Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=2)[CH:19]=1)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Br:54][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]3[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])=[O:13])[C:15]3[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CO)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(hydroxyl-methyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (2.6 g, 5.84 mmol) in DCM (50 mL), triphenyl phosphine (6.1 g, 23.23 mmol) was added and stirred it at room temperature for 10 min. Finally CBr4 (7.7 g, 23.23 mmol) was added portion-wise to it and resulting solution was stirred at room temperature for overnight. After completion of reaction, solid was filtered and dried to obtain the desired compound (1 g, 34.5%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:7]([N:14]=1)=[N:8][CH:9]=[C:10](Br)[C:11]=2[CH3:12])[CH2:2][CH3:3].C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>C1COCC1>[CH2:1]([C:4]1[N:5]=[C:6]2[CH:11]([CH3:12])[C:10]([CH:22]=[O:23])=[CH:9][N:8]=[C:7]2[N:14]=1)[CH2:2][CH3:3]
Reactant: CN(C)C=O
Reactant: CCCc1nc2ncc(Br)c(C)c2[nH]1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC1=NC2=NC=C(C=O)C(C)C2=N1
Temperature: -78 °C

Procedure:
To a cooled (-78° C.) stirred solution of 2-propyl-6-bromo-7-methylimidazo[4,5-b]pyridine (540 mg, 2.15 mmol) in THF (20 mL) was added tert-butyllithium (4.40 mL, 1.7M/pentane) over 30 seconds After 45 minutes, dimethylformamide (0.665 mL) was added and after 10 additional minutes the reaction was warmed to RT and quenched with 20% aqueous 4 NH4Cl. Extractive workup EtOAc (4×10 mL) and purification (SiO2, 4% MeOH/EtOAc) gave 2-propyl-7-methylimidazo[4,5-b]pyridine-6-carboxaldehyde (350 mg). To a stirred, cooled (0° C.) methanolic (15 mL) solution of the aldehyde (300 mg) was added NaBH4 (84 mg). After 30 minutes HOAc (0.1 mL) was added, the mixture was warmed (RT), concentrated, and purified (SiO2, 10% MeOH/CH2Cl2) to give 190 mg of 6-hydroxymethyl-7-methyl-2-propylimidazo[4,5-b]pyridineas an oil. The title compound was prepared by using a similar method to that described in Example 7, Part B. 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), 7.59-7.41 (m, 4H), 7.18-7.09 (ABq, 4H), 5.52 (s, 2H), 4.79 (s, 2H), 2.83 (t, 2H, J=7.5 Hz), 2.70 (s, 3H), 1.78-1.63 (m, 2H), 0.96 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:3]=[C:2]([CH2:4][C:5](=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]([OH:7])=[O:8]
Reactant: c1ccccc1
Reactant: C=C1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Product: C=C(CC(=O)c1ccccc1)C(=O)O
Yield: 70 %

Procedure:
From itaconic anhydride treated with a large excess of benzene in the presence of aluminum chloride, there is recovered with a yield of about 70% the derivative of the formula: ##STR8##
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[C:21]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:31]#[N:32])[CH:28]=5)[C:23]4=[O:33])=[CH:20][N:19]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(Cl)Cl.CO>[NH2:32][CH2:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:33])[N:22]([C:21]1[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=4)[N:14]=3)[N:19]([C:34]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:20]=1)[CH2:30]2
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(C#N)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3c(n2)c(N2Cc4cc(CN)ccc4C2=O)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 88 %

Procedure:
2-[2-(4-isopropylsulfonylphenyl)-5-trityl-pyrrolo[2,3-b]pyrazin-7-yl]-1-oxo-isoindoline-5-carbonitrile (111 mg, 0.1586 mmol) dissolved in a mixture of DCM (10 mL) and MeOH (5 mL) under N2. CoCl2 (41.18 mg, 0.3172 mmol) added and resulting green solution cooled in an ice bath. NaBH4 (60 mg, 1.586 mmol) added in one portion and the ice bath removed. After 2 h reaction re-cooled in an ice bath and water (˜5 mL) added. Mixture diluted with DCM (˜20 mL) and stirred vigorously for 20 mins. Layers separated and aqueous extracted with DCM. Aqueous phase basified by addition of sat NaHCO3 solution and extracted with DCM (×2). Combined organics dried and concentrated to give the title compound as a yellow solid 88% pure by UV (112 mg, 82%); MS (ES+) 704.0.
Reaction SMILES: [CH2:1](Br)/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].OC/C=C(/C)\CCC=C(C)C.[CH2:23]([O:25][CH:26]([O:35][CH2:36][CH3:37])[C:27](=[O:34])[CH2:28]C(OCC)=O)[CH3:24]>>[CH2:23]([O:25][CH:26]([O:35][CH2:36][CH3:37])[C:27](=[O:34])[CH2:28][CH2:1]/[CH:2]=[C:3](/[CH3:4])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:24]
Reactant: CC(C)=CCC/C(C)=C\CBr
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Agent: CC(C)=CCC/C(C)=C\CO
Product: CCOC(OCC)C(=O)CC/C=C(/C)CCC=C(C)C

