Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-dodecylsuccinic anhydride (42.17 g, 147.4 mmol), 3-(3,5-di-t-butyl-4hydroxyphenyl)propanoic acid hydrazide (43.31 g, 147.4 mmol) and 70 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (160° C.) melt for about 10 minutes. The resulting yellow liquid was then cooled under vacuum to about 120° C. The vacuum was released and the melt was quickly poured into a container. Upon cooling, the liquid became a clear yellow glass. The product was recrystallized from acetone/water at ice bath temperatures to afford, after drying, a nearly quantitative recovery of the product as a white powder having a melting range of 55°-60° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of 1.00 g (14.5 mmol) oxazole in 25 ml dry THF under argon at −78° C. was added 9.14 ml (14.6 mmol) n-butyllithium solution (1.6M in hexane) and stirring continued for 30 minutes at −78° C. 3.91 ml (14.5 mmol) tributyltin chloride was then added dropwise and stirring continued for 15 minutes at −78° C. and for 1 hour at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in 50 ml hexane. The insoluble lithium salts were removed by filtration and the filtrate was concentrated in vacuo to afford 4.90 g (95%) 2-tributylstannanyl-oxazole as a light yellow liquid which was used in the next step without further purification. 1H NMR 6 (CDCl3, 250 MHz): 7.84 (1H, s), 7.18 (1H, s), 1.67-1.53 (6H, m), 1.42-1.29 (6H, m), 1.20 (6H, t, J=8 Hz), 0.89 (9H, t, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[S:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([O:39]C)=[O:38])[CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[S:24][C:23]4=[O:31])[CH2:15][CH2:14]3)[C:12](=[O:32])[N:11]([CH2:33][C:34]3[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=3)[C:37]([OH:39])=[O:38])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccc(OC)cc3)C3(CCN(CCCn4c(=O)sc5ccccc54)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CN(Cc3cccc(C(=O)O)c3)C(=O)C23CCN(CCCn2c(=O)sc4ccccc42)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a solution of methyl 3-((1-(4-methoxyphenyl)-4-oxo-8-(3-(2-oxobenzo[d]thiazol-3(2H)-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.19 g, 0.32 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.027 g, 0.63 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.11 g, 59%); 1H NMR (DMSO-d6): δ 1.64 (d, 2H, J=13.6 Hz), 1.79 (t, 2H, J=6.4 Hz), 1.88-1.95 (m, 2H), 2.38 (t, 2H, J=6 Hz), 2.50-2.66 (m, 4H), 3.69 (s, 3H), 3.97 (t, 2H, J=6.4 Hz), 4.53 (d, 4H, J=26.8 Hz), 6.86 (d, 2H, J=7.2 Hz), 6.94 (d, 2H, J=7.6 Hz), 7.16 (t, 1H, J=7.2 Hz), 7.30 (t, 1H, J=7.6 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.47-7.53 (m, 2H), 7.58 (dd, 1H, J=8 and 1.2 Hz), 7.85-8.87 (m, 2H), 12.95 (br, 1H); MS for C32H34N4O5S m/z 587.02 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].C[N:46]([CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1)[C:47](=O)[C:48]1[CH:88]=CC=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=1.Cl.O1CCN(CCNC2CC2)CC1>>[CH:47]1([N:46]([CH2:90][CH2:91][N:92]2[CH2:93][CH2:94][O:95][CH2:96][CH2:97]2)[C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]3[CH:18]=[CH:19][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:21][C:16]=3[C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)=[O:30])[CH:32]=2)[CH2:48][CH2:88]1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: C(CN1CCOCC1)NC1CC1
Agent: Cl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(CCN3CCOCC3)C3CC3)c2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8. N-(2-morpholinoethyl)cyclopropanamine hydrochloride was used as the amine component in this coupling. MS (ES, m/z): 755 [M+H]+
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClP(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CN=C1.[I:37]I>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][I:37])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: II
Agent: ClP(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCCI)CC1

Procedure:
To a stirred mixture of 3-3 (22.7 g, 93 mmol), chlorodiphenylphosphine (21.7 mL, 0.12 mol), imidazole (19.0 g, 0.28 mol), and toluene (300 mL) at 0° C. was added iodine (30.6 g, 0.12 mol) in toluene (700 mL) followed by removal of the cooling bath. After 2.0 h the reaction mixture was washed with saturated Na2CO3, 5% Na2S2O3, 10% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 3-4 as a colorless oil, RF 0.41 (silica, 10% EtOAc/hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH:17]([OH:18])[C:28]([F:30])([F:29])[F:27])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cccc(C)c1-c1nc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1nc2ccc(C(O)C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
To 2-(2,6-dimethylphenyl)-6-formyl-benzoimidazole-1-carboxylic acid tert-butyl ester (565 mg) was added 16 mL of a 0.5 M solution of trifluoromethyltrimethylsilane in THF. When a solution formed the mixture was cooled to −30° C. then a solution of TBAF (1.76 mL of a 1.0M solution in THF) was added dropwise. The mixture was stirred at −30° C. for 45 min then was allowed to warm to 5° C. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting foam was purified by flash chromatography using 10% EtOAc/methylene chloride as eluent to give 2-(2,6-dimethyl-phenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)-benzoimidazole-1-carboxylic acid tert-butyl ester as a waxy solid. MS (ESI)m/z 421 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][CH:13]([NH2:15])[CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:16][CH:17]([F:28])[C:18]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[N:20]([CH3:27])[N:19]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:12][CH:13]([NH:15][C:23]([C:22]2[C:18]([CH:17]([F:28])[F:16])=[N:19][N:20]([CH3:27])[C:21]=2[F:26])=[O:24])[CH3:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1F
Reactant: CC(N)Cc1ncc(C(F)(F)F)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Cc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1c(C(F)F)nn(C)c1F
Reaction time: 8 h
Yield: 82.7 %

