Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[O:38]1[C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=[N:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:44][CH2:43][C:42]1[O:38][N:39]=[CH:40][CH:41]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1ccno1
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccno2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-isoxazol-5-yl-methylamine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[N:23]=[C:22]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:32])[N:21]=1>CN(C=O)C>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)=[N:21][C:22]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[O:32])=[N:23]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cc1)c1nc(Cl)c2ccc(F)cc2n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cc3)nc3cc(F)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A solution of 5-methyl-1H-pyrazol-3-amine (13 mg, 0.13 mmol), potassium iodide (15 mg, 0.088 mmol), and DIEA (0.016 mL, 0.088 mmol) in DMF (2 mL) was added to (4-chloro-7-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.027 mg, 0.088 mmol). The resulting solution was stirred at rt overnight and then purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O) to give (7-fluoro-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)(4-fluorophenyl)methanone (10 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 6.48 (s, 1H), 7.36 (t, 2H), 7.60 (m, 2H), 8.09 (m, 2H), 8.29 (t, 1H), 10.78 (s, 1H), 12.23 (s, 1H); LC-MS (ESI) m/z 366 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:18]([N:19](C)[C:20](=O)C)=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[N:24](C)[C:25](=O)C>CS(C)=O>[Cl:8][C:9]1[C:18]([NH:19][CH3:20])=[CH:17][C:12]([C:13](=[O:14])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])=[CH:11][C:10]=1[NH:24][CH3:25]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C(C)=O)c(Cl)c(N(C)C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(C(=O)CS(C)(=O)=O)cc(NC)c1Cl
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A suspension of 3.8 g. of sodium hydride (50% suspension in oil) and 11.2 g of dimethylsulfone in 40 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. 9.4 G. of methyl 4-chloro-3,5-bis-(N-methylacetamido)benzoate were then added, and the mixture was stirred at 80° C. for 3 hours. The solution was diluted with 200 ml. of ice water, the precipitated material extracted with ethyl acetate, the ethyl acetate solution purified over aluminum oxide, evaporated and the residue recrystallized from methanol, there being obtained 4'-chloro-3',5'-bis(methylamino)-2-methylsulfonylacetophenone having a melting point of 165°-167° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:37])=[C:33](F)[N:34]=3)[C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([C:33]4[N:34]=[C:35]5[C:30]([C:29](=[O:38])[C:28]([C:39]([OH:41])=[O:40])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:37])[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCNCC3)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(F)c(F)cc2c1=O
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCN(c2nc4c(cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI) AP+, 550. NMR (DMSO6)1.1 (m, 2H), 1.22 (m, 2H), 1.74 (s, 3H), 3.04 (m, 4H), 3.3 (m, 6H), 3.70 (m, 2H), 4.0 (m, 2H), 4.65 (m, 1H), 7.13 (d, 1H), 7.26 (dd, 1H), 7.35 (d, 1H), 8.0 (d, 1H), 8.14 (t, 1H), 8.52 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15](Br)[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:25]([OH:27])[CH3:26]>>[C:1]1([CH2:7][CH2:8][O:9][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([O:27][CH2:25][CH3:26])[N:16]3[CH2:19][CH3:20])=[C:12]([NH2:22])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CCn1c(Br)nc2c(N)nc(OCCc3ccccc3)nc21
Agent: [Na+]
Agent: [OH-]
Product: CCOc1nc2c(N)nc(OCCc3ccccc3)nc2n1CC
Temperature: 85 °C
Yield: 52 %

