Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=O)(C)(C)C.[C:25]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH2:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of (S)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (300 mg, 0.82 mmol) in 1,4-dioxane (2.5 mL) was treated with dioxane. HCl (5 mL) and the solution was stirred at rt 1 h. The solvent was reduced in vacuo to afford a residue which was then dissolved in water (5 mL). The aqueous solution was treated with solid Na2CO3 and the aqueous solution was extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, concentrated in vacuo to yield titled intermediate (217 mg, 92%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.36-7.26 (m, 5H), 5.13 (s, 2H), 4.20-3.82 (m, 2H), 2.94-2.60 (m, 5H), 1.94-1.92 (m, 1H), 1.69-1.68 (m, 1H), 1.47-1.28 (m, 3H), 1.09 (t, J=6.8 Hz, 3H). ES-MS: m/z [M+1]=263.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:11]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:10][C:9](=[O:20])[NH:8][C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[OH:38][C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:2]2[N:3]=[C:4]3[N:11]([CH2:12][CH2:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][C:9](=[O:20])[NH:8][C:5]3=[N:6][CH:7]=2)=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: O=C1CN(CCC2CCOCC2)c2nc(Br)cnc2N1
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(-c2cnc3c(n2)N(CCC2CCOCC2)CC(=O)N3)cc1
Temperature: 120 °C
Yield: 25.9 %

Procedure:
6-Bromo-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.250 g, 0.733 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (0.192 g, 0.733 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (0.030 g, 0.037 mmol) were combined in dimethylformamide (1.0 mL). Sodium carbonate (0.311 g, 2.93 mmol) in water (0.2 mL) was added and the reaction solution was then heated in a Biotage Emrys Optimizer microwave reactor at 120° C. for 15 min. The cooled reaction solution was filtered through Celite and the filter cake was washed with ethyl acetate. Filtrate and ethyl acetate wash were combined and solvent removed under reduced pressure. The resulting material was purified using Biotage column chromatography (0-5% methanol in ethyl acetate) followed by trituration with dimethylformamide and water to afford the title compound (0.074 g, 0.19 mmol, 25%) 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.39 Hz, 2H), 7.53 (d, J=8.39 Hz, 1H), 5.04 (s, 1H), 4.16 (s, 1H), 3.82 (dd, J=11.1, 2.39 Hz, 2H), 3.61 (t, J=7.59 Hz, 2H), 3.25 (t, J=9.59 Hz, 3H), 1.70 (s, 1H), 1.66 (s, 1H), 1.58 (m, 3H), 1.44 (s, 6H), 1.25 (m, 2H); MS (ESI) m/z 397.2 [M+1]+; mp 210-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (264 mg, 0.786 mmol), in 3.0 mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed by bistrimethyl-silyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 55 mg (21%) of the title compound as an orange solid. mp 205°-206°. FDMS m/e=334. α[D]589 =+57.23 (c=0.66, chloroform).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[N+:35]([C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1)([O-:37])=[O:36]>C(Cl)Cl>[N:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([CH2:15][CH2:16][C:17](=[O:19])[S:44][C:41]3[CH:42]=[CH:43][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=3)=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCC(=O)N1CCC(N2CCCCC2)CC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCC(N2CCCCC2)CC1)Sc1ccc([N+](=O)[O-])cc1
Temperature: 4 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
3-(4-Piperidinopiperidinocarbonyl)propionic acid (0.26 g, 0.97 mmol) and DCC (0.25 g, 1.2 mmol) were dissolved in methylene chloride, followed by the addition of 4-nitrothiophenol (0.23 g, 1.2 mmol). The resulting mixture was stirred for 16 hours at 4° C. and then overnight at room temperature. The reaction mixture was filtered. After the filtrate was concentrated, the residue was purified by chromatography on a silica gel column (chloroform-acetone mixed solvent [10:1→5:1], whereby S-4-nitrophenyl 3-(4-piperidinopiperidinocarbonyl)propanethioate (196 mg, 50%) was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:30])[C:12]([CH2:27][CH2:28][CH3:29])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[O:14]2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:30])[C:12]([CH2:27][CH2:28][CH3:29])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=3)[O:14]2)=[CH:9][CH:8]=1)=[O:4]
Reactant: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(N)ccc2c1=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCCc1c(-c2ccc(C(=O)OC)cc2)oc2cc(NC(=O)CCl)ccc2c1=O
Yield: 80 %

