Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH3:17][NH2:18]>C1COCC1>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:18][CH3:17])=[CH:4][CH:5]=1)#[N:16]
Reactant: CN
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C

Procedure:
62.1 g (228 mmol) 4-bromomethyl-2'-cyanobiphenyl (prepared according to . D. J. Carini et al., J. Med. Chem. 1992, 34, 2525) were dissolved in 3 l THF. After addition of 1.5 l of a 40% aqueous solution of methylamine the mixture was stirred over night at room temperature, and the THF distilled off in vacuo. The remaining aqueous layer was extracted with ethyl acetate, the extract dried by stirring over night with 0.4 nm mole sieve, and evaporated in vacuo. The title compound was obtained as a viscous oil, which was pure enough according to its 1H-NMR spectrum for further conversions,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][CH2:36][C:37]([O-])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:41][CH3:42])=[O:40])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (200 mg), N,N-di-isopropylethylamine (0.19 mL) and monomethyl succinate (79 mg) in dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium Hexafluoro-Phosphate. The solution was stirred at room temperature overnight and then loaded directly onto an SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated at reduced pressure and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a white foam (252 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: COCOC
Reactant: OCc1ccnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCOCc1ccnc(Cl)c1
Yield: 71 %

Procedure:
4.30 g of 2-chloro-4-pyridinemethanol, 20 ml of dimethoxymethane and 0.57 g of p-toluenesulfonic acid monohydrate were suspended in 200 ml of benzene. The suspension was passed through a Soxhlet extractor containing 25 g of 2 Å molecular sieves, and refluxed for 20 hours. After cooling, the reaction solution was washed with a saturated solution of sodium hydrogen carbonate and water, dried, and concentrated under reduced pressure. The residue was distilled to give 4.0 g (yield 71%) of 2-chloro-4-(methoxymethoxymethyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29]OS(C)(=O)=O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:28][CH:27]([CH2:29][O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])ccc2Cl)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To the mixture of 2-chloro-5-nitro-phenol (1.31 g, 7.54 mmol) and K2CO3 (1.57 g, 11.31 mmol) in 20 mL of DMF was added 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 7.54 mol). The reaction mixture was stirred at 50° C. for 1 h. After cooling to RT, the reaction mixture was diluted in 100 mL of EtOAc and quenched with 50 mL of water. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuum. The title compound was obtained via column chromatography (silica gel, 1;1 hexane/EtOAc) as yellow oil with 93% yield.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.104 g, 3.31 mmol) (from example 77, step 1) was dissolved in MeOH (10 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.132 g, 3.31 mmol) dissolved in water (1.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.203 mL, 3.31 mmol) was added during 6 min. The resulting solution was stirred at −40° C. for 2 h 30 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (14 mL, 84.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water was added. The phases were separated and the organic phase evaporated to yield a brown oil. The residue was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (722 mg, 72%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.66 (dq, 1H), 1.86-2.09 (m, 2H), 2.72 (d, 1H), 2.79-3.03 (m, 2H), 3.78 (s, 3H), 4.26 (br. s, 1H), 5.68 (br. s, 2H), 7.20-7.32 (m, 3H), 7.34-7.43 (m, 2H). MS m/z 303 (M+H)+
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:28]1([OH:36])[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1)#[CH:27].C(N(CC)CC)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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:27]#[C:26][C:28]2([OH:36])[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOC(=O)C1CCN(c2ccc(I)c(Cc3ccccc3)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc(C#CC3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 46.9 %

Procedure:
A mixture of 1.42 g of 2-benzyl-3-iodo-6-(4-ethoxycarbonylpiperidino)pyridine, 520 mg of 3-ethynyl-3-quinuclidinol, 110 mg of tetrakis(triphenylphosphine)palladium(0), 3 mg of cuprous iodide, 1.3 ml of triethylamine and 6 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 80° C. for 3 hours in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography and eluted with 20-100% ethyl acetate/hexane and then with 2.5% methanol/ethyl acetate, to give 700 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 20 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with dimethyl-piperidin-4-yl-amine using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine as an off white solid (45% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was purified by mass directed chromatography (20% yield) to give 337. NMR (CDCl3, 400 MHz), 1.60-1.65 (2H, m), 1.83-1.86 (2H, d, J 12.2), 2.11-2.17 (3H, m), 2.32 (6H, s), 3.04 (2H, d, J 11.4), 3.83 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.24 (2H, br s), 7.27 (1H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=455
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[CH2:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH2:31][CH2:30][O:29][CH:28]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:14]=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=5)[N:6]4[N:5]=3)=[CH:34][CH:33]=2)[CH2:27]1)[CH3:25]
Reactant: CCN1CCOC(c2ccc(N)cc2)C1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(NS(C)(=O)=O)c3)n2n1
Product: CCN1CCOC(c2ccc(Nc3ncc4ccc(-c5cccc(NS(C)(=O)=O)c5)n4n3)cc2)C1

