Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH:38]([C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1)C1C=CC=CC=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: c1ccc(Nc2ccncc2)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccncc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.10 mL, 0.57 mmol) and 4-amiinopyridine (76 mg, 0.59 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (39 mg, 28% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=1.[CH3:15]O>>[Br:2][C:3]1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2[CH:7]=[N:8][NH:9][C:10]=2[CH:11]=1
Reactant: O=C(O)c1cc(Br)cc2[nH]ncc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Br)cc2[nH]ncc12
Temperature: 70 °C

Procedure:
Concentrated hydrochloric acid (46.9 ml, 1543 mmol) was added to a stirred suspension of 6-bromo-1H-indazole-4-carboxylic acid (4.65 g, 19.29 mmol, available from Sinova) in methanol (100 ml) and the reaction mixture was heated to 70° C. for 18 h. The reaction mixture was allowed to cool to RT resulting in the precipitation of a solid. The mixture was cooled in ice and the yellow precipitate filtered off and washed with methanol to give the title compound as a yellow solid (2.54 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH3:14][C:15]1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C(O)CC/C=C/c1ccccn1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CCOC(=O)CC/C=C/c1ccccn1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of (4E)-5-(2-pyridyl)-4-pentenoic acid (1.6 g) in ethanol (50 ml) was added d-camphor-10-sulfonic acid (2.3 g), and the mixture was heated under reflux with a reflux condenser containing 3 Å molecular sieves. After 2 hours, the mixture was evaporated, diluted with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo to give ethyl (4E)-5-(2-pyridyl)-4-pentenoate (1.84 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Yield: 83.9 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 2-chloro-5-(trifluoromethyl)pyridine (181 mg, 1.0 mmol) to afford the title compound (180 mg), a white solid, in 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:21]=2[N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([NH2:49])[N:43]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[NH2:49][C:44]1[N:43]=[C:42]([C:24]2[CH:23]=[CH:22][C:21]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:25]=2)[CH:47]=[C:46]([CH3:48])[N:45]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCOCC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(N3CCOCC3)c(Nc3c(C)c(-c4ccccc4F)nc4ccccc34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 2-(2-fluorophenyl)-3-methyl-N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-4-amine (100 mg, 0.185 mmol; described herein), 4-chloro-6-methylpyrimidin-2-amine (26.6 mg, 0.185 mmol), sodium carbonate (58.9 mg, 0.556 mmol), dichlorobis(triphenylphosphine)-palladium(ii) (13.0 mg, 0.019 mmol), 1,4-dioxane (4.0 mL), and water (1.0 mL) was heated in a microwave at 120° C. for 60 min. The mixture was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concd, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)phenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine. 1H NMR (400 MHz, TFA) δ ppm 8.32 (1H, dd, J=8.8, 2.2 Hz), 7.95-8.17 (5H, m), 7.72 (2H, m), 7.55 (1H, m), 7.40-7.48 (1H, m), 7.24-7.37 (2H, m), 4.30-4.47 (4H, m), 4.07-4.25 (4H, m), 2.60 (3H, s), 2.09 (3H, br. s.). Mass Spectrum (ESI) m/e=521.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=O)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24](Br)[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)Sc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.1 %

Procedure:
To a solution of methyl 4-{[(4-fluorophenyl)sulfonyl]methyl}benzoate (0.26 g, 0.84 mmole) in DMF at 0° C. was added NaH (25 mg, 0.74 mmole) and the reaction was stirred for 15 minutes at 0° C. Then a solution of cinnamyl bromide (0.16 g, 0.81 mmole) in THF (1 mL) was added, and the reaction was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and evaporated. The residue was chromatographed to yield 0.35 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(Cc1cccc(F)c1)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3cccc(F)c3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:29]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.CC(O)=O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:29])[CH:9]=[C:10]([C:11]3[N:12]=[C:13]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[S:14][CH:15]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc4c(N)ncnn34)cs2)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cc(Br)c4c(N)ncnn34)cs2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 109.1 %