Procedure:
To a suspension of 2-(2-phenylethoxy)-8-bromo-9-ethyl-9H-purin-6-ylamine (145 mg, 0.4 mmol) and dry NaOH (80 mg, 2.0 mmol) was added ethanol (25 mL). This mixture was heated at 85° C. for 7 hours. The solvent was removed under reduced pressure and the residue was neutralized with 2N HCl and extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was recrystallized from acetonitrile to give 2-(2-phenylethoxy)-8-ethoxy-9-ethyl-9H-purin-6-ylamine (68 mg, 52%) as a white solid: mp 161–164° C.; 1H NMR (Me2SO-d6) δ 1.26 (t, 3H, J=7.1 Hz, OCH2CH3), 1.33 (t, 3H, J=7.0 Hz, NCH2CH3), 3.00 (t, 2H, J=6.9 Hz, CH2CH2Ph), 3.88 (q, 2H, J=7.1 Hz, OCH2CH3), 4.38 (t, 2H, J=6.9 Hz, CH2CH2Ph), 4.48 (q, 2H, J=7.0 Hz, NCH2CH3), 6.79 (s, 2H, NH2), 7.18–7.36 (m, 5H, H-Ph). Anal. (C17H21N5O2) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:18])[CH3:17]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromophenol (25 g, 0.145 mol) in 100 ml of chloroform was added at 0° C. with triethylamine (20.1 ml) and acetic anhydride (16.4 ml) stirring at room temperature for 2 h. After that the mixture was washed with a 0.2M HCl solution, dried and the solvent was evaporated off under reduced pressure, thereby obtaining the title compound as a colourless oil (quantitative yield).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(S(C)(=O)=O)C3)ccc1OCC2
Temperature: 0 °C
Yield: 63.9 %

Procedure:
An ice-cooled solution of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (0.16 g, 0.46 mmol) in DCM (5 mL) was treated with triethylamine (0.14 mL, 1.0 mmol) then methanesulfonyl chloride (40 L, 0.51 mmol) and the mixture stirred at RT for 2 h. The reaction mixture was washed with water and the aqueous layer extracted with DCM, the combined organic extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 100% ethyl acetate in cyclohexane) to give 148 as a white solid (126 mg, 64%). 1H NMR (400 MHz, CDCl3): δ 7.95 (d, J=2.49 Hz, 2H); 7.31 (dd, J=8.35, 2.29 Hz, 1H); 7.21 (d, J=8.32 Hz, 1H); 6.89 (s, 1H); 5.75-5.66 (m, 1H); 4.56 (t, J=5.89 Hz, 2H); 4.32 (t, J=8.24 Hz, 2H); 4.12 (t, J=7.34 Hz, 2H); 3.92-3.82 (m, 1H); 3.20 (t, J=5.89 Hz, 2H); 2.93 (s, 3H); 1.62 (d, 6H). LCMS: RT=9.68 min, M+H+=429
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][N:26]([S:32]([CH3:31])(=[O:34])=[O:33])[C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide (synthesized according to general procedure M, 13 mg, 0.029 mmol), MeSO2Cl (5 mg, 0.04 mmol), and pyridine (500 μL). The reaction was stirred for 1 hour. The solvent was subsequently removed in vacuo and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4-methanesulfonyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 524.1, found 524.0.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1[C:16]([Cl:17])=[N:15][C:13](Cl)=[N:12][C:10]=1[Cl:11]>C1COCC1>[Cl:11][C:10]1[N:9]=[C:16]([Cl:17])[N:15]=[C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylmagnesium bromide (97.6 ml of a 1.0 M solution in THF, 97.6 mmol, 1.0 equiv) was added dropwise to a THF (8 mL) solution of cyanuric chloride (18.0 g, 97.6 mmol, 1.0 equiv) at 0° C. The reaction mixture was stirred at room temperature for 1 h and was poured onto ice and stirred for 30 min. The product was extracted with ethyl acetate, and the combined organic layers were washed with (sat.) sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 16 g the title compound. The crude product was carried forward without purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[C:28]([O:34][CH2:35][C:36]([NH2:38])=[S:37])(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[C:16](=[O:26])[N:15]([CH3:27])[C:9]3[N:10]([CH3:14])[C:11]4[C:7]([C:8]=3[CH:18]=2)=[CH:6][C:5]([C:3]2[N:38]=[C:36]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[S:37][CH:2]=2)=[CH:13][CH:12]=4)=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 8 above, using compound A, 6-(2-bromo-acetyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-amino-2-thioxoethyl pivalate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
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: [Na+]
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1 H), 8.66-8.56 (m, 2 H), 8.06-7.94 (m, 2 H), 7.78 (t, J=7.2 Hz, 1 H), 7.66-7.56 (m, 3 H), 7.30-7.18 (m, 4 H), 6.98-6.88 (m, 3 H), 5.36 (s, 2 H), 1.36 (s, 6 H). MS: M+H: m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([O:31]C)[CH:16]=2)[CH2:6][CH2:5][CH2:4]1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:34][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:33])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[C:17]([OH:31])[CH:16]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc(C(=O)N2CCCC(N(C)C)c3ccccc32)ccc1NC(=O)c1ccccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
A solution of 5-dimethylamino-1-[3-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g) in dichloromethane (30 ml) is added dropwise to a solution of 1M boron tribromide in dichloromethane (5.46 ml) at -45° C. After completion of the dropping, the mixture is stirred for 1 day while the temperature of the reaction mixture is gradually raised to room temperature. To the reaction solution is added water and the mixture is neutralized with sodium hydrogen carbonate, and extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform:methanol=500:1), and recrystallized from methanol/diethyl ether to give 5-dimethylamino-1-[3-hydroxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.33 g) as white powder, m.p. 201.5-202.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2].[C:16]([O:20][C:21](=[O:28])[NH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:25]2[CH2:26][CH2:27][C@H:23]([NH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:28])[CH2:24]2)=[C:7]([F:13])[C:6]=1[F:14])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1F
Yield: 74.5 %

Procedure:
A solution of 2,3,4,5-tetrafluorobenzoic acid ethyl ester (Example 1a, 4.03 g, 18.1 mmol), (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.02 g, 21.6 mmol) (Sanchez J. P., Domagala J. M., Heifetz C. L., Priebe S. R., Sesnie J. A., Trehan A. K., J. Med. Chem., 1992; 35(10):1764–1773), and triethylamine (18.0 mL, 129 mmol) in acetonitrile (50 mL) is heated at 50° C. under a nitrogen atmosphere for 4.5 hours. The yellow solution is concentrated in vacuo and poured into a saturated NaHCO3 solution. The mixture is then extracted with chloroform, and the combined organic extracts are washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting residue is then purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound (5.24 g). 1H NMR (CDCl3): δ 7.35 (ddd, 1H), 4.70–4.65 (bs, 1H), 4.42–4.20 (m, 3H), 3.90–3.62 (m, 3H), 3.58–3.42 (m, 1H), 2.28–2.03 (m, 1H), 1.99–1.80 (m, 1H), 1.46 (s, 9H), 1.37 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([O:24]CC)=[O:23])=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1CCCOc1cccnc1Oc1cccc(Cl)c1
Yield: 97.4 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-ethoxycarbonylpyridin-4-yl)propoxy]pyridine (1.0 g, 2.4 mmol) obtained in Example 23 is dissolved in methanol (50 ml), and thereto is added a 1M aqueous sodium hydroxide solution (3.0 ml), and the mixture is heated under reflux for 2 hours. The methanol is evaporated under reduced pressure, and the pH value of the residue is adjusted to pH 4 with a 1M aqueous hydrochloric acid solution, and the mixture is extracted with chloroform/tetrahydrofuran (1:1) (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ethanol/diethyl ether to give the title compound (0.9 g) as colorless crystals, m.p. 142-144° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([CH3:19])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:21]2=[O:23])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(C)cccc2c1=O
