Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[C:69]([S:73][CH2:74][C@H:75]([C:77]([OH:79])=[O:78])[NH2:76])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:76][C@@H:75]([C:77]([OH:79])=[O:78])[CH2:74][S:73][C:69]([CH3:72])([CH3:70])[CH3:71])=[O:36])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)(C)SC[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)SC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (20 mg, 0.037 mmol) and N-methylmorpholine (20 μl, 0.18 mmol) were dissolved in DMF (3 ml). TBTU (14.6 mg, 0.046 mmol) was added and the mixture was stirred at 30° C. for 45 minutes. S-(tert-Butyl)-D-cysteine hydrochloride (9.7 mg, 0.045 mmol) was added and the reaction mixture was stirred for 1.5 h. The formation of the ketone of the title compound was confirmed. M/z: 700.0. Methanol (2 ml) and sodium borohydride (14.3 mg, 0.38 mmol) were added and the mixture was stirred for 30 minutes. Ammonium acetate buffer (0.1M, 2 ml) was added and the mixture was concentrated. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 45% MeCN in 0.1M N4OAc buffer was used as eluent. The MeCN was removed from the collected fraction under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was concentrated under reduced pressure and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (16.5 mg, 65%). H-NMR (400 MHz, DMSO-d6): 1.21 (s, 9H), 2.71-2.78 (m, 1H), 2.82-2.86 (m, 3H), 2.74-2.80 (m, 2H), 2.18-2.26 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 2.67-2.76 (m, 1H), 5.03 (d, 0.5H), 5.05 (d, 0.5), 6.98 (d, 2H), 7.05-7.17 (m, 4H), 7.20-7.25 (m, 2H), 7.30-7.39 (m, 4H), 7.94-8.06 (b, 1H), 8.26 (t, 1H). M/z: 700.0 (M−H) and 702.1 (M+H).
Reaction SMILES: Br.[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Na+].O1CCOCC1.Cl[C:33]([O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>O>[CH:10]1[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[C:8]([CH2:7][CH:3]([NH:2][C:33]([O:35][CH2:36][CH:37]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:43]=3[C:44]3[C:49]2=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:34])[C:4]([OH:6])=[O:5])[CH:9]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NC(Cc1ccc2[nH]c3ccccc3c2c1)C(=O)O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1ccc2[nH]c3ccccc3c2c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
Crude 2-Amino-3-(9H-carbazol-3-yl)-propionic acid HBr salt (50 mg, 0.15 mmol) was combined with aqueous sodium hydrogen carbonate (2 mL of a saturated solution) and dioxane (2 mL) and stirred at about 0° C. 9-Fluorenylmethyl chloroformate (100 mg, 0.39 mmol) was added and the reaction stirred at room temperature for about 8 h. The reaction mixture was diluted with water (25 mL), and extracted with diethyl ether (2×25 mL). The aqueous layer was acidified with hydrochloric acid to pH 3, and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extracts were concentrated under reduced pressure and dried in vacuo. The crude product was purified using column chromatography on silica gel with 10% methanol in dichloromethane as eluant to afford rac-3-(9H-Carbazol-3-yl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (ES-MS (M+H)+ 477.2 (calc. 477.17)), which was utilized directly in the synthesis of peptide analogs by solid phase peptide synthesis protocols.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[S:45][C:44]([C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=2[CH3:55])=[N:43][C:42]=1[C:56]([CH3:59])([CH3:58])[CH3:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[S:45][C:44]([C:46]5[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][C:47]=5[CH3:55])=[N:43][C:42]=4[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(Br)s1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(-c2sc(-c3ccc(C(=O)O)cc3C)nc2C(C)(C)C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Yield: 9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylsulfanyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 2.0 g, 3.46 m mol), 4-(5-bromo-4-tert-butylthiazol-2-yl)-3-methylbenzoic acid (INTERMEDIATE 41, 1.350 g, 3.81 mmol), potassium phosphate (8.18 mL, 1.27 M, 10.39 m mol) in THF (5 mL) and water (5.00 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.400 g, 0.346 mmol). It was degassed, and refilled with nitrogen. The reaction mixture was heated to reflux for 2 hours to see complete conversion by LCMS. It was distributed between 100 mL of water and 300 mL of ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified by silica gel chromatography, eluting with 30% ethyl acetate in hexanes to give the title compound as white solid (225 mg, 9.0% yield). LCMS (M+H)+: 725.0
Reaction SMILES: [CH2:1]([N:10]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.NN>CO>[CH2:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CC=Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CO