Procedure:
At ambient temperature, 150 mg (0.545 mmol) of 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-amine, 116 mg (0.60 mmol) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxylic acid, 81 mg (0.60 mmol) of 1-hydroxybenzotriazole and 55 mg (0.545 mmol) of triethylamine are stirred together in 1 ml of dimethylformamide until dissolution. This solution is pourred over a 2 g-containing basic alumina Chem-Elut™ cartridge packed with 1.48 g of Si-DCC resin (1.09 mmol of DCC per g of resin) and left overnight at ambient temperature. The cartridge is then washed three times by 2 ml of acetonitrile. The solvents are removed and the crude amide is purified by column chromatography on silica gel (gradient heptane/ethyl acetate) to yield 187 mg (78% yield) of N-{1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]propan-2-yl}-3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carboxamide as yellow solid (M+H=415).
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]([O-])(=[O:11])[CH3:10].[Na+]>C(OC(=O)C)(=O)C>[C:9]([O:8][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:11])[CH3:10]
Reactant: CCCCCC(C)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(C)OC(C)=O
Yield: 67 %

Procedure:
2-Heptanol (162 g, 1.4 mol, Aldrich) and sodium acetate (16 g, Aldrich) were heated to 100° C. and then acetic anhydride (190 ml, BDH GPR) was added over a 1 hour period at 100-130° C. The mixture was heated to reflux for 3 hours. The reaction mixture was then cooled, washed with water, washed with aqueous sodium bicarbonate to neutrality, dried over sodium sulfate, and then concentrated. Fractional distillation of the crude residue under vacuum provided 1-methylhexyl acetate (107-108°/95-100 mm Hg, 67% yield), the structure of which was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy, and infra red spectroscopy (not shown).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:38])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Si:45]([O:52][CH2:53][CH:54]=[O:55])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>O1CCCC1.CCCCCC>[Si:45]([O:52][CH2:53][CH:54]([OH:55])[CH:36]([C:37](=[O:38])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1)[CH2:35][CH2:34][CH2:33][O:32][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:48]([CH3:50])([CH3:51])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](OCCCCC(=O)c1cccnc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 0.93 ml (0.0044 mole) of hexamethyldisilazane in 14 ml of tetrahydrofuran, 2.15 ml (0.0044 mole) of 2.06 molar solution of n-butyllithium in hexane is added dropwise with stirring under argon at 0° C. The mixture is cooled to -20° C. and a solution of 1.68 g (0.004 mole) of 5-(t-butyldiphenylsilyloxy)-1-(3-pyridyl)pentan-1-one in 10 ml of tetrahydrofuran is added dropwise over a period of 15 min. The mixture is stirred at -20° C. for 15 min and a solution of 0.74 g (0.0042 mole) of t-butyldimethylsilyloxy acetaldehyde in 15 ml of tetrahydrofurane is added over a period of 1 min. The mixture is stirred at -20° C. for 15 min, quenched with 6 ml of concentrated aqueous ammonium chloride, diluted with ether and washed with water and brine, dried and evaporated. The residue is purified by flash chromatography using ethyl acetate-methylene chloride (1:1) as eluent to give 1-(t-butyldimethylsilyloxy)-6-(t-butyldiphenylsilyloxy)-3-nicotinoylhexan-2-ol described in example 3.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:10]1=[O:23].[Cl:24][C:25]1[CH:38]=[CH:37][C:28]2[S:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[C:31]([CH3:32])[C:27]=2[CH:26]=1>>[C:21]([C:17]1[CH:16]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][C@H:9]([NH:8][S:33]([C:30]3[S:29][C:28]4[CH:37]=[CH:38][C:25]([Cl:24])=[CH:26][C:27]=4[C:31]=3[CH3:32])(=[O:35])=[O:34])[C:10]2=[O:23])[CH:20]=[CH:19][N:18]=1)#[N:22]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)ccn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(=O)(=O)N[C@H]2CCN(Cc3ccnc(C#N)c3)C2=O)sc2ccc(Cl)cc12

