Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13][CH2:14][NH:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:21]=3)[CH2:8][CH2:7][C:6]=2[CH:29]=1
Reactant: Fc1ccc2c(c1)CC[C@H](CN(CCNc1ncccn1)Cc1ccccc1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(c1)CC[C@H](CNCCNc1ncccn1)O2
Yield: 54.1 %

Procedure:
A mixture of 8.4 g of (-)-(R)-N-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,2-ethanediamine and 150 ml methanol was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated and the residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.5 g (55.1%) of (-)-(R)-N-[(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(2-pyrimidinyl)-1,2-ethanediamine; mp. 103.2° C. [α]D20 =-76.58° conc.=1% in CH3OH) (comp. 46).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.[CH3:17][O:18][CH2:19][CH2:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH3:17][O:18][CH2:19][CH2:20][NH:21][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNC(=O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 0° C. solution of 500 mg of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, 328 mg of 2-methoxyethylamine, 736 mg of HOBt, and 1.82 mL of triethylamine in 9 mL of dichloromethane was treated with 836 mg of EDC.HCl. The mixture was stirred at 25° C. overnight and the solvent was evaporated at reduced pressure. The residue was dissolved in ethyl acetate, and the solution was sequentially washed with water, an aqueous solution of citric acid, an aqueous sodium bicarbonate solution, and brine. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was dissolved in a 4 M solution of HCl in dioxane. After 1 h the mixture was evaporated to give 406 mg of the product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:43]([O-])=O)=[C:25]([NH:27][C:28]3[S:29][C:30]([C:40]([NH2:42])=[O:41])=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[N:32]=3)[CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O1CCC[CH2:47]1.[Cl-].[NH4+].C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]3[N:43]=[CH:47][N:27]([C:28]4[S:29][C:30]([C:40]([NH2:42])=[O:41])=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=5)[N:32]=4)[C:25]=3[CH:26]=2)[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1sc(Nc2cc(CN(CCCN3CCOCC3)CCCN3CCOCC3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1sc(-n2cnc3ccc(CN(CCCN4CCOCC4)CCCN4CCOCC4)cc32)nc1-c1cccc(Cl)c1

Procedure:
To a mixture of 0.150 g (0.23 mmole) of 2-(5-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (VI.49a), 20 mL of tetrahydrofuran, and 20 mL of saturated ammonium chloride solution was added 0.089 g (1.38 mg-atom) of zinc powder. After 5 minutes the mixture was filtered and the filtrate partitioned between 50 mL of saturated ammonium chloride and 50 mL of tetrahydrofuran. The tetrahydrofuran layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was stirred for 3 hours with 30 mL of acetic acid and 0.178 g (1.2 mmole) of triethyl orthoformate. The mixture was concentrated under reduced pressure, diluted with 100 mL of dichloromethane and washed with saturated sodium bicarbonate solution, then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:1) to give 0.075 g of 2-(6-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.49) as a light pink solid. MH+/Z=638.