Procedure:
To a cooled (−20° C.) solution of tert-butyl 4-[4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (914 mg. 2.28 mmol) in DMF (12.6 mL) and AcOH (5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (326 mg, 1.14 mmol) in 3 portions over 10 minutes. The mixture was stirred at 0° C. for 3 h. The reaction was quenched with the addition 5% aqueous K2CO3 (50 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated. The crude material was purified by ISCO® chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 596 mg (54%) of the desired product. ES-MS m/z 480.85 [M+H]+, HPLC RT (min) 3.45.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N:15][N:16]4[C:21]([S:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-:29].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N:15][N:16]4[C:21]([S:22]([CH3:23])=[O:29])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(CC(C)C)nn12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Cc1nn2c(S(C)=O)cccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a cold (0° C.) solution of N-cyclopentyl-4-[2-isobutyl-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine (700 mg, 1.83 mmol) in dichloromethane (30 mL) was added sodium bicarbonate solid (500 mg), and m-chloroperbenzoic acid (451 mg, ˜70% pure, 1.83 mmol). The mixture was stirred at 0° C. for 20 minutes and then quenched by the addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The biphasic mixture was allowed to warm to room temperature and stirred vigorously for 15 minutes. The layers were separated and the organic layer washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration in vacuo provided N-cyclopentyl-4-[2-isobutyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine (720 mg, 99%) as a yellow solid. 1H NMR (CDCl3) δ 8.38–8.29 (m, 2H), 7.51–7.44 (m, 2H), 6.77 (d, 1H), 5.24 (m, 1H), 4.38 (m, 1H), 3.13 (s, 3H), 3.08–2.91 (m, 2H), 2.25–2.05 (m, 3H), 1.82–1.54 (m, 6H), 0.98 (m, 6H); MS m/z 398 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:28][CH3:29])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=2[CH2:8][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:30])[CH2:28][CH3:29])[CH:40]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Reactant: COC(=O)Cc1cncc(Br)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: [K+]
Solvent: COCCOC
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid tert-butyl ester (1.0 g, 2.33 mmol), (5-bromo-pyridin-3-yl)-acetic acid methyl ester (0.535 g, 2.33 mmol), potassium carbonate (0.807 g, 5.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.09 mmol) were combined in DME (8 mL) and H2O (4 mL). The solution was purged with N2, and then the reaction was stirred at 80° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([OH:26])[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[CH2:1]([C:8]1[C:9](=[O:27])[C:10]2[CH:11]=[C:12]([O:26][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:13]=[C:14]3[C:23]=2[N:22]([CH:24]=1)[C:21]1[CH:20]=[C:19]([Br:25])[CH:18]=[CH:17][C:16]=1[S:15]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(Cc2ccccc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1c(Cc2ccccc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 61.6 %

Procedure:
According to Example 34, the compound (200 mg) produced in Example 70 was reacted with 3-chloromethylpyridine hydrochloride (145 mg) to obtain the title compound (149 mg; 62%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)NCCCCCCCCCCC(=O)O

Procedure:
30.65 g (178.8 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (149 mmol) of 11-aminoundecanoic acid and 45.24 g (447.1 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 800 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 300 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(Cl)ccc43)nc12
Reaction time: 15 h
Yield: 38.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (144 mg, 289 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h then mixture was concentrated in vacuo then 25 mL Jan. 10, 1960 of a mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (40.9 mg, 38%). MS (M+H)+=369; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.60 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 7.61 (s, 1H), 1.50 (s, 9H).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:9][C:7]=1[NH2:8])([O-])=O.C.[H][H]>CO>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:6]=1[NH2:3]
Reactant: Nc1ccc(OCCCCOc2ccccc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(OCCCCOc2ccccc2)cc1N