Procedure:
The title compound is prepared as described in EXAMPLE 125, Part C using 4-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)pyridine-2-carbonitrile trifluoroacetate in place of 4-(3-(S)-amino-2-oxopyrrolidine-1-ylmethyl)-thiophene-2-carbonitrile hydrochloride and with 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1C(=O)OC
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate (212 mg, 0.72 mmol) in DMF (8 mL) was added pentafluorophenyl ester of the 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (346 mg, 0.72 mmol) and Et3 N (120 ml, 0.86 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give 413 mg (97%) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]phthalate as an oil. 1H-NMR (CDCl3) δ 1.92–2.12 (m, 4 H), 2.29 (br s, 3 H), 3.51–3.64 (m, 7 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.10–4.19 (m, 2 H), 4.44 (m, 1 H), 6.73–8.02 (series of m, total 12 H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.Br.[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1NC2CNC1C2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CC3CN4)c(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 0.54 g (2.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.57 g (2.2 mmol) of 2,5-diazabicyclo(2.2.1)heptane dihydrobromide [P. S. Portoghese and A. A. Mikhail, J. Org. Chem., 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)undec-7ene, and 20 ml of acetonitrile was heated under reflux for one hour and stirred at room temperature for two hours. The reaction mixture was filtered and the solid was washed with ethanol to give 0.60 g of the title compound, mp 275° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.Br[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[C:32]#[N:33].O>COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].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>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:27]4[CH:31]=[CH:30][S:29][C:28]=4[C:32]#[N:33])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2c1
Reactant: N#Cc1sccc1Br
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2c(-c3cccc(-c4ccsc4C#N)c3)cnc2c1
Yield: 57.1 %

Procedure:
A mixture of 7-methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]imidazo[1,2-α]pyridine (350 mg, 1.0 mmol) and 3-bromo-2-cyanothiophene (200 mg, 1.0 mmol) in 1,2-dimethoxyethane (10 ml) and caesium carbonate (5 ml of a 2M solution) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (125 mg, 0.1 mmol) was then added and the mixture heated at reflux for 20 hours, poured into water (50 ml) and extracted with ethyl acetate (2×25 ml). The combined organic phases were dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 3% methanol in dichloromethane gave the title compound as a colourless oil (180 mg, 57%). Oxalate salt, white powder, m.p. 193-195° C. (Found C, 62.07; H, 3.66; N, 10.19. C19H13N3S.C2H2O4 requires C, 62.21; H, 3.73; N, 10.36). 1H NMR (360 MHz, d6-DMSO) δH 2.42 (3H, s), 6.91-6.93 (1H, m), 7.53 (1H, s), 7.68-7.82 (6H, m), 7.89 (1H, s), 8.01 (1H, s), 8.18 (1H, d, J 5), 8.63 (1H, d, J 7); m/z (ES+) 316 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:43]([NH:50][CH2:51][CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([N:50]([CH2:51][CH3:52])[C:18](=[O:20])[C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:16][CH2:15]1)=[O:21])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCNCc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1

Procedure:
To a stirred solution of 2-(4-(2-tert-butylphenyl)piperazin-1-yl)-2-oxo-acetic acid (0.100 g, 0.34 mmol) in methylene chloride (6.0 mL) was added EDCI (0.085 g, 0.44 mmol) and HOBt (0.060 g, 0.44 mmol) at room temperature. After 1 h N-benzyl-N-ethyl amine (0.050 g, 0.37 mmol) was added at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 0:100 heptane/ethyl acetate, gradient elution) to provide N-benzyl-2-(4-(2-tert-butylphenyl)piperazin-1-yl)-N-ethyl-2-oxoacetamide as a mixture of cis and trans isomers (0.026 g, 19%) as a white foam.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[C:11]([CH:10]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:18]1=[O:36])[CH2:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21
Reaction time: 18 h
Yield: 56.7 %

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 272 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 228 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction, 200 ml of acetic acid are added and the mixture is hydrogenated for a further 18 h, at 3 atm at room temperature, after that the catalyst is filtered off through Celite and the solvent mixture is evaporated to dryness. The residue is taken up with isopropanol (500 ml) and the resulting precipitate is filtered, washed with 20 ml of dichloromethane and dried to give 3-[[1-(carboxy)-3-phenyl-propyl]amino]-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (15) (58.5 g, yield: 52%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][OH:7])[CH2:4][CH3:5].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].O>CN(C)C=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:7][N:6]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC(CC)=NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)=NOc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.6 %

Procedure:
To a solution of pentan-3-one oxime (6.00 g) in dimethylformamide (30 ml) was added sodium hydride (60% oil suspension, 2.37 g) under ice cooling. After 15 minutes, to the above mixture was added dropwise 1-fluoro-2-nitrobenzene (5.98 g) in dimethylformamide (30 ml). The mixture was stirred for 3 hours at ambient temperature and poured into a mixture of ice and water. The separated oil was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo to give pentan-3-one O-(2-nitrophenyl)oxime (10.51 g) as a brown oil.