Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:34]([C:36]1[N:41]=[N:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[NH2:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:35][NH:34][C:36]2[N:41]=[N:40][C:39]([C:42]3[CH:43]=[CH:44][C:45]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[CH:46][CH:47]=3)=[CH:38][CH:37]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2ccc(NN)nn2)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(-c2ccc(NNC(=O)Cc3ccc(Cl)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 2-(4-chlorophenyl)acetic acid (1.07 mmole), HOBT (1.07 mmole), and EDCI hydrochloride (1.61 mmole) in DMF (7 mL) were added N-(4-(6-hydrazinylpyridazin-3-yl)phenyl)methanesulfonamide (1.07 mmole) in 10 mL of DMF followed by diisopropylethylamine (3.77 mmole). The resulting mixture was stirred at room temperature for 22 hours and evaporated in vacuo. The desired product N-(4-(6-(2-(2-(4-chlorophenyl)acetyl)hydrazinyl)pyridazin-3-yl)phenyl)methanesulfonamide was precipitated out from water.
Reaction SMILES: COC1C=C(C=CC=1OC)C[C@@H](C)N.Cl.COC1C=C(C=CC=1OC)C[C@@H](C)N.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:35]=O.[N+:42]([CH2:45][CH3:46])([O-:44])=[O:43]>>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:35]=[C:45]([N+:42]([O-:44])=[O:43])[CH3:46])[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: COc1ccc(C[C@@H](C)N)cc1OC
Agent: Cl
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC

Procedure:
A process according to Claim 1, wherein said (R)-3,4-dimethoxy-amphetamine hydrodchloride of Formula (3) is prepared by condensing 3,4-dimethoxybenzaldehyde (10) with nitroethane (Henry's reaction) to form 3,4-dimethoxy-phenyl-2-nitro-propene (11), wherein said 3,4-dimethoxy-phenyl-2-nitro-propene is then reduced to 3,4-dimethoxy-phenyl-acetone (12) by means of a catalytic hydrogenation, wherein said 3,4-dimethoxy-phenyl-acetone (12) is then reacted with (R)-α-methyl-benzyl-amine (13) to form the corresponding chiral imine (14), wherein said chiral imine (14) is then diastereoselectively reduced to (R,R)-N-phenyl-ethyl-3,4-dimethoxy-amphetamine (15) hydrochloride intermediate by means of a catalytic hydrogenation with Raney nickel with the intermediate (15) being then debenzylated by a further hydrogenation, thus yielding (R)-3,4-dimethoxy-amphetamine hydrochloride, according to the following reaction scheme: ##STR25##
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=O)[C:8](=[O:17])[CH2:7][CH2:6]1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH2:18]1[O:21][C:12]([CH:9]2[CH2:10][CH2:11][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7][C:8]2=[O:17])([O:14][CH2:15][CH3:16])[O:20][CH2:19]1
Reactant: CCOC(=O)C1CCN(C(=O)OC)CCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(C2CCN(C(=O)OC)CCC2=O)OCCO1
Reaction time: 4 h

Procedure:
A mixture of ethyl 1-methoxycarbonyl-4-oxoperhydroazepine-5-carboxylate (VI; cf: Krogsgaard-Larsen, et al., Eur. J. Med. Chem.. 14 (1979) pp. 157-164) (26.9 g; 0.11 mol), ehtylene glycol (30.7 mL; 0.55 mol), 4-toluenesulphonic acid hydrate (2.11 g; 11 mmol), and toluene (200 mL) was refluxed in a Dean-Stark water separator for 4 h. Upon addition of toluene (200 mL) the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 mL), dried (K2CO3) and evaporated to give crude (V), which was used without further purification as starting material for the synthesis of (IV).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)CBr)c1ccccc1

Procedure:
To a mixture of N-methyl aniline (5 mL) and potassium carbonate (9.6 g) in 100 mL dichloromethane was added bromoacetyl bromide (8.1 mL) (exotherm). The mixture was stirred for 4.5h then water was added. The phases were separated and the organic layer was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane. The relevant fractions were combined and evaporated and the residue was taken up in dichloromethane and washed with water. The organic layer was stirred with another portion of water for a few minutes and then the layers were separated. Evaporation of the organic layer gave the sub-titled compound (10.2 g) as a straw coloured solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11]/[N:12]=[C:13](/[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1)\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:10][O:11]/[N:12]=[C:13](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)\[C:21]1[O:26][CH2:25][CH2:24][O:23][N:22]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CO/N=C(\C1=NOCCO1)c1ccccc1Oc1ncnc(Cl)c1F
Temperature: 82.5 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of 4,6-dichloro-5-fluoropyrimidine (DCFP) (100 g, 0.564 mol) in toluene (500 mL) was added (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) (77.8 g, 0.466 mol), K2CO3 (76 g, 0.55 mol), followed by the addition of DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 80-85° C. for 1-2 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was washed with water (500 mL) and 10% brine solution (250 mL) to obtain the product in toluene layer meeting the desired specifications. Yield—88-98%.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:18])[CH2:9]P(OCC)(OCC)=O)(C)(C)C.[C:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)[CH:20]([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][CH:20]([CH3:22])[CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:8]([OH:7])=[O:18]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(CC(=O)O)c1ccccc1
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (60%, 1.2 g) was added at 0° C. to a tetrahydrofuran solution (30 mL) of tert-butyldiethylphosphonoacetate (4.9 g). After 10 minutes, the temperature of the mixture was naturally returned to room temperature, and the mixture was stirred. After 1 hour, a tetrahydrofuran solution (10 mL) of isobutyrophenone (4.0 g) was added. After stirring for 13 hours, the organic layer was separated by adding water and ethyl acetate thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. 5.48 g among the resulting crude product (6.1 g) was dissolved in methanol (30 mL), a catalytic amount of 10% palladium carbon (250 mg) was added, and the mixture was reacted under pressuring by hydrogen (3.9 kg/cm2). After 1.3 hours, the catalyst was filtered off, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate system). The resulting product (3.0 g) was dissolved in acetone (50 mL) and 5N hydrochloric acid (20 mL), and the mixture was stirred for 3 hours under reflux conditions. The solution was evaporated, to give the title compound as a reddish yellow oil (1.96 g, 58%: 3 steps).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 211 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (350 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[NH2:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[N:12]=[CH:11]2)[S:5][C:6]=1[C:7]([NH:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)=[O:9]
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid (0.15 g, 0.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.97 g, 0.51 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.51 mmol) in N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.07 g, 0.51 mmol). The resulting mixture was stirred at ambient temperature for 15 minutes and followed by the addition of 3-(aminomethyl)pyridine (0.05 mL, 0.05 mmol). The reaction mixture was stirred for 17 hours at ambient temperature, diluted with ethyl acetate (30 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to afford the title compound as a white powder in 59% yield (0.11 g): mp 156-158° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.31-7.19 (m, 1H), 6.46 (t, J=5.8 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.4, 153.4, 150.9, 149.9, 149.3, 149.2, 138.9, 135.7, 131.2, 128.7, 125.8, 123.7, 121.8, 49.1, 41.6, 17.2; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:7]=1)(=O)=O.[CH2:43]([P:52](=[O:59])([O:56][CH2:57][CH3:58])[O:53][CH2:54][CH3:55])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[OH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:42])=[C:15]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[C:31](/[CH:32]=[CH:43]/[P:52](=[O:59])([O:53][CH2:54][CH3:55])[O:56][CH2:57][CH3:58])=[CH:30][N:29]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:28]=4)=[CH:21][C:20]=3[O:40][CH3:41])[N:16]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(O)c3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 15.2 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate (0.30 g), tetraethyl methylenediphosphonate (0.16 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.025 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals from a fraction eluted with ethyl acetate-hexane (5:1, v/v). To a mixture of the obtained crystal, tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.050 g, yield 15%) from a fraction eluted with ethyl acetate-hexane (8:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].Cl.Cl[CH2:7][C:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[OH:1][CH2:2][C:3]1([NH2:4])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:7][C:8]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CCl)CCCC1
Reactant: NCCO
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with 2-(bromomethyl)tetrahydro-2H-pyran according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(tetrahydro-2H-pyran-2-ylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:41][CH2:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: NCCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCCc4cccnc4)cc3)oc2C)cc1
Yield: 81 %

