Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH:36]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=[C:32]1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[CH3:7])[CH:31]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3ccccc3o2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)Nc2cc(-c3cc4ccccc4o3)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 2.8 mL of methylene chloride and 0.36 mL of triethylamine containing 50 mg of tert-butyl 2-amino-4-(benzofuran-2-yl)benzoate and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzofuran-2-yl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1.[CH3:15][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=[O:8])[CH:7]=1
Reactant: CCOC(=O)Cn1ncc(C)cc1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)n1ncc(C)cc1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate (0.132 g, 0.673 mmol) in tetrahydrofuran (4 mL) at −78° C. was added 1M lithium hexamethyldisilazane solution (0.74 mL). The reaction mixture was stirred at −78° C. for 15 min then was added methyl iodide (0.046 mL, 0.74 mmol). After being stirred at −78° C. for 2 h, the reaction mixture was allowed to warm to ambient temperature over 0.5 h. Removal of the volatiles in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl 2-[4-methyl-6-oxopyridazin-1(6H)-yl]propanoate as oil. To 88 mg (0.42 mmol) of the above oil in tetrahydrofuran (0.3 mL), water (0.2 mL) and methanol (0.2 mL) was added 5 N sodium hydroxide solution (0.2 mL). The reaction mixture was stirred at ambient temperature for 3 h then neutralized with 2 N hydrochloric acid and purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. LC/MS 183.2 (M+1).
Reaction SMILES: [C:1]([C:3]([C:15]#[N:16])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)#[N:2].[C:17](#[N:21])[CH2:18][C:19]#[N:20].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C>[NH2:20][C:19]1[C:18]([C:17]#[N:21])=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2)[C:3]([C:15]#[N:16])=[C:1]([S:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:2]=1
Reactant: N#CCC#N
Reactant: Sc1ccccc1
Reactant: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(-c2c(C#N)c(N)nc(Sc3ccccc3)c2C#N)cc1

Procedure:
19 g (0.09 mol) of N-[4-(2,2-dicyanovinyl)phenyl]acetamide, 5.95 g (0.09 mol) of malononitrile and 9.91 g (0.09 mol) of thiophenol are initially charged in 120 ml of ethanol, and 0.4 ml of triethylamine are added. The mixture is stirred at reflux for 2 h, during which the product crystallizes. After cooling, the product is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCOCC1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: Nc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, piperazine, and dioxane was refluxed for 5 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 263°-264° C.
Reaction SMILES: C([OH:5])(C)(C)C.[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:12][CH:13]=1)=[CH2:7].S([O-])([O-])=O.[Na+].[Na+].[OH2:24]>CC(O)C>[OH:24][C@H:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[N:12][CH:13]=1)[CH2:7][OH:5]
Reactant: O
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(NC(C)=O)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)Nc1ccc([C@@H](O)CO)cn1
Temperature: 5 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A suspension of AD-Mix-B® (56.33 g) in water (200 ml) and t-butanol (200 ml) was cooled to 5° C. and N-(5-Vinyl-pyridin-2-yl)-acetamide (6.52 g, 40.2 mmol) was added followed by 2-propanol (400 ml). The mixture was stirred at 5° C. for 12 hours and then at 20 ° C. for 12 hours. The reaction mixture was then treated with sodium sulfite (60.4 g), stirred for 30 minutes and then diluted with 500 ml of 2-propanol and stirred for an additional one hour. The mixture was filtered and the alcoholic phase was separated and evaporated to dryness. The residue was slurried in 500 ml of 2-propanol and evaporated again. The residue was dried to afford 6.35 g (80%) of the title product as colorless crystals. The crystals were recrystallized by dissolving in hot glacial acetic acid, diluting 7-fold with 2-propanol, cooling and seeding to give the title product as crystals. mp 184-185° C. 1H NMR (dmso-d6): δ=8.22 (d, 1 H); 7.99 (d, 1 H); 7.68 (d of d, 1 H); 4.52 (t, 1 H); 3.44 (m, 2 H); 2.07 (s, 3 H). MS (Cl): m/z=197 (M+H+). Optical Rotation: -4.52° (c=0.05, acetic acid). Analysis: Calculated for C9H12N2O3 : C, 55.09%; H,6.17%; N, 14.28%. Found: C, 55.43%; H, 5.97%; N,13.96%.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25](C)[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:1]([C@H:8]1[CH2:9][N:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:19][CH:20]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature under nitrogen overnight. The reaction was concentrated, the residue redissolved in DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as its freebase. Treatment with 1M HCl in dioxane gave 38 mg of the title compound as its hydrochloride salt Yield: 63%, ES MS (+) m/z 419.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Br[CH2:32][CH2:33]Cl.[OH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:35][C@H:36]1[CH2:40][CH2:39][N:38]([CH2:32][CH2:33][N:20]2[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:37]1