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH:22]=[CH:23][C:24](OC)=[O:25])[CH2:21][CH2:20][CH2:19]1>ClCCl.O>[CH2:1]([N:8]1[CH:22]([C:18]2([CH3:17])[CH2:21][CH2:20][CH2:19]2)[CH2:23][C:24](=[O:25])[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONCc1ccccc1
Reactant: COC(=O)C=CC1(C)CCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C2CC(=O)ON2Cc2ccccc2)CCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl 3-(1-methylcyclobutyl)acrylate, 114a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated with a phase separator and the aqueous layer was washed with dichloromethane. The organic layers were combined and the volatiles removed under reduced pressure. The residue was purified on silica gel (EtOAc/Hexanes) to afford the desired product as a racemic mixture: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.47 minutes (M+H) 246.10.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[F:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(F)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-fluoro-aniline (Aldrich, 38 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 60 mg.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(C1C=CC(C)=CC=1)(O[CH2:18][C@@H:19]1[CH2:33][C@H:32]2[C@@H:22]([CH2:23][C:24]3[C:34]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]2=4)[NH:26][CH:25]=3)[N:21]([CH3:35])[CH2:20]1)(=O)=O>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][N:7]([CH2:18][C@@H:19]2[CH2:33][C@H:32]3[C@@H:22]([CH2:23][C:24]4[C:34]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]3=5)[NH:26][CH:25]=4)[N:21]([CH3:35])[CH2:20]2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)ncn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
1.6 g of 50% sodium hydride in an oil was added in small portions to a mixture of 10 g of ethyl 4-methyl-5-imidazolecarboxylate and 70 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 4.1 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to alumina column chromatography eluting with ethyl acetate to obtain ethyl 4-methyl-1-(6-methylergolin-8β-ylmethyl)-5-imidazolecarboxylate from the first fraction. The product was recrystallized from dichloromethane-diethyl ether and was colorless prisms having a melting point of 225°-227° C. Yield, 0.7 g. This compound is hereinafter referred to as Compound 15A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Zn+])=[CH:32][CH:31]=1.Cl.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(OC)cc5)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (84 mg), 4-methoxy-benzylzinc chloride (0.5 mol/L in tetrahydrofuran, 1.2 mL) and tetrakis(triphenylphosphine)-palladium (23 mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, and the mixture is heated to 60° C. and shaken at this temperature overnight. After cooling to room temperature, the mixture is acidified with 4 N aqueous hydrochloric acid (1 mL) and then neutralized with saturated aqueous ammonia solution. The organic phase is separated, diluted with N,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=1.16 min.
Reaction SMILES: O1CCNC1=O.C[Si](C)(C)Cl.[C:12]1([CH:18]2[O:22][C:21](=[O:23])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:24]([Si:26]([CH2:30][CH3:31])([CH2:28][CH3:29])Cl)[CH3:25]>>[C:12]1([CH:18]2[O:22][C:21](=[O:23])[N:20]([Si:26]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:24][CH3:25])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1NCC(c2ccccc2)O1
Reactant: CC[Si](Cl)(CC)CC
Agent: C[Si](C)(C)Cl
Agent: O=C1NCCO1
Product: CC[Si](CC)(CC)N1CC(c2ccccc2)OC1=O

Procedure:
This example is performed in a similar way to example 1, with the 2-oxazolidinone and the trimethylchlorosilane being replaced by 5-phenyl-2-oxazolidinone (57.11 g; 0.35 mol) and triethylchlorosilane (63.3 g; 0.42 mol) respectively. Once the solvent has been evaporated off, the result is crude 5-phenyl-3-triethylsilyl-2-oxazolidinone with a virtually quantitative yield. By methanolysis 5-phenyl-2-oxazolidinone is obtained. Calculated: 69..33%; found: 69.05%.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.FC(F)(F)S(OC1[C@]2(CC[C@H]3[C@@H](CCC4[C@]3(C)CCCC4)[C@@H]2CC=1)C)(=O)=O.[C:39]([O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[C@@H:45]([CH2:46][CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH2:51][C:52]2=O)[CH2:44]1)(=[O:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>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.C1COCC1>[C:39]([O:42][C@@H:43]1[CH2:60][CH2:59][C@@:58]2([CH3:61])[C@@H:45]([CH2:46][CH2:47][C@@H:48]3[C@@H:57]2[CH2:56][CH2:55][C@@:53]2([CH3:54])[C@H:49]3[CH2:50][CH:51]=[C:52]2[C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:44]1)(=[O:41])[CH3:40]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[C@]12CCCCC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]12
