Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)=[CH:10][C:5]2=[C:4]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[Br:31]Br>C(Cl)(Cl)Cl>[Br:31][C:10]1[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[C:3]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:4]=2[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[S:8][C:9]=1[C:11]1[CH:15]=[N:14][NH:13][CH:12]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)cc2c1NS(=O)(=O)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a stirred solution of ethyl 6-methyl-4-[(phenylsulfonyl)amino]-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 68) (5.8 g, 13.11 mmol) in CHCl3 (160 mL) at 60° C. was added bromine (0.81 mL, 15.73 mmol), pre-diluted in CHCl3 (36 mL), dropwise. The resulting mixture was stirred at 60° C. for ca. 1 h and then cooled to RT. The reaction mixture was then concentrated and the residue triturated with water (50 mL 3) and dried, to give the title compound (6.1 g). LCMS (A) m/z: 521/523 [M+1]+, Rt 1.11 min (acidic).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1.O>C(#N)C>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A solution of methanesulfonylchloride (47.1 mL, 0.61 mol) in acetonitrile (160 mL) was added over 40 min to a solution of 4-nitroaniline (80.0 g, 0.58 mol) and pyridine (70.2 mL, 0.87 mol) in acetonitrile (400 mL) at 25° C. The mixture was stirred at 25° C. for 19 h, and then water (800 mL) was added. The resulting suspension was stirred at 25° C. for 30 min, and then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (2×150 mL) and air-dried overnight to afford the desired product, N-(4-nitro-phenyl)-methanesulfonamide (111.4 g, 0.52 mol, 89% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.17 (3H, s), 7.35 (2H, d, J=9.4 Hz), 8.20 (2H, d, J=9.1 Hz), 10.69 (1H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[C:34]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][CH:32]=[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:30]=1)=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:34]([NH:35][C:36]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:42])=[CH:33][CH:32]=[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:30]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.1 %

Procedure:
To a slurry of 60% of sodium hydride (110 mg, 2.76 mmol) in THF (8 mL) at 0° C. was added 1A (900 mg, 2.5 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 1E (680 mg, 2.3 mmol) in THF (8 mL) was added over 10 min at 0° C., then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an white foam (105 mg, 9%). LC/MS (method A): retention time=4.16 min, (M+H)+=504.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13]2([CH3:18])OCC[O:14]2)[CH:3]=1>C(O)(=O)C.O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:14])[CH3:18])[CH:3]=1
Reactant: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CCc1cc(O)n2nccc2n1
Temperature: 50 °C
Reaction time: 72 h
Yield: 60.7 %

Procedure:
The compound obtained in step (1) (22 g) was dissolved in 500 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the remaining acetic acid-water was azeotropically distilled off with benzene. The residue was recrystallized from ethanol-n-hexane to provide 11 g of 7-hydroxy-5-(3-oxobutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.Cl.[OH-].[Na+]>CN(C=O)C.CCOC(C)=O.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>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:10]1[C:5]2[CH:4]=[N:3][C:2]([C:24](=[O:26])[CH3:25])=[N:7][C:6]=2[CH:8]=[CH:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Cl)ncc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
To a stirred mixture of sodium hydride (12.5 g, 520 mmol, 60% in mineral oil) in anhydrous THF (300 mL) at 0° C. was added dropwise 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (40.0 g, 262 mmol) dissolved in anhydrous THF (200 mL). The reaction mixture was stirred at 0° C. for 15 min them SEMCl (52.5 g, 315 mmol) was added dropwise. The mixture was then stirred at RT for 1 h and then diluted with EtOAc. The organic layer was washed with water and brine, dried over (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 42 g (56.4%) of 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine as an orange oil. A high-pressure tube charged with 2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (2.23 g, 7.90 mmol), tributyl(1-ethoxyvinyl)stannane (3.7 g, 10.27 mmol), and Pd(PPh3)2Cl2 (200 mg) in degassed DMF (20 mL) under N2 was sealed and heated at 100° C. for 16 h. The reaction mixture was cooled, diluted with EtOAc, and filtered through a pad of Celite® to remove Pd solid. The filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was dissolved in anhydrous THF (0.3 M), and 2N HCl (5.0 eq.) was added. The reaction mixture was stirred at RT under N2 for 16 h, poured into 10% aq. NaOH solution, and then extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography to afford 1.5 g (66%) of 1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanone as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.66 (d, J=3.2 Hz, 1H), 6.89 (d, J=4.8 Hz, 1H), 5.60 (s, 2H), 3.49 (t, J=8.0 Hz, 2H), 2.88 (s, 3H), 0.901 (t, J=8.0 Hz, 2H), −0.053 (s, 9H); MS (ESI) m/z: 291 [M+].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].O1CCCC1.C([Li])CCC.[CH2:21]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])[CH3:22]>C(OCC)(=O)C.O>[CH2:21]([O:23][C:24]([N:26]1[CH2:27][CH2:28][C:29]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])([OH:32])[CH2:30][CH2:31]1)=[O:25])[CH3:22]
Reactant: COc1ccc(F)cc1Br
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCC(O)(c2cc(F)ccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
A mixture of 2-bromo-4-fluoro-1-methoxy-benzene (36.2 g, 176.7 mmol) and dry TBF (25 mL) was added to a cooled solution of n-butyl lithium (2.1 M in hexane, 101 mL, 212.1 mmol) in dry THE (100 mL) at rate so that the temperature was maintained below −40° C. The mixture was stirred for 30 min at −78° C. before 4-oxo-piperidine-1-carboxylic acid ethyl ester (30.4 g, 176.7 mmol) was added at a rate so that the temperature was maintained below −50° C. The resulting mixture was allowed to warm to rt and stirring was continued overnight. Water (100 mL) and ethyl acetate (100 mL) was added. The organic layer was washed with saturated aqueous ammonium chloride (100 mL), dried over magnesium sulfate, and evaporated in vacuo to afford 52.3 g (>95%.) of 4-(5-fluoro-2-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid ethyl ester, which was sufficiently pure for the next step. This material was dissolved in triethyl-silane (100 mL) and TFA (200 mL) and stirred at rt for 3 days. The volatiles were removed in vacuo and the residue was purified by chromatography on silica gel (eluent: ethyl acetate/heptane 1:3) to afford 44.4 g (ca. 90%) of 4-(5-fluoro-2-methoxy-phenyl)-piperidine-1-carboxylic acid ethyl ester. This material was refluxed overnight in a mixture of 33% hydrogen bromide in acetic acid (75 mL) and concentrated aqueous hydrobromic acid (75 mL). The crude mixture was cooled on an icebath, and 18.9 g (43%) of 4-fluoro-2-piperidin-4-yl-phenol as the hydrobromic acid salt. A slurry of this compound (23.9 g, 86.5 mmol) in dichloromethane (200 mL) was treated with triethyl amine (13.2 mL, 95.2 mmol) for 1 h before Boc2O (18.9 g, 86.5 mmol) was added and stirring was continued for 30 min. The crude mixture was washed with saturated aqueous ammonium chloride (50 mL) and water (25 mL). The organic layer was dried over magnesium sulfate and the volatiles were removed in vacuo. The residue crystallized to yield 14.2 g (55%) of 4-(5-fluoro-2-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester. This compound was transformed into 4-(5-fluoro-2-tri-iso-propylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester in a similar way as described for 4-(2-fluoro-6-tri-iso-propylsilanylsulfanyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][C:34]3([C:38]([O:40]CC)=[O:39])[CH2:37][CH2:36][CH2:35]3)[C:30]3[C:25](=[CH:26][C:27]([CH3:43])=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35]3)[C:30]3[C:25](=[CH:26][C:27]([CH3:43])=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)O)CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 3 h