Procedure:
8 cc of chloroacetyl chloride are added, with stirring, to a mixture consisting of 9.5 g of methyl 7-amino-3-propyl-4'-flavonecarboxylate made according to Example 7a, 1 liter of benzene and 9 g of anhydrous K2CO3. The mixture is heated to reflux of the benzene for 2 hours, then cooled. The benzene phase is washed with water. A precipitate is formed which is filtered and dissolved in chloroform. The benzene and chloroform phases are evaporated. Methyl 7-(2-chloracetamido)-3-propyl-4'-flavonecarboxylate is obtained with a yield of 80%. MP=162° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]>O1CCOCC1>[CH3:9][O:10][C:11]([C:13]1([N:18]([CH:20]=[O:21])[CH3:19])[CH2:17][CH2:16][N:15]([CH2:23][C:24](=[O:25])[N:26]2[CH2:27][CH:28]=[C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[N:39]=[CH:40][CH:41]=[CH:42][N:43]=4)=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)[CH2:14]1)=[O:12]
Reactant: COC(=O)C1(N(C)C=O)CCNC1
Reactant: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1(N(C)C=O)CCN(CC(=O)N2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1

Procedure:
Added triethylamine (0.3 ml, 2.15 mmol) to a solution of (3-(Formyl-methyl-amino)-pyrrolidine-3-carboxylic acid methyl ester, Hydrochloride.(4T) (90 mg, 0.405 mmol) and 2-Chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-ethanone (140 mg, 0.447 mmol) in dioxane (5 ml) at room temperature, then stirred at 90° C. for 5 hours. The reaction was cooled and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 7% MeOH/MeCl2 containing 2% NH4OH yielding 5T as a white solid (100 mg, 53%) ESMS (MH 464).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Cc1cccc(Cl)c1N
Reactant: S=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1N=C=S
Yield: 27.2 %

Procedure:
The title compound was prepared following the procedure described for Intermediate-2 using 2-chloro-6-methylaniline (1.0 g, 0.01 mol), thiophosgene (1.15 g, 0.01 mol) and N-ethyl di-isopropyl amine (2.58 g, 0.020 mol) to afford 0.500 g of the desired product. 1HNMR (CDCl3): δ 2.39 (s, 3H), 7.10 (s, 2H), 7.21-7.25 (m, 1H); MS [M+H]+: 183.32.
Reaction SMILES: FC(F)(F)C1C=C(N[C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Br:22])[N:12]=2)=[O:10])NN=1.C[O:26][C:27]([C:29]1[N:33]=[C:32]([NH2:34])[NH:31][N:30]=1)=[O:28]>>[NH2:17][C:16]1[C:11]([C:9]([NH:34][C:32]2[NH:31][N:30]=[C:29]([C:27]([OH:26])=[O:28])[N:33]=2)=[O:10])=[N:12][C:13]([Br:22])=[C:14]([C:18]([F:19])([F:21])[F:20])[N:15]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Reactant: COC(=O)c1n[nH]c(N)n1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1nc(C(=O)O)n[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) by replacing 3-(trifluoromethyl)-1H-pyrazol-5-amine with 5-amino-1H-[1,2,4]triazole-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][C:4]([C:10]([F:11])([F:12])[F:13])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid BB4a (837 mg, 4.3 mmol) is dissolved in anhydrous tetrahydrofurane (10 mL), then LiAlH4 (2.16 mL of 2.0 M in tetrahydrofurane, 4.3 mmol) is added dropwise and stirred at rt for 1 h. The mixture is quenched by dropwise addition of 1N HCl, then is made basic by addition of saturated NaHCO3 and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried (MgSO4), filtered and concentrated to provide (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol BB4b as a clear oil. 1H NMR (400 MHz, CDCl3) δ=6.46 (s, 1H), 4.69 (d, J=5.6 Hz, 2H), 3.95 (s, 3H); MS calcd. for C6H8F3N2O ([M+H]+): 181.0, found: 181.1.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:13][C:14]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:15]=1[C:16](OCC)=[O:17]>>[NH2:13][C:14]1[CH:24]=[C:23]([Cl:25])[C:22]([O:26][CH3:27])=[CH:21][C:15]=1[C:16](=[O:17])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CN(C)S(C)(=O)=O
Reactant: CCOC(=O)c1cc(OC)c(Cl)cc1N
Agent: [Li]CCCC
Product: COc1cc(C(=O)CS(=O)(=O)N(C)C)c(N)cc1Cl

