Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]3[C:18]2=[O:30])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:44]([O:51][NH:52][C:14](=[O:16])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)ccc1OC
Yield: 59 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)propanoic acid (2.84 g, 6.85 mmol), carbonyldiimidazole (1.22 g, 7.52 mmol) and O-benzylhydroxylamine hydrochloride (1.32 g, 8.27 mmol) in tetrahydrofuran (15 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(4-nitrophthalimido)-propionamide as a yellow solid (2.1 g, 59% yield): mp, 159.0–161.0° C.; 1H NMR (DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H, CH3), 3.03 (dd, J=7.7, 14.8 Hz, 1H, CHH), 3.15 (dd, J=8.0, 14.9 Hz, 1H, CHH), 3.72 (s, 3H, CH3), 3.96 (q, J=6.9 Hz, 2H, CH2), 4.64 (s, 2H, PhCH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.87–6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.23–7.41 (m, 5H, Ar), 8.06 (t, J=7.7 Hz, 1H, Ar), 8.14–8.18 (m, 1H, Ar), 8.26–8.31 (m, 1H, Ar), 11.24 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.66, 34.09, 50.62, 55.46, 63.72, 76.69, 111.86, 112.46, 119.83, 122.47, 126.94, 128.18, 128.67, 130.28, 133.08, 135.79, 136.38, 144.36, 147.69, 148.68, 162.99, 165.69, 166.18. Anal. Calcd for C27H25N3O8: C, 62.42; H, 4.85; N, 8.09. Found: C, 62.12; H, 4.92; N, 7.82.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:32][CH2:31][CH2:30][O:29]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.Cl[C:43]([O:45][CH2:46][CH2:47][F:48])=[O:44]>ClCCl>[F:48][CH2:47][CH2:46][O:45][C:43](=[O:44])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]4[CH2:34][CH2:33][C:28]5([O:29][CH2:30][CH2:31][O:32]5)[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCCF
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1)OCCF
Reaction time: 0.5 h

Procedure:
was also prepared by an alternative route: 36 mg 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was dissolved in dichloromethane (0.5 mL) containing triethylamine (100 uL). 93 uL 2-fluoroethyl chloroformate was added and the mixture was stirred for 30 minutes. The mixture was concentrated and the title compound was obtained after HPLC purification. MS: 553.2 [M+H], RT 2.42.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-nitroaniline according to general procedure A provided methyl ester of Compound 5 as an orange solid (59% yield). 1H NMR (CDCl3, 500 MHz): δ=8.16 (d, J=9.1 Hz, 2H), 7.89 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.41 (m, 1H), 6.98 (d, J=9.1 Hz, 2H), 6.31 (s, 1H), 3.94 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=166.7, 149.7, 140.7, 140.3, 132.2, 130.1, 126.5, 125.9, 125.7, 122.6, 114.4, 52.6.
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]/[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12]([CH3:13])=[O:38])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 71 mg of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 577 dissolved in 2 ml of dichloromethane was added a solution of 45 mg of 3-chloroperbenzoic acid in 2 ml of dichloromethane, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 27 mg (yield 38%) of low polarity isomer and 25 mg (yield 35%) of high polarity isomer of 5-[(E)-4,7-dihydroxyheptenylidene]-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2.Cl>CCO.CO.N>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)[C:2]([NH:35][C:36]3[C:37]4[CH:38]=[CH:39][NH:40][C:41]=4[CH:42]=[CH:43][CH:44]=3)=[N:3][CH:4]=2)=[CH:32][CH:31]=1
Reactant: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Reactant: Nc1cccc2[nH]ccc12
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: COc1ccc(COCc2cnc(Nc3cccc4[nH]ccc34)c(-c3nc(C)nc4[nH]cnc34)c2)cc1
Temperature: 100 °C
Reaction time: 1.75 h
Yield: 7.2 %

