Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C)C(CC)CN(C)C.N#N.CCO.[Li]C(CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.CI>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:1])[CH:23]=1
Reactant: CCC(CN(C)C)N(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: N#N
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCO
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3I (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[C:16]3[C:10]([CH2:11][CH2:12][N:13]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH2:14][CH2:15]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[CH:18]1([N:13]2[CH2:14][CH2:15][C:16]3=[CH:17][N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:26]5[C:27](=[O:28])[CH2:29][N:23]([CH3:22])[C:24]5=[O:25])=[CH:3][CH:4]=4)[N:9]=[C:10]3[CH2:11][CH2:12]2)[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CC(=O)NC1=O
Reactant: Brc1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN1CC(=O)N(c2ccc(-n3cc4c(n3)CCN(C3CCC3)CC4)cc2)C1=O
Temperature: 150 °C

Procedure:
A mixture of 2-(4-bromophenyl)-6-cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Example 35) (80 mg, 0.23 mmol), 1-methylhydantoin (52 mg, 0.46 mmol), potassium carbonate (95 mg, 0.7 mmol), copper (I) iodide (13 mg, 0.07 mmol) and N,N′-dimethyl-1,2-ethanediamine (8 μl, 0.07 mmol) in dioxane (2 ml) was heated in the microwave (normal absorption) at 150° C. for 2 hours. The reaction mixture was purified by SCX cartridge, followed by Mass Directed Autopreparation and column chromatography on silica gel, eluting with a mixture of 2M ammonia in methanol/dichloromethane (0-5%) to afford the title compound (E38). MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].Cl.[F:27][C:28]([F:37])([F:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C@H:15]1([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]4[CH2:32][CH2:31][N:30]([CH2:29][C:28]([F:36])([F:37])[F:27])[CH2:35][CH2:34]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(CC(F)(F)F)CC1)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 76.6 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and commercially available 1-(2,2,2-trifluorethyl)piperazine hydrochloride (CAS 13349-91-2) (87 mg, 0.422 mmol) in acetonitrile (1 ml) with diisopropylethyl amine (0.24 ml, 1.405 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (105 mg, 77%), MS (ISP) m/e=488.3 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1.[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:23][OH:24])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: C=O
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Solvent: Cc1ccccc1C
Product: OCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, 8bromo-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in xylene is heated in an oil bath at 105°-110° C. with formaldehyde gas bubbling through the solution to give 8-bromo-1-(2-hydroxyethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1([O:25][CH2:24]1)[CH3:23]>C(#N)C>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][N:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: CC1(C)CO1
Reactant: O=C(c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)CN1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.63 mmol) 1-benzoylpiperazine and 1.10 g (7.96 mmol, 3.0 eq.) potassium carbonate were suspended to 20 ml acetonitrile at room temperature. After adding 570 mg (7.90 mmol, 3.0 eq.) isobutylene oxide, it was heated at reflux and stirred overnight. After cooling to room temperature and adding 30 ml purified water, it was extracted twice with 30 ml ethylacetate. After collecting organic layer and drying with anhydrous magnesium sulfate, it was concentrated with decompression. The obtained residue was purified by chromatography using silicagel (mobile phase: dichloromethane/methanol=20:1) and 276 mg (40%) target compound as light-yellow solid was yielded.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:10]=[C:9]([C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1
Reactant: Brc1nccs1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1c2n(c3c(-c4nccs4)cc(F)cc13)CCNC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.3 %

