Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C([O-])(=O)C.[Na+]>>[Na:1].[C:32]([O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][S:28]([OH:31])(=[O:30])=[O:29])=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CCOC(=O)C(c1ccc(O)cc1)(c1ccc(OS(=O)(=O)O)cc1)c1ccccn1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Product: CCOC(=O)C(c1ccc(OC(C)=O)cc1)(c1ccc(OS(=O)(=O)O)cc1)c1ccccn1
Reaction time: 1 h

Procedure:
15 g. of the above-described ethyl α-(4-hydroxyphenyl)-α-(4-sulphoxyphenyl)-2-pyridine-acetate sodium salt were treated with 75 ml. acetic anhydride and 15 g. anhydrous sodium acetate for 18 hours at ambient temperature and then heated and stirred for 1 hour. The reaction mixture was filtered and the solution treated with excess diethyl ether to give an abundant precipitate. The product was filtered off and purified with ethanol-ether to give the desired ethyl α-(4-acetoxyphenyl)α-(4-sulphoxyphenyl)-2-pyridine-acetate sodium salt in the form of colourless crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])Cl)=[CH:19][C:18]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>C(OCC)C>[O:6]1[C:5]2[CH:9]=[CH:10][C:2]([Si:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:19]=3)([CH3:29])[CH3:28])=[CH:3][C:4]=2[O:8][CH2:7]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: C[Si](C)(Cl)CCCc1ccc(F)c(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(CCCc1ccc(F)c(Oc2ccccc2)c1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To a solution of 1.21 g (0.0060 mole) of 5-bromo-1,3-benzodioxole in 30 mL of dry diethyl ether that had been cooled to -78° C. was added during a 15 minute period 0.42 g (0.0065 mole) of butyllithium as a 2.5 M solution in hexanes. Upon completion of addition this mixture was stirred at -78° C. for one hour. During a 20 minute period 1.9 g (0.006 mole) of [3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylchlorosilane was added as the solution prepared in Part D. The reaction mixture was allowed to warm to room temperature and to stir for an additional hour. Water was added to the reaction mixture which was then extracted With diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated under reduced pressure, leavinq a residue weighing approximately 3 g. This residue was passed through a column of silica gel, eluting with methylene chloride/hexane (1/9). This procedure yielded 1.0 g of (1,3-benzodioxol-5-yl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a clear, colorless liquid, compound 43 of Table 1. The ir spectrum and the proton, carbon, and fluorine nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([CH3:22])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[ClH:23]>O1CCOCC1.C(OCC)C>[ClH:23].[CH3:22][C@@H:11]1[NH:12][CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1
Reactant: C[C@H]1CN(c2ccc(C#N)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccc(C#N)cc2)CCN1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
(S)-tert-butyl 4-(4-cyanophenyl)-2-methylpiperazine-1-carboxylate (0.404 g, 1.340 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford a white solid (300 mg, 94%). [M+H] calc'd for C12H15N3, 201. found, 201.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH3:33])[CH2:10][N:11]1[C:23]2[CH:22]=[CH:21][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Br[C:35]1[CH:36]=[CH:37][C:38]2[N:39]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:40]3[C:45]([C:46]=2[CH:47]=1)=[CH:44][C:43]([Br:48])=[CH:42][CH:41]=3.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Br:48][C:43]1[CH:44]=[CH:45][C:40]2[N:39]([CH2:49][CH:50]([CH3:51])[CH3:52])[C:38]3[C:37]([C:41]=2[CH:42]=1)=[CH:36][C:35]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:10][CH:9]([CH3:33])[CH3:8])[C:23]4[C:18]([C:17]=2[CH:16]=1)=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:47][CH:46]=3
Reactant: CC(C)Cn1c2ccccc2c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
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: Cc1ccccc1
Solvent: O
Product: CC(C)Cn1c2ccccc2c2cc(-c3ccc4c(c3)c3cc(Br)ccc3n4CC(C)C)ccc21