Product: NCC=Cc1ccccc1
Temperature: 70 °C
Yield: 30 %

Procedure:
N-cinnamyl phthalimide (3 mmol) was mixed with 65% hydrazine hydrate (6 mmol, 2 equiv) and MeOH (10 mL), and the mixture was heated at 70° C. for 2 h. After the solvent was removed by a rotary evaporator, the solid residue was treated with 1 N NaOH (30 mL), and the resulting mixture was extracted with EtOAc (4×50 mL) and dried. Evaporation of the solvent under reduced pressure afforded the crude product, which was purified by flash silica gel column chromatography (eluting with 5-20% MeOH in DCM) to give cinnamyl amine. Compound 117 (white solid) was obtained at 30% yield, and compound 119 (off-white solid) was obtained at 80% yield. Identity was confirmed by 1H NMR (400 MHz, CD3OD).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[S:20][C:21]([CH:24]=[CH2:25])=[CH:22][CH:23]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[S:20][C:19]([CH3:18])=[CH:23][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(C)s1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)s2)C=CN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (150 mg, 0.75 mmol) in NMP (1 mL) were added powdered KOH (294 mg, 5.25 mmol) and 2-methyl-5-vinyl-thiophene (186 mg, 1.50 mmol), and the reaction mixture stirred at 90° C. for 5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3% MeOH-DCM) followed by reverse phase HPLC to yield 2,8-dimethyl-5-[2-(5-methyl-thiophen-2-yl)-ethyl]-2,5-dihydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.22 (s, 1H), 7.08 (d, 1H), 6.5 (d, 1H), 6.3 (d, 1H), 4.6 (d, 1H), 4.2-4.4 (m, 3H), 3.7 (m, 2H), 3.2 (m, 3H), 3.03 (s, 3H), 2.7 (m, 1H), 2.38-2.42 (m, 6H).
Reaction SMILES: C(O[P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16]CC)=O)=[C:12](I)[S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])C.[Cu]C#N.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)CCC.[F-].[K+]>>[CH2:20]([O:19][P:14](=[C:13]1[C:9](=[P:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][S:11][CH:12]1[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:16])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOP(=O)(OCC)c1c(I)sc(I)c1P(=O)(OCC)OCC
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Product: CCO[P+]([O-])=C1CSC(c2cccs2)C1=[P+]([O-])OCC
Temperature: 70 °C
Reaction time: 13 h

Procedure:
3,4-bis(diethoxyphosphoryl)-2,5-diiodothiophene obtained in Example 7, commercially available tetrakistriphenylphosphine palladium (0.10 equivalent) and copper(I) cyanide (commercial product) in amounts indicated in Table 8 were dissolved in different types of solvents indicated in Table 8, to which 2-tributylstannylthiophene (2.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 6 to 20 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([C:20]#[N:21])=[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1.[BH4-].[Na+]>C1COCC1>[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH:20]([NH2:21])[CH3:1])=[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:12]=2)[CH:7]=[CH:6]1
Reactant: Cn1ccc2nc(C#N)c(N3CCOCC3)cc21
Reactant: C[Mg]Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methylmagnesium bromide (3.0 M in THF, 0.60 mL, 1.8 mmol) was added to a stirred solution of 1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (145 mg, 0.60 mmol) in dry THF (6 mL) at RT. The reaction mixture was stirred for 1 h, then cooled to 0° C. and quenched with MeOH (5 mL). Sodium borohydride (45 mg, 1.2 mmol) was added. The reaction mixture was stirred for 20 minutes, quenched with 1N HCl (1.5 mL), and stirred for an additional 20 minutes. Next, the solution was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (6×). The organic layers were combined, dried over MgSO4, and concentrated to give the title compound as a yellow oil (83%). 1H NMR (500 MHz, CD3OD) δ ppm 7.83 (s, 1H), 7.46 (d, 1H, J=3.5 Hz), 6.56 (d, 1H, J=3.5 Hz), 4.97 (q, 1H, J=7.0 Hz), 3.83-3.90 (m, 4H), 3.84 (s, 3H), 3.01-3.07 (m, 2H), 2.88-2.94 (m, 2H), 1.54 (d, 3H, J=7.0 Hz); ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([OH:19])(=[O:9])=[O:18].[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred and cooled (ice-water bath) mixture of 14.1 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethylethananmine and 195 parts of dichloromethane are added dropwise 7.8 parts of methanesulfonyl chloride. Upon completion, stirring is continued first for 15 minutes while still cooling an further for 1 hour at reflux temperature. The dichloromethane is evaporated and the residue is dissolved in 4-methyl-2-pentanone and water while heating. The layers are separated and the organic phase is stirred with 100 parts of water, while cooling in an ice-bath. The precipitated product is filtered off and dried, yielding 10 parts (53%) of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate; mp. 140° C.
