Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[O:13][C:14]([CH3:57])=[C:15]([CH2:17][O:18][C:19]2[CH:56]=[CH:55][C:22]([CH2:23][N:24]3[CH:28]=[C:27]([C:29](OCC)=[O:30])[C:26]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[N:45]=[C:46]([C:50]6[O:51][CH:52]=[CH:53][CH:54]=6)[O:47][C:48]=5[CH3:49])=[CH:38][CH:37]=4)=[N:25]3)=[CH:21][CH:20]=2)[N:16]=1.O>O1CCCC1>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[O:13][C:14]([CH3:57])=[C:15]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][N:24]3[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]5[N:45]=[C:46]([C:50]6[O:51][CH:52]=[CH:53][CH:54]=6)[O:47][C:48]=5[CH3:49])=[CH:40][CH:41]=4)=[N:25]3)=[CH:55][CH:56]=2)[N:16]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccco5)oc4C)cc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Lithium aluminium hydride (0.98 g) was added to a solution of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazole-4-carboxylate (19.16 g) in tetrahydrofuran (75 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxy]-1H-pyrazol-4-yl]methanol (17.25 g, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].C1(C)C=CC=CC=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[C:1]([C:3]1[CH:17]=[C:16]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1cc(-c2ccncc2)c2c(c1)ncn2-c1ccccc1
Yield: 32.4 %

Procedure:
5-Cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), pyridin-4-yl boronic acid (62 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) were combined and the mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the crude product was purified on a 2 g silica Isolute® SPE column, eluting with dichloromethane/methanol (95:5). The eluent was concentrated under reduced pressure and the crude product was suspended in acetonitrile then treated with diethyl ether to precipitate the product. The mother liquors were removed by filtration and the residual solid was further purified on a Biotage silica gel cartridge, eluting with dichloromethane/methanol (98:2). Recrystallisation from dichloromethane/diethyl ether afforded the title compound (48 mg, 32%) m/z, 297.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:40][CH2:39]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)c2ccccc21
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cn2)c2ccccc21
Temperature: 110 °C
Yield: 74.1 %

Procedure:
10.12 g of 4-(5-bromopyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester and 5.7 g of 4-(benzyloxycarbonyl)piperazine are placed in 118 ml of toluene and then 0.95 g of tris(dibenzylideneacetone)dipalladium(0), 1.7 g of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 3.5 g of sodium tert-butoxide are added. The reaction medium is heated at 110° C. for 3 h. Ethyl acetate is subsequently added and the mixture is washed once with water and once with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of a mixture of heptane/ethyl acetate (90/10 to 0/100). 10.16 g of 4-[5-(4-(benzyloxycarbonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[CH2:20][CH:19]([CH2:21][CH3:22])[CH2:18][CH2:17][CH:16]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH2:21]([CH:19]1[CH2:20][N:15]([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])[CH:16]([CH3:23])[CH2:17][CH2:18]1)[CH3:22]
Reactant: CCC1CCC(C)N(C(=O)CN(C(=O)CN)c2ccccc2)C1
Reactant: Cc1cccc(N=C=O)c1
Product: CCC1CCC(C)N(C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)C1
Yield: 18.5 %

Procedure:
The procedure is analogous to that described in Example 1, but 2.0 g of 2-amino-N-[2-(5-ethyl-2-methylpiperidino)-2-oxoethyl]-N-phenylacetamide, as a mixture of the cis and trans isomers, and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 50 g of silica (0.065-0.200 mm) contained in a column 1.5 cm in diameter [eluent: methylene chloride/methanol (98-2 by volume)], collecting 20 cm3 fractions. Fractions 2 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from an ethyl acetate/diethyl ether mixture (40-60 by volume), 0.5 g of N-[2-(5-ethyl-2-methylpiperidino)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide is obtained as a mixture of the cis and trans isomers melting at 158° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:18][C:14]=3[CH2:13]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(NC(NCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=S)CCCCC1>C(O)(=O)C.O>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH2:13]2)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=C(NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1)NC1CCCCC1
Agent: S=C(NCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1)NC1CCCCC1
Solvent: CC(=O)O
Solvent: O
Product: S=C(NCC1CCc2[nH]cnc2C1)NC1CCCCC1
Temperature: 90 °C

Procedure:
A solution of a mixture of 1-cyclohexyl-3-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)thiourea and 1-cyclohexyl-3-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)thiourea (770 mg, 1.44 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 400 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24](O)=[O:25])[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:25])[CH2:18][CH2:17]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)CCC1CCN(C(=O)c2ccccc2)CC1
Reactant: Fc1ccccc1
Product: O=C(CCC1CCN(C(=O)c2ccccc2)CC1)c1ccc(F)cc1
Yield: 125.1 %

