Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:16])[CH2:13][OH:14])=O)C1C=CC=CC=1.[ClH:44].O.[H][H]>CO.[Pd]>[ClH:44].[NH2:11][C@H:12]([C:15]([NH:17][C@H:18]([C:27]([NH:29][C@@H:30]([C:32]([NH:34][C@H:35]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:33])[CH3:31])=[O:28])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)=[O:16])[CH2:13][OH:14]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
A solution of 3 g. of Nα -benzyloxycarbonyl-L-seryl-L-tyrosyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol containing 3.7 ml. of 1.35 N hydrogen chloride in methanol is stirred with 200 mg. of 20% palladium on carbon under one inch of water pressure of hydrogen for three hours. Thin layer chromatography of samples of the solution shows disappearance of the starting material in about two hours. The reaction mixture is filtered to remove the catalyst and the filtrate evaporated at 30°-40° C. to yield the product as a foam. The product is used without further purification.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH:15]2[CH2:16][CH:9]3[CH:10]([CH:14]2I)[O:11][C:12](=[O:13])[CH:8]13)=[O:6])#[N:2].O1CCCC1.OP([O-])(O)=O.[K+]>O.C(OCC)(=O)C.[Zn]>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[C@@H:15]2[CH2:16][C@@H:9]([CH:10]=[CH:14]2)[C@H:8]1[C:12]([OH:13])=[O:11])=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1C2CC3C(OC(=O)C31)C2I
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCNC(=O)[C@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-N-(cyanomethyl)-6-iodo-2-oxohexahydro-2H-3,5-methanocyclopenta[b]furan-7-carboxamide (1.45 g, 4.18 mmol) was added tetrahydrofuran (10 mL) and zinc dust (11.0 g, 170 mmol). 1 M aqueous KH2PO4 (21 mL, 21 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate and filtered through Celite™ and the Celite™ was washed well with water and ethyl acetate. The product was extracted into ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution. The organics were dried with anhydrous sodium sulfate and then concentrated on a rotary evaporator to give (1S,2R,3R,4R)-3-{[(cyanomethyl)amino]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a faint-yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[C:35]([CH3:36])=[C:34]2[C:29]([CH:30]=[C:31]([NH2:37])[CH:32]=[CH:33]2)=[N:28]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:37][C:31]2[CH:32]=[CH:33][C:34]3[C:29]([CH:30]=2)=[N:28][N:27]([CH3:26])[C:35]=3[CH3:36])=[N:3][CH:4]=1
Reactant: Cc1c2ccc(N)cc2nn1C
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CC5CN(C(=O)OC(C)(C)C)CC5C4)n3)cc2nn1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (621.8 mg, 1.666 mmol) and 2,3-dimethylindazol-6-amine hydrochloride (999.6 mg, 5.057 mmol) in n-BuOH (6 mL) was added DIPEA (1.10 g, 8.43 mmol). The reaction mixture was stirred at 150° C. under microwave for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale brown solid (452.1 mg, 54.5%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][NH:62][CH2:61][C:60]=12>CN(C=O)C>[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][N:62]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[CH2:61][C:60]=12
Reactant: c1nnc2n1CCNC2
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCn3cnnc3C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and 5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride (1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (605 mg, 86%) which was obtained as a white foam. MS: m/e=417.4 [M+H]+.
