Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)O
Reactant: O[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-[5-(2,6-difluoro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (236 mg), (R)-pyrrolidin-3-ol (2 eq.), HATU (1.2 eq.) and TEA (0.2 mL) in DMF (3 mL) was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with water (2×), sodium carbonate (2×), dried and concentrated. The residue was purified on a silica gel column to give 16 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.O1CCOCC1.Cl[CH:19]([F:21])[F:20]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:19]([F:21])[F:20])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(O)cc(Cl)n1
Reactant: FC(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 84.6 %

Procedure:
6.8 g (0.036 mole) of 4-chloro-6-hydroxy-2-methylthiopyrimidine are suspended in 25 ml 50% potassium hydroxide solution, 25 ml of water and 100 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 10 g of chlorodifluoromethane are subsequently introduced over 3 hours. The mixture is then cooled to room temperature, the phases are separated and the organic phase is evaporated to dryness. The residue is crystallised from methanol/water, affording 6.9 g (84.4% of theory) of 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine with a melting point of 36°-37° C. The substance has a boiling point of 76°-78° C. at 0.15 mbar.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 22.5 l of methylene chloride and 3030 ml of tert-butylamine is cooled to 0° C. Then a solution of 3 kg of 4-bromo-benzoyl chloride in 15 l of methylene chloride is added in portions. The mixture is cooled to 0°-5° C. and then stirred over night at room temperature. The reaction mixture is filtered and the filtrate washed with 5 l of methylene chloride, three times with 5 l of 3 N HCl, twice with 4 l of NaHCO3 and twice with 2 l of brine. The organic layer is dried over Na2SO4 and evaporated. The crude crystals are stirred with 8 l of ether for 30 minutes and the mixture is cooled to 0° C. and filtered. Thus 4-bromo-N-tert-butyl-benzamide is obtained in form of white crystals, m.p.133°-134° C.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:27])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Reactant: OB(O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (180.0 mg, crude) in dioxane (6 mL) was added benzofuran-2-ylboronic acid (149.0 mg, 0.92 mmol), K3PO4 (195.0 mg, 0.92 mmol), Pd(PPh3)4 (30.0 mg, 0.03 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90° C. and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%-20% ethyl acetate in petroleum ether to afford methyl 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (95.0 mg, 39% 2 steps).
Reaction SMILES: [NH2:1]/[C:2](/[N:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][CH2:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[N:3]\[OH:4].C(N(CC)CC)C.[C:41](Cl)(=O)[CH:42]([CH3:44])[CH3:43].C1(C)C=CC=CC=1>ClCCl>[CH:42]([C:44]1[O:4][N:3]=[C:2]([N:5]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[CH2:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:19])([CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)[N:1]=1)([CH3:43])[CH3:41]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)/C(N)=N/O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2noc(C(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
A solution of ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (1 g; 2.14 mmol) and triethylamine (0.30 ml; 2.14 mmol) in 10 ml of dichloromethane was cooled in an ice bath and treated under nitrogen with isobutyryl chloride (0.20 ml; 1.93 mmol). The mixture was allowed to warm to rt. After 1 hr, 8 ml of toluene were added and the reaction mixture was heated to 110C under a reflux condenser. After 5 hr, it was partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5 N HCl (twice), 1N NaOH (three times) and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography using ethyl acetate-hexane mixtures (5–50% gradient) afforded ethyl 2-[4-(2-{(5-isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (470 mg; 43% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[C:34](=[N:37][OH:38])([NH2:36])[CH3:35].[CH2:39](N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:20]([C:4]2[C:5](=[O:19])[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:7]([CH3:8])=[C:2]([C:39]3[O:38][N:37]=[C:34]([CH3:35])[N:36]=3)[CH:3]=2)=[O:21])=[CH:29][CH:28]=1)(=[O:31])=[O:32]
Reactant: CCN(CC)CC
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CC(N)=NO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.236 g, 0.4 mmol), acetamide oxime (0.088 g, 1.2 mmol), Pd(PPh3)2Cl2 (0.014 g, 0.020 mmol), triethylamine (0.081 g, 0.8 mmol), toluene (15 ml) and a magnetic stirrer bar were loaded into a pressure safe steel reactor. The reactor was degassed with CO, and when all air had been removed, a 4 atmospheres pressure of CO was applied, and the reactor was heated to 95° C. The reaction was allowed to proceed overnight. LC-MS showed that almost all starting iodide had been consumed to give a main product. The crude mixture was evaporated and the residual oil was partitioned between EtOAc and water. The organic phase was collected, and was dried and evaporated. Purification on silica (heptane:EtOAc 1:2) gave pure material (0.083 g, 38%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1O)[CH3:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CN([CH:31]=[O:32])C>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19](=[O:21])[C:6]3[C:7](=[CH:8][C:9]([OH:10])=[C:3]([CH2:1][CH3:2])[CH:4]=3)[O:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CN(C)C=O
Reactant: CCc1c(O)cccc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1cc2c(=O)c(-c3ccc(Br)cc3)coc2cc1O
Yield: 82.3 %