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Yield: 82 %

Procedure:
The method followed that described in Example 1, using in step (b) diethyl(3-pyridyl)borane (1.41 g, 9.6 mmol), 3,,-acetoxy- 5,,-androst-16-en-17-yl trifluoromethanesulphonate (3.44 g, 7.4 mmol), prepared from the 3α-acetoxy-5α-androstan-17-one by the method of step (a), THF (40 ml), bis(triphenylphosphine)palladium(II) chloride (52 mg, 0.07 mmol), and aqueous sodium carbonate (2M, 15 mmol). Chromatography, on elution with light petroleum-diethyl ether (2:1), afforded the title compound (2.39 g, 82%), 1H-NMR (CDCl3) inter alia δ 0.85(3H,s,19-CH3), 1.01(3H,s, 18-CH3), 2.06(3H,s,CH3CO2), 5.02(1H,m,3β-H), 6.00(1H,m, 16-H), 7.24(1H,m,Py 5-H), 7.68(1H,m,Py 4-H), 8.47(1H,m,Py 6-H), 8.63(1H,m,Py 2-H); MS m/z 393 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[Br:1][C:2]1[C:3]2[O:4][CH2:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8](=[O:10])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1COc1ccccc1Br
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccccc2COc2c(Br)cccc21
Temperature: 0 °C
Yield: 53 %

Procedure:
A suspension of 2-(2-bromophenoxymethyl)benzoic acid (18.8 g, 0.06 mole) in 100 mL of trifluoracetic anhydride containing ten drops of boron trifluoride-ether complex was refluxed for four hours. The mixture was poured into ice water and then extracted with diethyl ether. Concentration of the ether solution under reduced pressure gave the pure product (9.2 g), mp 127°-130° C. pmr (CDCl3) δ: 7.28-8.19 (m, 76H, aromatic H); 6.99 (t, 1H, H2); 5.30 (s, 2H, ArCH2O).
Reaction SMILES: [CH2:1](N1C(=O)OC(=O)C2=CC=C(C3C=CN=CC=3)C=C12)[CH3:2].[CH2:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:31]=2)[C:26](=[O:39])[C:25]([C:40]([OH:42])=[O:41])=[CH:24]1)[CH3:22].[K]>>[CH2:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH:31]=2)[C:26](=[O:39])[C:25]([C:40]([O:42][CH2:1][CH3:2])=[O:41])=[CH:24]1)[CH3:22]
Reactant: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Agent: [K]
Product: CCOC(=O)c1cn(CC)c2cc(-c3ccccn3)ccc2c1=O

Procedure:
It was found that the N-ethyl 4-(4-pyridinyl)isatoic anhydride prepared in the preceding examples cound be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reacting it with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (b) hydrolyzing that ester.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:21]([NH:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:24])[CH2:22][CH3:23]>CN(C=O)C.O>[C:21]([NH:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:28][CH:27]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Reactant: CCC(=O)Nc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
265 mg (1 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are dissolved in 5 ml of DMF and after the addition of 300 mg (1.8 mmol) of 4-propionylamino-aniline stirred for 8 hours at 150° C. After cooling, it is diluted with water, the crystalline product is suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:45]=[CH:44][CH:43]=[CH:42][C:6]=1[CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]2[CH:18]=[C:17]([CH3:19])[C:16]([C@H:20]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]([O:23]C)=[O:22])=[C:15]([N:30]3[CH2:35][CH2:34][C:33]([CH2:37][CH2:38]C=C)([CH3:36])[CH2:32][CH2:31]3)[N:14]2[CH:41]=1)=[O:10])[CH:2]=[CH2:3].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+].C([O-])(O)=O.[Na+].O[Li].O>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.O>[C:26]([O:25][C@@H:20]([C:16]1[C:17]([CH3:19])=[CH:18][C:13]2=[N:12][C:11]3=[CH:41][N:14]2[C:15]=1[N:30]1[CH2:35][CH2:34][C:33]([CH3:36])([CH2:37][CH2:38][CH2:3][CH2:2][CH2:1][O:4][C:5]2[CH:45]=[CH:44][CH:43]=[CH:42][C:6]=2[CH2:7][NH:8][C:9]3=[O:10])[CH2:32][CH2:31]1)[C:21]([OH:23])=[O:22])([CH3:29])([CH3:27])[CH3:28]