Temperature: 90 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
Toluene (30 ml) and H2O (10 ml) were added into a mixture of 4 (1.2 g, 3.43 mmol), 2 (3.27 g, 8.59 mmol), Pd(PPh3)4 (0.22 g, 0.17 mmol) and Na2CO3 (3.43 g, 34 mmol). The reaction mixture was stirred at 90° C. for 12 hours, cooled to room temperature, and then extracted with methylene chloride. The organic extracts were combined, washed with water, and dried over MgSO4. Upon evaporating off the solvent, the crude product was purified by gradient column chromatography on silica gel with hexane/methylene chloride 9:1 to 3:1 (v/v) to yield 5 (0.62 g, 34%) as a white powder. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.40-8.33 (dd, 2H), 8.30-8.28 (d, 1H), 8.21-8.35 (d, 1H), 7.88-7.76 (m, 2H), 7.56-7.40 (m, 5H), 7.33-7.20 (m, 2H), 4.14-4.09 (m, 4H), 2.46-2.37 (m, 2H), 1.10-0.90 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17](O)=[O:18])=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:15])[CH3:16])=[CH:10][C:9]=2[CH2:17][OH:18])=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(-c2ccc(Br)cc2)c(C(=O)O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2ccc(Br)cc2)c(CO)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
4′-bromo-4-(dimethylamino)biphenyl-2-carboxylic acid (1.34 g, 4.19 mmol) in THF (40 mL) was cooled to 0° C. Borane tetrahydrofuran complex (8.37 mL, 8.37 mmol) was added dropwise over 15 min. and allowed to warm up to r.t. overnight. The reaction was diluted with EtOAc and washed with water, saturated ammonium chloride, and then brine. The organic layer was dried over MgSO4, filtered and evaporated to give (4′-bromo-4-(dimethylamino)biphenyl-2-yl)methanol (1.25 g, 4.08 mmol, 98% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.93-3.05 (m, 6H) 4.58 (s, 2H) 6.72 (dd, J=8.55, 2.75 Hz, 1H) 6.90 (d, J=2.75 Hz, 1H) 7.14 (d, J=8.55 Hz, 1H) 7.21-7.25 (m, 2H) 7.44-7.55 (m, 2H).
Reaction SMILES: [NH2:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:1][NH2:2])=[O:11]
Reactant: NN
Reactant: CCOC(=O)c1ccccn1
Solvent: CCO
Product: NNC(=O)c1ccccn1

Procedure:
Pyridine-2-carboxylic acid hydrazide is prepared as follows: 230 g (228 mL) of anhydrous hydrazine is added, over a period of 10-15 minutes, to a stirred solution of 977.4 g of ethyl pyridine-2-carboxylate ((ethyl picolinate) in 1750 mL of anhydrous ethanol. The reaction is exothermic. The solution is stirred and refluxed for 5 hours, then stirred at room temperature overnight. The crystalline product is filtered off, washed first with anhydrous alcohol and then with anhydrous ether, and air-dried to yield pyridine-2-carboxylic acid hydrazide, m.p. 95°-100°.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+]>C(O)C>[CH2:25]([O:24][C:22]([CH2:21][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:23])[CH3:26]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)CN1CCc2ccc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
1.5 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was dissolved in 20 ml of ethanol, and 2.9 g of sodium hydrogencarbonate, 2.3 g of ethyl bromoacetate, and a catalytic amount of potassium iodide were added to the solution. The resulting solution was heated and stirred overnight under reflux. The resulting solution was extracted with ethyl acetate, washed with the water and saturated aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was purified by silica gel column chromatography to obtain 1.1 g of 2-(ethoxycarbonylmethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (yield: 57%, oily product).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[C@@H:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:9]1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:32][C:24]1[CH:23]=[C:22]([C@@H:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:14]([NH:13][C:10]2[CH:11]=[CH:12][N:8]([CH2:7][C:6]([OH:34])=[O:5])[N:9]=2)=[O:33])[CH:27]=[CH:26][C:25]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