Procedure:
In a similar manner to tht described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product reacted with ethyl 2-amino-4-chloro-5-methoxybenzoate to give the novel compound 1-(2-amino-4-chloro-5-methoxyphenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 59°-62°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(#N)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
4-Methylpiperidine (0.17 ml, 1.48 mmol), ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol), and TEA (0.21 ml, 1.48 mmol) were dissolved in acetonitrile (6 ml) and stirred at room temperature for 48 hours. The volatiles were evaporated and the crude residue was purified by flash chromatography (petroleum ether/AcOEt=95/5) to obtain ethyl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (225 mg, 69.8% yield) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](O)=O)([O-])=O.[CH2:14]([N:17]1[C:24]([NH2:25])=[C:23]([N:26]=O)[C:21](=[O:22])[N:20]([CH2:28][CH2:29][CH3:30])[C:18]1=[O:19])[CH2:15][CH3:16].C(N=C=NC(C)C)(C)C>CO>[CH2:28]([N:20]1[C:21](=[O:22])[C:23]2[NH:26][C:6]([C:5]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:4]=3[NH2:1])=[N:25][C:24]=2[N:17]([CH2:14][CH2:15][CH3:16])[C:18]1=[O:19])[CH2:29][CH3:30]
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Agent: CC(C)N=C=NC(C)C
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(CCC)c1=O
Yield: 2.1 %

Procedure:
1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine was synthesized by a modification of the method of Pfleiderer and Kempter (Ang. Int. Ed. 6:259-260, 1967). 2-nitro-4-chlorobenzoic acid (0.02 mol) was dissolved in 30 ml of methanol. 1,3-dipropyl-5-nitroso-6-aminouracil (0.01 mol) was added with stirring, followed by 0.2 mol diisopropylcarbodiimide (DICD).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[CH3:26])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (583 mg) in DMF (6 mL) was added potassium carbonate powder (900 mg) and 2-methylbenzyl bromide (1.2 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by washing solid with hexanes to yield the title compound as a tan solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:31][CH3:32])[C:4]([N:6]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:10][CH:9]=1)=[O:5].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([NH:2][C@H:3]([CH2:31][CH3:32])[C:4]([N:6]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[CH:12][CH:13]=1)=[O:5])=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC[C@@H](N)C(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared as in Example 1, Step N from (R)-2-amino-N-phenyl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]butanamide, hydrochloride and 3-t-butoxycarbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O.Cl>C(Cl)Cl>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
52 was prepared according to the method of Synth. Comm. 26(12), 2257-2272 (1996). To a nitrogen purged flask was charged 2-chloro-nicotinic acid (1000.0 g, 6.0 moles, 1.0 eq) followed by 9 L methylene chloride. To this was added thionyl chloride (1.4 L, 19.7 moles, 3.2 eq.) and the reaction was heated to 40° C. with vigorous stirring under nitrogen overnight. The acid chloride solution was cooled in an ice bath and methanol (3 L, 74 moles, 12 eq.) was slowly added while keeping the temperature at 20° C. The rate limiting parameter is the vigorous evolution of copious quantities of HCl gas. After the addition, HPLC analysis [Tret starting material=7.5 min, Tret 52=11 min] showed the product had formed immediately. The volatiles were removed in vacuo and the residue extracted from 10% Na2CO3 with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated to a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C([Mg]Cl)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH:21]=[O:22].[NH4+].[Cl-]>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]([OH:22])[C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[O:10][CH3:11])[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc(C#N)ccc1Br
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1C(O)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of 4-bromo-3-methoxybenzonitrile (606 mg, 2.86 mmol) in dry THF (10 mL) was added iso-propylmagnesium chloride (2 M in diethylether, 1.54 mL, 3.09 mmol) slowly via microsyringe. To the reaction mixture was added 3,4-dichlorobenzaldehyde (270 mg, 1.54 mmol) in dry THF (1 mL) via syringe. After 1 hour at room temperature saturated aqueous NH4Cl (20 mL) was added and the mixture extracted with EtOAc (3×20 mL). The combined organics were concentrated in vacuo and taken through to the next step as crude.
Reaction SMILES: O/[CH:2]=[C:3](/[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)\[C:4]([O:6]C)=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)(C)C>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][C:3]2[C:4](=[O:6])[NH:17][C:18](=[S:19])[NH:20][CH:2]=2)=[CH:14][N:13]=1
Reactant: NC(N)=S
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Solvent: CC(C)O
Product: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Temperature: 83 °C
Yield: 39.8 %