Procedure:
The titled compound was prepared in analogous fashion as Example 113 using N-[3-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide and 4-(4-ethyl-morpholin-2-yl)-phenylamine to give N-(3-{2-[4-(4-ethyl-morpholin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}phenyl)methanesulfonamide as a yellow foam (47.3, 31.4% yield). LCMS (E/I+) 493 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.01 (s, 1H), 7.89 (d, 1H, J=7.8 Hz), 7.58 (d, 2H, J=8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.36 (m, 3H), 7.02 (m, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 4.57 (d, 1H, J=10.2 Hz), 4.05 (d, 1H, J=11.4 Hz), 3.85 (t, 1H, J=11.4 Hz), 3.03 (s, 3H), 2.98 (d, 2H, J=11.6 Hz), 2.83 (d, 1H, J=11.5 Hz), 2.47 (q, 2H, J=7 Hz), 2.23 (t, 1H, J=11.5 Hz), 2.08 (t, 1H, J=10.5 Hz), 1.12 (t, 3H, J=7 Hz).
Reaction SMILES: [OH2:1].[O:2]=[C:3]1[N:8]([Na:9])[C:7](=[O:10])[CH:6]=[N:5][NH:4]1>O.C(O)C.[Pt]=O>[OH2:2].[OH2:1].[O:2]=[C:3]1[N:8]([Na:9])[C:7](=[O:10])[CH2:6][NH:5][NH:4]1
Reactant: O=c1cn[nH]c(=O)n1[Na]
Agent: O=[Pt]
Solvent: CCO
Solvent: O
Product: O=C1CNNC(=O)N1[Na]

Procedure:
3,5-Dioxo-4-sodio-2,3,4,5-tetrahydro-1,2,4-triazine monohydrate (770 mg) dissolved in water (60 ml) is hydrogenated for 4 hours in the presence of platinum oxide (100 mg) at atmospheric pressure. The catalyst is filtered off, and the filtrate is concentrated in vacuo to give a colorless transparent liquid. The liquid is dissolved in ethanol (30 ml), and the solvent is then removed in vacuo to give amorphous solids of 3,5-dioxo-4-sodio-hexahydro-1,2,4-triazine dihydrate (Compound No. 4). Yield, 850 mg (98.2%). Softening temperature, 122.3° C.
Reaction SMILES: N.[C:2]([C:4](=[C:7](SC)[S:8][CH3:9])[C:5]#[N:6])#[N:3].CS.C(#[N:17])C=C>C(O)C>[NH2:17][C:7]([S:8][CH3:9])=[C:4]([C:5]#[N:6])[C:2]#[N:3]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: C=CC#N
Agent: CS
Agent: N
Solvent: CCO
Product: CSC(N)=C(C#N)C#N

Procedure:
Two liters of ethanol were saturated with ammonia gas at 15°. At ambient temperature, 278.3 g of 2-cyano-3,3-bis(methylthio)propenenitrile were added portionwise. A sodium hydroxide trap was used to trap the methyl mercaptan by-product. After complete addition of the propenenitrile the reaction mixture was cooled to approximately 10°. The solid which separated was collected by filtration and washed with cold ethanol to give, after drying, 206.3 g of white 3-amino-2-cyano-3-(methylthio)propenenitrile, m.p. 228°-230°. The nmr was consistent with the assigned structure.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[CH:35][N:34]=1>O1CCCC1>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:10])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:35][N:34]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCCc1cncc2ccccc12
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cncc3ccccc23)c2ccc(OC)cc2)cc1
Yield: 29.6 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (0.841 g) and 4-isoquinolinebutanamine (0.39 g) in tetrahydrofuran (8 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate-hexane; 3:1) and then was crystallized from ethyl acetate-ether to provide 0.284 g of (E)-N-[4-(4-isoquinolinyl)butyl]-5.5-bis(4-methoxyphenyl)-2,4-pentadienamide, mp 91°-93° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=C(C)ON=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C[O:27]CC1.C([Li])CCC.C(=O)=O>O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1CCOC1
Reactant: COc1ccc(-c2noc(C)c2-c2ccc(SC)cc2)cc1F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(=O)Cc2ccc(SC)cc2)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(3-Fluoro-4-methoxyphenyl)-5-methyl-4-[4-(methylthio)phenyl]isoxazole (326 mg, 0.99 mmol) was charged to an oven-dried 100 mL 3-neck round-bottom flask equipped with a thermometer, nitrogen inlet, rubber septum and a magnetic stirring bar. Anhydrous THF (35 mL) was added, and the solution was cooled to -78° C. under a dry nitrogen blanket. To this solution, n-butyllithium (1.6 N in hexane; 0.74 mL) was added, via syringe over approximately 3 minutes, keeping the reaction temperature <-75° C. The deep red suspension was stirred at -78° C. for 1 hour. Simultaneously, anhydrous tetrahydrofuran (80 mL) was cooled to -78° C. in an oven-dried 250 mL round-bottom flask. This solvent was saturated with carbon dioxide gas. The red reaction solution was quenched into the carbon dioxide-saturated THF. The yellow reaction was warmed to room temperature over 2 hours, then diluted with water (50 mL) and ether (80 mL). The solution was extracted with aqueous sodium hydroxide (5%, 2×50 mL), and the combined aqueous solution was acidified to pH <2 with aqueous hydrochloric acid (conc.). The acidic solution was extracted with dichloromethane (2×50 mL). The combined organic solution was dried over magnesium sulfate, filtered and evaporated under reduced pressure to a crude solid. The solid was dissolved in methanol (20 mL) in a 100 mL round-bottom flask equipped with a magnetic stirring bar and a nitrogen gas inlet. Oxone® (2.13 g, 3.47 mmol) and water (3 mL) were added, the suspension was stirred at room temperature for 2 hours, warmed to reflux and held for an additional 2 hours. Upon cooling to room temperature, water (35 mL) and aqueous hydrochloric acid (6 N, 1 mL) were added. The resulting suspension was cooled to 0° C., held for 30 minutes, filtered and washed with cold water to yield, upon drying, [3-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]isoxazol-5-yl]acetic acid as white crystals (173 mg, 43%): mp 89° C. Mass spectrum: MH+=406. Anal. Calc'd. for C19H16NO6FS: C, 56.29; H, 3.98; N, 3.46; S, 7.91. Found: C, 56.22; H, 4.00; N, 3.44; S, 7.85.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([Cl:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([Cl:18])[C:12]([C:13]#[N:14])=[C:15]([Cl:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile (0.121 g, 0.41 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.063 g, 0.41 mmol), HOBt (0.083 g, 0.615 mmol), DIPEA (0.214 mL, 1.23 mmol) and EDCI (0.118 g, 0.615 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 6.3 mg. 1H NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 2.55 (s, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 6.64 (d, 1H), 7.40 (s, 1H), 7.58 (d, 1H), 7.83 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([O:38]CC)=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]=2[C:9]1=[O:34].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:35][C:36]([OH:38])=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[C:16](=[O:17])[C:15]2[C:14]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:13]3[CH:24]=[CH:25][CH:26]=[CH:27][C:12]3=[C:11]([O:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:10]=2[C:9]1=[O:34]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Temperature: 25 °C