Procedure:
6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (171.2 mg, 0.3694 mmol) and 4-aminoindole (Aldrich, St. Louis, Mo., 69.2 mg, 0.524 mmol) were suspended in EtOH (2.0 mL) and hydrochloric acid (J.T. Baker, Phillipsburg, N.J., 5 N, 0.090 mL, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred for about 105 minutes. Then, the reaction was cooled to room temperature and diluted with MeOH and 2 N ammonia in MeOH. The reaction was concentrated and treated with DMF and DCM and filtered. The filtrate was filtered again, and the solid was again washed with DCM. This filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 ml/min). The fractions with product were collected, concentrated, and filtered through a silica gel filter (about 1 inch, 10:1 DCM/2 N ammonia in MeOH) to give N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (13.1 mg, 7% yield). MS (ESI pos. ion) m/z 492 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.49 (s, 1H), 11.17 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=6.85 Hz, 1H), 7.38-7.32 (m, 3H), 7.12-7.04 (m, 2H), 6.93 (d, J=8.80 Hz, 2H), 6.72 (s, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 3.75 (s, 3H), 2.92 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24].ClCCl>CCOCC>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([N:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2)=[O:24]
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Reactant: O=C(Cl)Cc1ccccc1Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1ccccc1Cl)N1CCCc2ncc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Powdered 1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (8.29 g) was added to ice cold, stirred 2-chlorophenylacetyl chloride (30 ml) without external cooling. A thick suspension of crystalline material formed and a mild exothermic reaction was observed. After stirring overnight at room temperature the suspension was gradually diluted with anhydrous ether to give a tacky solid which formed a gummy mass. On continued stirring the material solidified and disintegrated to give a suspension. The material was isolated by vacuum filtration and washed well with ether. A solution of the filter cake and water (300 ml) was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×250 ml). The combined turbid organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. A solution of the oil and toluene (150 ml) was concentrated to remove any residual moisture, whereupon the material solidified. Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated the presence of 40-50% starting material. A solution of the solid in dichloromethane (200 ml) was added to stirred, ice-cold 2-chlorophenylacetyl chloride (27 ml) without external cooling. After three hours, the solution was concentrated to reduce the reaction volume, whereupon a suspension formed. Sufficient dichloromethane (200 ml) was added to afford a solution which was allowed to stand for 48 hours at room temperature. The solution was concentrated to remove most of the dichloromethane and the residual oil was treated with excess ethereal hydrogen chloride and diluted with ether (400 ml) to give a tacky precipitate. The ether was decanted and the precipitate was triturated with fresh ether (solidified). The solid was isolated by vacuum filtration, washed well with ether and converted to the free base. Thin layer chromatographic analysis (silica gel, ethyl acetate) indicated the presence of a small amount of starting amine, the product and two higher Rf spots. The mixture was separated by HPLC (silica gel; sample applied in 200 ml of dichloromethane; eluted with ethyl acetate; 200 ml/min flow rate; recycle technique utilized to optimize the separation). The appropriate fractions were combined and concentrated to give a solid (7.97 g) which was triturated with ether, filtered, and dried in vacuo at 40° C., m.p. 176°-178° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:32][CH:33]=2)[CH:21]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(-c5cccnc5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyridin-3-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyridin-3-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3ccccc32)cc1

Procedure:
(10.9 mg, 27%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4e, 24.8 mg, 0.12 mmol) and 4-methoxybenzoyl chloride (35 uL, 0.24 mmol); HRMS-FAB+ for C22H22N2O2 : calculated MH+ : 347.17596; found: 347.17819.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[C:25]([NH2:46])=[N:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:32]([O:44][CH3:45])[CH:31]=2)[CH:29]=1>O1CCOCC1.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>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:24]2[C:25]([NH2:46])=[N:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:32]([O:44][CH3:45])[CH:31]=3)[CH:29]=2)=[CH:15][CH:14]=1
Reactant: COc1cc(-c2cnc(N)c(Br)c2)ccc1OCCN1CCCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OCCN1CCCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 105.3 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (285 mg), tetrakis(triphenylphosphine)palladium (110 mg) and potassium carbonate (396 mg) were added to a solution of the compound obtained in Step 1 of Example 39 (375 mg) in dioxane (10 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 100° C. for five hours. The reaction mixture was returned to room temperature, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography [chloroform:methanol=19:1 (v/v)] to give 407 mg of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15]>C(O)C>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][C@H:3]3[NH:13][C:14](=[S:15])[NH:1][C@@H:2]32)=[CH:7][CH:8]=1
Reactant: S=C=S
Reactant: N[C@@H]1CCc2ccc(Br)cc2[C@H]1N
Solvent: CCO
Product: S=C1N[C@@H]2c3cc(Br)ccc3CC[C@H]2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Trans-1,2-diamino-7-bromo-1,2,3,4-tetrahydronaphthalene (6.75 g, 28.0 m mol) was dissolved in ethanol (70 ml) and carbon disulfide (1.9 ml, 31.7 m mol) was added to the solution. After stirring at room temperature for 20 minutes, they were heated under reflux for 5.5 hours. The reaction mixture was cooled in an ice bath and crystals precipitated were collected by filtration, whereby trans-8-bromo-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (5.57 g) was obtained in 70% yield. The crystals were recrystallized from methanol-acetonitrile to give pale-yellow crystals melting at 259.5°-260.5° C. (decomposition). The product gave the following data on spectroscopy and elemental analysis.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)=[CH2:18])[CH3:14]>CC#N>[CH2:13]([O:15][C:16](=[O:34])[CH:17]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])=[CH:24][CH:25]=1)[CH2:18][P:10]([OH:11])([CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[CH3:14]
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: O=[PH](O)CCCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)CCCc1ccccc1
Reaction time: 72 h
Yield: 45.9 %

