oxo-2H-quinolin-1-yl]acetic acid, (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removing the pyridine, the residue was recrystallized in acetone to yield a white crystal solid as the product, 2-[3-benzenesulfonylamino-2-oxo-2H-quinolin-1-yl]acetic acid, (EX-4A)(0.117 g, y=41%). HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50° C.): retention time 2.85 min, M+H+=359.2 for formula C17H15N2O2S. 1H NMR (400 MHz, Acetone-d6): d 5.12 (s, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.48-7.63 (m, 4H), 7.75 (dd, J=8, 1.6 Hz, 1H), 7.74 (s, 1H), 8.00-8.03 (m, 2H). 13C NMR (101 MHz, Acetone-d6): d (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129.4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1.
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[F:25][C:26]([F:43])([F:42])[C:27](=[O:41])[CH2:28][C:29]([C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][CH3:40])([CH3:31])[CH3:30]>C1COCC1>[F:43][C:26]([F:25])([F:42])[C@@:27]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:41])[CH2:28][C:29]([C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][CH3:40])([CH3:31])[CH3:30].[F:43][C:26]([F:25])([F:42])[C@:27]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:41])[CH2:28][C:29]([C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][CH3:40])([CH3:31])[CH3:30]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1ccc([S@@](C)=O)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(C[S@@](=O)c1ccc(C)cc1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)C[C@](O)(C[S@@](=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 62 %
Yield: 29 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (28.2 g, 183 mmol) in 200 mL of anhydrous THF at −78° C. was added lithium diisopropylamide (LDA) mono(tetrahydrofuran), 1.5 M solution in cyclohexane (122 mL, 183 mmol) over 30 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (46.3 g, 166 mmol) dissolved in 125 mL of THF was then added via cannula over 30 minutes. After 1.5 hours at −78° C., the reaction mixture was quenched with 600 mL of water and extracted first with a 600 mL portion of EtOAc and then a 400 mL portion of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate (NaHCO3) solution, washed with brine, dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 10%-30% EtOAc/hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (44.2 g, 62%) and (R)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (20.6 g, 29%). The diastereomeric excess was determined to be >99% for both isomers (HPLC peak area).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.8 %

Procedure:
72.15 g (0.3 mole) of 2-(4-chlorophenoxy-methyl)-2-tert.-butyl-oxirane and 24.15 g (0.35 mole) of 1,2,4-triazole were heated under reflux in 120 ml of ethanol for 48 hours. The mixture was then concentrated, the residue was taken up in 200 ml of ethyl acetate and the ethyl acetate mixture was heated. It was then cooled in an ice bath and the solid was filtered off and rinsed with ethyl acetate. The filtrate was concentrated, the residue was dissolved in ether/hexane and the solution was gassed with hydrogen chloride. The precipitate was filtered off and rinsed with ether and the free base was obtained by adding ethyl acetate/1N sodium hydroxide solution. 60.2 g (65% of theory) of 2-(4-chlorophenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-ol of melting point 84°-87° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:18]1([S:24]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[CH:4]=[CH:5]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)ccnc21
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A stirred suspension of 4-chloro-7-azaindole (1.00 g, 6.55 mmol) in dichloromethane (DCM) (50 ml) was treated with 4-(dimethylamino)pyridine (80.0 mg, 0.66 mmol), triethylamine (1.36 ml, 9.83 mmol) and benzenesulfonyl chloride (0.93 ml, 7.21 mmol) at ambient temperature. The mixture was left to stand overnight and then diluted with DCM and washed with 1M aqueous HCl solution, saturated sodium hydrogen carbonate solution, water, and brine, dried with sodium sulfate and concentrated under vacuum to give crude product. Trituration (diethyl ether) afforded 1.59 g (83%) of 1-benzenesulfonyl-4-chloro-1H-pyrrolo[2,3-b]pyridine. LCMS (Method B, ESI): RT=4.48 min, m+H=293.3; 1H NMR (400 MHz, CDCl3) δ: 8.31 (d, 1H), 8.18 (m, 2H), 7.78 (m, 1H), 7.62-7.56 (m, 1H), 7.52-7.45 (m, 2H), 7.20 (m, 1H), 6.72 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.C([Mg]Br)(C)C.[CH3:28][CH:29]1[CH2:31][O:30]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:28][CH:29]([OH:30])[CH3:31])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(I)cc(Br)cc3c2C1
Reactant: CC1CO1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CC(O)Cc1cc(Br)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Temperature: -40 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl 8-bromo-6-iodo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (200 mg, 0.42 mmol) in anhydrous THF (2 mL) at −78° C. was added isopropylmagnesium bromide (2 M solution in THF, 0.4 mL, 0.84 mmol). The reaction mixture was stirred at −40° C. for 1 h and Cu(I) iodide (96 mg, 0.50 mmol) was added. The reaction mixture was stirred at −40° C. for a further 30 min then 2-methyloxirane (0.29 mL, 4.18 mmol) was added. After 1 h, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 8-bromo-6-(2-hydroxypropyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (110 mg, 17%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.42 (d, J=1.5 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 4.50 (s, 2H), 4.30-4.16 (m, 1H), 3.82 (br s, 2H), 3.05-2.91 (m, 2H), 2.85 (br s, 2H), 1.50 (s, 9H), 1.27 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[C:16]3[CH:25]=[CH:26][C:13]([NH:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 23, 4-[4-[[7-(chloro)-4-quinolinyl]amino]benzoyl]piperazine is reacted with m-chlorophenyl isocyanate to give 1-[[(3-chlorophenyl)amino]carbonyl]-4-[4-[[(7-chloro)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [OH:1][C:2]1[C:9](O)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CN(C)[CH:13]=[O:14].[C:16](=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[CH2:16]1[CH2:13][O:14][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=Cc1cccc(O)c1O
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: O=Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
Into a 100 ml round bottom flask fitted with a nitrogen gas inlet, condenser, and a magnetic stirring bar were placed 2,3-dihydroxybenzaldehyde (4.00 g, 29.0 mmol), 70 ml anhydrous dimethylformamide, and cesium carbonate (14.15 g, 43.5 mmol). The mixture was heated to 110° and stirred for 2.5 hours. The reaction was allowed to cool to room temperature and ethyl acetate was added. This solution was washed four times with brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed (0-10% ethyl acetate/hexanes to give 4.07 g of subtitled product (86%) which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:19]#[C:20][Si](C)(C)C.[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:19]#[CH:20]
Reactant: CCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)c(F)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#Cc1ccc(C#Cc2ccc(CCC)cc2)cc1F
Yield: 98.8 %