Procedure:
The procedure of the first paragraph of Example 26 is repeated substituting 4-phenxoybutyl bromide for the 3-phenoxypropyl bromide to afford 2-nitro-4-(4-phenoxybutoxy)acetanilide. After treatment at 20°-25° with methanolic-5N aqueous sodium hydroxide, 1.2 g. of the resultant 2-nitro-4-(4-phenoxybutoxy)aniline in a mixture of 20 ml. of methanol and 0.3 g. of 5% palladized charcoal is hydrogenated under ambient conditions. When the theoretical amount of hydrogen has been taken up, the mixture is filtered and the filtrate stripped to afford 1,2-diamino-4-(4-phenoxybutoxy)benzene as a gum.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH:23]([C:25]1[C:34]([O:35][CH2:36][C:37]#[C:38][CH2:39][CH3:40])=[CH:33][C:32]2[C:31]([CH3:42])([CH3:41])[CH2:30][CH2:29][C:28]([CH3:44])([CH3:43])[C:27]=2[CH:26]=1)=O>CN(C=O)C>[CH2:36]([O:35][C:34]1[C:25](/[CH:23]=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=2)=[CH:26][C:27]2[C:28]([CH3:44])([CH3:43])[CH2:29][CH2:30][C:31]([CH3:42])([CH3:41])[C:32]=2[CH:33]=1)[C:37]#[C:38][CH2:39][CH3:40]
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CCC#CCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
193 mg of NaH (55% in mineral oil) were placed in 10 ml of abs. DMF under argon and 1.66 g of diethyl (4-carbethoxybenzyl)-phosphonate were added thereto at 0° and the mixture was subsequently stirred at room temperature until the H2 evolution had finished. Then, 1.08 g of 2-formyl-3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene without addition solvent were added at 0°. After 30 min. at room temperature the mixture was extracted with hexane and washed twice with ethanol/H2O=8/2. Drying, evaporation and direct crystallization from hexane yielded 1.45 g of ethyl (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoate as yellowish crystals of m.p. 80°-82°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:7]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].Cl.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:12]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([C:7]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: ClCCCN1CCOCC1
Reactant: CCCC(=O)c1cnc2c(N)cccc2c1Nc1ccccc1C
Agent: Cl
Product: CCCC(=O)c1cnc2c(NCCCN3CCOCC3)cccc2c1Nc1ccccc1C
Yield: 5 %

Procedure:
8-Amino-3-butyryl-4-(2-methylphenylamino)quinoline (6.5 g, 0.02 moles) and 3-chloropropylmorpholine hydrochloride (5.0 g, 0.025 moles) were heated together in fusion (150° C) for 20 minutes. The product was partitioned between ethyl acetate and dil. ammonia solution. The organic layer was washed twice with sodium dihydrogen phosphate solution (pH5), dried, filtered and evaporated. Chromatography (silica gel/chloroform/30-0% hexane) and crystallization from hexane gave 3-butyryl-4-(2-methyl phenylamino)-8-(3-morpholinopropylamino)quinoline as orange crystals (0.45 g, 5%), m.p. 110°-11° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCCCCn1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCCCn2ccc3ccccc32)C1
Temperature: 90 °C

Procedure:
A mixture of 4.8 g (30 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl)indole and 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated at 90° C. for 3 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 5.7 g (17.3 mmol). of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>C(Cl)(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
A solution of 4-chlorobenzenesulphonyl chloride (6 mmol) in chloroform (2.5 ml) was added to a solution of 8-aminooctanoic acid (6 mmol) in 10% sodium hydroxide solution (10 ml). The mixture was stirred at room temperature for 24 hours and was then extracted with chloroform (4×40 ml), the chloroform layers being discarded. The aqueous layer was acidified to pH1 with conc. HCl and was extracted with chloroform (4×100 ml). The combined chloroform extracts were then dried (Mg SO4). Concentration and crystallisation from isopropanol-water gave 8-(4-chlorobenzenesulphonamido)-octanoic acid (1.22 g; 58%); m.p. 122°-124° C.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:10]([O:19][CH3:20])=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc(OC)c(OC2CCCC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ncc(C(=O)O)cc1OC1CCCC1
Reaction time: 4 h
Yield: 59.3 %

Procedure:
A solution of potassium hydroxide (168 mg) in water (1 mL) is added to a solution of methyl 5-cyclopentyloxy-6-methoxynicotinoate (250 mg) in methanol (3 mL) and the mixture stirred for 4 hours then allowed to stand at room temperature overnight. The mixture is concentrated, the residue dissolved in water and the mixture adjusted to pH 6 by the addition of concentrated hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts dried (MgSO4) and concentrated to give a cream solid. The solid is dried at 100° C. to give 5-cyclopentyloxy-6-methoxynicotinic acid (140 mg), m.p. 191-2° C. [Elemental analysis: —C, 60.7; H, 6.43; N, 5.78%. calculated: —C, 60.75; H, 6.37; N, 5.90%.].