Procedure:
To a mixture of 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Step A) (48 mg, 139 μmol) and 2-bromothiazole (34.3 mg, 18.6 μl, 209 μmol) in 1,2-dimethoxyethane (1 ml), 2M potassium carbonate solution (232 μl, 464 μmol) was added and the reaction mixture purged with argon in an ultrasonic bath during 5 min. Then triphenylphosphine (7.32 mg, 27.9 μmol) and palladium(II)acetate (3.13 mg, 13.9 μmol) were added and the reaction mixture was allowed to stir for 3 h under reflux conditions. The reaction mixture was cooled to room temperature, filtered (MgSO4) and purified by flash chromatography on silica gel [dichloro methane/methanol (0-5%)] and subsequent trituration (diethyl ether) to yield the title compound as a light brown solid (6 mg, 15%), MS (ISP) m/z=302.5 [(M+H)+], mp 268° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9]Br)=[C:7]([Cl:11])[N:6]=[N:5][C:4]=1[Cl:12].C(=O)([O-])[O-].[Na+].[Na+].[CH:19]([NH2:22])([CH3:21])[CH3:20].CCCCCCC>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:7]1[C:8]2=[CH:9][N:22]([CH:19]([CH3:21])[CH3:20])[CH:2]=[C:3]2[C:4]([Cl:12])=[N:5][N:6]=1
Reactant: CC(C)N
Reactant: Clc1nnc(Cl)c(CBr)c1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)n1cc2c(Cl)nnc(Cl)c2c1
Temperature: 70 °C
Yield: 58.2 %

Procedure:
To a suspension of 4,5-bis(bromomethyl)-3,6-dichloropyridazine (700 mg, 2.09 mmol) in 66 mL anhydrous THF was added with sodium carbonate (443 mg, 4.18 mmol) and tetrabutylammonium iodide (77.2 mg, 0.21 mmol). The reaction mixture was added with isopropyl amine (0.18 mL, 2.09 mmol) in 10 mL THF dropwisely for 2 h. The reaction mixture was heated at 70° C. for 3 h. The reaction mixture was concentrated, dissolved in DCM and washed with water and brine. The organics solution was dried over Na2SO4 and concentrated to afford a crude oil. The mixture was purified by flash chromatography on silica gel, eluting with 10-80% EtOAc:heptane to afford a off-white solid (280 mg, yield: 47%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]12([C:32](O)=[O:33])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([C:29]([OH:31])=[O:30])([CH2:22]3)[CH2:20]1)[CH2:26]2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:32]([C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][C:21]([C:29]([OH:31])=[O:30])([CH2:22]4)[CH2:20]2)[CH2:26]3)=[O:33])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C23CC4CC(CC(C(=O)O)(C4)C2)C3)CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 1,3-adamantanedicarboxylic acid (628 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (316 mg), 1-hydroxy-1H-benzotriazole monohydrate (253 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (352 mg, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CCCCCCC.CCOC(C)=O.O>[C:9]([C:3]1[N:4]=[CH:5][C:6]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][S:20]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=3[Cl:12])(=[O:21])=[O:22])=[CH:29][CH:28]=2)=[N:7][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Reactant: CC(=O)c1ncc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Temperature: 100 °C