Procedure:
22 mmol of 1-[2-fluoro-4-[2-(4-propylphenyl)-ethynyl]phenyl]-2-trimethylsilylacetylene and 10 g of potassium hydroxide were dissolved in 100 ml of ethanol and 10 ml of water, and the solution was stirred at 40° C. for 6 hours. After completion of the agitation, the reaction solution was poured into dilute hydrochloric acid and extracted with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a brown oily product. This product was isolated and purified by a silica gel column chromatography to afford 5.7 g of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]phenyl acetylene as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:13])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:19]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:19][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:13])=[CH:12][CH:11]=1
Reactant: BrBr
Reactant: Cc1cc(Br)ccc1-c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1-c1ccc(Br)s1
Reaction time: 1 h

Procedure:
To a stirred homogeneous solution of 2-(4-bromo-2-methylphenyl)thiophene (5.0 mmol, from Step A) and sodium acetate (10 mmol) in acetic acid (25 mL), bromine (5.0 mmol) was added dropwise via syringe at rt over 20-30 min and the resulting mixture was stirred for 1 h. The reaction mixture was combined with 1 M sodium hydroxide (250 mL) and ethyl acetate (250 mL). Organic layer was separated, washed sequentially with 1M sodium hydroxide (100 mL) and brine (100 mL), and dried over sodium sulfate. Silica gel chromatography using hexanes as the eluant afforded the title compound: 1H NMR (CDCl3) 7.46 (d, J=0.6, 1H), 7.38 (dd, J=3.9, 0.6, 1H), 7.24 (d, J=3.9, 1H), 7.09 (d, J=2.9, 1H), 6.83 (d, J=2.9, 1H), 2.43 (s, 3H); HPLC A 4.41 min, ESI-MS (m/z)=334.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC#C)C=CC=CC=1.[N:22]([C:25]1[S:26][C:27]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]([CH3:30])[N:29]=1)=[N+:23]=[N-:24]>>[CH3:30][C:28]1[N:29]=[C:25]([N:22]2[CH:10]=[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:24]=[N:23]2)[S:26][C:27]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reactant: C#CCCCc1ccccc1
Agent: C#CCCc1ccccc1
Product: CCOC(=O)c1sc(-n2cc(CCc3ccccc3)nn2)nc1C
Yield: 62 %

Procedure:
Following the procedure as described in Example 12, making variations as necessary to replace 5-phenyl-1-pentyne with 4-phenyl-1-butyne to react with ethyl 2-azido-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 62% yield: 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.33-7.19 (m, 5H), 4.34 (q, J=7.1 Hz, 2H), 3.17-3.03 (m, 4H), 2.71 (s, 3H), 1.39 (t, J=7.1 Hz, 3H); MS (ES+) m/z 343.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=C(C(OC)=O)C=C(OC)N=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:22](OC)=O)[CH:19]=[C:18]([O:26][CH:27]([CH3:29])[CH3:28])[N:17]=1.N1C=CC=C[CH:31]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20](/[C:22](/[CH3:31])=[CH:7]/[CH:2]=[O:1])[CH:19]=[C:18]([O:26][CH:27]([CH3:28])[CH3:29])[N:17]=1
Reactant: COC(=O)c1cc(O)nc(OC)c1
Reactant: c1ccncc1
Reactant: COC(=O)c1cc(OC)nc(OC(C)C)c1
Product: COc1cc(/C(C)=C/C=O)cc(OC(C)C)n1

Procedure:
2-Hydroxy-6-methoxy-4-carbomethoxy-pyridine was isopropylated into 2-methoxy-6-isopropoxy-4-carbomethoxy-pyridine in a similar manner to that described in Step 1 of Example 1. The pyridine derivative thus obtained was converted into an aldehyde in a similar manner to that described in Step 2 of Example 1. This aldehyde was treated in a similar manner to that described in Steps 3 to 5 of Example 1 and Steps 1 and 2 of Example 2 to give the title compound.