Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=O)[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])=[O:22])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F

Procedure:
2-[5-Benzyloxycartonylamino-2-(4-chlorophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(4-chlorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 13, 2.50 g, 6.04 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.39 g, 6.34 mmol), WSCI hydrochloride (1.39 g, 7.25 mmol) and HOBT (1.63 g, 1.21 mmol) in DMF (20 mL) to give 3.72 g (100%) of the target compound as colorless crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[N+:15]([O-:17])=[O:16].[C:18]([O:22][C:23](=[O:26])[CH2:24]Cl)([CH3:21])([CH3:20])[CH3:19]>CN1C(=O)CCC1>[F:7][C:8]1[CH:13]=[C:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH:11]=[C:10]([F:14])[C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Cc1cc(F)c([N+](=O)[O-])c(F)c1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A mixture of potassium tert-butoxide (248 g) in NMP (2000 ml) was cooled under nitrogen to −20° C. A mixture of 2,6-difluoronitrobenzene (100 g) and tert-butylchloroacetate (160 g) in NMP (2000 ml) was added slowly at −10° C. to −20° C. over 1.5 hours. After 30 minutes, a further portion of potassium tert-butoxide (88 g) was added. The reaction mass was quenched into 1600 ml of 2M HCl and 1 kg crushed ice, then 2000 ml hexane was added and the mixture stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with hexane (2×1500 ml). The combined hexane layers were washed with saturated brine (2×1000 ml), then dried over anhydrous sodium sulphate, then filtered and washed with 200 ml hexane. The solution was then evaporated to give the title compound as a brown liquid (152 g).
Reaction SMILES: Br[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>CO>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: CN1CCNCC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)N1CCN(C)CC1
Yield: 14.3 %

Procedure:
Ethyl 2-bromo-3-phenylpropionate (1.95 g) was treated with 3.05 g N-methylpiperazine as described in Example 95 to afford 0.30 g pure product after chromatography (9:1 CH2Cl2 :MeOH). NMR (300 MHz, CDCl3) delta 1.10 (d, J=7 Hz, 3H), 2.26 (s, 3H), 3.37 (m, 1H), 4.00 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:14])[CH2:10][CH2:11][CH2:12]O>ClCCCl.C(Cl)(Cl)Cl.CC(O)C.F[Sb-](F)(F)(F)(F)F.[Ag+].[Pt](Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][CH2:12][O:14]1
Reactant: OCCCC(O)c1ccc(F)cc1Br
Agent: Cl[Pt]Cl
Agent: [Ag+]
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: Fc1ccc(C2CCCO2)c(Br)c1
Temperature: 110 °C
Yield: 77.3 %

Procedure:
Combine 1-(2-bromo-4-fluoro-phenyl)-butane-1,4-diol (1 g, 3.8 mmol), silver (I)hexafluoroantimonate (131 mg, 0.4 mmol), platinum(II) chloride (40 mg, 0.2 mmol) in 1,2-dichloroethane (10 mL) in a pressure tube. Seal the tube and heat the mixture overnight at 110° C. Dilute the mixture with chloroform-IPA (3:1, 100 mL). Wash the organic phase with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (20% ethyl acetate in hexane) to give the title compound as a pale yellow oil (0.72 g, 77%).
Reaction SMILES: [N+:1]([N:4]1[CH:8]([N+:9]([O-:11])=[O:10])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][NH:5]1)([O-:3])=[O:2].[BH4-:15].[Na+:16].[H][H]>>[N+:1]([N:4]1[CH:8]([N+:9]([O-:11])=[O:10])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][N:5]1[B-:15]([N:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]([N+:9]([O-:11])=[O:10])[N:4]1[N+:1]([O-:3])=[O:2])([N:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]([N+:9]([O-:11])=[O:10])[N:4]1[N+:1]([O-:3])=[O:2])[N:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]([N+:9]([O-:11])=[O:10])[N:4]1[N+:1]([O-:3])=[O:2])([O-:3])=[O:2].[Na+:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])C1=CNN([N+](=O)[O-])C1[N+](=O)[O-]
Reactant: [BH4-]
Agent: [Na+]
Product: O=[N+]([O-])C1=CN([B-](N2C=C([N+](=O)[O-])C([N+](=O)[O-])N2[N+](=O)[O-])(N2C=C([N+](=O)[O-])C([N+](=O)[O-])N2[N+](=O)[O-])N2C=C([N+](=O)[O-])C([N+](=O)[O-])N2[N+](=O)[O-])N([N+](=O)[O-])C1[N+](=O)[O-]
Temperature: -196 °C
Reaction time: 0.5 h

