Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C[CH2:23][N:24](CC)CC.C[Si](C#N)(C)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:23]#[N:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Br)c[n+]3[O-])cc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Br)cc32)cc1
Temperature: 76 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred mixture of 6-bromo-1-tosyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (5.66 g, 15.41 mmol), Et3N (21.5 mL, 154 mmol) and DCE (40 mL) was added trimethylsilyl cyanide (10.33 mL, 77 mmol), and the reaction mixture was stirred at 76° C. for 16 hours. The dark reaction mixture was concentrated in vacuo and purified by silica gel chromatography (1% to 2% MeOH/DCM) to give the title compound as a white solid (3.48 g, 60%). 1H NMR (500 MHz, CDCl3) δ ppm 8.56 (d, 1H, J=1.0 Hz), 7.90 (d, 1H, J=4.0 Hz), 7.79 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 6.88 (d, 1H, J=4.0 Hz), 2.41 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C15H10BrN3O2S, 376, 378; found 376, 378. Further elution of the silica gel column with 4% MeOH/DCM gave a second major fraction, which was the tosyl-deprotected product, which was collected to give impure 6-bromo-1H-pyrrolo[3,2-b]pyridine 5-carbonitrile as a brown solid (1.25 g, 36%). ESI-MS m/z [M+H]+ calc'd for C8H4BrN3, 222, 224; found 222, 224.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[CH2:28]([NH:32][CH3:33])[CH2:29][CH2:30][CH3:31]>>[CH2:28]([N:32]([CH3:33])[C:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)=[O:27])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCNC
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Product: CCCCN(C)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester and n-butyl-methyl-amine. The crude product was subjected to preparative HPLC (20%, oil). HPLC-MS: m/z=341.2 (M+1); Rt: 3.96 min.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirred suspension of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH) afforded the title compound (226 mg, 69% yield). MS m/z=247.1 [M+H]+. Calc'd for C10H10N6S: 246.30.
Reaction SMILES: [I:1][C:2]([I:34])=[CH:3][C@@H:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]1[CH:11]([OH:33])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[I:34][C:2]([I:1])=[CH:3][C@@H:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]1[C:11](=[O:33])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)O[C@@H](C=C(I)I)[C@@H](C(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)O[C@@H](C=C(I)I)[C@@H](C(=O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
Compound 3 (38 kg, 55.7 mol) was dissolved in 100 L of dichloromethane and the solution was added into a 1000 L reactor charged with dichloromethane (500 L) followed by addition of 4 Å molecular sieves (42.9 kg) and neutral alumina (84 kg). To the stirred suspension at ambient temperature was added PDC (pyridinium dichromate) (25.1 kg, 66.8 mol) and the mixture was stirred 16 hours, until HPLC indicated complete conversion. The suspension was filtered using a centrifuge. The filtrate from the centrifuge was collected. The cake from the centrifuge (mainly alumina, molecular sieves and PDC residue) was washed with 2×100 L of methyl tert-butyl ether. The combined filtrate and wash was introduced into a 1000 L reactor and concentrated to dryness while keeping the heating below 50° C. To the residue was added 600 L of methyl tert-butyl ether, followed by 5 kg of activated carbon. The dark suspension was heated 1 hour at 60° C., then cooled down to 30° C. It was filtered through a pad of Celite to remove activated carbon. The filtrate was concentrated to dryness. The oily residue was diluted with 60 L of methanol and precipitates started to form. The thick suspension was stirred 1 hour at ambient temperature, then the precipitates were collected by filtration. The cake was washed twice with 50 L of petroleum ether and dried at 40° C. to afford 25.3 kg of 4 (yield 67%, purity>99%) as white solid. The Rf for 3 was ˜0.7, while Rf for 4 was ˜0.75 on silica gel TLC plate run in petroleum ether/ethyl acetate=4:1 and visualized under UV254 light or by using iodine treatment. 1H-NMR-(300 MHz, CDCl3) δ 7.23-7.48 (m, 15H), 6.80 (d, J=7.5 Hz, 1H), 4.75-4.85 (m, 2H), 3.95 (d, J=18.0 Hz, 1H), 3.80 (d, J=18.0 Hz, 1H), 1.41 (s, 3H), 1.34 (s, 3H); 13C-NMR (75 MHz, CDCl3) δ 203.22, 145.93 (—CH═CI2), 143.07, 128.62, 128.52, 128.21, 128.08, 127.43, 111.01, 87.57, 82.95, 80.00, 69.10, 26.85, 25.11, 18.53 (═CI2).