Procedure:
A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline (220 mg, 0.29 mmol) in 50% trifluoroacetic acid-methylene chloride (6 mL) was stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in methanol (5 ml). LiOH (5 mL, 0.025 M) was added and the reaction stirred for 3 hours. The solvent was evaporated and the residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-carboxycyclobut-1-oxy)quinoline, as a white solid (190 mg, 95%, trifluoroacetic acid salt); NMR (DMSO-d6) 1.15 (t, 3), 1.82 (m, 1), 2.00 (m, 3), 2.30 (m, 2), 2.51 (s, 3), 2.56 (m, 2), 2.68 (m, 2), 3.40 (m, 6), 3.62 (m, 2), 4.00 (q, 2), 4.98 (m, 1), 6.98 (s, 1), 7.52 (dd, 1), 7.88 (s, 1), 8.14 (d, 1), 8.85 (d, 1) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cn2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(-c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ccn1

Procedure:
5-Bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.6 g, 1.76 mmol), 2-methylpyridine-4-boronic acid (264 mg, 1.9 mmol), bis(triphenylphosphine)-palladium(II)chloride (0.06 g, 0.09 mmol), 1 M Na2CO3 (4 ml) and acetonitrile (4 ml) were mixed in a 5 ml microwave vial. Another (2 ml) and acetonitrile (2 ml) were added. The reaction mixture was heated for 1500 sec. at 85° C. Water layer was removed. The acetonitrile phase was added DCM (20 mL). The organic phase was filtered and evaporated in vacuo. The crude mixture was purified on a silicagel column with EtOAc/heptane (4:1) and then EtOAc/heptane (9:1). The product was collected as a clear oil (540 mg, 87%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[N-:11]=[N+:12]=[N-:13].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])=[N+:12]=[N-:13]
Reactant: OCCOCCOCCCl
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCO
Temperature: 120 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
In a 250 mL flask, 2-[2-(2-chloroethoxy)ethoxy]ethanol (1) (6000 mg, 35.7 mmol), NaN3 (6964 mg, 107 mmol) and tetrabutylammonium iodide (TBAI) (656 mg, 1.7 mmol) were added to 80 mL DMF. The temperature was slowly raised to 120° C. and the reaction mixture was stirred under argon overnight. The solvent was evaporated and the residue was purified by FCC to afford 2 as slightly yellow oil (4150 mg, 66%). 1H NMR (400 MHz, CDCl3): δ 3.29 (t, J=5.2 Hz, 2H), 3.50 (m, 2H), 3.57-3.64 (m, 8H). 13C NMR (100 MHz, CDCl3): δ 50.59, 61.60, 69.98, 70.34, 70.59, 72.56.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17].Cl>[Cu](I)I.O1CCCC1>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10]
Reactant: ClC[C@@H]1CO1
Reactant: Fc1cc(F)c(Br)cc1F
Agent: I[Cu]I
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
84.4 g of 1-bromo-2,4,5-trifluorobenzene and 42.1 mL of tetrahydrofuran were added to 250 mL flask, and the resulting reaction solution was cooled to −15-20° C. Under nitrogen atmosphere, 20 mL of isopropylmagnesium chloride [2.0 M tetrahydrofuran solution] was dropped to the reaction solution, and stirred at 0-5° C. for 2 hours to produce Grinard reagent. 31.6 mL of (S)-epichlorohydrin and 42.1 mL of tetrahydrofuran were added to another 250 mL flask; the resulting reaction solution was cooled to −15-−20° C.; and then 7.6 g of copper iodide was added thereto. 42.1 mL of the Grinard reagent produced under nitrogen atmosphere was dropped, and stirred for 3 hours while the reaction temperature was maintained at −15-−20° C. 297 mL of 2 N hydrochloric acid aqueous solution that was cooled at 0-5° C. was dropped to the reaction solution, and then extracted with 297 mL of isopropylether. An organic layer was dehydrated with sodium sulfate, and then concentrated under reduced pressure to obtain 89.8 g of a title compound.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=4)[C:15]3=[O:25])=[CH:10][C:9]=2[O:26][CH3:27])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30]>CN1C(=O)CCC1>[OH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:25])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:3][CH2:2]3)=[C:9]([O:26][CH3:27])[CH:10]=1)[CH2:23][CH2:22]2
