Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]2[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl:20]N1C(=O)CCC1=O>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:20])=[C:4]([N:8]2[CH2:18][C@@H:17]([CH3:19])[CH2:16][C@H:9]2[C:10]([NH:12][CH2:13][C:14]#[N:15])=[O:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cccc(Br)c2)C1
Solvent: CC(C)O
Product: C[C@H]1C[C@@H](C(=O)NCC#N)N(c2cc(Br)ccc2Cl)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a hot (60° C.) solution of (4S)-1-(3-bromophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide (630 mg, 1.96 mmol) in isopropyl alcohol (20 mL) was added N-chlorosuccinimide and the reaction mixture was stirred at 60° C. for 2 hours. The reaction was concentrated in vacuo and the product purified by flash chromatography over silica gel (MTBE/Hex, 1/1, then 6/4, then 8/2) to afford (4S)-1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)-4-methyl-L-prolinamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]O)([CH3:7])[CH3:6])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:53].CCOC(C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:53])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A 100 mL round bottomed flask was charged with 2-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (1.0 g, 2.25 mmol), dissolved in anhydrous THF (75 mL), and then of triphenylphosphine (1.18 g, 4.50 mmol) and CBr4 (1.49 g, 4.50 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was poured into EtOAc (135 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 15:85) to give a the title compound as a colorless oil (0.95 g, 76%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:21]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH:21]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCC(c1cc(F)ccc1F)S(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
After addition of 3-chloroperbenzoic acid (98.8 mg, 0.571 mmol) to a solution of 2-[1-[(4-chlorophenyl)sulfinyl]pentyl]-1,4-difluorobenzene (Isomer 2-B) (150 mg, 0.439 mmol) in methylene chloride (5 ml), the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with methylene chloride, washed successively with a 1N aqueous solution of sodium hydroxide, water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (10% ethyl acetate-hexane), whereby the title compound (122 mg, 77%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[O:17]1C[CH2:20][CH2:19][CH2:18]1>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[CH3:4]/[C:3](/[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:9])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:2]\[CH2:1][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCO
Reaction time: 1 h

Procedure:
A solution of 37.5 mL (20.3 mmol, 5.1 eq.) of a 0.54M solution of Grignard reagent (Part B) in tetrahydrofuran and 9 mL of hexamethylphosphoramide at room temperature under argon was treated over 10 minutes with a solution of 955.5 mg (3.97 mmol) of farnesyl chloride (Part A) in 5 mL of tetrahydrofuran. After one hour, the reaction mixture was diluted with a mixture of 1:1 diethyl ether : hexane and quenched with 1M HCl. The organic phase was washed with three 25 mL portions of saturated NaHCO3, three 25 mL portions of H2O, and 25 mL of brine, dried over MgSO4 and evaporated to obtain 995.0 mg of crude product. Purification required two chromatographies. The first was run on 70 g of silica gel, eluting with 1:99 ethyl acetate:CH2Cl2 to provide 484.3 mg of impure material and 307.7 mg of pure title compound. The second chromatography, of the impure fractions, on 50 g of silica gel eluted with 0.75:99.25 ethyl acetate:CH2Cl2 gave 117.2 mg of slightly impure material and 302.8 mg of pure title compound. Combination of pure material from both columns gave a yield a yield of 610.5 mg (58%) of pure desired title isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of 2-(4-amino-3-nitrobenzoyl)benzoic acid (50 g, 175 mmol) and potassium carbonate (50 g, 350 mmol) in N,N-dimethylformamide (200 ml), was added benzyl bromide (22.8 ml, 192 mmol). The mixture was stirred at 60° C. for 16 hours, and then partitioned between ethyl acetate (500 mL) and water. The organic portion was washed with 0.2N sodium hydroxide, water, brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The resultant residue was re-crystallized from chloroform and hexanes (1:1) to afford benzyl 2-(4-amino-3-nitrobenzoyl)benzoate (53 g, 81%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.11 (br s, 1H), 8.06-8.01 (m, 2H), 7.79-7.75 (m, 1H), 7.72-7.65 (m, 2H), 7.46 (d, 1H), 7.28-7.19 (m, 5H), 7.02 (d, 1H), 5.12 (s, 2H); MS (EI) for C21H16N2O5: 377 (MH+)
Reaction SMILES: II.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13]C)[CH:12]=1)[C:7]([OH:9])=[O:8]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1cc(Cl)cc(C(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: II
Agent: [I-]
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
Alumina (1.65 g, 60 mmol) and iodine (21 g, 82 mmol) were refluxed in toluene (200 mL) for 2 hours. Then, 3-chloro-5-methoxybenzoic acid (11.2 g, 60.2 mmol; see step (i) above) dissolved in toluene (50 mL) was added, together with tetrabutylammonium iodide (1.5 g, 4 mmol), and the mixture was refluxed for another 2 hours. After cooling to ambient temperature, extractive work up gave 8.7 g, 50 mmol (yield: 83%) of the sub-title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: O=C(c1ccccc1)N1CCC(CCCl)CC1
Product: CN(CCC1CCN(C(=O)c2ccccc2)CC1)Cc1ccccc1