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CCCCCOc2ccccc2CNC3=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A solution of (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.023 g, 0.037 mmol, 1 equiv) and TsOH (7 mg, 0.037 mmol, 1 equiv) in DCE (19 mL) was heated to 80° C. The Hoveyda Grubbs 2nd generation catalyst (5 mg, 0.007 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 2 h. Upon cooling to ambient temperature, the reaction was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The dark residue was then taken up in MeOH (2 mL) and NaBH4 (2 mg, 0.052 mmol, 1.4 equiv) was added. After stirring 1 h, the reaction was added to saturated aqueous NaHCO3 and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was taken up in 9:1 MeOH:water (2 mL) and LiOH.H2O (78 mg, 1.684 mmol, 50 equiv) was added. The reaction was heated to 60° C. for 6 h. Upon cooling to ambient temperature, the reaction was filtered and purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to provide the product (7.1 mg, 31%). 1H NMR (500 MHz, DMSO-d6) δ 8.71-8.61 (m, 1H), 8.08 (s, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 5.90 (s, 1H), 4.44-4.28 (m, 2H), 4.14 (td, J=10.6, 6.0 Hz, 2H), 3.68 (br. s., 2H), 3.06 (d, J=7.9 Hz, 1H), 2.57 (br. s., 1H), 2.37 (s, 3H), 2.09-1.93 (m, 3H), 1.68-1.25 (m, 9H), 1.17 (s, 9H), 0.98 (s, 3H); LCMS (ESI, M+1): 577.5.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[N:8]=2)[CH2:3]1.C(N(CC)CC)C.[O:32]=[C:33]1[NH:37][CH:36]([C:38](O)=[O:39])[CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[N:8]=[C:7]([N:4]2[CH2:5][CH2:6][CH:2]([NH:1][C:38]([C@H:36]3[CH2:35][CH2:34][C:33](=[O:32])[NH:37]3)=[O:39])[CH2:3]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[N:10]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: O=C1CCC(C(=O)O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(NC(=O)[C@H]4CCC(=O)N4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (71 mg, 0.22 mmol) was added 890 μL of CH2Cl2. To this solution was added sequentially triethylamine (47 μL, 0.34 mmol) and 5-oxo-pyrrolidine-2-carboxylic acid (34.8 mg, 0.27 mmol) and BOP (119 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 h and diluted with water and CH2Cl2 (10 mL). The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (R)-5-oxo-pyrrolidine-2-carboxylic acid {1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide. LC/MS: m/z 432.5 (M+H)+ at 2.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([C:30]([OH:46])([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([CH3:45])([O:38]C3CCCCO3)[CH3:37])[CH3:31])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:46][C:30]([C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1)([CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])([CH3:45])[CH3:37]
Reactant: CCOCOc1cc(C=Cc2cccc(C(C)(O)CCCCC(C)(C)OC3CCCCO3)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCCCC(C)(O)c1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.6 ml of concentrated sulphuric acid in 7.5 ml of methanol with 369 mg (0.65 mmol) of 2-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl}phenyl}-7-methyl-7-(tetrahydropyran-2-yloxy)octan-2-ol in 7.4 ml of THF, after purification on a silica column (ethyl acetate 70-heptane 30), a yellowish paste (m=220 mg; Y=92%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:19]>C(Cl)Cl>[CH2:18]([O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:29])=[O:28])=[CH:25][CH:26]=1)[CH3:19]
Reactant: Cc1ccc(N)cc1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-Amino-4-methylbenzene (1.821 g, 17.0 mmol) was dissolved in DCM (25 mL). N,N-Diisopropylethylamine (3.1 mL, 18.1 mmol) and 4-ethoxy-benzenesulfonyl chloride (2.50 g, 11.3 mmol) were added successively. The reaction mixture was stirred at room temperature overnight and then washed with 10% HCl (2×20 mL) and brine (1×20 mL). Organic phase was dried with sodium sulfate before filtering and removal of solvent. The desired product, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (3.087 g, 94%), was obtained as a colorless solid, in 99.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).