Procedure:
Reaction of neryl bromide which has been prepared from 31 g of nerol with 41.5 g of ethyl 4,4-diethoxyacetoacetate was carried out in the same manner as in Referential example 1 to yield 20 g of the desired product, b.p. 122° C/0.02 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].Cl>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:3][CH:4]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.5 %

Procedure:
To a solution of Pd(PPh3)4 (542 mg) and TEA (4 mL) in DMF (16 mL) were added 1-bromo-4-isobutylbenzene (1 g) and ethynyl(trimethyl)silane (553 mg) at room temperature, followed by stirring at 60° C. for 4 hours. To the reaction liquid was added 1 M hydrochloric acid, followed by extraction with ether. The insoluble materials were filtered through celite. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to obtain [(4-isobutylphenyl)ethynyl](trimethyl)silane (459 mg) as a yellow liquid.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=[C:32]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:31]=12>>[Cl:29][C:30]1[C:35]([C:36]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[CH:34][N:33]=[C:32]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:31]=12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: Cc1nn(C)c2ncc(C(=O)Cl)c(Cl)c12
Product: Cc1nn(C)c2ncc(C(=O)N[C@@H](CCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c3ccccc3)c(Cl)c12

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonyl chloride: ESMS m/e: 587.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].CS(O)(=O)=O.N1C=CC=CC=1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 3.0 mg (0.03 mmol) of methanesulfonic acid and 11.9 mg (0.15 mmol) of pyridine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]2[C@@H:11]([CH2:12][CH3:13])[CH2:14][O:15][C:29]2=[O:31])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:19]([CH3:26])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H]1COC(=O)N1c1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester (106 mg, 0.27 mmol), triphosgene )27 mg, 0.090 mmol), triethylamine (27 mg, 0.27 mmol) in dry THF was stirred at room temperature for 2 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, arid concentrated to dryness to give 13.6 g of crude product as a white glass foam. The foam was triturated with hexane/diethyl ether to give a white solid, mp. 144-145.5° C., Anal. For C21H23ClN2O5 calc.: C, 60.22; H, 5.53; N, 6.69; found: C, 60.10, H, 5.79; N, 6.66.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4][CH:3]1[CH:18]([CH3:20])[CH3:19].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](ON1C(=O)CCC1=O)=[O:31]>CN(C)C=O>[CH:18]([CH:3]1[CH:2]([NH:1][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1)([CH3:20])[CH3:19]
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Reactant: CC(C)C1Sc2ccccc2N(CC(N)=O)C(=O)C1N
Solvent: CN(C)C=O
Product: CC(C)C1Sc2ccccc2N(CC(N)=O)C(=O)C1NC(=O)c1cc2ccccc2[nH]1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
A solution of 1 g of 3-amino-2-isopropyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide and 1 g of succinimido 2-indolecarboxylate in 35 ml of dimethylformamide is stirred with heating at 70° C. Twenty-four hours later, the reaction mixture is concentrated under reduced pressure, whereto 50 ml of saturated sodium hydrogencarbonate and 50 ml of ethyl acetate are added. The mixture is stirred for a while. The resulting crystals are collected by filtration and recrystallized from a mixed solvent of dimethylformamidemethanol to give 0.92 g of 2-isopropyl 3-(2-indolecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5 acetamide, the decomposition temperature being not less than 300° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:6].[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)=[O:6])[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(Br)cc1
Yield: 78 %

