Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]([CH3:36])[C@@H:8]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1)[C:9]([NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:5]([O:6][C@@H:7]([CH3:36])[C@@H:8]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:25]=1)[C:9]1[O:10][C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)=[N:12][N:11]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:38])[CH3:37]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of N′-((2R,3S)-3-(tert-butyldimethyl-silyloxy)-2-(4-cyano-3-(trifluoromethyl)phenylamino)butanoyl)-4-cyanobenzohydrazide (1.05 g, 1.92 mmol) in CH2Cl2 (40 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.01 g, 3.85 mmol), iodine (980 mg, 3.85 mmol) and Et3N (1.1 mL, 7.70 mmol). The reaction mixture was warmed to room temperature, stirred for 30 min and quenched with sat. aq. sodium thiosulfate (200 mL). The solution was extracted with CH2Cl2 (150 mL). The organic extract was washed with sat. aq. sodium thiosulfate (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a light brown solid, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes) to provide the title compound as a light yellow oil (900 mg, 89%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.8 Hz, 2H), 8.02 (dm, J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.17 (dd, J=2.3, 8.6 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 5.36 (dd, J=3.3, 9.4 Hz, 1H), 4.73 (dq, J=3.1, 6.1 Hz, 1H), 1.45 (d, J=6.3 Hz, 3H), 0.78 (s, 9H), 0.07 (s, 3H), −0.13 (s, 3H
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[CH:4]=[CH:5][C:6]([O-:8])=[O:7])[CH3:2]>O1CCCC1.C(O)C.[Pd]>[CH2:1]([CH:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCC(C=CC(=O)[O-])CC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)CCC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 83.2 %

Procedure:
Eethyl 4-ethyl-2-hexenoate (55.3 g) was dissolved in a mixture of tetrahydrofuran (150 mL) and ethanol (150 mL). To the solution was added 5 w/w % palladium on activated carbon (5.5 g). The mixture was stirred at RT for 3.5 hr under hydrogen atmosphere (1 atm). The 5 w/w % palladium on activated carbon was filtered off using Celite. To the filtrate was added aqueous 4 N sodium hydroxide (111 mL). The mixture was stirred at RT overnight. The reaction mixture was washed with hexane. To the aqueous layer was added 4 N hydrochloric acid (113 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with water/brine=1/1 (300 mL) and brine (150 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (47.0 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.CCCCCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(O)c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanol (10.2 mmol, 1660 mg, commercial) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 mol/L) in hexane (2.4 equiv., 24.4 mmol, 9.8 mL) dropwise. The mixture was stirred at −78° C. for 2 hours. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.50 equiv., 25.4 mmol, 5.29 mL) was added, and the reaction mixture was stirred over night allowing to warm to room temperature. The reaction mixture was quenched with saturated NaHCO3(aq.) And extracted with etoac. The organic layer was washed with brine, dried with Na2SO4, filtered, and the filtrated was concentrated to afford the desired product which was used without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[NH2:13][NH2:14]>>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:13][NH2:14])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(I)c1
Product: Cc1ccc(C(=O)NN)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8): 1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: [C:1]1([C:7](=[C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[C:1]1([C:7](=[C:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20]2)[C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCl
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(O)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
An O-alkylation procedure described for 9 (example 5, step 2) employed using 32 (800 mg, 2.50 mmol), K2CO3 (1.04 g, 7.49 mmol), ethyl 4-chlorobutanoate (715 uL, 5 mmol), and acetone (30 mL). The mixture was refluxed for 15 h and cooled to RT. The mixture was filtered, concentrated, and purified to give ˜1.05 g (purity 80%) of the title product 36. This material was used as such without purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([OH:6])=[O:5].O[Li].O.S(OC)(O[CH3:19])(=O)=O.[NH4+].[Cl-]>C1COCC1>[CH3:19][O:5][C:4](=[O:6])[C:3]1[C:7]([I:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1c(F)cccc1I
Agent: [Cl-]
Agent: [Li]O
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(F)cccc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a 200 mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g, 28.2 mmol), LiOH.H2O (1.42 g, 33.8 mmol), and THF (100 mL). The resulting mixture was warmed to 50° C. and stirred for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmed to 65° C. After 2 h, the mixture was cooled to room temperature and NH4Cl(aq) (50 mL, 13 wt % solution) was added. The two resulting layers were thoroughly mixed and then separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to a light brown oil (7.79 g, 99% yield). 1H NMR (400 MHz, CDCl3): 7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=O)[NH:32][CH:33]=2)=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:26][C@H:24]1[NH:25][C@@H:20]([CH3:19])[CH2:21][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:32][CH:33]=2)=[O:28])[CH2:23]1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (42 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.C([O-])(=O)C.[Na+].[N:17]#[C:18]Br>C(O)(=O)C>[OH2:6].[C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: N#CBr
Reactant: Nc1cccc(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CNc1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 174.9 %

Procedure:
To a 3-aminobenzoic acid (Aldrich, 9.05 g, 66 mmol) in acetic acid:water (70 mL, 1:1) was added sodium acetate (8.12 g, 99 mmol) and the mixture was cooled in an ice-water bath. Cyanogen bromide (8.38 g, 79.2 mmol) was added in two batches in 10 min and the stirring was continued for 18 h at room temperature. The reaction mixture was poured into 350 g of an ice-water mixture with stirring. The precipitate was collected through filtration, washed with cold water (about 70 mL), dried in air, and crystallized from methanol-water. The white solid was separated through filtration, dried in air followed by drying in a pistol at toluene reflux in vacuo to give 10.40 g (95%) of the title compound, mp 238°-240° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[CH:10]=[O:11].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: Nc1c(C=O)cnn1CCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: Nc1c(C=O)cnn1CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
To a solution of 5-amino-1-(2-hydroxyethyl)-1H-pyrazole-4-carbaldehyde (40.2 g) in pyridine (400 ml) was added triphenylmethyl chloride (86.7 g) at room temperature. The mixture was stirred at 60° C. for 5 hours. The reaction mixture was evaporated under reduced pressure and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (3:2) to give 5-amino-1-(2-triphenylmethyloxyethyl)-1H-pyrazole-4-carbaldehyde (62.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N+:16]([O-])([OH:18])=[O:17].O.[K+].[Br-]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 88 %

Procedure:
Into a 250 mL three-necked round-bottom flask equipped with a magnetic stirrer, a condenser, and nitrogen inlet, dimethyl 4-hydroxyisophthalate (15.0 g, 71.4 mmol) was dissolved in acetic acid (150 mL). Nitric acid (10 ml) was then added dropwise. The mixture was warmed at 60° C. for 12 h. Then, the cool mixture was poured into water. The light yellow precipitate was collected, air-dried and recrystallized from ethanol to give 16.0 g (88% yield) of light yellow crystals: mp=74-76° C. Anal. Calcd. for C10H9NO7: C, 47.07%; H, 3.55%; N, 5.49%; O, 43.89%. Found: C, 47.75%; H, 4.01%; N, 5.44%; O, 43.51%: FT-IR (KBr, cm−1): 3076, 2992, 1722, 1690. Mass spectrum (m/e): 255 (M+, 100% relative abundance), 241, 237. 1H-NMR (DMSO-d6, ppm) δ 3.89 (s, 3H, CH3), 3.97 (s, 3H, CH3), 8.46-8.47 (d, 1H, Ar), 8.55-8.56 (d, 1H, Ar). 13C-NMR (CDCl3, ppm) δ 52.72, 53.38, 117.60, 120.19, 130.61, 135.31, 138.50, 156.13, 163.70, 166.87.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:19].[CH:21](OCC)(OCC)OCC>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:17]3[N:18]=[CH:21]2)=[CH:7][C:6]=1[CH3:19]
Reactant: COC(=O)Cc1ccc(Nc2ncccc2N)cc1C
Reactant: CCOC(OCC)OCC
Product: COC(=O)Cc1ccc(-n2cnc3cccnc32)cc1C
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of [4-(3-amino-pyridin-2-ylamino)-2-methyl-phenyl]-acetic acid methyl ester (1.92 g, 7.08 mmol) and triethyl orthoformate (30 mL, 181 mmol, 26 equiv) is stirred for 3 h at 150° C. The resulting mixture is allowed to cool to rt and concentrated in vacuo to provide the title compound: ES-MS: 282.1 [M+H]+; tR=3.39 min (System 1).
Reaction SMILES: Cl[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=2)[N:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:3]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:4][C:5]3[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=4)[N:10]=3)[N:7]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a flame-dried round bottom flask was placed 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (44 mg, 0.1 mmol), 4-chlorophenylboronic acid (31 mg, 0.2 mmol), K3PO4 (42.5 mg, 0.2 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (1:1) (16 mg, 0.02 mmol). The flask was purged with argon for 15 min before addition of degassed anhydrous THF (1 mL). The reaction mixture was stirred at 70° C. under argon for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with 1 N aqueous NaOH, water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, hold at 100% B for 6 min (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 18.2 mg (35%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.94 min, (M+H)+=516. 1H NMR (CDCl3, 400 MHz): δ 8.83 (d,J=1.71 Hz, 1H), 7.98 (dd, J=7.95, 2.08 Hz, 1H), 7.69 (d,J=8.07 Hz, 1H), 7.41 (s, 1H), 7.25-7.32 (m, 4H), 7.20-7.23 (m, 2H), 7.00-7.04 (m, 2H), 5.33 (s, 2H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][C@H:38]([CH2:41][CH3:42])[CH2:39][OH:40]>>[OH:40][CH2:39][C@H:38]([NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1)[CH2:41][CH3:42]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: CC[C@H](CO)NC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 87.8 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 50 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH2:39])=[S:38])[CH3:28]>>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:30]=1[NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=3)[N:12]=2)[CH:6]=1)=[O:3])=[S:38])[CH3:28]
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CCc1cccc(C)c1NC(N)=S
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) and isolated as an off-white solid (0.212 g, 50%).
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]([C:9](O)=O)=[CH:8][C:4]2=[CH:3][S:2]1.[CH3:12][O:13][C:14]1[C:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:16][C:17]2[O:21][CH2:20][CH2:19][C:18]=2[CH:22]=1>>[CH2:1]1[C:5]2=[CH:6][C:7]([CH2:9][N:26]3[CH2:27][CH2:28][N:23]([C:15]4[C:14]([O:13][CH3:12])=[CH:22][C:18]5[CH2:19][CH2:20][O:21][C:17]=5[CH:16]=4)[CH2:24][CH2:25]3)=[CH:8][C:4]2=[CH:3][S:2]1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: O=C(O)C1=CC2=CSCC2=C1
Product: COc1cc2c(cc1N1CCN(CC3=CC4=CSCC4=C3)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from (cyclopenta[c]thien-5-yl)carboxylic acid (Preparation 7) and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The title compound melts at 156°-158° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1ncn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2ncn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 4-difluoromethyl-8-ethynyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.31) (190 mg, 0.56 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (136 mg, 0.56 mmol) according to general procedure II. Obtained as an orange solid (236 mg, 84%). MS (ISN) 497.1 [(M−H)−]; mp 223° C.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[OH:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1OC
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Methyl 2-(2-methoxypyridin-3-yl)-5-nitrobenzoate (Reference Compound No. 1-3-(1), 200 mg, 0.694 mmol) was dissolved in anhydrous dichloromethane (2 mL), then boron tribromide (118 μL, 1.25 mmol) was added thereto at −78° C. The reaction mixture was stirred at 0° C. for 3 hours, and then poured into ice-water (30 mL). Ethyl acetate (50 mL) was added, and then separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (102 mg) as a yellow solid. (Yield 54%)
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][CH:11]=[O:12])=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:2])[CH3:3]
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CCO)c1-c1ccc(F)cc1
Yield: 70.4 %

Procedure:
To the intermediate obtained in Step A (20 mg, 0.054 mmol) in dry THF (10 mL) was added dropwise LAH (2 eq., 1M, 0.11 mL) under argon and the mixture was stirred at reflux for 1 h. The reaction was quenched with water (3.9 μL), 20% NaOH (3.9 μL), and water (7.8 μL) again. Concentration afforded a white solid. The product was subjected to a pad of silica gel (CH2Cl2) to afford the title compound as a white solid (14 mg, 0.038mmol, 70%). 1H NMR (300 MHz, CDCl3): δ 7.39 (m, 2 H), 7.12 (m, 2 H), 3.52 (t, J=5.5 Hz, 2 H), 3.23 (m, 2 H), 2.60 (t, J=2.9 Hz, 2 H), 2.20 (t, J=3.7 Hz, 2 H), 1.30 (m, 14 H), 1.11 (m, 4 H), 0.771 (t, J=6.3 Hz, 3 H). FAB-MS: calcd for (C24H34FNO) 371, found 372 (M+H). Anal. Calcd for C24H34FNO: C, 77.59; H, 9.22; N, 3.77. Found: C, 77.57; H, 9.44; N, 3.05. mp 81-83° C. Rf=0.6 (10% ether/hexane).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH:6]([CH2:11][C:12]([OH:14])=O)[C:7]([O:9][CH3:10])=[O:8]>ClCCl.CN(C)C=O>[Br:5][CH:6]([CH2:11][C:12]([Cl:3])=[O:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(Br)CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(Br)CC(=O)Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (6.54 g, 54.9 mmol) in dichloromethane (7 mL) was added dropwise over 30 minutes to a mixture of 1-methyl hydrogen bromobutanedioate (i.e. the product of Step A) (10 g, 47.4 mmol) and N,N-dimethylformamide (5 drops) in dichloromethane (20 mL) heated at reflux. The mixture was heated at reflux for an additional 60 minutes and then allowed to cool to room temperature. The solvent was removed under reduced pressure to leave the title product as an oil (11 g, about 100% yield).