Reaction SMILES: [N:1](OCCC(C)C)=[O:2].[C:9]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=O.Cl.N([O-])=O>CO>[C:9]1(=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[N:1][OH:2]
Reactant: O=C1Cc2ccccc2C1=O
Reactant: CC(C)CCON=O
Agent: Cl
Agent: O=N[O-]
Solvent: CO
Product: O=C1C(=NO)Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
Isoamyl nitrite (15 ml, 108 mmol) was added to a solution of indan-1,2-dione (12 g, 90 mmol) in MeOH (380 ml) at 45° C. followed by concentrated HCl (12 ml) dropwise over 5 minutes. The reaction mixture was stirred for 3 hours at room temperature. Excess isoaamyl nitrite (1 ml) and concentrated HCl (1 ml) was added and the suspension stirred for a further 15 minutes. On cooling to room temperature a white precipitate formed. The precipitate was filtered off and washed with cold MeOH (40 ml) followed by Et2O (40 ml) to afford indan-1,2-dione-2-oxime (6.2 g, 43%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl([O-])=[O:14].[Na+].O1CCOCC1.S(=O)(=O)(O)N>O>[F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: O=Cc1cccc([N+](=O)[O-])c1F
Reactant: [O-][Cl+][O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
In a round bottom flask, 2-fluoro-3-nitro-benzaldehyde (15, 1.02 g, 6.03 mmol) is combined with sodium chlorite (1.26 g, 11.15 mmol), 60 mL of 1,4-dioxane, 20 mL of water, and sulfamic acid (4.47 g, 46.0 mmol) and the reaction is stirred at room temperature for 30 minutes. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with water, then brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is purified on column chromatography, eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum, then suspended in dichloromethane. The resulting solid is collected by filtration to provide the desired compound (16, 151 mg). MS (ESI)[M−H+]−=184.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:41][N:42]([CH3:51])[C:43](=[O:50])[CH2:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1>[Cu]I>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:47]3[CH2:48][CH2:49][CH:45]([CH2:44][C:43]([N:42]([CH3:41])[CH3:51])=[O:50])[CH2:46]3)[CH:3]=2)[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Reactant: CN(C)C(=O)CC1CCNC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Product: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(N3CCC(CC(=O)N(C)C)C3)cc12
Yield: 21.4 %

Procedure:
A microwave reaction vial was charged with 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (347 mg, 0.8 mmol), copper(I)-iodide (31 mg, 0.067 mmol), proline (37 mg, 0.13 mmol), potassium carbonate (332 mg, 1.6 mmol) and N,N-dimethyl-2-pyrrolidin-3-yl-acetamide (250 mg, 1.6 mmol) obtained from step 1. The vial was flushed with nitrogen and dimethylsulfoxide (2.0 ml) was added. The reaction tube was sealed irradiated in the microwave to 140° C. for 1 hour. The crude was partitioned between ethyl acetate (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (10 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give 87 mg (30%) of 2-{1-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrrolidin-3-yl}-N,N-dimethyl-acetamide as a yellowish oil. MS: m/z 509.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:17])=[C:11]2[N:10]=[CH:9][C:8]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20]
Reactant: O=C(O)c1cnn2c(NCc3cccc(Cl)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3cccc(Cl)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 22 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-chlorobenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.16 mmol) obtained in step 2 and methanesulfonamide (0.08 g, 0.82 mmol), the title compound (0.02 g, 22%) was obtained.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([O:43][C:44]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:46]1[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:44]([O:43][CH:40]2[CH2:41][CH2:42]2)[CH:45]=1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CC1