Procedure:
The procedure is as in Example 1, starting from 8.8 g of fluorobenzene instead of the 9.9 g of anisol and from 20 g instead of from 15.7 g of 3-(1-benzoyl 4-piperidyl) propionic acid. 25.5 g of crude 3-(1-benzoyl 4-piperidyl) 1-(4-fluorophenyl) 1-propanone in the form of an oil are obtained.
Reaction SMILES: C[O:2][CH:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)C.C([Li])CCC.[CH:19]([O:21][CH2:22][CH3:23])=O>CCCCCC>[CH3:19][O:21][CH:22]([C:13]1[C:7]2[NH:6][C:5]([CH:3]=[O:2])=[N:9][C:8]=2[CH:10]=[CH:11][CH:12]=1)[CH3:23]
Reactant: CCOC=O
Reactant: COC(C)c1nc2ccccc2[nH]1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COC(C)c1cccc2nc(C=O)[nH]c12

Procedure:
Following the procedure of Example 1D, 2.36 g of 1-methoxyethylbenzimidazole, 5.15 ml of 2.6M n-butyl lithium in hexane, 1.08 ml of ethyl formate gave on work-up 1.73 g of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH:4]=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH2:4][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC=O)cn1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted with morpholine to afford the title compound: MS m/z 492.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br)([O-:27])=[O:26]>CN(C)C=O>[OH:9][CH2:8][CH:7]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N+:25]([O-:27])=[O:26])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COc1ccc(S(=O)(=O)NC(CO)C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2[N+](=O)[O-])C(CO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 129.1 %

Procedure:
To 6.16 g (18.6 mmol) of 3-hydroxy-2-(4-methoxybenzenesulfonylamino)-propionic acid tert-butyl ester in 50 ml of N,N-dimethylformamide, cooled in an ice bath, was added 0.781 g (19.5 mmol) of sodium hydride. After gas evolution ceased, a solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of N,N-dimethylformamide was added dropwise. The mixture was stirred under nitrogen at room temperature for 4 hours and 1.0 g of 2-nitrobenzyl bromide was added. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was diluted with water and extracted with CH2Cl2. The organic extract was washed with H2O, brine and dried with Na2SO4. The solvent was removed to give 11.2 g of solid which was chromatographed on silica gel with hexane-ethyl acetate (1:1) as eluent followed by hexane-ethyl acetate (35:65) as eluent. The fractions containing product were combined and the solvent was then removed to gave 7.7 g (89%) of solid. A sample from a 3 mmol run gave a gum. Anal. for C21H26N2O8S: Calc'd: C, 54.1; H, 5.6; N, 6.0; Found: C, 54.0; H, 5.7; N, 6.0.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10](I)[N:5]2[N:4]=1.[CH3:17][O-:18].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10]([O:18][CH3:17])[N:5]2[N:4]=1
Reactant: O=Cc1ccc(I)n2nc(C(F)(F)F)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reaction time: 2 h
Yield: 90.5 %

Procedure:
The compound of Example 113 (2.97 g) was dissolved in methanol (50.0 mL). To this solution, sodium methoxide (1.42 g) was added and the mixture was stirred for 2 hours under reflux. After cooling, the solvent was evaporated. Water was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was suspended in diisopropyl ether. The solid product was collected by filtration to afford the title compound as a yellowish green powder (1.93 g).
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Cl[CH2:53][C:54]1[N:58]([CH3:59])[N:57]=[C:56]([CH3:60])[CH:55]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:53][C:54]3[N:58]([CH3:59])[N:57]=[C:56]([CH3:60])[CH:55]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cc1cc(CCl)n(C)n1
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: Cc1cc(Cn2nc3nc(C(C)(C)C)nc(N4CC[C@H](O)C4)c3n2)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light yellow gum. MS (m/e): 371.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:24]O>>[CH3:24][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[CH:17]=2)=[CH:22][CH:23]=1)=[O:3]
Reactant: CO
Reactant: Cc1cc(CCCCCCCOc2ccc(C(=O)O)cc2)on1
Product: COC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Yield: 95 %

Procedure:
[I; R is CH3, n is 7, X is O, Ar is 4--CH3OOCC6H4 ], m.p. 60° C. in 95% yield from 5-[7-(4-carboxyphenoxy)heptyl]-3-methylisoxazole (Example 16) and methanol; MIC vs. rhinovirus Type 2 in vitro=3 μg/ml.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][N:8]=1.[I:17]N1C(=O)CCC1=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:17][C:11]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][O:9][C:10]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1onc(-c2ccccn2)c1I
Temperature: 120 °C
Yield: 40.6 %