Procedure:
1-(3,5-Dichloro-pyrazin-2-yl)-ethanone (200 mg) and 2,3-dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide (448.3 mg), prepared as in example 1, was added to a reaction vessel containing a magnetic stirring bar together with 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (61 mg) and cesium carbonate (1.0 g), followed by 9 ml dioxane and 1 ml water, and the mixture heated to 100° C. under stirring. After 2 h the reaction mixture was cooled to RT and quenched with a saturated aqueous sodium bicarbonate solution (30 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product as a brown oil-Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide as a colorless solid after evaporation of the solvents under reduced pressure. Yield: 230 mg (48%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>COCCOC.CCCCCC.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>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(Cl)c2)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: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)c4)cnc32)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (100 mg, 0.301 mmol, 1 eq) and 2-(3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95) (71 mg, 0.301 mmol, 1 eq) in 1,2-dimethoxyethane (10 mL) was added Cs2CO3 (244 mg, 0.752 mmol, 25 eq) 2M aqueous solution followed by degassing, purging with N2 for 15 min and addition of Pd(PPh3)4 (13 mg, 0.012 mmol, 0.04 eq). The reaction mixture was heated at 100° C. in a sealed tube overnight. After completion of the reaction the mixture was partitioned between ethyl acetate and water and the organic layer was separated and again extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent completely distilled off to get the crude. The crude was passed through 100-200 mesh silica gel eluting the pure compound at 50% ethyl acetate in hexane as off-white coloured solid compound 96 (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Fc1cccc(CCl)c1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A suspension of 1.035 g (5 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.865 g (6 mmol) of 3-fluorobenzyl chloride and 1.38 g (10 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred for 24 h at 60° C. The reaction mixture is subsequently cooled and poured into a mixture of ice-cold water and of ethyl acetate. After separation by settling out, the organic phase is separated and is then washed with twice 200 ml of water then with 200 ml of a saturated solution of sodium chloride. The solution is dried over magnesium sulphate and filtered and the filtrate is then concentrated under reduced pressure. 0.97 g of an oil is obtained, which oil is used as it is in the subsequent step.
Reaction SMILES: CC([O:4][C:5]([C:7]1[N:40]=[CH:39][C:10]2[N:11]([CH2:26][C:27]([N:29]([CH3:38])[CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:28])[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:41][O:42][CH3:43])=[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:15]=[CH:14][CH:13]=3)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C(O)(C)C.O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]1[C:8]([CH2:41][O:42][CH3:43])=[C:7]([CH:5]=[O:4])[N:40]=[CH:39][C:10]=1[N:11]2[CH2:26][C:27]([N:29]([CH3:38])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2CC(=O)N(C)CCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
200 mg of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is dissolved in 3 ml of tetrahydrofuran. Then, 0.29 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is added in drops to the solution at 0° C., and it is stirred for 30 minutes at 0° C. Then, the reaction mixture is mixed with 0.1 ml of isopropanol and then with 0.1 ml of water, it is stirred for 2 hours at room temperature, filtered, and the filtrate is concentrated by evaporation in a vacuum. The residue is recrystallized from ethyl acetate, and 43 mg of 5-benzyloxy-4-methoxymethyl-9-{2-[N-methyl-N-(2-phenylethyl)-amino]-2-oxoethyl}-9H-pyrido[3,4-b]indole-3-carbaldehyde is obtained as colorless crystals with a melting point of 192°-197° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:61]2[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]2)=[O:23])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OCCC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(CCO)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Piperidinethanol (33.6 mg, 260 μmol, 3 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (26 mg, 48% of theory, purity about 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu](I)I.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][C:11]2[CH:12]=[C:13]([CH3:21])[C:14]([C:18](=[O:20])[CH3:19])=[C:15]([CH3:17])[CH:16]=2)=[N:3][CH:4]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COc1ccc(Br)nc1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Oc2cc(C)c(C(C)=O)c(C)c2)nc1
Temperature: 120 °C
Yield: 107 %

Procedure:
A mixture of 2-bromo-5-methoxypyridine (18-1, 1.03 g, 5.46 mmol), 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 0.80 g, 4.89 mmol), N,N-dimethylglycine HCl salt (0.28 g, 1.95 mmol), copper iodide (0.24 g, 1.24 mmol), and cesium carbonate (3.57 g, 10.96 mmol) in dioxane (10 mL) was heated at 120° C. for 4.0 h. The reaction mixture was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated to give 1-{4-((5-methoxypyridin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (18-2, 1.42 g) as a yellow oil in 96% yield, which was used directly for the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6]O.S(Cl)(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[Na+].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: OCc1nccs1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cc1nccs1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 11 h

Procedure:
To a chloroform (15 ml) solution of thiazole-2-methanol (171 mg, 1.49 mmol) was added thionyl chloride (0.33 ml, 4.47 mmol) and the resulting mixture was stirred at 50° C. for 11 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in butanol (10 ml). To the resulting solution were added sodium 4-chlorobenzenesulfinate (296 mg, 1.49 mmol) and potassium acetate (292 mg, 2.98 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure, whereby the title compound (169 mg, 41%) was obtained as a pale yellow solid.
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl.[CH3:16][O:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:16][O:17][N:18]=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
0.560 g (2.96 mmol) of N-(2-oxoethyl)phthalimide was dissolved in 20 ml of ethanol and to the solution was added 0.330 g (3.95 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 10 ml of 0.35M aqueous sodium carbonate solution, followed by being stirred at room temperature for 3 days. The reaction mixture was poured into 100 ml of water and extracted with chloroform (20 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with petroleum ether to give 0.291 g (yield 45%) of the titled compound as colorless crystals.