Reaction SMILES: [Li].[Cl:2][C:3]1[C:11]2[CH:10]=[C:9]([S:12]([O-:14])=[O:13])[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:15].[Li+].[Cl:17][C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([S:25]([O-:27])=[O:26])=[CH:24][C:20]=2[CH:19]=1.[Li+]>CCOCC.C1CCCCC1.ClCCl>[Cl:2][C:3]1[C:11]2[CH:10]=[C:9]([S:12]([Cl:17])(=[O:14])=[O:13])[O:8][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:15].[Cl:17][C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([S:25]([Cl:2])(=[O:27])=[O:26])=[CH:24][C:20]=2[CH:19]=1
Reactant: O=S([O-])c1cc2c(Cl)c(Cl)ccc2o1
Reactant: O=S([O-])c1cc2cc(Cl)c(Cl)cc2o1
Agent: [Li+]
Agent: [Li]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCCCC1
Product: O=S(=O)(Cl)c1cc2c(Cl)c(Cl)ccc2o1
Product: O=S(=O)(Cl)c1cc2cc(Cl)c(Cl)cc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the mixture obtained in Step 2 (100 g) in anhydrous ether (440 ml) was added dropwise 1.5 M lithium diisopropylnmide mono(tetrahydrofuran) in cyclohexane (440 ml) under nitrogen atmosphere at -70° C. over 1 hour, then into the solution was bubbled sulfur dioxide for 1.5 hours at -70° C. After stirring for 1 hour at room temperature, the solvent was removed in vacuo and ether was added to the residue. The formed precipitate was separated by filtration to give a mixture of lithium 4,5-dichlorobenzo[b]furan-2-sulfinate and lithium 5,6-dichlorobenzo[b]furan-2-sulfinate. To the suspension of the products in dichloromethane (1.8 l) was added N-chlorosuccimimide (92.1 g) at -50° C. and stirred for 1.5 hours. At room temperature, insoluble matters were filtered off and dichloromethane was removed in vacuo and the residue was purified by silica gel column chromatography to give 17.4 g of 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride and 7.4 g of 5,6-dichlorobenzo[b]furan-2-ylsulfonyl chloride, respectively. 4,5-dichlorobenzo[b]furan-2-ylsulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH2:56][N:50]([C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:51][CH2:52]2)([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]1=[O:28]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Product: CCOCCn1c(N2CCCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound: Rf=0.39 (silica gel, 2%triethylamine/20% methanol/ethyl acetate).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[CH3:34][N:35]([CH3:45])[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:42]5[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:34])[CH3:45])[CH2:40][CH2:41]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: CN(C)CCCN1CCNCC1
Agent: OC1CCNC1
Product: CN(C)CCCN1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with 1-(3-dimethylaminopropyl)piperazine. A yellow solid 134 was obtained (0.0401 g, 73%). MS (APCI) m/z 559 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.CCOCC.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(Br)c2ccccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 101A (5.9 g) in N,N-dimethylformamide (50 mL) was added 1-(bromomethyl)-4-methoxybenzene (4.85 g) and Cs2CO3 (25 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether twice. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration of the solvent gave EXAMPLE 101B.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31]Cl)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:31][C:30](=[O:33])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1cccc(F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg of 1-[bis(4-fluorophenyl)methyl]piperazine and 234 mg of N-(3-fluorophenyl)chloroacetamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide, and 400 mg of anhydrous potassium carbonate were added to the solution. The reaction mixture was then stirred at 70° C. for 2 hours, after which ethyl acetate was added to it and the organic layer was separated. The organic layer was washed three times with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to give a purified 1-[bis(4-fluorophenyl)methyl]-4-(3-fluorophenylcarbamoylmethyl)piperazine.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O1CCOCC1.[C:33]([O:37][C:38]([N:40]=[N+]=[N-])=[O:39])([CH3:36])([CH3:35])[CH3:34].[N:43]1[CH:48]=CC=[CH:45][CH:44]=1>>[C:33]([O:37][C:38]([N:40]1[CH:45]=[CH:44][N:43]=[C:48]1[C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:26][CH:25]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)c2nccn2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 10 g. of 4-(n-hexadecylamino)benzoic acid in 100 ml. dioxane is treated with 4.0 g. of t-butylazidoformate and 10 ml. pyridine. After stirring at room temperature for 18 hours, the protected amido-acid is precipitated from solution by addition of 150 ml. of water. The product is collected and thoroughly dried. The crude product is dissolved in 200 ml. of a mixture consisting of methylene chloride/dimethoxy ethane/pyridine (1:4:1), and to this is added 5.4 g. of 1,1'-carbonyldiimidazoye. The solution is stirred overnight at room temperature and the solvents are evaporated to yield the title compound as a thick, orange oil.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CC>[OH:1][CH:2]([CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC2CO2)cc1
Solvent: CCCO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Yield: 90.1 %

Procedure:
4-[N-(2,3-Epoxypropyl)sulphamoyl]nitrobenzene (Method 116, 1 g, 3.88 mmol) and piperidine (0.34 g, 4 mmol) in 1-propanol (75 ml) were heated at reflux for 20 hours. The mixture was cooled and the solvent evaporated. The resulting yellow oil was triturated with diethyl ether collected by filtration and dried under vacuum to give the title compound 1.2 g (90%). NMR: 1.26-1.50 (m, 6H), 2.10-2.28 (m, 6H), 2.70 (dd, 1H), 2.90 (dd, 1H), 3.55 (m, 1H), 8.04 (d, 2H), 8.40 (d, 2H); m/z: 344.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:40](=[O:42])[CH3:41])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 3-[4-amino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg, 0.54 mmol) and acetyl chloride (45 mg, 0.57 mg) in methylene chloride (10 mL) was added triethylamine (58 mg, 0.57 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in ethyl acetate (50 mL). The resulting solution was extracted with 0.1N HCl (50 mL) and brine (50 mL), dried (MgSO4), and evaporated to give 3-(4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg) as an amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:7])[CH2:3]1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][N:32]=[CH:31][C:30]=2[C:34](O)=[O:35])=[CH:25][CH:24]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[NH:33][N:32]=[CH:31][C:30]=2[C:34]([N:6]2[CH:2]([CH3:1])[CH2:3][C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([OH:7])[CH2:5]2)=[O:35])=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2[nH]ncc2C(=O)O)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2[nH]ncc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
A solution of 5-methyl-3-phenylpyrrolidin-3-ol (9 mg, 0.05 mmol) and triethylamine (28 μL, 0.2 mmol, 4 equ.) in DMF (0.2 mL) was added to a solution of 5-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid (11 mg, 0.05 mmol, 1.2 equ.) and 1-propanephosphonic acid cyclic anhydride (70 μL, 0.115 mmol, 2.3 equ., 50% solution in ethyl acetate) in DMF (0.1 mL) at rt. The reaction mixture was stirred at 60° C. overnight. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C22H23N3O3: 377.1739, found 377.1739.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=[O:37])/C/2=C\C1NC=CC=1)#C.IC1C=C(O)C=CC=1.C(N(CC)CC)C>[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.CN(C=O)C>[OH:37][C:7]1[CH:6]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Oc1cccc(I)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccc(O)c3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner to analogous to the preparation of (Z)-I,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) was coupled with 3-iodophenol (110 mg, 0.50 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst in 1 mL DMF and 3 mL triethylamine at 70° C. for 13 hours to give (Z)-1,3-dihydro-5-(3-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 100 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[CH3:29][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])([CH3:29])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a −78° C. solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone (500 mg, 1.19 mmol) in THF (12 mL) is added methylmagnesium bromide (2.0 mL, 5.98 mmol, 3.0 M in THF) dropwise. The reaction mixture is warmed to room temperature. After 4 h, the reaction is cooled to 0° C., quenched with NH4Cl and warmed to room temperature. The reaction mixture is concentrated and the residue is partitioned between Et2O and 1N HCl. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed eluting with 0% to 30% EtOAC/Hexane to yield the title compound (414 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89 (s, 2H), 3.20 (sept, 1H, J=6.6 Hz), 2.04 (s, 3H), 1.53 (s, 6H), 1.45 (d, 6H, J=6.6 Hz).
Reaction SMILES: [N:1]([C:4]([C:7](=[O:13])[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)([CH3:6])[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36](Cl)=[O:37]>O.O1CCCC1.C(N(CC)CC)C>[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1[C:36]([NH:1][C:4]([CH3:6])([C:7](=[O:13])[C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH3:5])=[O:37]
Reactant: CC(C)(N=[N+]=[N-])C(=O)c1ccsc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1c(F)cccc1F)C(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
4 ml of tetrahydrofuran and 0.08 ml of water were added to 0.68 g of 2-azido-2-(3-thenoyl)propane, then 1.10 g of triphenylphosphine was gradually added thereto with stirring at room temperature, and after completion of addition, a reaction was carried out for 18 hours. 15 ml of tetrahydrofuran was added to the reaction mixture, then 0.30 g of triethylamine was added, followed by cooling with ice, and a mixed solution of 0.46 g of 2,6-difluorobenzoyl chloride and 5 ml of tetrahydrofuran was dropwise added thereto. After completion of the dropwise addition, a reaction was carried out for 30 minutes under cooling with ice, and then a further reaction was carried out for 2.5 hours at room temperature. After completion of the reaction, the reaction mixture was put into 100 ml of water and extracted by ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=4/6) to obtain 0.60 g of the desired product having a melting point of from 139 to 142° C. The NMR spectrum data of this product were as follows.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19][N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:17]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19][N:18]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COCc1cc(Cl)ncn1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COCc1cc(Oc2ccc3c(C(=O)OC)cccc3c2)ncn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A suspension of 3.4 g (16.8 mMol) 6-hydroxy-naphthalene-1-carboxylic acid methyl ester (see Step 3.1), 3.2 g (20.2 mMol) 4-chloro-6-(methoxymethyl)pyrimidine (preparation see: BE 64 1253, p. 38; or WO 2002/45652, p. 102) and 7.85 g (37 mMol) K3PO4 in 85 ml NMP is stirred for 4 h at 90° C. The cooled mixture is diluted with 0.4 l EtOAc and 0.4 l water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; CH2Cl2/EtOAc 19:1→9:1→4:1) gives the title compound: m.p.: 87-88° C.; MS: [M+1]+=325; TLC (CH2Cl2/EtOAc 4:1): Rf=0.28.