Procedure:
A suspension of ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (Preparation 63B, 6.25 g, 28.6 mmol), Palladium(II) acetate (1.61 g, 7.16 mmol) and 1-iodopyrrolidine-2,5-dione (12.9 g, 57.3 mmol) in acetonitrile (20 mL) was heated in the microwave for 30 minutes at 120° C. LC/MS analysis indicated that approximately 50% conversion had occurred. Additional 1-iodopyrrolidine-2,5-dione (12.9 g, 57.3 mmol) was added, and the reaction mixture heated for an additional 30 min. at 120° C. The reaction mixture was diluted with acetonitrile (25 mL) and filtered through a plug of Celite. The filtrate was concentrated and purified by silica gel column chromatography using an ISCO setup to afford ethyl 4-iodo-3-(pyridin-2-yl)isoxazole-5-carboxylate (4.00 g, 11.6 mmol, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, 3H), 4.51 (q, J=7.04 Hz, 2H), 7.44 (ddd, J=7.48, 4.84, 1.32 Hz, 1H), 7.82-7.88 (m, 1H), 7.89-7.94 (m, 1H), and 8.81 (ddd, J=4.18, 1.32, 1.10 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[O:22][CH3:23]>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:18])=[CH:15][C:14]=1[O:22][CH3:23]
Reactant: Nc1ccc2cccnc2c1
Reactant: COc1cc(C(=O)O)ccc1Br
Product: COc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1Br

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (36 mg, 0.25 mmol) and 4-bromo-3-methoxybenzoic acid (69 mg, 0.3 mmol) as a white solid (84 mg). MS(ES): MH+ 357/359, M-H+ 355/357.
Reaction SMILES: N[C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].N([O-])=O.[Na+].Cl.C([O-])(=O)C.[K+].CCOC([S-])=[S:29].[K+]>O>[SH:29][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C)c(N)c(C(=O)O)c1
Reactant: CCOC(=S)[S-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1cc(C)c(S)c(C(=O)O)c1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
A mixture of 2-amino-3,5-dimethylbenzoic acid (5.6 g, 33.9 mmol), sodium hydroxide (1.5 g, 37.5 mmol), sodium nitrite (2.3 g, 34.0 mmol) and water (40 ml) was added dropwise to a mixture of concentrated hydrochloric acid (10 ml) and ice (10 g) under cooling with ice while adding ice in order to keep the reaction temperature under 5° C. The reaction mixture was stirred under ice-cooling condition for 30 minutes, neutralized with potassium acetate and added to a solution of potassium o-ethyl dithiocarbonate (16.9 g, 105.4 mmol) in water (50 ml) at 80° C. After stirring at the same temperature for 20 minutes, the reaction mixture was acidified (pH 3) by use of concentrated hydrochloric acid. The water layer was separated. 10% aqueous sodium hydroxide solution (30 ml) was added to the oily substance and the mixture was stirred at 80° C. for 2 hrs. Furthermore, sodium hydrogen sulfite (4.0 g) was added to the mixture, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was filtered and the filtrate was acidified (about pH 4) by use of concentrated hydrochloric acid. The precipitate was collected by filtration and dissolved in a mixture of methanol (5 ml) and diisopropylether (80 ml), dried and concentrated under reduced pressure to give the titled compound as crystals (3.6 g, 58%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:22]#[N:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO>[C:22]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])[N:6]=1)#[N:23]
Reactant: COC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O
Reactant: CC(C)(CN)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(-c3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 61.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenyl-isoquinoline-3-carboxylic acid methyl ester (47 mg, 0.15 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (143 mg, 0.62 mmol) and NaOMe (67 mg, 1.24 mmol) in EtOH (3 mL) was heated at 150° C. in a microwave reactor for 2 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 36 mg of the title compound as a light brown solid. MS: (−) m/z 388.13 (M−1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:22])=[O:21])[C:3]=1[CH3:23].[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH2:36])=[CH:34][C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([NH:36][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[S:20]([CH3:22])=[O:21])[C:3]=3[CH3:23])=[CH:34][C:33]([N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1
Reactant: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using (+/−)-4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinoline (22.0 mg, 0.063 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give (+/−)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-(methylsulfinyl)phenyl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.21 (1H, d, J=8.0 Hz), 7.91 (1H, br. s.), 7.76 (1H, td, J=7.6, 1.4 Hz), 7.66-7.71 (1H, m), 7.65 (1H, d, J=2.5 Hz), 7.54 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.08 (1H, ddd, J=13.5, 8.5, 2.4 Hz), 6.38 (1H, br. s.), 3.92 (4H, br. s.), 3.84 (4H, t, J=4.8 Hz), 3.19-3.54 (3H, m), 3.00-3.18 (5H, m), 2.55-2.97 (3H, m), 2.01 (3H, br. s.). Mass Spectrum (ESI) m/e=580.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=1)=[O:11].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=1)[CH2:9][C:10](=[O:11])[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C(CC(=O)c2ccc(OC)nc2)c2ccccc2Cl)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 162, step 2, methyl 4-(1-(2-chlorophenyl)-3-(6-methoxypyridin-3-yl)-3-oxopropyl)-2-fluorobenzoate was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless foam, MS (ESI+): m/z=414.2 [M+H]+.