Reactant: ClCCBr
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: O[C@H]1CCNC1
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CC[C@H](O)C5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-3-{2-[(3S)-3-Hydroxypyrrolidin-1-yl]ethyl}-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8), 1-bromo-2-chloroethane and (3S)-3-hydroxypyrrolidine following General Procedure G.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[O:12])[CH3:11])=[CH:2]1.CC(C)[O-].[Na+].C(O)(=O)C>C(O)(C)C.[Rh]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@@H:10]([OH:12])[CH3:11])=[CH:2]1
Reactant: CC(=O)c1csc2ccccc12
Agent: [Rh]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: C[C@H](O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 4.45 g of 1-(1-benzothiene-3-yl)ethanone in 95 mL of isopropanol was added the asymmetric rhodium catalyst solution prepared as described above. Under reduced pressure (about 6600 Pa), an isopropanol solution of sodium isopropoxide (0.1 M, 10.0 mL) was added thereto. Further, the pressure was reduced to about 3700 Pa, followed by stirring at room temperature for 2 hours. To the reaction mixture was added acetic acid (2 mL) to stop the reaction, followed by concentrating under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (1S)-1-(1-benzothiene-3-yl)ethanol (4.48 g, 94% ee) as a pale yellow oily substance. (HPLC analysis condition: CHIRALCEL OD-H column manufactured by (DAICEL CHEMICAL INDUSTRIES. Ltd., eluting solvent hexane/isopropanol=90/10, flow rate 1.0 mLmin−1, retention time: 8.1 min (S-isomer), 12.6 min (R-isomer)) EI: 178
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:25])([F:24])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>CN(C=O)C.CC(OC)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:24][C:9]([F:25])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=1)[O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH3:38])=[O:36])=[CH:3][CH:4]=1
Reactant: FC(F)(F)CCCOc1ccc(C(F)(F)Oc2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
554 mg (2.469 mmol) of Pd(OAc)2, 2.70 g (7.41 mmol) of dicyclohexyl(2′-methylbuphenyl-2-yl)phosphine, 35 g (82 mmol) of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-benzene, 17.2 ml (123 mmol) of triethylamine and 14.84 ml (165 mmol) of methyl acrylate are solubilised in 500 ml of DMF and heated to 130° C. After 2 hours, the solution is diluted to room temperature and diluted with 500 ml of TBME. The solution is filtrated over a plug of Hyflo. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallisation from toluene/heptane mixture yields 26.7 g of methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)-prop-2-enoate.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:47])[CH2:18][N:19]2[CH:23]=[C:22]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[N:32][C:31]=34)=[O:26])[C:21]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[O:43][CH:44]([F:46])[F:45])=[N:20]2)[CH2:13][CH2:12]1.FC(F)(F)S(O[CH2:54][CH:55]1[CH2:59][CH2:58][C:57](=[O:60])[O:56]1)(=O)=O>CC#N>[CH:57]([OH:60])=[O:56].[Cl:42][C:40]1[CH:39]=[CH:38][C:37]([O:43][CH:44]([F:45])[F:46])=[C:36]([C:21]2[C:22]([NH:24][C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[N:32][C:31]=34)=[O:26])=[CH:23][N:19]([CH2:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:10]4[CH2:54][CH:55]([OH:56])[CH2:59][CH2:58][C:57]4=[O:60])[CH2:12][CH2:13]3)=[O:47])[N:20]=2)[CH:41]=1
Reactant: NC1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Reactant: O=C1CCC(COS(=O)(=O)C(F)(F)F)O1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCC(N3CC(O)CCC3=O)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Product: O=CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (71 mg, 0.55 mmol) was added to a solution of N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.18 mmol) and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate (69 mg, 0.28 mmol) in CH3CN (30 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% up to 46.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 41.6 mg (33%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 25) [M+H]+=643.2, RT=1.49 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.26-5.24 (m, 2H), 4.89 (br, 1H), 4.59-4.45 (m, 2H), 4.08-3.90 (m, 2H), 3.25-2.97 (m, 3H), 2.68-2.58 (m, 1H), 2.46-2.21 (m, 2H), 1.86-1.65 (m, 3H), 1.57-1.50 (m, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:15][CH2:16][C:17](=O)[CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:18][C:17]1[CH2:16][CH2:15][C@@H:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1