Reaction SMILES: [C:1]([C:4]([CH3:26])=[CH:5][CH2:6][CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:16]([OH:17])=[C:15]([O:18][CH3:19])[C:14]([O:20][CH3:21])=[C:13]([O:22]C)[C:12]=1[CH3:24])([OH:3])=[O:2].CCOCC>C(OCC)(=O)C>[C:1]([C:4]([CH3:26])=[CH:5][CH2:6][CH2:7][C:8]([CH3:25])=[CH:9][CH2:10][C:11]1[C:16](=[O:17])[C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[C:13](=[O:22])[C:12]=1[CH3:24])([OH:3])=[O:2]
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
2 g of 6-(7-carboxy-3-methyl-2,6-octadienyl)-2,3,4-trimethoxy-5-methylphenol as prepared in Example 1 was dissolved in 20 ml of ethyl acetate and 5 g of ferric chloride hexahydrate was added thereto. The reaction mixture was stirred at room temperature for 30 min. After adding 100 ml of ether, it was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by means of silica gel chromatography with the use of ethyl acetate/benzene as the eluent to give 1.8 g of the title compound as an orange oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35](O)=[O:36])[N:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[NH:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[C:33]2[C:28](=[N:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH2:34][C:35]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([O:17][CH2:18][CH3:19])[CH:6]=3)[CH2:11][C@@H:12]2[CH3:16])=[O:36])[N:26]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: CCOc1cc(N2CCN[C@@H](C)C2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)ccc1Cl
Temperature: 30 °C

Procedure:
The title compound was prepared following Protocol A. To a vial containing (S)-1-(4-chloro-3-ethoxyphenyl)-3-methylpiperazine dihydrochloride (70 mg, 0.21 mmol) was added 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (51 mg, 0.21 mmol), HBTU (81 mg, 0.21 mmol), DMF (0.7 mL), and DIPEA (0.15 mL, 0.87 mmol). The reaction mixture was maintained at 30° C. for 24 h. The solution was diluted with EtOAc (30 mL) and washed with 1N HCl (2×10 mL) and sat. aq. NaCl (2×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the indicated compound (11 mg, 11% yield): MS (ES) [M+H]+expected 480.2, found 480.5; 1H NMR (CDCl3, 400 MHz) δ 9.94 (br s, 1H), 8.79 (dd, J=1.6, 8.0, 1H), 8.55 (dd, J=1.6, 4.4, 1H), 7.19-7.26 (m, 4H), 6.37-6.43 (m, 2H), 5.40 (br s, 2H), 2.78-4.81 (m, 10H), 4.07 (q, J=6.8, 2H), 1.46 (t, J=6.8, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=[N:3]1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([F:23])=[O:14])[CH:4]=[N:3]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: Cn1ncc(C(=O)O)c1-n1cccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ncc(C(=O)F)c1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (7.65 g, 40 mmol) in dry dichloromethane (150 mL) and pyridine (3.2 mL, 40 mmol) under a nitrogen atmosphere was added cyanuric fluoride (5.4 g, 40 mmol) at 0° C. The reaction mixture was stirred for two hours during which time the reaction temperature was allowed to rise to room temperature. Crushed ice was then added along with additional dichloromethane. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. Concentration of the combined organic layers under reduced pressure gave 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carbonyl fluoride which was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:9]1[CH2:12][CH:11]([N:13]2[CH:17]=[C:16]([C:18](OCC)=[O:19])[N:15]=[CH:14]2)[CH2:10]1)[CH3:8]>O1CCCC1.C(OCC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH2:7]([CH:9]1[CH2:10][CH:11]([N:13]2[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[CH:14]2)[CH2:12]1)[CH3:8]
Reactant: CCOC(=O)c1cn(C2CC(CC)C2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC1CC(n2cnc(CO)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (92%, 80 mg) was suspended in tetrahydrofuran (4 mL). To this suspension, a solution of ethyl 1-(3-ethylcyclobutyl)-1H-imidazole-4-carboxylate in tetrahydrofuran (5 mL) was slowly added dropwise at 0° C. After stirring at 0° C. for 30 minutes, the reaction solution was diluted with diethyl ether, and saturated aqueous sodium sulfate was added thereto. After stirring at room temperature for 1 hour, the formed inorganic salt was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=5/1) to obtain the title compound (119 mg, diastereomeric mixture, trans:cis=1:1).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])=[O:7])C.Cl[C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1>>[CH3:17][C:11]([CH3:16])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][CH2:13][CH2:14][O:15][C:19]1[C:20]([CH3:28])=[CH:21][C:22]2[N:23]([N:25]=[CH:26][N:27]=2)[N:24]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CCCO