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Yield: 65.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 400 mg (1.07 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 468 mg (1.61 mmol) of 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(e) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 322 mg of the title compound was obtained as a pale yellowish solid. (Yield: 65%)
Reaction SMILES: [CH3:1][N:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].B(F)(F)F.CCOCC.[Li]CCCC.[Sn:29](Cl)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:30][Sn:29]([CH3:32])([CH3:31])[C:5]1[C-:4]([N:2]([CH3:3])[CH3:1])[CH:8]=[CH:7][CH:6]=1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: CN(C)[c-]1cccc1
Reactant: C[Sn](C)(C)Cl
Agent: [Fe+2]
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)[c-]1cccc1[Sn](C)(C)C
Yield: 90.8 %

Procedure:
A solution of 11 (300 mg, 1.31 mmol) in THF (13 mL) was sequentially treated with BF3.OEt2 (0.17 mL, 1.37 mmol), n-BuLi (0.59 mL, 2.45 M, 1.44 mmol) and Me3SnCl (1.57 mL, 1.57 mmol). Standard workup followed by column chromatography (basic alumina, hexanes) gave 12h (466 mg, 91%) as an orange oil; IR (KBr, neat) vmax 3093, 2980, 2940, 2910, 2825, 2775 cm−1; 1H NMR (300 MHz, CDCl3) 4.16 (s, 6H), 4.06 (m, 1H), 3.81 (m, 1H), 2.59 (s, 6H), 0.32 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) 120.2, 70.9, 67.8, 66.4, 60.4, 58.0, 45.1, −7.6 ppm; EIMS [m/z (%)] 393 (M+, 100), 348 (88); HRMS (EI) calcd for C15H23N118Sn56Fe: 391.0198. Found 391.0194.
Reaction SMILES: C(=O)C1C=CC=CC=1.C(C1C=C(C=CC=1)C[NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34])#N.C(C1C=C(C=CC=1)CNC1C=C2C(=CC=1)N=C(N1C=C(C(O)=O)C=N1)NC2=O)(=O)N>>[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34]
Reactant: N#Cc1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1
Agent: NC(=O)c1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1
Solvent: O=Cc1ccccc1
Product: Nc1ccc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 171, substituting 3-cyanobenzaldehyde for benzaldehyde in step A. Step C yielded a mixture of 1-[6-(3-cyano-benzylamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, 1-[6-(3-carbamoyl-benzylamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, and the titled compound. The mixture was separated by reverse-phase HPLC; the titled compound was recovered as the trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O.S(Cl)([Cl:19])=O.O.C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(C)c1-c1cccc(CCl)c1

Procedure:
To 3-(2,6-dimethylphenyl)benzyl alcohol (51.9 g) synthesized according to a method described in [WO 2004/041266 pamphlet, (Reference Example 200)], thionyl chloride (130 mL) was gradually added and the resultant reaction mixture was heated under reflux for 3 hours. The reaction mixture was gradually dropped into ice-cooled methanol (inside temperature: 15° C. or less) and the resultant reaction mixture was adjusted to around pH 8 with saturated sodium bicarbonate water, followed by extracting the reaction mixture with ethyl acetate. The resultant organic phase was washed sequentially with a saturated aqueous sodium bicarbonate, water, and saturated saline, and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluate: n-hexane:ethyl acetate=70:1) to obtain the subject compound (36.1 g) as a colorless oil.