{3-[2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (95 mg, 0.19 mmol) was dissolved in 20% trifluoroacetic acid/methylene chloride (2 mL) and allowed to stir at 25° C. for 4 h, after which time the solvent was removed by blowing nitrogen into the reaction vessel. The crude material was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0% ethyl acetate/hexanes to 75% ethyl acetate/hexanes), afforded {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (67 mg, 79%) as a white powder: ESI-LRMS m/e calcd for C20H24ClN3O5S [M+] 453.1, found 454.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.24 (m, 2H, CH2), 1.37-1.97 (m, 8H, 4×CH2), 2.12-2.26 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.62 (t, J=7.5 Hz, 1H, CH), 4.72 (AB, Jgem=17.4 Hz, 2H, NCH2), 6.82 (d, J=1.2, 1H, Ar), 7.39 (d, J=1.2, 1H, Ar), 7.43 (d, Jo=8.2 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 8.01 (d, Jo=8.2 Hz, 1H, Ar), 9.82 (s, 1H, NH).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][Si](C(C)(C)C)(C)C)[C:10]=1[C:23]1[C:24]([C@H](O)CC=C)=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:34])([CH3:33])[CH:27]=[C:26]2[CH3:35])(C(C)(C)C)(C)C.N#N.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-].[CH2:63]1[CH2:67][O:66][CH2:65][CH2:64]1>C(O)(=O)C.CC(OC)(C)C>[OH:66][C@@H:65]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([C:10]3[C:11]([OH:15])=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])=[CH:32][CH:31]=2)[C:26]([CH3:35])=[CH:27][C:28]1([CH3:34])[CH3:33])[CH2:64][CH:63]=[CH2:67]
Reactant: C=CC[C@@H](O)c1c(-c2c(O[Si](C)(C)C(C)(C)C)cccc2O[Si](C)(C)C(C)(C)C)ccc2c1C(C)=CC(C)(C)N2
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: C=CC[C@@H](O)N1c2ccc(-c3c(O)cccc3O)cc2C(C)=CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 4 (1.0 g, 1.7 mmol) in THF (15 mL) and acetic acid (0.1 mL) was purged with N2 for 10 minutes at room temperature and then treated with a 1.0 M solution of TBAF in THF (7.6 mL). The reaction mixture was stirred at room temperature overnight under N2. HPLC indicated that the de-silylation was complete. The reaction mixture was poured into a solution of saturated NH4Cl (30 mL) and stirred briefly before MTBE (30 mL) was added. After stirring for 5 minutes, the organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness to give light yellow solid. The solid was then recrystallized with EtOAc/heptane to give the title compound (520 mg) as an off-white solid. 1H NMR [(CD3)2SO] δ1.10(3H, s), 1.22(3H, s), 2.17(3H, s), 2.23 (2H, m), 4.76˜4.80 (3H, m), 5.12 (1H, d), 5.40 (1H, br), 5.52(1H, m), 5.88 (1H, br), 6.43 (1H, dd), 6.53 (2H, m), 6.93 (1H, t), 8.92 (1H, s), 9.09 (1H, s); 13C NMR [(CD3)2SO]δ23.3, 27.2, 28.6, 39.8, 48.9, 71.2, 107.1, 107.4, 113.0, 115.3, 119.3, 122.2, 122.5, 127.6, 129.6, 131.6, 132.2, 136.8, 138.3, 145.0, 154.8, 155.9; ESI-MS: m/z 352 (M+H)+; HRMS-FAB: calcd 351.1834, found 351.1829.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:35](=[O:45])[N:36]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)(=[O:23])=[O:22])=[CH:15][C:9]=2[C:10]([O:12]CC)=[O:11])[C:6]=1[CH3:7].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[C:3]([C:35](=[O:45])[N:36]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])=[N:4][N:5]([C:8]2[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][S:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)(=[O:22])=[O:23])=[CH:15][C:9]=2[C:10]([OH:12])=[O:11])[C:6]=1[CH3:7]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)OCC)c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