Product: Cc1cc2ncnn2nc1OCCCC(C)(C)CCS(N)(=O)=O

Procedure:
Using 6-(N,N-dimethylaminomethylene)aminosulfonyl-4,4-dimethyl-1-hexanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 154°-155° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)C(=O)OC(C)(C)C)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:28][N:29]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[N:38]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH:12][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:28][NH:29][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[N:38]=1
Reactant: Cc1cc(C)nc(N(Cc2ccc3cc(CN(C(=O)OC(C)(C)C)c4cc(C)cc(C)n4)ccc3c2)C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)nc(NCc2ccc3cc(CNc4cc(C)cc(C)n4)ccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 6a (590 mg, 1.0 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (TFA, 8 mL) The reaction mixture was allowed to stir at room temperature for 8 h then was concentrated. The crude product was purified by flash column chromatography (2-5% MeOH in CH2Cl2) to yield 3a (355 mg, 90%) as a white solid: 1H NMR (500 MHz, CD3OD/CDCl3) δ 2.28 (s, 6H), 2.48 (s, 6H), 4.60 (s, 4H), 6.46 (s, 4H), 7.45-7.47 (d, J=8.5, 2H), 7.78 (s, 2H), 7.84-7.86 (d, J=8.5, 2H); 13C NMR (125 MHz, CD3OD/CDCl3) δ 18.6, 22.0, 45.9, 106.8, 114.5, 125.6, 129.0, 133.1, 134.3, 147.6, 153.8, 158.0; ESI (M+H+) calcd for C26H29N4 397.23922, found 397.23999.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: CC1CCCCN1
Product: CC1CCCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and 2-methylpiperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.1-3.8 (m, 7H), 1.6-2.1 (m, 6H), 1.45 (d, 3H, J=6 Hz); MS (DCI) m/z 345 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C.[C:42]([O:46][C:47](=[O:50])[CH:48]=[CH2:49])([CH3:45])([CH3:44])[CH3:43]>C(#N)CC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:42]([O:46][C:47](=[O:50])[CH:48]=[CH:49][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:45])([CH3:44])[CH3:43]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=Cc1cc(O)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (200 g, 1.0 mole) in propionitrile (6 L) under N2 was added tri-o-tolyl phosphine (75.4 g, 0.25 mol) and diisopropylethylamine (350 mL, 260 g, 2.0 mol). The solution was degassed and purged with N2 three times. To this solution was added tert-butylacrylate (440 mL, 385 g, 3.0 mol) and palladium acetate trimer (27.8 g, 0.12 mol). The mixture was degassed three times and heated to 80° C. over 30 min. After 30 min, the reaction was cooled to ambient temperature and filtered. The solids were washed with acetonitrile. The filtrate was transferred to a separatory funnel with acetonitrile (4 L total) and was extracted with hexanes (4×5 L). The propionitrile/acetonitrile layer was concentrated by rotary evaporation. The residue was dissolved in toluene (4 L) and washed successively with 1N HCl (1 L), water (1 L), and brine (1 L). The organic layer was dried (Na2SO4), filtered, and concentrated to afford crude product as a wet brown solid (293 g). The crude product was dissolved in CH2Cl2 (600 mL) with stirring. To this solution was added hexanes (1.8 L) over ˜2 h, and the resulting slurry was stirred at ambient temperature for 1 h. The slurry was cooled in an ice water bath and stirred for 1 h. The product was isolated by filtration, washed with hexanes, and dried under vacuum to afford the product as a tan solid (199.5 g, 80.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=2[CH3:18])=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1nn(C)c(C)c1N
Product: Cc1ccc(Cl)cc1NC(=S)Nc1c(C)nn(C)c1C
Yield: 71.4 %

Procedure:
