Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][C:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:36])[C:27]([OH:29])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 1.2 g of the product of Step A, 2 ml of methanolic 1 N potassium hydroxide solution and 4 ml of methanol was refluxed for 2 hours and was then cooled during which 390 mg of the starting material crystallized which meant 810 mg of the starting product was saponified. The mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 1 ml of dimethylformamide and 2 ml of N hydrochloric acid solution (pH=2). The mixture was stirred and 10 ml of water were added thereto. The mixture was extracted with methylene chloride and the organic phase was washed with water. The wash waters were extracted with methylene chloride and the combined organic phases were dried and vacuum filtered. The filtrate was evaporated and the oil residue was taken up in 4 ml of chloroform. The solution was diluted with 30 ml of ether and crystallization was effected. After 30 minutes with stirring, the mixture was vacuum filtered and the product was rinsed with ether and dried to obtain 472 mg of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-tert.-butoxycarbonyl-1-methylethyloxyimino)-acetic acid melting at 190° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5](OS(C(F)(F)F)(=O)=O)[CH2:6]2.[Cl-].[Li+].[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=1)[CH2:6]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CN1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
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: [Cl-]
Solvent: COCCOC
Product: CN1C2C=C(c3cccc([N+](=O)[O-])c3)CC1CC2
Reaction time: 4.5 h
Yield: 40.7 %

Procedure:
8-Methyl-3-trifluoromethylsulphonyloxy-8-azabicyclo[3.2.1]oct-2-ene (D9) (0.400 g, 1.48 mmol) was dissolved in DME (10 ml) and lithium chloride (0.188 g, 4.44 mmol) was added followed by 3-nitrobenzeneboronic acid (0.284 g, 1.70 mmol), and 2M sodium carbonate solution (4 ml). Argon was then bubbled through the mixture and after 5 minutes Pd(PPh3)4 (0.086 g, 0.074 mmol) was added. The mixture was then heated to reflux with stirring. After 4.5 h the reaction mixture was allowed to cool and was left at room temp. for 12 h, before being partitioned between chloroform and water. The aqueous layer was then extracted with chloroform (2×) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a brown oil that was dried in vacuo. The oil was purified by silica-gel chromatography (200:10.1, CH2Cl2MeOH:NH3 as eluant) to give the title compound as a brown oil (0.147 g, 46%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13](C(O)=O)=[CH:12][N:11]=1)=[O:9])([CH3:3])[CH3:2].C1(P([N:44]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[ClH:54]>C(O)(C)(C)C.C(Cl)Cl.CCOCC>[ClH:54].[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][CH:29]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([NH2:44])=[CH:12][N:11]=1)=[O:9])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(N)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 1-(3-isopropoxybenzoyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid (198 mg) in 8 ml of tert-butanol was added diphenylphosphoryl azide (DPPA, 0.119 ml, 1.10 eq) and triethylamine (0.084 ml, 1.20 eq). The mixture was refluxed for 3 hrs and then solvents were evaporated. The residue was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried and then evaporated. The residue was dissolved in a mixture of 4 ml of methylene chloride and 4 ml