Procedure:
4-Chloro-4'-bromobutyrophenone (2.61 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were reacted together in the manner of Example 68 to give the title compound (3.34 g.) as the hydrochloride, colourless microcrystals, m.p. 268.0° .
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:27]C(OC(C)(C)C)=O)[C:11]([O:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@@H:10]([CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:11]([O:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 48 %

Procedure:
2-Hydroxy-3-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate (2.05 g, 4.3 mmol) was treated with 4.0M HCl in 1,4-dioxane at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure and purified by prep-HPLC. The HPLC fractions were pooled, treated with 10 mL of 0.5N HCl, and dried by lyophilization to yield 0.85 g (48%) of the title compound as a white solid. 1H NMR (400 MHz, D2O): δ 3.11 (t, J=6.6 Hz, 2H), 4.38-4.44 (m, 6H), 6.60 (dd, J=2.2, 7.8 Hz, 1/2H), 6.61 (dd, J=2.4, 8.0 Hz, 1/2H), 6.70 (d, J=2.0 Hz, 1/2H), 6.71 (d, J=2.0 Hz, 1/2H), 6.77 (d, J=8.0 Hz, 1/2H), 6.78 (d, J=8.0 Hz, 1/2H), 7.46-7.52 (m, 2H), 7.60-7.68 (m, 1H), 7.96-8.02 (m, 2H); MS (ESI) m/z 376.15 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:41])=[N:27][N:28]4[CH:33]=[CH:32][C:31]([CH:34](OCC)[O:35]CC)=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=2)=[CH:4][CH:3]=1.Cl.C(O)(=O)C.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:41])=[N:27][N:28]4[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:42][CH:43]=1
Reactant: CCOC(OCC)c1ccn2nc(C)c(-c3nc(Cc4ccc(Cl)cc4)c(-c4ncn(COCC[Si](C)(C)C)n4)s3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.1 %

Procedure:
3-[4-(4-Chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-5-(diethoxymethyl)-2-methylpyrazolo[1,5-a]pyridine (1.17 g, 1.83 mmol) was dissolved in 1,4-dioxane (45 mL) and cooled in a water bath. 12 M hydrochloric acid (15 mL) was added and the mixture was stirred at rt for 15 hours. Acetic acid (40 mL, 700 mmol) was added and the suspension was stirred at rt for 24 hours then heated to 70° C. for 2 hours, then evaporated. The solid residue was stirred with 1.00 hydrochloric acid (100 mL) and methanol (120 mL) at rt for 14 hours. The mixture was evaporated on a rotovap at 45° C. to dryness and then azeotroped with DCM to give a crude product. The crude product was suspended in water, basified with NaHCO3 to ˜pH 8, extracted with EtOAc (300 mL, 3×80 mL), washed with brine, dried over Na2SO4, filtered, and evaporated to afford a yellow solid product (0.773 g, yield 97.2%). LCMS: (FA) ES+ 435, 437. 1H NMR (400 MHz, CDCl3) δ: 10.84 (s, br, 1H), 9.99 (s, 1H), 8.75 (m, 1H), 8.43-8.46 (d, J=7.28 Hz, 1H), 8.36 (s, 1H), 7.41-7.44 (d, J=8.53 Hz, 2H), 7.32-7.35 (dd, J=7.03, 2.01 Hz, 1H), 7.27-7.30 (d, J=8.53 Hz, 2H), 4.69 (s, 2H), 2.79 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:28][CH3:29])=[C:5]([O:30][CH3:31])[C:4]=1[O:32][CH3:33].[H-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:28][CH3:29])=[C:5]([O:30][CH3:31])[C:4]=1[O:32][CH3:33]
Reactant: CCOC(=O)c1ccc(OCCC2CCc3c(c(OC)c(OC)c(OC)c3OC)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(C(=O)O)cc1)CC2
Yield: 80.6 %

Procedure:
The mixture of ethyl 4-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]benzoate (1.77 g), aqueous sodium hydride (3N, 1.93 ml), and methanol (30 ml) was heated under reflux for 6 hr. The reaction mixture was concentrated in vacuo, diluted with water, made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from THF-diisopropylether to yield the entitled compound (1.34 g) as crystals.
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[N+:6]([C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15]([NH2:17])=[NH:16])=[CH:11][CH:10]=1)([O-])=O>O.[Ni]>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][NH:14][C:15]([NH2:17])=[NH:16])=[CH:11][CH:10]=1
Reactant: N=C(N)NCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.2 %

Procedure:
4-Nitrobenzylguanidine sulfate (0.243 g, 1.0 mmol) was dissolved in water (50 ml) by gentle warming and then cooled to ambient temperature. Activated Raney-Nickel catalyst (Wet form, Aldrich Chemical Co.) (500 mg) was added and the mixture was hydrogenated at 50 p.s.i. for 90 min. The catalyst was filtered and washed with water. To the clear, colorless filtrate was added 2N H2SO4 to pH 1.5. The solution was concentrated to approximately 25 ml; 95% ethanol (150 ml) was added and the solution stored at 4° C. overnight. The colorless needles were filtered and recrystallized from 1N H2SO4 (8 ml) to give stout prisms (0.205 g, 78%), m.p. 248°-250° C. (dec); IR (cm-1) Nujol 3395 (NH), 3260 (NH), 1675 and 1655 (C=N), 1060 (S=O) 835 (1,4 disubstituted benzene); PMR (DMSO-d6) 7.52 (t, 1H, J=5 Hz, CH2NH--), 6.90 (m, 7H) 6.40 (d, 2H, J=8.5 Hz) and 3.98 (d, 2H, J=5 Hz, CH2NH). Anal. calcd. for C8H12N4.H2SO4 : C, 36.64; H, 5.34; N, 21.37. Found: C, 36.70; H, 5.30; N, 21.39.
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].O>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:9](=[O:18])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1C(c2ccccc2)=CC(=O)N1C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 0° C. solution of ethyl 2-(N-methyl-3-phenylprop-2-ynoylamino)acetate (prepared according to the procedure described for Intermediate A, 20 g, 82 mmol) in THF (100 mL) was added a solution of Li(SiMe3)2 (1M in THF, 82 mL, 82 mmol). The resulting mixture was stirred for 2 h, then was slowly treated with water (20 mL) and diluted with CH2Cl2 (200 mL). The organic layer was washed with water (150 mL), a 1N HCl solution (150 mL) and water (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient from 0% to 50% EtOAc/hex) to give racemic ethyl 1-methyl-5-oxo-3-phenyl-3-pyrroline-2-carboxylate (14 g, 70%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.13; 1H NMR (CDCl3) δ 1.10 (t, J=7.4 Hz, 3H), 3.03 (s, 3H), 4.12 (m, 2H), 5.13 (s, 1H), 6.46 (s, 1H), 7.39-7.41 (m, 3H), 7.53-7.60 (m, 2H); HPLC ES-MS m/z (rel abundance) 246 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH2:18].CCN(CC)CC>C1COCC1>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
To a stirred solution of 2-chloro-nicotinoyl chloride (1.75 g, 10 mmol) in 40 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (1.88 g, 10 mmol) in 20 mL THF at 0° C., followed by 1.5 mL Et3N. The solution was stirred at room temperature overnight and precipitate was observed. It was filtered and the solid was washed with MeOH, dried to yield the title compound (3.63 g, 90%). 1H NMR (acetone-d6): 11.08 (s, 1H), 8.53 (d, J=4.5 Hz, 2H), 8.27 (s, 1H), 7.72 (m, 3H), 7.57 (m, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=1[F:16])(=O)=O.[C:19]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[F:36])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:21][C:19](=[O:20])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[C:8]=2[F:16])=[CH:29][C:28]=1[F:36])([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1F
Yield: 16.5 %

Procedure:
A solution of 3.75 g of 4-cyano-2,3-difluorophenyl trifluoromethanesulfonate in 220 mL of dioxane is admixed at ambient temperature with 5 g of N-Boc-4-amino-3-fluorophenylboronic acid, 3.87 g of sodium carbonate in solution with 56 mL of distilled water and then 1.81 g of tetrakistriphenylphosphinepalladium. The reaction mixture is heated for 3 h at reflux and then poured, after cooling, into the distilled water. This mixture is extracted with ethyl acetate, the organic phase is decanted, washed a number of times with distilled water, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is chromatographed on a silica column (eluent: cyclohexane/ethyl acetate, 90/10 by volume). Evaporation to dryness under reduced pressure of the fractions containing the expected product gives 0.75 g of tert-butyl(4′-cyano-3,2′,3′-trifluorobiphenyl-4-yl)carbamate in the form of a pale pink solid, whose characteristics are as follows: