Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][CH:13]1[CH2:15][O:14]1)[CH:7]=[CH:6][CH:5]=2.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:33][CH:32]4[NH:34][CH2:35][CH:27]3[CH2:28][CH:29]=[CH:30][CH2:31]4)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(Cl)(Cl)Cl>C(O)C>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:33][CH:32]4[N:34]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]5[CH:7]=[CH:6][CH:5]=[C:4]6[C:9]=5[CH:10]=[C:2]([CH3:1])[NH:3]6)[CH2:35][CH:27]3[CH2:28][CH:29]=[CH:30][CH2:31]4)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2c(OCC3CO3)cccc2[nH]1
Reactant: C1=CCC2CNC(C1)CN2c1ccc2c(c1)OCCO2
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(OCC(O)CN3CC4CC=CCC3CN4c3ccc4c(c3)OCCO4)cccc2[nH]1

Procedure:
2-Methyl-4-oxiranylmethoxy-1H-indole (25 mg, 0.123 mmol), 7-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (34 mg, 0.125 mmol), chloroform (1 mL), ethanol (3 mL) were heated for 900 sec. at 130° C. in a μW reaction tube. The solvent was evaporated under reduced pressure to yield a crude solid that was purified with flash chromatography gradient [20% Ethyl acetate/heptane to 100% Ethyl acetate] to yield the title compound as a residue.
Reaction SMILES: BrC1C(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)=C2C([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=CNC2=NC=1.[ClH:33]>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl.CCOCC>[ClH:33].[O:15]1[CH2:16][CH2:17][CH2:18][CH:14]1[C:12]([NH2:11])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCO4)c23)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C1CCCO1
Yield: 21 %

Procedure:
A solution of tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate in TFA (3 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue obtained was purified by C-18 reverse phase chromatography (Biotage Flash 12 M+, C-18) on Biotage SP4 unit eluting with a gradient of 1-50% CH3CN/water (14 CV). The pure fractions containing the R-isomer (by comparing the retentions times of S-isomer, Example 71A) were pooled, concentrated in vacuo and evaporated from CH3CN (3×5 mL). The solid residue obtained was dissolved in minimal methanol, diluted with CH2Cl2 (1 mL) and treated with 2M HCl in ether (3 mL). The resulting suspension was concentrated in vacuo and evaporated from CH2Cl2 (3×5 mL) and dried under high vacuum for 24 hours to provide (R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2, 3-1)]pyridin-3-yl)tetrahydrofuran-2-carboxamide hydrochloride (16 mg, 21% yield) as a solid. NMR (400 MHz, (CD3)2SO) δ 11.72 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 8.16 (br s, 3H), 7.89 (s, 1H), 4.37 (t, 1H), 3.96-3.91 (m, 1H), 3.85-3.79 (m, 1H), 3.55-3.48 (m, 3H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.28-2.20 (m, 1H), 2.15-2.09 (m, 1H), 1.94-1.81 (m, 5H), 1.48-1.40 (m, 1H); LCMS (APCI+) m/z 408.1, 410.1 (M+H)+, Retention time=2.32 minutes (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]2[CH2:43][CH2:44][CH:39]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:40][CH2:41]2)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 4-pyrrolidin-1-yl-piperidine using HOBt, EDAC.HCl and TEA in DMF to give the titled compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])C=C>[PH4+].C(Cl)Cl>[C:11]1([CH3:14])[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:1][CH:17]=[CH:16][CH2:15]2)(=[O:6])=[O:7])=[CH:13][CH:12]=1
Reactant: C=CCN(CC=C)S(=O)(=O)c1ccc(C)cc1
Agent: [PH4+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC=CC2)cc1
Yield: 99.5 %

Procedure:
A solution of N,N-Diallyl-4-methyl-benzenesulfonamide (251 mg, 1.0 mmol, 1.0 equiv), phosphonium catalyst (10) (30 mg, 0.025 mmol, 0.025 equiv) in CH2Cl2 (20 mL, 0.05 M) were heated under reflux for 3 h under argon. The mixture was concentred under reduced pressure. The crude product was diluted with CH2Cl2 (1 ml) and the catalyst was precipitated with Et2O (10 mL). Filtration produced the phosphonium catalyst (10) in quantitative yield (85% purity). Evaporation of the filtrate afforded pure 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole (99.5%). Second cycle: 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole was obtained in 98% yield and the phosphonium catalyst (10) could be recovered in quantitative yield in 83% purity. Third cycle: 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole was obtained in 97% yield and the phosphonium catalyst (10) could be recovered in quantitative yield in 77% purity. Fourth cycle: 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole was obtained in 97% yield and the phosphonium catalyst (10) could be recovered in quantitative yield in 68% purity. Fifth cycle: 1-(toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole was obtained in 95% yield and the phosphonium catalyst (10) could be recovered in quantitative yield in 67% purity.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:41]=5)[CH:36]=[CH:37][C:38]=4[CH3:39])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2C)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCNCC4)c3)ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-4-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.15 mmol) in DCM (2 mL) was added tert-butyl 1-homopiperazine carboxylate (0.04 mL, 0.23 mmol), AcOH (0.01 mL, 0.18 mmol) followed by NaBH(OAc)3 (64.3 mg, 0.30 mmol). The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. LC-MS m/z 844 (M+H)+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16].C([O-])(O)=O.[Na+].O>CO>[CH2:2]([NH:13][C@H:14]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])[C:3]1([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:5]1[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@H](C)[C@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)N[C@@H](CC(=O)O)C(=O)O