of trifluoroacetic acid. The mixture was kept at room temperature for 1 hr and then solvents were evaporated. The residue was extracted with ethyl acetate and saturated sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a flash column chromatography using ethyl acetate and hexane (2/1 ratio) to give an oil. This oil was dissolved in methylene chloride and hydrogen chloride (gas) in ether was added. After the evaporation of solvents, a yellow solid was obtained as 1-(3-isopropoxybenzoyl)-4-amino-6,7-dimethoxyisoquinoline hydrochloride (106 mg, 48% in two steps).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH2:24]([N:26]=[C:27]=S)[CH3:25].O>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:27]([NH:26][CH2:24][CH3:25])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(OC)cc2)c1=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c2c(NCC)n[nH]c2n(Cc2ccc(OC)cc2)c1=O
Reaction time: 14 h
Yield: 70 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-methoxybenzyl)uracil 0.64 g, 2 mM) and ethyl isothiocyanate (0.53 ml, 6 mM) in DMF (6 ml) was stirred at 90° C. for 14 hours and then at 110° C. for 14 hours. To the solution was added water (2 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/ethanol/water gave colorless needles (0.52 g, 70%), m.p. 234°-236° C.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:27]([CH3:28])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11]>C(#N)C.O>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:27]([CH3:28])=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.80 mL) was added to a solution of (S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethanol (3J) (51.7 mg, 0.14 mmol) in wet acetonitrile (2.0 mL), 0.75% H2O) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and quenched with 1.5 M K2HPO4 solution. Ethyl acetate was added and organic layer separated and washed with 1:1 brine/H2O (2×), then saturated NaHSO3/brine. The organic layer was dried (MgSO4), filtered and concentrated and purified by reverse phase HPLC (Gemini, 50 to 95% ACN/H2O+0.1% TFA) and the product lyophilized to give 3K as a white powder (27.8 mg). 1H-NMR: 300 MHz, (CDCl3) δ 7.73 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.50-7.38 (m, 3H), 7.28-7.22 (m, 3H), 5.25 (s, 1H), 2.54 (s, 3 H), 0.98 (s, 9H). LCMS-ESI− (m/z): [M−H]− calcd for C23H22ClO3: 381.88. Found: 380.9, 382.9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18](=[S:20])[NH2:19]>>[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: Cc1ccncc1C(N)=S
Reactant: O=C(CBr)c1ccncc1
Product: Cc1ccncc1-c1nc(-c2ccncc2)cs1
Yield: 24 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(pyridin-4-yl)ethanone hydrobromate (460 mg) and 4-methylpyridine-3-thiocarboxamide (248 mg), the title compound (99 mg) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)OC)cn2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)O)cn2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 8, (700 mg, 1.56 mmoles) was taken up in a mixture of THF (14 ml), 2 eq. 1N NaOH (3.3 ml) and H2O (10 ml). The reaction mixture was stirred at room temperature under N2 for 2 hours. The THF was removed in vacuo. The aqueous phase was extracted with ether, then acidified with HCl and extracted into CHCl3. The combined organic extracts were dried and concentrated. The residue was triturated with ether to afford the title compound, m.p. 154°-156°.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)COc1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1ccc(CBr)cc1
Yield: 56.1 %