Prepared using Method A from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 3.06 g (24.5 mmol) of 4-amino-1,3,5-trimethylpyrazole to give 5.4 g of title compound as a white solid, m.p. 176-177° C. (71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([NH:34][C@@H:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:33])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)N[C@H](C)c1cccc2ccccc12)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100.0 mg (0.325 mmol) of 2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionic acid from Example 105A are placed in 2 ml of DMF and treated with 61.2 mg (0.357 mmol) of (1R)-1-(1-naphthyl)ethanamine, 52.7 mg (0.390 mmol) of HOBt and 81.0 mg (0.422 mmol) of EDC hydrochloride. The mixture is stirred overnight at room temperature, then partitioned between dichloromethane and water, and the organic phase is separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromato-graphy on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) and then further separated by preparative HPLC on chiral phase [Method 16]. 44 mg (29% of theory) of the diastereomerically pure target compound are thus obtained (see also Example 189).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].[Br-].P(Br)(Br)[Br:23].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:23])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CO)cc1Oc1ccccc1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CBr)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
To a solution in DMF (10 mL) of 4-hydroxymethyl-2-phenoxybenzoic acid methyl ester (2.82 g), prepared as in Example 157C, was added LiBr (1.04 g) and PBr3 (3.65 g) and the reaction mixture was stirred for 20 minutes at ambient temperature. The reaction mixture was poured into water and extracted with toluene. The organic phase was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo to give 4-bromomethyl-2-phenoxybenzoic acid methyl ester (3.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].C[C:22]1(C)[O:26][C@H:25]([CH2:27][CH2:28]OS(C)(=O)=O)CO1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:28][CH2:27][C@@H:25]3[CH2:22][O:26]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)OC[C@@H](CCOS(C)(=O)=O)O1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(F)c(Cl)c2)CCN1
Product: O=C(/C=C/c1ccc(F)c(Cl)c1)N1CCC(=O)N(CC[C@@H]2CO2)CC1

Procedure:
In analogy to the procedure described for example 172A to 172C, 1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 54) and methanesulfonic acid 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester gave the title compound as pink oil. MS: 367.0 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:26]1[O:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=1)CCC>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:26]1[O:30][N:29]=[C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:27]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Product: CCOC(=O)c1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)on1

Procedure:
The procedure is identical to that used in Example 1 except (5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 6, 582 mg, 1.50 mmol) and ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (Sakamoto, T. et al., Tetrahedron, 1991, 47, 5111–5118); 806 mg, 1.87 mmol) were used as starting materials. The crude product was purified by chromatography on silica gel using EtOAc, followed by recrystallization from acetone/hexanes to give 175 mg of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[F:17][C:18]1[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O.O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]2[CH:36]=[CH:37][CH:38]=[CH:39][C:18]=2[F:17])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3F)cc2)OC1(C)C
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3F)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C

Procedure:
Combine 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 38, 0.46 mmol), 2-[4-(2-fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (1.3 Eq), tetrakis(triphenylphosphine)-palladium(0) (0.1 Eq) and 2.0 M sodium carbonate/water (6.5 Eq) in 1,4-dioxane (10 mL) and heat at −80° C. to 90° C. overnight. Let the reaction cool to room temperature and pour into water. Extract the quenched reaction mixture with ethyl acetate. Combine the organic extracts, wash with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Chromatotron™) eluting with hexane/ethyl acetate 4:1 to provide the final title compound, 4-cyano-5-ethyl-3-[4-(2-fluoro-phenoxy)-phenyl]-1-methyl-1H-pyrole-2-carboxylic acid ethyl ester, as a tan solid. Mass spectrum (m/e): 393.1 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.27-7.31 (3H, d), 7.07-7.20 (3H, m), 6.95-6.99 (2H, d), 4.04-4.11 (2H, dd), 3.84-3.88 (3H, s), 2.74-2.86 (2H, dd), 1.23-1.34 (3H, t), 1.00-1.06 (3H, t).