Procedure:
A mixture of (Z)-methyl 3-hydroxy-2-((2-methoxypyrimidin-5-yl)methyl)acrylate (10 g, 42.0 mmol) and thiourea (6.39 g, 84 mmol) in isopropanol (200 mL) was heated at 83° C. overnight. After removing the solvent, the residue was dissolved in water, washed with diethyl ether twice and acidified with AcOH to pH=4.5. The resulting solid was filtered and concentrated in vacuo to afford the title compound (4.4 g, 16.70 mmol, 39.8% yield) as yellow solid. LCMS: rt=1.31 min, [M+H+]=251
Reaction SMILES: [F: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]>>[F: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(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3cccc(F)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-fluorobenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.09 g, 0.18 mmol) obtained in step 2 and methanesulfonamide (0.1 g, 1.08 mmol), compound a-6 (0.06 g, 64%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:21]=2[CH3:36])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C1C=[N:41]C2N(O)N=NC=2C=1.[OH-].[NH4+].C(Cl)CCl>C1COCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:22]2[C:21]([CH3:36])=[C:20]([C:7]3[C:8]4[C:9]5[C:14](=[CH:13][C:12]([C:17]([NH2:41])=[O:18])=[CH:11][CH:10]=5)[NH:15][C:16]=4[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=3)[CH:25]=[CH:24][CH:23]=2)=[O:35])=[CH:33][CH:32]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Reactant: On1nnc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(N)=O)ccc3c12
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 32.2 %

Procedure:
A mixture of 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid (Example 23-1, 30 mg, 0.062 mmol) and HOAT (12.72 mg, 0.093 mmol) in THF (0.4 mL) was treated with 28% aqueous ammonium hydroxide (0.052 mL, 0.374 mmol) and EDC (23.89 mg, 0.125 mmol) and the mixture was stirred at rt. After 22.5 h, the mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was treated with NaHCO3 (aq) and extracted three times with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1,7-dicarboxamide as an off-white solid (9.6 mg, 29%). 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J=1.3 Hz, 1H) 8.03-8.08 (m, 2H) 8.01 (d, J=7.9 Hz, 1H) 7.51-7.55 (m, 1H) 7.41-7.48 (m, 2H) 7.29 (dd, J=7.5, 1.3 Hz, 1H) 7.24 (t, J=8.8 Hz, 2H) 7.08-7.12 (m, 2H) 1.98 (s, 3H). Mass spectrum m/z 481.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][PH:10](=[O:12])[CH3:11].CC#N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([P:10](=[O:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[PH](C)=O
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CP(C)(=O)c1ccc(Br)cc1
Yield: 25.7 %

Procedure:
A solution of 1,4-dibromobenzene (2.35 g, 10 mmol), dimethylphosphine oxide (0.78 g, 10 mmol), and tetrakis(triphenylphosphine) palladium (0) (0.5 g) in nitrogen-purged CH3CN (20 mL) and triethylamine (5 mL) was heated at reflux for overnight. Then, the reaction mixture was concentrated and the residue was chromatographed on silica gel (0˜20 percent MeOH/DCM) to afford the product (600 mg, 26%) as a colorless solid; 1H NMR (CD3OD): δ 7.80-7.70 (m, 4H), 1.75 (d, 6H).