Procedure:
To a solution of the methyl 2-(p-tolyloxy)acetate (3.10 g, 17.2 mmol) in carbon tetrachloride (60 mL) was added N-bromosuccinimide (3.57 g, 20 mmol) followed by benzoyl peroxide (463 mg, 1.9 mmol). The resulting solution was heated at reflux overnight, and then diluted with methylene chloride. The mixture was washed with brine, dried on MgSO4, and concentrated. The resulting colorless oil was purified by chromatography on silica gel (Hexane/ethyl acetate 9/1) to afford a colorless oil (2.5 g, 56%).
Reaction SMILES: [S:1]1[C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].ClC(OCC(C)C)=O.[CH3:34][S:35]([NH-:38])(=[O:37])=[O:36].[Na+].Cl>CN(C)P(N(C)C)(N(C)C)=O.C(N(CC)CC)C.CN(C)C=O>[CH3:34][S:35]([NH:38][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:1][C@H:12]2[CH2:13][C@@H:14]([OH:25])[C@H:15](/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C@H:11]2[CH2:10]1)(=[O:37])=[O:36]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Reactant: CS([NH-])(=O)=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)NS(C)(=O)=O)S[C@H]2C[C@H]1O
Reaction time: 0.42 h
Yield: 62.1 %

Procedure:
To a mixture of 100 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15- dihydroxyprost-13-enoic acid (prepared as described in Example 2), 1.5 ml of N,N-dimethylformamide and 37 μl of triethylamine was added 35 μl of isobutyl chloroformate at 0° C., and the mixture was stirred at that temperature for 25 minutes. To it was added a mixture of 128 mg of sodium methanesulphonylamide and 0.233 ml of hexamethylphosphoramide at room temperature, and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was acidified to pH 4-5 with dilute hydrochloric acid, extracted with ethyl acetate, the extract washed with water, and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 5% v/v solution of methanol in ethyl acetate as eluent to give 75 mg of the title compound having the following physical characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:25]1[C:26]([C:31]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]([NH2:38])[CH:32]=2)=[N:27][CH:28]=[CH:29][N:30]=1>C1COCC1>[NH2:38][C:33]1[N:34]=[C:35]([CH3:37])[N:36]=[C:31]([C:26]2[C:25]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:30][CH:29]=[CH:28][N:27]=2)[CH:32]=1
Reactant: Cc1nc(N)cc(-c2nccnc2F)n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)cc(-c2nccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
To a solution of N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2) (0.091 g, 0.413 mmol) in THF (2.5 mL) at 0° C. was added NaHMDS (1.0 M solution in THF) (1.876 mL, 1.876 mmol). After the addition, the reaction mixture continued to stir at 0° C. under N2 for 30 min. 6-(3-fluoropyrazin-2-yl)-2-methylpyrimidin-4-amine (0.077 g, 0.375 mmol) was added into the reaction mixture. The reaction mixture continued to stir at 0° C. for 10 min and was then slowly warmed up to RT. After 1 hour, the reaction mixture was partitioned between pH 7 buffer (1M TRIS-HCl) and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by HPLC (10-90% CH3CN and H2O with 0.1% NH4OH, flow rate equal to about 5 mL/min). The fractions containing the desired product were concentrated under a vacuum. The material was further purified by chromatography through a silica gel column (4 g), eluting with a gradient of 0% to 10% MeOH in CH2Cl2, to provide N-(5-((3-(6-amino-2-methyl-4-pyrimidinyl)-2-pyrazinyl)amino)-2-chloro-3-pyridinyl)methanesulfonamide (0.0080 g, 0.020 mmol, 5.24% yield) as a yellow solid. m/z (ESI, +ve) 407.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 10.12 (s, 1H); 8.85 (s, 2H); 8.35 (s, 1H); 8.23-8.30 (m, 1H); 7.22 (s, 1H); 6.87 (br. s., 1H); 3.14 (s, 3H); 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([C:19]#[N:20])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N=C(C(O)=O)SC=2C2C=CC(F)=C(C#N)C=2)C=CC=1[F:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])[S:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([C:19]#[N:20])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[F:37]
Reactant: N#Cc1cc(-c2sc(C(=O)O)nc2-c2ccc(F)c(Cl)c2)ccc1F
Reactant: N#Cc1cc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2cccc(Cl)c2)ccc1F
Product: N#Cc1cc(-c2sc(C(=O)N3CNC(=O)C3)nc2-c2ccc(F)c(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 5 starting with the compound from Example 15A. 17.3 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:34]([O-:36])=O)[CH2:27][CH2:26]1.[NH2:44][C:45]1[CH:46]=[C:47]([C:51]2[CH:59]=[C:58]3[C:54]([C:55]([C:68]4[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=4)=[CH:56][N:57]3[C:60]3[N:65]=[CH:64][N:63]=[C:62]([NH:66][CH3:67])[CH:61]=3)=[CH:53][CH:52]=2)[CH:48]=[CH:49][CH:50]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:75][O:74][C:71]1[CH:70]=[CH:69][C:68]([C:55]2[C:54]3[C:58](=[CH:59][C:51]([C:47]4[CH:46]=[C:45]([NH:44][C:34](=[O:36])[C:33]5[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=[C:31]([N:28]6[CH2:27][CH2:26][O:25][CH2:30][CH2:29]6)[CH:32]=5)[CH:50]=[CH:49][CH:48]=4)=[CH:52][CH:53]=3)[N:57]([C:60]3[CH:61]=[C:62]([NH:66][CH3:67])[N:63]=[CH:64][N:65]=3)[CH:56]=2)=[CH:73][CH:72]=1
Reactant: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(N)c4)cc32)ncn1
Reactant: O=C([O-])c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(NC(=O)c5cc(N6CCOCC6)cc(C(F)(F)F)c5)c4)cc32)ncn1