Procedure:
30 g of anhydrous D-glucose were dissolved together with 3 g of isoleucyl-aspartic acid in 1.2 l of methanol, and 200 mg of NaHCO3 were added. The mixture was subsequently heated under reflux for 2 hours. The water which had formed was then removed by distillation with butanol, and the reaction mixture was diluted with methanol and again heated for 2 hours. After completion of the reaction, solvent was removed from the solution in vacuo, and the residue, in 300 ml of water, was applied to a 600 ml-capacity chromatography column (diameter 5 cm) packed with QAE-®Sephadex A-25. Whereas the excess glucose was located in the fore-run, it was possible to obtain selectively N-(1-deoxyfructopyranos-1-yl)-isoleucylaspartic acid using an acetic acid gradient (0 to 0.5 molar). These eluates from the column were collected and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([N:25](CC1C=CC(OC)=CC=1OC)[C:26]1[S:30][N:29]=[CH:28][N:27]=1)(=[O:24])=[O:23])=[CH:17]2.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:25][C:26]1[S:30][N:29]=[CH:28][N:27]=1)(=[O:23])=[O:24])=[CH:17]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)cccc3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)cccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (3.27 g, 4.92 mmol) in DCM (49.2 mL, 4.92 mmol) was added TFA (1.896 mL, 24.60 mmol). The resulting mixture was stirred at room temperature. After 30 min, LC/MS showed mainly desired product. The mixture was stirred for an additional hour at room temperature until the reaction was complete. The mixture was partially concentrated until a white solid crashed out. The solid was filtered, washed with diethyl ether and dried to afford 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (2.4 g, 4.67 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.76 Hz, 1H) 7.68-7.74 (m, 1H) 7.74-7.83 (m, 2H) 7.87 (d, J=8.01 Hz, 1H) 8.16-8.24 (m, 2H) 8.34 (d, J=8.34 Hz, 1H) 8.52-8.57 (m, 2H); m/z (ESI) 513.7 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Yield: 68.7 %

Procedure:
A mixture of 3-bromo-4-chloronitrobenzene (5.17 g, 21.9 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (4.27 g, 26.2 mmol) in ethanol (30 ml) and toluene (30 ml) together with 2 N Na2CO3 solution (13.9 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction was heated at reflux for over 24 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. This was extracted with ethyl acetate (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography (silica gel, 50% Et2O/CH2Cl2), to yield the title compound (3.53 g, 69%): 1H NMR (360 MHz, CDCl3) δ 7.42-7.48 (1H, m), 7.70 (1H, d, J 8.7 Hz), 7.81 (1H, dt, J 8.0, 1.8 Hz), 8.17-8.27 (2H, m), 8.68-8.77 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:6]2=[O:11]
Reactant: COC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C(C)=O