Procedure:
A 150 mL glass ampule equipped with a grease free high-vacuum PTFE valve and a TEFLON™ coated stir bar was flamed-out under vacuum. Inside the dry-box, the ampule was loaded with 812 mg (4.00 mmol) 2,3,4-trinitro-1H-pyrazole and 37.8 mg (1.00 mmol) sodium borohydride. The ampule was connected to a vacuum line, evacuated and cooled to −196° C. About 5 mL of dry dimethoxyethane was slowly condensed into the ampule. The ampule was closed and allowed to warm to ambient temperature. As soon as the solvent melted and contacted the solid mixture at the bottom of the ampule gas evolution started. The mixture was then stirred for about 30 minutes at ambient temperature. The clear, light yellow solution was cooled to −196° C., and the evolved hydrogen pumped off. The ampule was closed off and heated to 60° C. while stirring. After 3 hours, an orange solution was obtained and the temperature was raised to 120° C. After 24 hours, the solution was allowed to cool to ambient temperature and then cooled to −196° C., the evolved hydrogen pumped off and the reaction mixture allowed to warm to ambient temperature. Subsequent evacuation to a constant weight over 24 hours resulted in a yellow solid of sodium tetrakis(2,3,4-trinitro-1H-pyrazolyl)borate, 1.0 mmol.
Reaction SMILES: O1CCCC1.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].CS[C:19]1[S:23][CH:22]=[CH:21][S+:20]=1>C(O)C>[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].[S:20]1[CH:21]=[CH:22][S:23][C:19]1=[N+:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CSc1scc[s+]1
Reactant: C1COCCN1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: c1csc(=[N+]2CCOCC2)s1
Temperature: 25 °C

Procedure:
To 20 ml of tetrahydrofuran, 1.0 ml of morpholine was dissolved, and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration and recrystallized from ethanol, whereby 2.4 g (yield: 83.3%) of 4-(1,3-dithiol-2-ylidene)morpholinium perchlorate (Compound No. 26) was obtained as crystals having a melting point of from 177° to 178° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]1[CH2:16][CH2:15]C[CH2:13][CH:12]=1.Cl[CH2:18]Cl>>[CH3:10][C:4]1([CH3:18])[CH2:5][C:6]2([CH3:8])[CH:9]([CH:13]3[CH:7]2[CH2:15][CH2:16][CH2:11][CH2:12]3)[C:2](=[O:1])[CH2:3]1
Reactant: ClCCl
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: C1=CCCCC1
Product: CC1(C)CC(=O)C2C3CCCCC3C2(C)C1
Yield: 82 %

Procedure:
To a photoreactor fitted with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 30.0 g. (0.217 mol.) of isophorone and 145 ml. of freshly distilled cyclohexene. Enough dichloromethane was added to fill the 825 ml. internal volume of the photoreactor. After the solution was bubbled with nitrogen for 1 hour, it was irradiated through a Corning 9700 glass filter for 71/4 hours with an Hanovia 450 watt medium pressure mercury arc. At the end of this period, the solution was concentrated in vacuo to yield an oil which was distilled through a short Vigreux-column. The product, which is a mixture of two major isomers in approximately a 3:1 ratio had b.p. 93°-106° C./0.2 mm.Hg. Yield 39.2 g. (0.178 mol., 82% yield). The two major isomers could be separated by distillation on a spinning band column. Isomer A: b.p. 85° C./0.1 mm.Hg. m.p. 76.6°-77.4° C., IR: 1690 cm-1 ; NMR: (deuterochloroform) 1.20δ (S-3H); 1.07δ (S-3H); 0.90δ (S-3H); 1.32δ-2.70δ (complex multiplets-15H). Isomer B: b.p. 95° C./0.1 mm.Hg. IR: 1690 cm-1, NMR: (deuterochloroform); 1.08δ, 1.05δ (2 singlets-6H); 0.90δ (S-3H) 1.18δ-2.82δ (multiplets-15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:33](=[O:35])[CH3:34])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: -15 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/30 mg, 0.07 mmol) was dissolved in DMA and the mixture was cooled to −15° C. Acetic anhydride (6 μL, 0.07 mmol) was added and the mixture was stirred for 1 hour. Water was then added and the precipitated solid was filtered and dried to give the title compound (22 mg, 67%); NMR Spectrum (mixture of rotamers): (major isomer) 2.08 (s, 3H), 3.49 (t, 2H), 3.56-3.59 (m, 2H), 3.80 (t, 2H), 4.40 (t, 2H), 4.90 (t, 1H), 5.28 (s, 2H), 7.26 (d, 1H), 7.37 (t, 1H), 7.58 (d, 1H), 7.84-7.98 (m, 2H), 8.16 (d, 1H), 8.28 (s, 1H), 8.30 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([NH2:21])[C:19]#[CH:20].C(OCC)(=O)C>ClCCl>[CH2:18]([NH:21][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:19]#[CH:20]
Reactant: O[C@H]1CCc2ccccc21
Reactant: C#CCN
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN[C@@H]1CCc2ccccc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Methanesulfonyl anhydride (3.0 g, 17.2 mmol) as a solution in dichloromethane (8 mL+4 mL) was added to a stirred solution of (S)-1-indanol (1.02 g, 7.6 mmol) and triethylamine (4.4 mL, 31.5 mmol) in dichloromethane (20 mL) at −26° C. (internal, −35° C. external) over 10 minutes. During the addition the internal temperature rose to −20° C. The reaction was maintained at −29° C. (internal, −35° C., external) for 45 minutes before propargylamine (5 mL, 78 mmol) was added over 2 minutes. The reaction was allowed to warm slowly to room temperature overnight before being portioned between ethyl acetate (50 mL) and ice-water (75 mL, pH of solution 9.7). The organic layer was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 40 mL, pH of solution <1). The aqueous layer was basified to pH>12.5 by addition of aqueous sodium hydroxide solution (2M, 30 mL) before being extracted with ethyl acetate (50 mL+30 mL). The combined final organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a brown liquid (0.81 g, 68%). Analysis of this material by chiral GC indicated it to be 46% e.e.
Reaction SMILES: [CH2:1]([Cl:3])[CH3:2].[CH2:4]([N:6]([CH2:8][CH3:9])[NH2:7])[CH3:5]>>[Cl-:3].[CH2:4]([N+:6]([CH2:1][CH3:2])([CH2:8][CH3:9])[NH2:7])[CH3:5]
Reactant: CCN(N)CC
Reactant: CCCl
Product: CC[N+](N)(CC)CC
Product: [Cl-]

Procedure:
Similarly, when Example 1(a) is repeated except that methiodide is replaced by a stoichiometrically equivalent amount of ethyl chloride and reacted with 1,1-diethylhydrazine to produce a similar amount of 1,1,1-triethylhydrazinium chloride.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12]C=C(Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[Cl:31][C:32]([Cl:38])(Cl)[C:33](Cl)(Cl)Cl>>[ClH:31].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:33]=[C:32]([Cl:38])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(Cl)cc2OCc2ccccc2)n1
Yield: 27.2 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.225 g, 0.598 mmol), MeLi (0.467 mL, 0.747 mmol), butyllithium (0.299 mL, 0.747 mmol), and perchloroethane (0.991 g, 4.19 mmol) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-chloro-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.060 g, 30.2% yield). 1H NMR (CDCl3) δ 12.43 (bs, 1H), 7.91 (d, 1H), 7.59 (m, 2H), 7.41 (m, 2H), 7.33 (m, 1H), 7.20 (d, 1H), 6.41 (s, 1H), 5.36 (s, 2H), 2.47 (s, 3H). Mass spectrum (apci) m/z=332.1 (M+H-HCl).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:29]([OH:30])[C:28]4[C:23](=[N:24][CH:25]=[CH:26][N:27]=4)[C:22]3=[O:31])=[N:18]2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:29]([O:30][C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[C:28]4[C:23](=[N:24][CH:25]=[CH:26][N:27]=4)[C:22]3=[O:31])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NC1CCCCC1)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 41.2 %

Procedure:
Cyclohexyl isocyanate (1.38 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (3.12 g.) in anhydrous acetonitrile (60 cc.) in the presence of triethylamine (1 cc.), and the reaction mixture is heated at the reflux temperature for 13 hours. After cooling, the insoluble product is filtered off and washed successively with acetonitrile (2 × 10 cc.) and diisopropyl ether (2 × 20 cc.). It is then dissolved in methylene chloride (300 cc.) and the solution obtained is stirred for 15 minutes with 1N sodium hydroxide solution (50 cc.). The organic layer is decanted, washed with water (2 × 50 cc.), dried over anhydrous sodium sulphate in the presence of decolourising charcoal, filtered and then evaporated to dryness under reduced pressure. The residue is recrystallised from acetonitrile (95 cc.) and the product obtained is heated for 10 minutes with ethanol (65 cc.) at the reflux temperature. The insoluble product is then isolated from the boiling solution by filtration, after which it is washed with boiling ethanol (2 × 10 cc.). After drying, 6-(7-chloro-1,8-naphthyridin-2-yl)-5-cyclohexylaminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (1.8 g.), melting at 264° C., is obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Br:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][CH3:16])=[CH:26][C:25]=3[CH3:27])[CH2:21][CH2:22]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 152-154° C.; 1H NMR (300 MHz, CDCl3): δ 6.73 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=1.9 Hz, 1 H), 4.84-4.76 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.05 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.87-1.73 (m, 2 H), 1.70-1.59 (m, 2 H), 0.89 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C19H25N3O2Br (M+H)+: 406.1130; found m/z 406.1125.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1.Cl.O1CCOCC1.C(OC(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[NH:24][C:25]([C@H:27]2[CH2:32][CH2:31][C@H:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C:34]3=[O:39])[CH2:29][CH2:28]2)=[O:26])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)[C@H]2CC[C@H](N3CCOCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-Butyl 4-{[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)-benzoate (293 mg) obtained in Example 2 is dissolved in chloroform (10 ml), and thereto is added 4N hydrogen chloride-dioxane solution (10 ml) followed by stirring at room temperature for 3 days. To the reaction solution is poured diisopropyl ether, and the solid precipitates are collected by filtration to give the title compound (280 mg). ESI-MS M/Z: 499/501[M−H]−
Reaction SMILES: [CH3:1][N:2]([O:12][CH3:13])[C:3](=[O:11])[C:4](=[O:10])[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.B1([C@H]2[C@H](C)[C@@H]3C(C)(C)[C@H](C3)C2)C2CCCC1CCC2.C(=O)C(C)C.C(CN)O>C1COCC1.CCOCC>[CH3:1][N:2]([O:12][CH3:13])[C:3](=[O:11])[C@@H:4]([OH:10])[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]1
Reactant: CON(C)C(=O)C(=O)CC1CCC1
Agent: CC(C)C=O
Agent: C[C@@H]1[C@H]2C[C@H](C[C@H]1B1C3CCCC1CCC3)C2(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: NCCO
Product: CON(C)C(=O)[C@@H](O)CC1CCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 11.40 g (61.5 mmol) of N-methyl-N-methoxy 2-oxo-3-cyclobutyl propanamide (from Step B) and 250 mL 0.5 N (R)-Alpine Borane® solution in THF was concentrated and stirred at rt for 5 days. The mixture was cooled to 0° C. and quenched with 6.8 mL (75.0 mmol) of isobutyraldehyde. The resulting mixture was diluted with 200 mL of ether and treated with 7.5 mL (125 mmol) of ethanolamine. The precipitate that formed was filtered and the filtrate was concentrated. Flash chromatography on 500 g of silica gel using 9:1 v/v CH2Cl2 as the eluant afforded 11.48 g (99%, 91% ee) of the title compound: 1H NMR (500 MHz) δ1.59-1.70 (m, 2H), 1.67 (s, 1H), 1.77-1.83 (m, 2H), 1.82-1.92 (m, 1H), 2.03-2.13 (m, 2H), 2.53-2.60 (m, 1H), 3.23 (s, 3H), 3.72 (s, 3H), 4.31 (app d, J=5.5, 1H); HPLC: Chiralpak AS 4.6×250 mm column, 75/25 hexanes/iPrOH, 0.5 mL/min, 210 nm. Retention Times: (S)-Enantiomer, 13.3 min; (R)-enantiomer, 17.2 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27](=[O:29])[CH3:28].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:26][C:25]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([C:27](=[O:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CC(=O)c1cccc(C)c1F
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1cccc(C)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.4 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (71 mg; 0.295 mmol) and 90 mg (0.592 mmol) of 1-(2-fluoro-3-methylphenyl)ethanone were added to a solution of 82 mg (0.732 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 130° C. for 5 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 6 mg (yield: 5%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](=[O:23])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-methylpyridine (308 mg, 3.31 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium solution (1.6 M in hexane, 2.07 mL, 3.31 mmol). The reaction mixture was stirred for 1 hour at room temperature and cooled down again to −78° C. (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1; 400 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. A saturated solution of sodium hydrogencarbonate and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to yield the title compound as a yellow oil (51%), MS (ESI+): m/z=394.0 ([M+H]+).
Reaction SMILES: O=S(Cl)[Cl:3].[OH-].[Na+].[NH2:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11].[CH:16]1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(O)C.CO>[ClH:3].[CH3:16][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[NH2:7]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: O=S(Cl)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COC(=O)[C@@H](N)CC(C)C
Product: Cl
Temperature: 66 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust. After stirring for 1 h, 8 mmol of L-leucine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h. The reaction was tracked by TLC until the raw material disappears, with a solution of 2% ninhydrin in ethanol as chromogenic reagent. The solvent was evaporated out to obtain L-leucine methyl ester hydrochloride. Yield: 100%.