Procedure:
A solution of (3-Phenyl-propyl)-phosphinic acid (0.579 g, 3.143 mmol) and 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.327 g, 1.067 mmol) in MeCN (7.5 mL) was degassed using the freeze-thaw technique. BSA (2.55 g 12.57 mmol) was added and the mixture was stirred for 3 days and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with NaHCO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (CH2Cl2/MeOH, 8:2) gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid ethyl ester (0.240 g, 16%).
Reaction SMILES: [CH3:1]I.[Mg].C[C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16].[Cl-].[NH4+]>C(OCC)C>[CH3:1][CH:9]([OH:10])[C:8]1[C:7]([F:15])=[C:6]([F:16])[CH:5]=[C:12]([F:13])[C:11]=1[F:14]
Reactant: Cc1c(F)c(F)c(C=O)c(F)c1F
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1c(F)c(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3 2 ml of methyl iodide were introduced over the course of 30 minutes into a suspension of 1 g of magnesium and 30 ml of ethyl ether and the mixture was stirred for 30 minutes. The mixture was cooled to 0° C. and 4 g of 4-methyl-2,3,5,6-tetra fluorobenzaldehyde and 100 ml of ethyl ether were introduced over the course of 30 minutes. The reaction mixture was stirred for 1 hour at 0° C. and was poured into 150 ml of a saturated aqueous ammonium chloride solution. Extraction was carried out with ether and the ethereal phases were dried and evaporated to dryness under reduced pressure. The crude product was chromatographed on silica and eluted with a hexane:isopropyl ether (8:2) mixture to obtain 3.85 g of the product with a Rf=0.10.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:21]=4)[CH:8]=2)[CH2:5][CH2:6]1)(=[O:36])[CH3:34]
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccn5)nc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccn5)nc4c3)c3c(N)ncnn23)CC1
Yield: 83 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 7 7-piperidin-4-yl-5-[2-(pyridin-2-ylmethyl)-2H-indazol-6-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 43 mg (83%) of the desired product was isolated. 1H NMR (400 MHz, CD2Cl2) δ 8.58 (d, 1 H) 8.41 (s, 1 H) 7.65-7.81 (m, 3 H) 7.39 (s, 1 H) 7.19-7.26 (m, 3 H) 6.57 (s, 1 H) 5.78 (s, 2 H) 4.68 (d, 1 H) 4.02 (d, 1 H) 3.21-3.41 (m, 2 H) 2.76 (dd, 1 H) 2.01-2.19 (m, 5 H) 1.87 (dt, 2 H) LC-MS [M+H]+=467.4, RT=2.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@H:35]([O:38][CH3:39])[CH2:36][CH2:37]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: COc1cn(C(C[C@H]2CC[C@H](OC)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.5 h

Procedure:
1.10 g (1.86 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoate (racemate) in 67 ml of ethanol/water (2.6/1) were reacted with 3.09 g (9.48 mmol) of caesium carbonate according to General Method 4. After complete conversion, the pH was adjusted to 5-6 with hydrochloric acid (1N) and the mixture was stirred for another 30 min. The precipitate was filtered off with suction, washed with a little water and dried under high vacuum. Yield: 690 mg (purity 89%, 59% of theory)
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([C:20](O)=[O:21])[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:27])[C:15]2=[O:28])=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]2[CH:19]=[C:18]([CH2:20][OH:21])[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:16]([Cl:27])[C:15]2=[O:28])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(C(=O)O)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(CO)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Yield: 100 %

Procedure:
A BH3-THF solution (100 ml, 100 mmol) was added carefully to compound (10) (8.4 g, 23.88 mmol) in a 100 ml round-bottomed flask. The resulting solution was stirred at about r. t. overnight. MeOH was added. The solution was concentrated to dryness to give the title compound (8.15 g, 23.89 mmol, 100% yield) as a yellow solid. LC-MS (ESI+): m/e 338(M+H)+, Rt: 1.65 min.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]>>[Cl:6][C:7]1[CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: COc1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Under N2 atmosphere, 41.25 mL chlorosulfonic acid was cooled in an ice bath, and under stirring 22.26 mL 2-chloroanisole was added dropwise. The mixture was heated to 55° C.; after 10 min. the heat source was removed and the mixture was stirred overnight at room temperature. The mixture was poured into ice water and extracted twice with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (PA/EA 9:1) to give 24.94 g (50%) of a beige oil. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 7.08 (d, J=8.73 Hz, 1H), 7.94 (dd, J=9.03, 2.41 Hz, 1H), 8.06 (d, J=2.41 Hz, 1H).