Procedure:
Methyl 2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (71 mg, 34%) in the same manner as described in the above example 6 (1) from methyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.23 g, 0.70 mmol) and p-toluenesulfonic acid monohydrate (20 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:17][S:18][CH:19]=[C:3]12
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylate (2.0 g., 0.0072 mol) and m-chloroperbenzoic acid (1.47 g., 0.0072 mol) in chloroform (75 ml) is stirred at room temperature overnight. The solvent is evaporated at reduced pressure to give a syrup, which crystallizes from ethanol. Recrystallization from ethanol, silica gel chromatography and a further recrystallization from ethanol gives the product as yellow crystals (mp 175° C.).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:32](=[O:33])[CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CCc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 3-phenylpropionyl chloride (11 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:22])=O>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (2.14 g, 7.08 mmol, 1.0 equiv; Example 80, Step 1) in dichloromethane (15 mL) was added thionyl chloride (16.4 g, 10 mL, 138 mmol, 19.5 equiv; [CAS RN 7719-09-7]) and the reaction mixture heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and remaining thionyl chloride removed by azotropic distillation with toluene. The crude material was used in the consecutive reaction step without further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-methoxy-phenyl)-acetic acid methyl ester (1.07 g, 5.94 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (14.8 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.37 g, 6.53 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This solution was diluted with water (100 mL) and extracted into ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 89.1%) as a clear oil: EI-HRMS m/e calcd for C16H22O3 (M+) 262.1568, found 262.1561.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)[CH3:2].[CH:19]1([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:29][C:28]2[CH:30]=[CH:31][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:26][CH:27]=2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCNC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a well stirred solution of 3-(4-formylbenzoylamino)propionic acid ethyl ester (13.8 g, 55.3 mmol) in ethanol (150 mL) was added a solution of 4-cyclohexylaniline (9.70 g, 55.3 mmol) in ethanol (75 mL). The mixture was heated to reflux for 30 minutes, and then acetic acid (50 mL) and sodium cyanoborohydride (3.50 g, 55.5 mmol) were added. After 10 minutes of additional heating, the mixture was cooled on an ice-bath. The solid precipitate was collected by filtration, washed several times with cold water and dried in a vacuum oven overnight to afford 18.16 g (80%) of 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}propionic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([NH2:18])=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:11]1[C:12]2[C:13]3([C:16]#[N:18])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)C12CC(c3ccccc31)c1ccccc12
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9,10-dihydro-9,10-methanoanthracene-9-carboxamide (30 mg) and thionyl chloride (0.15 ml) in toluene (1 ml) was refluxed for 18 hours. Evaporation of toluene and excess thionyl chloride gave 9,10-dihydro-9,10-methanoanthracene-9-carbonitrile. M.P. 120°-123° C.
Reaction SMILES: C([O:4][C:5]1([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([O:20][C:21]4[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]5[C:31](=[O:43])[N:32]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[N:33]([CH3:36])[C:34]=5[CH3:35])=[O:29])=[CH:23][C:22]=4[F:44])=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+]>CO>[F:44][C:22]1[CH:23]=[C:24]([NH:27][C:28]([C:30]2[C:31](=[O:43])[N:32]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:33]([CH3:36])[C:34]=2[CH3:35])=[O:29])[CH:25]=[CH:26][C:21]=1[O:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([O:9][CH2:8][C:5]3([OH:4])[CH2:6][CH2:7]3)=[CH:11][CH:12]=2)[N:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC1(COc2ccc3c(Oc4ccc(NC(=O)c5c(C)n(C)n(-c6ccccc6)c5=O)cc4F)ccnc3c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(O)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of compounds 1-((4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)quinolin-7-yloxy)methyl)cyclopropyl acetate (110 mg, 0.18 mmol) in 8 mL of methanol was added KOH (100 mg, 1.78 mmol) slowly. After stirring at rt for 0.5 hr, the reaction mixture was filtered and the solid was washed with ethyl acetate (10 mL×2) to give the title compound as a white solid (100 mg, 29%).
Reaction SMILES: N[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][C:4]=2[N:3]=1.N([O-])=[O:24].[Na+]>C(O)(=O)C.O>[C:13]([C:7]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][C:4]2[NH:3][C:2](=[O:24])[NH:11][C:10](=[O:12])[C:9]=2[CH2:8]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2nc(N)[nH]c(=O)c2C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCc2[nH]c(=O)[nH]c(=O)c2C1

Procedure:
To a solution of 2-Amino-6,6-dicarboethoxy-5,6,7,8-tetrahydro-4(3H)-quinazolinone (75 g) in acetic acid (250 mL) at reflux was added a solution of sodium nitrite (75 g) in water (100 mL) in a dropwise fashion over a period of 45 min. The solution was cooled and the solvent removed in vacuo. The subsequent addition of 300 mL of water precipitated a solid which was collected and dried to yield 6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:1]1([CH2:7][CH2:8][NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCc1ccccc1
Reactant: COc1ccc(N)cc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: COc1ccc(NCCc2ccccc2)cc1
Temperature: 250 °C
Yield: 89 %

Procedure:
244 parts of phenylethyl alcohol, 450 parts of p-anisidine and 30 parts of triphenyl phosphite are mixed and heated, using a water separator, initially to 210° C, at which temperature the elimination of water commences. The internal temperature is raised to 250° C in the course of 8 hours. After this time, the elimination of water has ended (36 parts of water). The mixture is worked up by distillation under reduced pressure. After distilling off excess alcohol and amine, the N-(2'-phenylethyl)-4-methoxy-aniline distils at a boiling point of 187° - 190° C/5 mm Hg. 372 parts of N-(2'-phenylethyl)-4-methoxyaniline (89% of theory) are obtained.