Procedure:
HATU (100 mg, 0.260 mmol) was added to a mixture solution of 3-morpholino-5-(trifluoromethyl)benzoate (54 mg, 0.195 mmol), 6-(6-(3-aminophenyl)-3-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (55 mg, 0.130 mmol) and DIPEA (45 μL, 0.26 mmol) in THF (2 mL) at room temperature. 12 hours later, the mixture was added to saturated sodium bicarbonate aqueous solution and then extracted with methylene chloride. The collected organic layer was washed with brine and then concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound was obtained as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:32]([CH3:33])[CH3:31])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: CNC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 1 g (2.38 mmol) of 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile and 0.07 g of sodium iodide in 17.85 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 3.5 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and ether was added. One standing, the crystals were deposited giving 0.93 g of the tide compound as a white solid: mass spectrum (electrospray, m/e) M+H 428.9.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)=[O:4].[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(CC)=O>[CH2:23]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1O
Solvent: CCC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Yield: 45 %

Procedure:
5-Bromoacetyl salicylamide (515 g) was added to a stirred solution of dibenzylamine (750 g) in ethyl methyl ketone (3.0 l). The mixture was heated at reflux for one hour and the dibenzylamine hydrobromide was filtered and dried. The filtrate was allowed to cool, when the crude product crystallised. This was filtered off, dried, and recrystallised from ethyl acetate, (5 l), to give 5-(N,N-dibenzylglycyl)salicylamide as an off-white solid (336 g), m.p. 168°.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(O)=O.O>CCO>[CH2:28]([NH:36][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCCc4ccccc4)ncc3c2=O)c(OC)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and phenethylamine (0.020 mL, 0.142 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 13 mg of the title compound. MS: (+) m/z 460.36 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16](=[O:33])[CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([S:27][CH2:28][CH2:29][CH:30]=O)=[CH:21][C:20]=1[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:14][O:15][C:16](=[O:33])[CH2:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([S:27][CH2:28][CH2:29][CH2:30][NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][N:11]=2)=[CH:21][C:20]=1[CH3:32]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: COC(=O)COc1cc(OC)c(SCCC=O)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)COc1cc(OC)c(SCCCNc2ccc(-c3ccccc3)cn2)cc1C
Reaction time: 18 h

Procedure:
Commercially available 5-phenyl-pyridin-2-ylamine (631 mg, 3.7 mmol) and Compound 64A were dissolved in 20 ml methanol with catalytic p-TsOH (ca. 20 mg) and stirred at 25 C for 18 h to give a yellow solution. NaH3CN was added and the reaction was allowed to stir for 1 h. 2N HCl was added to pH<3 and stirred 5 minutes. Saturated sodium bicarbonate was added and the product was extracted in to 100 ml ethyl acetate, dried over anhydrous sodium sulfate, decanted and concentrated. Liquid chromatography gave the title compound as a white solid. MS m/z 453 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][N:26]([CH:28]=O)[CH3:27]>>[C:25]1([N:26]2[CH2:28][CH2:6][N:5]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:18]=[C:17]5[C:12]([CH:13]=[CH:14][CH:15]=[N:16]5)=[CH:11][CH:10]=4)[CH:3]=3)[CH2:4][CH2:27]2)[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: Clc1cc(Nc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(c3cc(Nc4ccc5cccnc5c4)ncn3)CC2)cc1

Procedure:
This compound could be prepared from (6-chloro-pyrimidin-4-yl)-quinolin-7-yl-amine and I-phenyl-piperazine in the presence of K2CO3 and DMF.