Procedure:
Ethyl (3-chloro-4-{1,3-dioxo-4,9-bis[(2,2,2-trifluoroethyl)oxy]-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.375 g, 0.64 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (20 ml) for 5 hours. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration and washed with water (0.315 g, 0.56 mmol). LC/MS: Rt=3.57, [MH]+ 562.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)([OH:5])[CH3:4])#[CH:2].[OH:20][C:21]1[CH:30]=[C:29](I)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>>[OH:20][C:21]1[CH:30]=[C:29]([C:2]#[C:1][C:3]([OH:5])([CH3:4])[C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: C#CC(C)(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(C#CC(C)(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
Following the basic procedure of Example 11(d), by reacting 2 g (7.8 mmol) of 1-ethynyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethanol with 2.2 g (7.9 mmol) of methyl 2-hydroxy-4-iodobenzoate, there were obtained, after chromatography on a silica column eluted with a mixture of dichloromethane and heptane (50/50), 2.77 g (87%) of the expected ester, with a melting point of 110°-115° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:19][CH3:20])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.F[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:19]([C:3]1([CH2:2][NH:1][C:28]2[CH:27]=[C:24]([CH:23]=[CH:22][C:29]=2[N+:30]([O-:32])=[O:31])[C:25]#[N:26])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:6]2)[CH2:4]1)[CH3:20]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCC1(CN)CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(CN(CC(C)(C)C)C(=O)O2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a yellow solution containing 7-(aminomethyl)-7-ethyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (0.195 g, 0.690 mmol) and 3-fluoro-4-nitrobenzonitrile (0.126 g, 0.760 mmol) in MeCN (6.90 ml) was added potassium carbonate (0.191 g, 1.381 mmol). The reaction was stirred at rt for 16 h. The reaction was filtered through a frit, and the filtrate was concentrated onto florisil for purification on a 12 g silica gel column (5-25% EtOAc/hexanes, 30 min gradient; 25-55% EtOAc/hexanes, 5 min gradient; 30 mL/min elution; 254 nm detection) to afford the title compound (0.232 g, 75% yield) as an orange solid. MS (m/z) 429.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])([CH3:9])[CH3:8].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23]C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])([CH3:9])[CH3:8])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)cc1O
Reactant: CCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCOC(=O)CCCC(C)(C)c1ccc(O)cc1O

Procedure:
5.5 parts of methyl-5-(2,4-dihydroxyphenyl)-5-methylhexanoate, 50 parts of n-hexanol, and 0.5 parts of p-toluene sulphonic acid are heated on a steam-bath for 6 hours. The excess hexanol is then removed under reduced pressure and then residual oil taken up in ether, washed with sodium bicarbonate solution, water, and evaporated. Short path distillation of the residual oil at a pressure of 0.5 mm of mercury yields 5.8 parts of n-hexyl-5-(2,4-dihydroxyphenyl)-5-methylhexanoate of the formula ##STR19## with the following percentage composition by weight: