Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([C@@H:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)[CH3:22])[CH2:28][CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 84 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (103 mg, 0.5 mmol), (R)-1-[1-(4-fluorophenyl)ethyl]piperazine (125 mg, 0.6 mmol) (prepared as described in J. Med. Chem. 2007, 50, 3528) and DIPEA (97 mg, 0.75 mmol, 129 μl) in DMF (2 mL) was heated at 100° C. for 2 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-(difluoromethyl)-6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (158 mg, 84%) as a crisp foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH2:50][CH2:51]O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:53]([OH:56])(=[S:55])[CH3:54]>O1CCCC1>[CH2:34]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH2:50][CH2:51][S:55][C:53](=[O:56])[CH3:54])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(O)=S
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCC1CCCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (3.99 g in 35 mL dry tetrahydrofuran) was added 3.0 mL diisopropyl azodicarboxylate and the mixture stirred at 0° C. for 30 minutes. At this time, 2.0 g of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester was added followed by the dropwise addition of a solution of 1.16 g thioacetic acid in 19 mL tetrahydrofuran. After 2 hours, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane:methylene chloride, 1:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].Cl[C:19]1[S:20][C:21]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:19]3[S:20][C:21]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccc(N)c2)no1
Reactant: Fc1ccc2nc(Cl)sc2c1
Product: CCOC(=O)c1cc(-c2cccc(Nc3nc4ccc(F)cc4s3)c2)no1

Procedure:
The title compound was prepared by reacting 3-(3-amino-phenyl)-isoxazole-5-carboxylic acid ethyl ester with 2-chloro-6-fluoro-benzothiazole as described in Example 1, step 3. The solid was separated, filtered, washed with EtOH and dried to give the title compound in 90% yield. Mass (ES+), 384 (M++1); IR (KBr): 3423 (br), 2666 (br), 1723, 1629, 1598; 1H NMR (DMSO-d6) δ: 1.33 (t, 3H), 4.39 (q, 2H), 7.15 (m, 1H), 7.52 (m, 1H), 7.61 (m, 2H), 7.82 (s, 1H), 7.74 (m, 1H), 7.97 (m, 1H), 8.34 (m, 1H), 10.97 (br, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH2:25][C:26](=O)[CH2:27][CH3:28].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH:23][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)CC
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CO
Product: CCC(CC)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 8 and making non-critical variations but starting with 1-[benzyloxycarbonyl]-4-[(3-amino)-2-pyridinyl]piperazine (PREPARATION 100 10.5 g), 3-pentanone (0.15 g) sodium cyanoborohydride (0.11 g), acetic acid (52.3 ml) and methanol (3.2), the title compound is obtained, NMR (300 MHz, CDCl3) 7.66, 7.38-7.33, 6.90, 6.79, 5.17, 4.21, 3.65, 3.15, 3.04, 1.66-1.46 and 0.93 δ.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[N:20]=[N:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:17]2)=[CH:13][CH:12]=1>>[CH3:6][N:4]([CH3:5])[CH:3]=[C:21]([C:18]1[N:19]=[N:20][N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:28][CH:27]=2)[N:17]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 100 °C
Yield: 47.8 %

Procedure:
Dimethylformamide dimethylacetal (13 ml, 97.3 mmol) was dissolved in ethyl 2-[2-(4-methoxybenzyl)-2H-1,2,3,4-tetrazol-5-yl]acetate (24 g, 88.4 mmol) and heated to 100° C. for 3 hours with stirring. The reaction solution was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→1:1→1:3) to obtain 14 g (48%) of yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13]C)=[CH:7][CH:6]=[CH:5][C:4]1=2.[BrH:15]>>[BrH:15].[NH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([OH:13])=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: COc1cccc2c1CCCC2N
Agent: Br
Agent: Cl
Product: NC1CCCc2c(O)cccc21
Yield: 80 %

Procedure:
0.15 mol of 5-amino-1-methoxy-5,6,7,8-tetrahydronaphthalene hydrochloride is heated at a bath temperature of 125° C. in 75 ml of aqueous 48% strength HBr for 3 hours. The mixture is evaporated, the residue is dissolved in a little ethanol and the products are precipitated as the hydrobromides by addition of ether. Yield: 80% of theory; melting point: 152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](N)=[N:6][CH:7]=1.[Br:10]Br.N([O-])=O.[Na+].[OH-].[K+]>Br.O>[Br:10][C:5]1[C:4]([CH3:9])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: BrBr
Reactant: Cc1cc(Br)cnc1N
Agent: Br
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Br)cnc1Br
Temperature: -15 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
(J. Med. Chem. 2007, 50, 3730-3742.) 5-Bromo-3-methylpyridin-2-amine (48, 69 g, 0.37 mol) was suspended in hydrobromic acid (200 mL, 48% in water), and the mixture was cooled to −15° C. Bromine (95 g, 0.59 mol) was added dropwise to the mixture, followed by addition of sodium nitrite (69 g, 1 mol) in water (100 mL). Temperature of the reaction mixture was kept below −15° C. during addition. After addition, the cooling bath was removed and the reaction mixture was stirred for 3 h. The reaction mixture was cooled to −15° C. and quenched with potassium hydroxide (112 g, 2 mol) in water (500 mL). The cooling bath was removed, and the mixture was stirred for 1.5 h. The products were extracted with ethyl acetate (3×300 mL). The combined extracts were washed with water (2×200 mL), saturated aqueous sodium bicarbonate (200 mL), dried with sodium sulfate, and evaporated to dryness. The oily residue was redissolved in chloroform (100 mL), and the solution was filtered through a pad of silica gel, washing with chloroform. The combined filtrates were evaporated to provide 49 as light-yellow solid (87 g, 94%): mp 38-40° C. (lit. (Red. Tray. Chim. Pays-Bas 1965, 84, 951-964) mp 41-42° C.). 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J=2.4 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 2.33 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.29, 143.05, 141.15, 137.15, 119.68, 22.06.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32]([OH:34])=O)[CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:49][CH2:48][CH2:47][C@H:46]2[C:50]([O:52][CH3:53])=[O:51])[CH2:41][CH2:40]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[C:23]([NH2:30])=[C:22]([Cl:31])[CH:21]=3)[C:32]([N:39]3[CH2:40][CH2:41][CH:42]([N:45]4[CH2:49][CH2:48][CH2:47][C@H:46]4[C:50]([O:52][CH3:53])=[O:51])[CH2:43][CH2:44]3)=[O:34])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: COC(=O)[C@@H]1CCCN1C1CCNCC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: COC(=O)[C@@H]1CCCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.18 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 42 mg (0.20 mmol) methyl(S)-1-piperidin-4-yl-pyrrolidine-2-carboxylate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:8]=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]=1[N+:11]([O-])=O.C1COCC1>[Pd].CO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[CH:8]=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]=1[NH2:11]
Reactant: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c(N)c(OCCCl)c2)CC1
Reaction time: 20 h

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-(naphthalene-1-sulfonylmethyl)-4-nitrophenyl]-4-methylpiperazine (0.45 g, 0.85 mmoles) and 10% Pd/C in a 1:1 mixture of THF and methanol was hydrogenated on a Parr hydrogenator at 40 lb/in2 for 20 hours. The reaction mixture was filtered through Celite. The filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.4 g, 0.82 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:24]1[NH:23][CH:22]=[C:21]2[C:25]=1[CH:26]=[C:18]([NH:17][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[O:10][C:3]=13)[CH:19]=[CH:20]2
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: c1ccc(-c2cc3nccc(Nc4ccc5c[nH]nc5c4)c3o2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To a 10 mL sealed tube with stirbar was added 7-chloro-2-phenylfuro[3,2-b]pyridine (50.00 mg; 0.22 mmol; 1.00 eq.), 6-aminoindazole (34.79 mg; 0.26 mmol; 1.20 eq.), palladium(II) acetate (2.44 mg; 0.01 mmol; 0.05 eq.), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10.38 mg; 0.02 mmol; 0.10 eq.), and sodium tert. butoxide (62.77 mg; 0.65 mmol; 3.00 eq.). The reagents were suspended in dioxane (2.00 ml) under a N2 atmosphere and stirred at 110° C. overnight. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (0-10% MeOH/CH2Cl2, 30 column vol) to afford the title compound as a brown solid (6.6 mg, 9%). (HPLC (method F): 97%, RT: 3.97 min); MS (m/z) 327 [M+H]+, RT: 2.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12]
Reactant: CCOc1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C=O)ccc1Cl
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K2CO3 (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na2SO4 and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. After stirring for 1 h, the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO2 (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4]>O1CCCC1CO.[Ni]>[CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Ni]
Solvent: OCC1CCCO1
Product: COC(=O)C1Cc2c(ncn2Cc2ccc(N)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Reaction time: 26 h

Procedure:
A solution of 31.2 g methyl-1-(4-nitro-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in tetrahydrofuran-methanol (2:1, 600 mL) is treated with 8.0 g Raney Nickel and placed under an atmosphere of hydrogen at 50 psi for 26 hr. The catalyst is removed by filtration and filtrate is evaporated to give a crisp foam. NMR (CDCl3) 6.77 (s+d, 2H, 2, 6-Ar); 6.60 (d, 1H, 5-Ar). mp 182°-188° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[CH:3]=[C:4]([N:8]3[CH:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
1-(3-Bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 1.10 mmol) prepared in Step 4 of Preparation 14, 1-BOC-piperazine (266.0 mg, 1.43 mmol), Pd2(dba)3 (50.0 mg, cat.), BINAP (68.0 mg, cat.) and sodium t-butoxide (158.0 mg, 1.65 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 300.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1(/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1cccc(CCCOc2ccc(/C=C/C3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(CCCOc2ccc(/C=C/C(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Compound 93-9 (560 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (370 mg) as a white powder.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)(C)C.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(Cc2ccc(C#C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In Step III, a suspension of 1.00 g (2.78 mmoles) of bis(4-trimethylsilylethynylphenyl) methane [Compound (4)] in 50 ml anhydrous deaerated methanol was treated with enough anhydrous ethyl ether to dissolve all solid particles at 25° C. Anhydrous potassium carbonate (300 mg) was added and the mixture was stirred at 25° C. under argon for 16 hours. The solvent was removed and the solid residue was dissolved in 50 ml dichloromethane, treated with 5 g of silica gel and evaporated to dryness. The powder was placed on top of a 40-cm (I.D. 30 mm) column of silica gel (EM Labs, 70-230 mesh) and the column was developed with passage of hexane. A crystalline white solid [Compound (6)] was recovered from the the eluate: 0.60 gm (2.78 mmoles, 100%); mp 63°-64° C. After drying at 56° C./0.01 mm Hg inside an Abderhalden apparatus for 2 hours, the mp increased to 65.5°-66.5° C. IR (KBr) 3280 (very strong, sharp, --C≡CH), 2100 (weak, sharp, --C≡C--), and 1500 cm-1 (medium, sharp, C=C); MS (70 eV) m/e 216 (molecular ion); NMR (CDCl3) δ3.03 (s,2H,C≡C--H), 3.95(s,2H,CH2), 7.10 and 7.43 ppm (q,8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=O)[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)=[O:10].Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.[F:48][C:49]([F:59])([F:58])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>CN(C=O)C.C(N(CC)CC)C>[F:48][C:49]([F:58])([F:59])[C:50]1[CH:57]=[CH:56][CH:55]=[CH:54][C:51]=1[CH2:52][NH:53][C:21]([C:14]1[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=[C:12]([NH:11][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:25])([F:24])[F:1])=[O:10])[CH:13]=1)=[O:23]
Reactant: O=C(Nc1cc2c(c(C(=O)O)c1)OCC2)c1ccccc1C(F)(F)F
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc2c(c(C(=O)NCc3ccccc3C(F)(F)F)c1)OCC2)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxylic acid (35 mg) in DMF (2 mL), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride (23 mg), 1-hydroxybenzotriazol (23 mg) and triethylamine (17 μL) were added. Under ice-cooling, to the mixture was added 2-(trifluoromethyl)benzylamine (15 μL), and it was stirred at room temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was washed with n-hexane/ethyl acetate (1:1) and collected by filtration to obtain the titled compound (43 mg) as colorless powder. MS (ESI+) m/z 509 (M+H)+, Rt=2.31 minutes (method A)
Reaction SMILES: C[Li].[CH2:3](OCC)C.CON(C)[C:11]([C@H:13]1[CH2:17][C@@H:16]([OH:18])[CH2:15][N:14]1[C:19]1[C:33]([O:34][C:35]2[CH:36]=[N:37][C:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])=[CH:39][CH:40]=2)=[CH:32][C:22]2[N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[NH:25][C:21]=2[CH:20]=1)=[O:12].[Cl-].[NH4+]>O1CCCC1>[CH2:44]([S:41]([C:38]1[N:37]=[CH:36][C:35]([O:34][C:33]2[C:19]([N:14]3[CH2:15][C@H:16]([OH:18])[CH2:17][C@@H:13]3[C:11](=[O:12])[CH3:3])=[CH:20][C:21]3[NH:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:23][C:22]=3[CH:32]=2)=[CH:40][CH:39]=1)(=[O:42])=[O:43])[CH3:45]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2C[C@H](O)C[C@@H]2C(=O)N(C)OC)cn1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2C[C@H](O)C[C@@H]2C(C)=O)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.360 ml of methyl lithium (1.0 M diethyl ether solution was added to a tetrahydrofuran (1 ml) solution of 20 mg of (2R,4R)-1-(6-(6-ethanesulfonyl-pyridin-3-yloxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-4-hydroxy-pyrrolidin-2-carboxylic acid methoxy-methyl-amide obtained in (step 1), at −78° C. The reaction liquid was stirred at −78° C. for 1 hour, heated up to 0° C. and stirred for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.