To ethyl 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoate (1.39 g, 2.13 mmol) in THF (12.0 mL) and MeOH (4.0 mL) was added 0.5N aq. NaOH solution (21.3 mL, 10.7 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 h. The mixture was then neutralized with 1N aq. HCl solution (pH=7) and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was triturated with CH2Cl2 (3×) to give the title compound (1.04 g, 78%) as a white solid. 1H NMR (DMSO-d6) δ 13.36 (br s, 1H), 8.71 (s, 1H), 8.43 (d, J=2.0 Hz, 1H), 8.26 (d, J=8.1 Hz, 1H), 8.17 (dd, J=8.4, 2.2 Hz, 2H), 8.07 (d, J=8.1 Hz, 1H), 7.99 (dd, J=8.7, 1.9 Hz, 1H), 7.78-7.64 (m, 3H), 3.38 (t, J=7.4 Hz, 2H), 3.29 (t, J=7.4 Hz, 2H), 2.10 (s, 3H), 1.58-1.38 (m, 4H), 1.36-1.22 (m, 2H), 1.13 (dq, J=14.8, 7.4 Hz, 2H), 0.90 (t, J=7.4 Hz, 3H), 0.74 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 625.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16]CC.N[CH:22]([CH3:26])[C:23]([O-:25])=[O:24].[NH4+]>>[C:23]([O:25][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:24])[CH2:22][CH2:26][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC(N)C(=O)[O-]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)Cl
Agent: [NH4+]
Product: CCCCC/C=C\C/C=C\CCCCCC(=O)OC(=O)CCCCC/C=C\C/C=C\CCCCC
Temperature: 0 °C

Procedure:
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 17.93 g (60 mmol) of the prepared (9Z,12Z)-octadeca-9,12-dienoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 7.64 g (72 mmol) of ammonium 2-aminopropanoate. The round bottomed flask is placed in an ice bath and the (9Z,12Z)-octadeca-9,12-dienoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]([CH2:43][CH:44]([CH3:47])[CH2:45][OH:46])[C:39](=[O:48])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(CO)Cn1ccc(Br)cc1=O
Product: CC(CO)Cn1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1-(3-hydroxy-2-methyl-propyl)-1H-pyridin-2-one following a procedure analogous to that described in Example 75. Mass spectrum (ESI+): m/z=519 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=3)[C:10]=2[CH:11]=1)=[CH2:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:20])[C:6]2[CH:7]=[N:8][N:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=3)[C:10]=2[CH:11]=1)[CH3:2]
Reactant: C=Cc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 18.9 %

Procedure:
A solution of 6-ethenyl-1-(3-fluoro-4-hydroxyphenyl)-1H-indazol-4-ol (E6) (190 mg, 0.70 mmol) in ethanol (6 mL) and ethyl acetate (6 mL) was hydrogenated over a weekend at room temperature and a pressure of 50 psi over a 10% palladium on charcoal catalyst (20 mg). After filtration to remove the catalyst, the filtrate was concentrated and the crude product purified using MDAP to yield the title compound (E7) (36 mg).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[O:1][N:2]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.62 (s, 1H), 7.92 (dt, J=8.5, 1.7 Hz, 2H), 8.13 (dt, J=8.5, 1.7 Hz, 2H), 8.71 (d, J=2.4 Hz, 1H), 8.77 (dd, J=2.6, 1.4 Hz, 1 H), 9.31 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: Cl[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:21][NH:22][CH3:23]>C1COCC1>[CH3:21][N:22]([CH3:23])[S:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A solution of 190 mg (0.6 mmol) of benzyl 4-(chlorosulfonyl)-1-piperidinecarboxylate in 10 mL THF was treated with a 10-fold excess of 40% aq. dimethylamine and the mixture was stirred at room temperature for 2 hrs. The THF was removed under vacuum. The residue was diluted with water, extracted with CH2Cl2, and dried. Chromatography on alumina, eluting with CH2Cl2, gave 175 mg (89% yield) of benzyl 4-[(dimethylamino)sulfonyl]-1-piperidinecarboxylate as an oil: 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.13 (s, 2H), 4.31 (m, 2H), 3.10 (tt, J=12.0, 3.7 Hz, 1H), 2.92 (s, 6H), 2.85-2.75 (m, 2H), 2.04 (br d, J=13.7 Hz, 2H), 1.76 (dq, J=12.6, 4.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:36](OC(=O)C)([F:38])[F:37]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
A mixture of [2-ethyl-8-fluoro-3-(4-fluorobenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (1.5 g), N/N-dimethylformamide (30 mL), potassium carbonate (5.2 g) and acetic acid chlorodifluoromethyl ester (5.5 mL) was stirred at 70° C. for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3:1 by volume) to afford title compounds, 0.50 g.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH2:23]Br>>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: COc1cc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc(OC)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,5-dimethoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.