Procedure:
Reaction of oxalyl chloride (71 λL, 0.82 mmol) and benzoic acid 4 (202 mg, 0.54 mmol) with subsequent reaction with 2-(3-pyridinyl)ethylamine (71 λL, 0.59 mmol) gave benzamide 12 (208 mg, 81%) as a white powder: mp (EtOAc) 207-208° C.; 1H NMR δ 8.68 (t, J=5.6 Hz, 1H, CONH), 8.46 (d, J=1.7 Hz, 1H, H-2′), 8.41 (dd, J=4.7, 1.6 Hz, 1H, H-6′), 7.93 (dd, J=8.6, 2.0 Hz, 2H, H-2, H-6), 7.87 (dd, J=8.6, 2.0 Hz, 2H, H-3, H-5), 7.65-7.69 (m, 3H, H-4′, H-2″, H-6″), 7.42 (d, J=8.3 Hz, 2H, H-3″, H-5″), 7.31 (ddd, J=7.8, 4.7, 0.7 Hz, 1H, H-5′), 4.62 (s, 2H, CH2SO2), 3.54 (dt, J=7.0, 5.8 Hz, 2H, CH2N), 2.89 (t, J=7.1 Hz, 2H, CH2), 2.40 (s, 3H, CH3), 2.13 (s, 3H, CH3); 13C NMR δ 165.4, 158.0, 149.9, 149.8, 147.4, 144.5, 136.2, 135.8, 135.6, 134.9, 129.6 (2), 128.7, 128.3 (2), 127.9 (2), 126.0, 125.4 (2), 123.4, 53.0, 40.4, 32.0, 21.0, 9.7; MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.53; H, 5.18; N, 8.75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:37][O:38][C:39](=[O:54])[CH2:40][CH:41]1[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]1>CN(C=O)C>[ClH:1].[NH:44]1[CH2:45][CH2:46][CH:41]([CH2:40][C:39]([O:38][CH2:37][N:14]2[C:11]3=[N:12][CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=[C:10]3[C:16]([C:17](=[O:18])[C:19]3[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=3[F:33])=[CH:15]2)=[O:54])[CH2:42][CH2:43]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)OCCl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CC3CCNCC3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Product: Cl
Yield: 126.2 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) in DMF (0.9 mL), KOH (23 mg, 0.4 mmol) and a solution of tert-butyl 4-(2-(chloromethoxy)-2-oxoethyl)piperidine-1-carboxylate (60 mg, 0.2 mmol) in DMF (100 μL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=3/1 to 2/1) to afford the title compound as a white solid (86 mg, 56.6%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>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.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: C#CCN1CCCCC1
Reactant: Cc1nc[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: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCCCC3)c21

Procedure:
Using Method C above, 1-(2-propynyl)-piperidine (41.3 mg, 0.34 mmol) (prepared according to Kano et al. supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(1-pipendinyl)-1-propynyl]-2H-indol-2-one. (Yield 15 mg, 31%).
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(C)cc(CI)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C)cc(CNc3ccccc3)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 87.8 %

Procedure:
A mixture of ethyl 8-(iodomethyl)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.14 g, 0.32 mmole) and aniline (0.03 mL, 0.32 mmole) was dissolved in anhydrous DMF (2 mL), the solution was warmed to 90° C. and treated with K2CO3 (0.05 g, 0.39 mmole). The reaction was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite. The filtrate was condensed to give an oil. The oil was purified by flash chromatography (silica gel) with 70% methylene chloride in hexane to give a light yellow oil (0.11 g, 88%): GCMS m/z 391.00 (M+). 1H NMR (CDCl3/400 MHz) 7.70 (s, 1H), 7.19 (m, 3H), 6.94 (s, 1H), 6.74 (m, I1H), 6.65 (m, 2H), 5.77 (q, 1H, J=7.0 Hz), 4.33 (m, 4H), 4.18 (brs, 1H), 2.25 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCOc1ccc(-c2ccccc2)cc1
Yield: 94.7 %

Procedure:
To a 4 L three-necked round bottom flask fitted with a mechanical stirrer and a condenser were added 125.0 g of 4-hydroxybiphenyl (0.734 mol), 154.5 g of 6-bromo-1-hexanol (0.853 mol), 690 g of potassium carbonate, and 2500 ml of acetone. The reaction mixture was stirred and heated at reflux for 4 days and then filtered. The acetone was removed on a rotary evaporator, the residue was recrystallized from a mixture of ethyl acetate and hexanes to afford 188 g of white crystals (95%): mp 92-94° C.; 1H-NMR (CDCl3) δ (ppm) 1.30-1.84 (m, 8H), 3.65 (t, 2H), 3.99 (t, 2H), 6.98 (d, 2H), 7.32-7.56 (m, 7H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].C(C(O)=[O:22])(F)(F)F>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:22])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3 CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.