Reactant: CCOC(=O)[C@H](CCC(C)=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CCC(C)=N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-ethyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate in a 1 L flask was treated with a trifluoro acetic acid/dichloromethane solution (1:1 mixture, 100 mL). Effervescence was observed and the mixture was allowed to stir for 4 hours at room temperature. After which time the volatiles were removed in vacuo to yield (S)-ethyl 5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate as an oil, and used directly in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([C:33]3([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:45].O1CCOCC1>C(Cl)Cl>[ClH:45].[ClH:45].[ClH:45].[ClH:45].[NH2:37][C:33]1([C:30]2[CH:29]=[CH:28][C:27]([C:26]3[N:12]4[C:13]5[CH:25]=[CH:24][CH:23]=[N:22][C:14]=5[NH:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:11]4=[N:10][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH:3]=3)[NH2:1])=[CH:32][CH:31]=2)[CH2:34][CH2:35][CH2:36]1
Reactant: Cc1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
tert-Butyl (1-{4-[2-(3-amino-4-methylphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (28.2 mg, 0.0482 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 2 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (30.2 mg, 99.3%) as pale yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.86-8.70 (m, 2H), 8.63 (s, 1H), 8.11 (dd, J=4.8, 1.4 Hz, 1H), 7.92 (dd, J=8.0, 1.8 Hz, 1H), 7.70-7.64 (m, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 1H), 7.35-7.28 (m, 3H), 7.19-7.10 (m, 3H), 6.91 (dd, J=8.0, 1.4 Hz, 1H), 6.75 (dd, J=8.0, 4.8 Hz, 1H), 2.64-2.37 (m, 4H), 2.30 (s, 3H), 2.26-2.13 (m, 1H), 1.89-1.75 (m, 1H); LCMS: 485 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:46][S:47]([O:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1)(=[O:49])=[O:48]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ncnn12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), triethylamine (0.38 mL), methanesulfonyl chloride (0.21 mL), N,N-dimethylpyridin-4-amine (0.028 g) and acetonitrile (20 mL) was stirred at room temperature for 3 hr. The reaction mixture was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 89%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccc2F)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Fluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.02 (m, 4H), 5.00 (s, 2H), 3.80 (m, 2H), 3.70 (m, 2H), 3.53 (m, 2H), 3.25 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected=427.0, found 427.0.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:49])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:29][CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:23][C@@H:22]1[OH:48].[N+](=C)=[N-].C(=O)(O)[O-].[Na+]>CCOCC.O.N1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:49])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH2:29][CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:23][C@@H:22]1[O:48][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC#CCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC#CCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OS(=O)(=O)c2ccc(C)cc2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
At 0°, 1.38 g. of p-toluenesulfonyl chloride is added to a solution of 2 g. of (5Z,13E)-(9S,11R,15S)-11,15-bis(tetrahydropyran-2-yloxy)-9-hydroxy-5,13-prostadien-18-ynoic methyl ester (prepared from the corresponding acid with ethereal diazomethane solution) in 4 ml. of pyridine. The mixture is stirred for 6 hours at room temperature and then allowed to stand at 5° for 60 hours. The mixture is then diluted with ether, shaken in succession once with water, once with ice-cold 3% sulfuric acid, once with water, once with 5% sodium bicarbonate solution, twice with water, and dried over magnesium sulfate and evaporated under vacuum, thus obtaining 2.45 g. of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#N.[OH:33]S(O)(=O)=O.[OH-:38].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]([OH:33])=[O:38]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3ncccc3c2)n1
Agent: [Na+]
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(=O)O)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 120 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
2-Fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 76) (300 mg, 0.715 mmol) was treated with conc. H2SO4 (2.4 mL) and H2O (0.8 ml) and the mixture was stirred at 120° C. for 10 hours. The reaction mixture was cooled to room temperature and basified to pH 9-10 with 5N NaOH solution in the ice bath. The solution was extracted with CH2Cl2 (5 mL, 3 times), and then the aqueous layer was acidified to pH 4 with 2N HCl solution. The precipitate was filtered, washed with H2O, and dried under vacuum for overnight to afford the title compound (213 mg, 49%). (300 MHz, CDCl3+CD3OD) δ 2.48 (3H, s), 4.15 (2H, s), 6.97 (1H, d), 7.05 (1H, dd), 7.14 (1H, d), 7.35-7.42 (2H, m), 7.47-7.52 (1H, m), 7.83 (1H, dd), 7.90 (1H, dd), 8.01 (1H, d), 8.08 (1H, d), 8.16 (1H, dd), 8.80 (1H, dd). MS (ESI) m/z 439 (MH+).