Reactant: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCNCC1
Reactant: CC1(C)CO1
Solvent: CN1CCCC1=O
Product: COc1cc(N2CCc3cc(O)ccc3C2=O)ccc1N1CCCN(CC(C)(C)O)CC1

Procedure:
A solution of 2-(4-[1,4]diazepan-1-yl-3-methoxy-phenyl)-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (193 mg) and isobutylene oxide (300 mg) in NMP (0.8 mL) was stirred at 65° C. for 16 h. The reaction mixture was purified by preparative HPLC. In this way the product was obtained with molecular weight 439.56 (C25H33N3O4); MS (ESI): 440 (M+H+).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)(C)(C)C.C(O)(=O)C.[CH3:46][NH:47][CH3:48].C([BH3-])#N.[Na+]>C(O)C>[CH3:46][N:47]([CH3:48])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][CH3:6])=[CH:22][CH:21]=2)=[O:25])=[CH:28][C:29]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CC=O)c(C(F)(F)F)c2)cc1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CCN(C)C)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
In 1 mL of ethanol, 25 mg (0.04 mmol) of methyl-[9-(4-{3-[4-(2-oxoethyl)-3-(trifluoromethyl)phenyl]ureido}-phenyl)-9H-purin-6-yl]-carbamic acid tert-butyl ester was dissolved, and 10 μL of acetic acid and 0.1 mL (0.20 mmol) of 2N dimethylamine were added thereto and the mixture solution was stirred at room temperature for 30 minutes. Furthermore, 7 mg (0.11 mmol) of sodium cyanoborohydride was added to the obtained solution and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated and to the residue, 0.5 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and a target product was obtained by a reversed phase HPLC (a product of Wako Pure Chemical, Combi ODS, 28 mm×50 mm, 0.05% acetonitrile-water, 30 mL/min). The fraction containing the target product was concentrated, and then dissolved in methanol and neutralized by addition of amino silica gel R 66030 B (a product of Silicycle), and then a solid was removed by filtration and the filtrate was concentrated to obtain 15 mg (52%) of a title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:32][CH3:33])[CH:4]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:32]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:20][CH:21]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:33]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3ccccc3c2C)C(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a mixture of ethyl 3-{[(4-{[2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}phenyl)carbonyl]amino}propanoate (330 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (272 mg, 91%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:12]=[CH:11][O:10][CH:9]=2)=[CH:6][N:5]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:4]=1)#[N:2].[Br:25]N1C(=O)CCC1=O.CCOCC.O>O1CCCC1>[Br:25][C:9]1[O:10][CH:11]=[CH:12][C:8]=1[C:7]1[C:3]([C:1]#[N:2])=[N:4][N:5]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:17][C:18]=2[Cl:19])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1Br
Reaction time: 24 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.19 g) in tetrahydrofuran (5 ml) was added portionwise N-bromosuccinimide (0.093 g). The mixture was left at room temperature for 24 hours and then poured into ether (15 ml) and water (15 ml). The layers were separated and the organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane:dichloromethane (1:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 111° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])=[CH:23][C:22]=1[CH3:28]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cc(N)ccc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Benzyloxycarbonylpiperidine-4-carboxylic acid (1.00 g, 3.80 mmol) and 4-chloro-3-methyl-aniline (0.592 g, 4.18 mmol) in CH2Cl2 (5 mL) were treated with HOBT (0.582, 3.80 mmol) and EDC (1.46 g, 7.60 mmol), and stirred at rt for 16 h. The mixture was directly purified on SiO2 (50 to 100% EtOAc, hexanes) to afford the title compound. HPLC/MS: 387.2/389.1 (M+1); Rt=1.22 min (LC2).