Yield: 91.3 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide (1.71 g, 5.36 mmol) and triphosgene (2.07 g, 6.96 mmol) in THF (20 mL) was heated at reflux for 1 h. The mixture was cooled on an ice-water bath and treated with saturated aqueous NaHCO3. Stirring was continued until gas evolution ceased. The resulting mixture was extracted 3 times with DCM. The combined organic phases were washed with water, dried and concentrated. The residue was triturated with ether to give a white solid, collected by filtration. A second trituration of the concentrated filtrate gave additional solid, collected by filtration. The filtrate from this was concentrated and purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to provide additional solid. The three solids were combined to provide 3-(3-bromo-2-methylphenyl)-8-methylquinazoline-2,4(1H,3H)-dione as a white solid (1.69 g, 91% yield). Mass spectrum m/z 345, 347 (M+H)+. 1H NMR (400 MHz, chloroform-d): δ 8.07 (d, J=7.9 Hz, 1H), 7.70 (dd, J=7.9, 1.3 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H), 7.27-7.17 (m, 3H), 2.41 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:11]1[CH2:22][CH2:21][CH2:20][C@H:12]1[C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14]
Reactant: [H][H]
Reactant: NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)CNC(=O)[C@@H]1CCCN1

Procedure:
A mixture consisting of 33.5 g. of N-benzyloxycarbonyl-L-prolylglycinamide (this compound has been reported in Synthetic Peptides, Vol. 1, G. R. Pettit, Van Nostrand Reinhold Company, New York, 1970, page 151), 1 g. of 20% palladium-on-carbon, and 500 ml. of methanol is hydrogenated at 50 lbs./in.2 hydrogen pressure and room temperature for one hour. The mixture is filtered to remove the catalyst, and the filtrate is evaporated to dryness to give a solid residue of L-prolylglycinamide; m.p. 124°-127° C., following crystallization from acetonitrile-toluene; [α]D25 -48.5° (2% in water).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:53]=[CH:54][CH:55]=1)[CH2:12][N:13]1[CH:17]=[C:16]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[C:24]([C:27]4[CH:28]=[CH:29][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH2:39][C@@H:40]([OH:42])[CH3:41])[CH2:35][CH2:34]5)=[N:31][CH:32]=4)[CH:25]=3)[N:20]([S:43]([C:46]3[CH:52]=[CH:51][C:49]([CH3:50])=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH:19]=2)[CH:15]=[N:14]1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[OH:42][C@@H:40]([CH3:41])[CH2:39][N:36]1[CH2:37][CH2:38][N:33]([C:30]2[N:31]=[CH:32][C:27]([C:24]3[CH:25]=[C:26]4[C:18]([C:16]5[CH:15]=[N:14][N:13]([CH2:12][C:11]6[CH:10]=[C:9]([OH:8])[CH:55]=[CH:54][CH:53]=6)[CH:17]=5)=[CH:19][N:20]([S:43]([C:46]5[CH:47]=[CH:48][C:49]([CH3:50])=[CH:51][CH:52]=5)(=[O:44])=[O:45])[C:21]4=[N:22][CH:23]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(O)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
To the solution of (S)-1-(4-(5-(3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (200 mg, 0265 mmol) in toluene/TFA (10/5 mL) was heated at 100° C. for 16 hours and distilled out the solvent. This was basified with triethylamine and distilled out the solvent to get 180 mg (crude) of the titled compound. MS: m/z=664.2 (M+1).
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:10][OH:11].N1C=CC=CC=1>C(O)C>[CH:1]1([CH:7]=[N:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=CC1CCCCC1

Procedure:
A solution of cyclohexanecarboxaldehyde (11.2 g, 100 mmol), hydroxylamine hydrochloride (7.2 g, 104 mmol) and pyridine (8.5 mL) in ethanol (150 mL) was stirred for 18 hours, then concentrated in vacuo. The residue was taken up in 10% aqueous citric acid and extracted with ethyl acetate (3×150 mL). The organics were combined, dried over MgSO4 and concentrated to afford cyclohexanecarboxaldehyde oxime which was used directly in the next step.