Procedure:
This compounds was synthesised in the same manner as described above. Ethyl resorcinol (0.83 g, 6 mmol), 4-bromophenylacetic acid (1.29 g, 6 mmol), BF3Et2O (5 ml), PCl5 (1.99, 9.1 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(4-bromo-phenyl)-6-ethyl-7-hydroxy-chromen-4-one as a pale pink solid (1.7 g, 82.3%); Rf 0.84 ethyl acetate.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)=O.[OH-].[Li+]>CO.O>[N:22]1([S:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([NH2:5])=[CH:7][CH:8]=3)[CH2:18][CH2:17]2)(=[O:21])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC2CCN(S(=O)(=O)N3CCCCC3)CC2)cc1
Temperature: 60 °C
Yield: 80.1 %

Procedure:
A mixture of 2,2,2-trifluoro-N-[4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenyl]acetamide (0.48 g, 1.11 mmol) and lithiumhydroxide (0.23 g, 5.54 mmol) in methanol (10 mL) and water (1 mL) was heated at 60° C. for about 2 hours. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with dichloromethane. The organic extracts were washed with water and brine, and dried (Na2SO4). The residue was crystallized from ethyl acetate/hexanes, to give 4-(1-piperidinesulfonylpiperidin-4-ylmethyl)-phenylamine (0.30 g) as a white solid, m.p. 144-145° C.; Analysis for C17H27N3O2S: Calc.: C, 60.50; H, 8.06; N, 12.45; Found: C, 60.76; H, 8.07; N, 12.56.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35]2[N:43]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:38]3=[N:39][CH:40]=[CH:41][CH:42]=[C:37]3[N:36]=2)[CH2:30][CH2:29]1.[OH2:49]>ClCCl>[C:6]([OH:8])(=[O:7])[C:3]([OH:46])=[O:49].[CH2:47]([O:46][CH2:45][CH2:44][N:43]1[C:38]2=[N:39][CH:40]=[CH:41][CH:42]=[C:37]2[N:36]=[C:35]1[NH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][NH:25][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH2:29][CH2:30]1)[CH3:48]
Reactant: O
Reactant: CCOCCn1c(NC2CCN(CCN)CC2)nc2cccnc21
Reactant: O=C(O)c1ccoc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCn1c(NC2CCN(CCNC(=O)c3ccoc3)CC2)nc2cccnc21
Product: O=C(O)C(=O)O
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a stirred mixture of 1.12 parts of 3-furancarboxylic acid, 2.02 parts of N,N-diethylethanamine and 195 parts of dichloromethane were added 2.6 parts of 2-chloro-1-methylpyridinium iodide at room temperature. After stirring for 1 hour, 3.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-amine were added and stirred overnight at room temperature. The mixture was poured into water and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in ethanol. The salt was filtered off and dried, yielding 2.19 parts (36.1%) of N-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]ethyl]-3-furancarboxamide ethanedioate(1:2); mp. 160.7° C. (compound 142).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][O:12]2.C1C(=O)N([I:24])C(=O)C1.CN(C=O)C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[I:24])[CH:14]=[CH:13][O:12]2
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccoc3n2)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A solution of 6-(2,4-difluorophenyl)imidazo[2,1-b]oxazole (30.0 g, 136 mmol; Example #8, step B), NIS (31.6 g, 140 mmol), and DMF (350 mL) was stirred at ambient temperature. After about 1 h, the reaction was poured into water (2 L) and the resulting precipitate was filtered and washed with additional water. The brown solid was dissolved in DCM and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. The solid was dissolved in DCM, filtered through Florosil® and then concentrated under reduced pressure to a volume of about 0.5 L. The organic layer was washed with 5% aqueous NaS2O3, dried over MgSO4, filtered, and concentrated under reduced pressure to dryness to give the title compound as a yellow solid (34.5 g, 73%): LC/MS (Table 1, Method a) Rt=2.67 min; MS m/z: 346.9 (M+H)+.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[N:38]=[CH:37][CH:36]=[N:35]1)=[O:27])[CH2:20]2.Cl[C:40]1N=C(C2C=CC=CC=2)C=CN=1>>[CH3:12][C:11]1[CH:16]=[C:15]([CH3:14])[N:8]=[C:9]([N:24]2[CH2:25][CH:19]3[CH:23]2[CH2:22][N:21]([C:26]([C:28]2[CH:33]=[C:32]([CH3:40])[CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[CH2:20]3)[N:10]=1
Reactant: O=C(c1ccccc1-n1nccn1)N1CC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: Clc1nccc(-c2ccccc2)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4nc(C)cc(C)n4)C3C2)c1

Procedure:
The title c compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 25 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C25H23N7O, 437.51; m/z found, 438.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:11]([C:12]2([OH:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[NH:14][C:13]2=[O:22])=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:4].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[S:34](Cl)(=[O:36])=[O:35].O>CN(C=O)C.C(OCC)C>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[S:34]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([I:21])=[CH:17][CH:16]=2)[C:12]([C:11]2[C:6]([O:5][CH2:3][CH3:4])=[N:7][CH:8]=[CH:9][CH:10]=2)([OH:23])[C:13]1=[O:22])(=[O:35])=[O:36]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2ccc(I)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(I)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 255 %

Procedure:
Sodium hydride (145 mg of a 50% strength dispersion in mineral oil, 3.03 mmol) was added to an ice-cooled solution of 3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydroindol-2-one (1.0 g, 2.52 mmol) in DMF (20 ml). The reaction mixture was stirred at 0° C. for 15 minutes and then 2,4-dimethoxyphenylsulfonyl chloride (99 mg, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, water was added, and the resulting precipitate was filtered off. The precipitate formed after stirring in ethyl ether (50 ml) overnight was filtered off with suction, resulting in 730 mg of the title compound (45% yield).
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH3:12].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[CH3:12])=[CH:14]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1C(=O)c2ccccc2C1O
Product: CN1C(=O)c2ccccc2C1c1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
The product from example 20, step a) (650 mg, 3.98 mmol) and indole (780 mg, 6.67 mmol) were heated (neat) to 180° C. for 30 minutes. The reaction was cooled to rt and the product was recrystallized from ethanol/water to give 452 mg of the sub-title compound as a tan solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH3:8])=[CH:6][CH:7]=1)#[CH:2].C(NC(C)C)(C)C.I[C:17]1[CH:22]=[CH:21][C:20](/[C:23](/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:24]\[CH2:25][O:26][C:27]2[CH:38]=[CH:37][C:30]([O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:29]([CH3:39])[CH:28]=2)=[CH:19][CH:18]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][C:29]1[CH:28]=[C:27]([O:26][CH2:25]/[CH:24]=[C:23](\[C:20]2[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]3[S:4][C:5]([CH3:8])=[CH:6][CH:7]=3)=[CH:18][CH:19]=2)/[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[CH:38]=[CH:37][C:30]=1[O:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: C#Cc1ccc(C)s1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(C)s3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Ethynyl-5-methylthiophene (176 mg, 1.442 mmol) and diisopropylamine (0.475 mL, 3.39 mmol) were added to a solution of methyl (E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate (420 mg, 0.721 mmol; prepared as described in example 34) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (11.0 mg, 0.0576 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25.3 mg, 0.0361 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 19:1) yielding methyl (E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethyl phenyl)allyloxy]phenoxy]acetate as yellow oil.
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:17].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1.O>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH3:17])[O:23]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2ccccc2c1Br
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h

Procedure:
1,2-Dibromoethane (˜0.3 ml) was added to 6.10 g (250 mmol) magnesium turnings in 1000 cm3 of THF. This mixture was stirred for 10 min, and then 55.3 g (250 mmol) of 1-bromo-2-methylnaphthalene was added for 1 h by vigorous stirring at room temperature for 3.5 h. Further on, 46.5 g (250 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added in one portion. The resulting mixture was stirred for 15 minutes and then was poured into 1000 cm3 of cold water. The product was extracted with 3×300 ml of ethyl acetate. The organic layer was separated, washed by water, brine, then dried over MgSO4, and, finally, evaporated to dryness. The resulting white solid was washed by 2×75 ml of pentane and dried in vacuum. Yield 47.3 g (70%). 1H NMR (CDCl3): 8.12 (m, 1H, 8-H), 7.77 (m, 1H, 5-H), 7.75 (d, J=8.4 Hz, 1H, 4-H), 7.44 (m, 1H, 7-H), 7.38 (m, 1H, 6-H), 7.28 (d, J=8.4 Hz, 1H, 3-H), 2.63 (s, 3H, 2-Me), 1.48 (s, 12H, CMe2CMe2).
Reaction SMILES: [Cl-].CC([O-])(C)C.[K+].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:14]2[C:22]=1[C:21](=O)[CH:20]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]1.O.[O:26]1[CH2:31]COC[CH2:27]1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:24])=[C:21]2[C:22]=1[C:14](=[CH:27][O:26][CH3:31])[CH:15]1[CH:20]2[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C)c2c1C(=O)C1CCCCC21
Reactant: C1COCCO1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COC=C1c2c(OC)ccc(C)c2C2CCCCC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50.00 Grams of methoxymethyltriphenylphosphnium chloride was suspended in 400 ml of dioxane and 16.37 g of t-BuOK was added thereto under ice-cooling and nitrogen atmosphere, followed by stirring at room temperature for 2 hours. To this dark red solution was added 6.72 g of 8-methoxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone, followed by further stirring at room temperature for 2 hours. Then, the reaction mixture was refluxed for 3 hours and left to stand for cooling. Thereafter, 400 ml of water was added and extraction was effected with diethyl ether. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluent:n-hexane) to obtain 4.54 g of 8-methoxy-9-methoxymethylene-5-methyl-1,2,3,4,4a,9a-hexahydrofluorene which was a yellow oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].[C:17]1([P:23](OC2C=CC=CC=2)[O:24]C2C=CC=CC=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[P:23]2(=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC(=O)NC
Reactant: c1ccc(OP(Oc2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1C(=O)N(C)P(=O)(c2ccccc2)C1c1ccc(C#N)cc1

Procedure:
A mixture of 0.12 mole each of 4-cyanobenzaldehyde, 1,3-dimethylurea, and diphenyl phenylphosphonite in 150ml of toluene is warmed at reflux (112°) for 3.5 hr and then stripped to 120°/10mm, leaving a viscous, light yellow oil having 31P nmr peaks at -31.2 and -25.7 ppm (~2:1 areas). Dilution of the oil with ether results in separation of a solid from which two isomers are isolated by fractional crystallization. Isomer I: mp 176°-179°; 31P nmr (CDCl3) -30.6 ppm; 1H nmr δ7.3 (m, 9, aryl), 5.1 (d, 1, J = 22Hz, PCH), 3.0 (s, 3, NCH3), 2.95 (d, 3, J = 8Hz, PNCH3). Isomer II: mp 180°-182.5°; 31P nmr -26.7 ppm; 1H nmr δ7.8 (m, 9, aryl), 4.7 (d, 1, J = 7Hz, PCH), 2.9 (s, 3, NCH3), 2.9 (d, 3, J = 8Hz, PNCH3). There is a sharp depression of the mixed melting point of I and II.