Procedure:
A mixture of 1-benzoyl-4-(2-chloroethyl)piperidine (11.61 g), N-methylbenzylamine (16.75 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness and then 4M hydrochloric acid (50 ml) was added to the residue. The mixture was washed with ether and the acidic layer was then basified with 4M sodium hydroxide solution and extracted with dichloromethane to give an oil. Excess amine was distilled off at 13 mbar and the residue was triturated with petroleum ether b.p. 40°-60° C. The supernatant petroleum ether was decanted off and the residual oil was dried under vacuum to give 1-benzoyl-4-[2-(N-benzyl-N-methylamino)ethyl]piperidine. A small portion of the oil was dissolved in ether and acidified with ethereal oxalic acid. The supernatant liquid was decanted off and the solid residue was triturated with acetone and filtered to give the oxalate salt, m.p. 141°-142° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CN(CCN(C)C)C.[BH4-].[Na+].Cl>C1COCC1.COCCOCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: COCCOCCOC
Product: Clc1ncc2cc[nH]c2n1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol), palladium(II)acetate (70 mg, 0.31 mmol) and BINAP (240 mg, 0.39 mmol) are dissolved in 6 mL THF and stirred for 20 min at 20° C. Then TMEDA (300 μL; 2.0 mmol) is added, the mixture is stirred for 20 min and then sodium borohydride (189 mg; 5.11 mmol) dissolved in 10 mL diglyme is added. After 1 h at 20° C. the mixture is combined with 1 N HCl and the solvent is eliminated in vacuo. The residue is purified by column chromatography (method prep. HPLC2; 3% acetonitrile to 55% in 12 min) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (HPLC-MS: tRet.=1.25 min; MS(M+H)+=154; method FEC3) is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]([O:31]C)=O)=[N:23][N:22]4[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:40]>CO.C1COCC1>[C:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:21]2[N:22]([C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10]4)=[CH:14][CH:15]=3)[N:20]=2)[N:23]=1)(=[O:31])[NH2:40]
Reactant: N
Reactant: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Yield: 63 %

Procedure:
A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-9 (0.20 g, 0.38 mmol) in a solution of ammonia in MeOH (7 N, 15 mL) and THF (1 mL) was irradiated in a microwave apparatus at 130° C. for 90 min. The solids were collected by filtration to give tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 63%):
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1>C(#N)C>[NH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:18]1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC1CCCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1CCCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Yield: 92.3 %

Procedure:
p-Chlorobenzyl chloride (463 mg, 2.9 mmol) and K2CO3 (828 g, 6 mmol) were added to an acetonitrile (45 mL) solution of 3-aminohomopiperidine (1.71 g, 15 mmol), and the resulting mixture was stirred at 70° C. with heating for 9 hours, cooled to 25° C. and concentrated to afford a yellow solid. The resulting residue was partitioned between H2O (5 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (20 mL), dried (over MgSO4) and concentrated. The obtained yellow oil was purified by column chromatography (SiO2, 5-20% methanol/dichloromethane gradient elution) to afford the objective compounds as yellow oil (639 mg, 93%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:16][CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[N:18]1([CH2:24][CH2:25][C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1(N=C=NC2CCCCC2)CCCCC1>>[N:18]1([CH2:24][CH2:25][C:26]([O:1][C:2]2[C:7]3[C:8]4[CH2:16][CH2:15][S:14][C:9]=4[C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: O=C(O)CCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
Following a procedure similar to that described in Example 8 hereinabove, 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran is reacted with methyl magnesium bromide to give 1,2-dihydro-9-hydroxy-4,4,7-trimethyl-4H-thieno-[2,3-c] [1]benzopyran. The benzopyran is then reacted with β-piperidinopropionic acid and dicyclohexylcarbodiimide to yield the desired ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:20])[CH:15]=[C:16]([NH:18][CH3:19])[CH3:17].N1C=CC=CC=1.Cl.N1C=CC=CC=1>>[CH3:12][O:13][C:14](=[O:20])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)/[C:16](=[N:18]/[CH3:19])/[CH3:17]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: CNC(C)=CC(=O)OC
Agent: Cl
Solvent: c1ccncc1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-methyl-benzoyl chloride (40.0 mmoml) in tertahydrofuran (300 mL) wad added 3-methylamino-but-2-enoic acid methyl ester (5.12 g, 40.0 mmol), followed by pyridine (3.2 mL, 40.0 mmol), and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride coated the flask, so the mixture was decanted, and the solid was washed three times with EtOAc. The combined solutions were concentrated and diluted with EtOAc (500 mL), and the mixture was washed three times with water. The aqueous layer was separated and back-extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:7](=O)[C:6]=2[CH:20]=1.C1(C)C(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=CC=1.[O-]CC.[Na+].[Na]>O1CCCC1.C(O)C>[C:30]([CH:7]1[C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8]1)#[N:31]
Reactant: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC1CC(CCc2ccccc2)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (8.9 gm) was dissolved in anhydrous tetrahydrofuran, and toluenesulfonylmethylisocyanide (12.9 gm) added, followed by freshly prepared sodium ethoxide in ethanol (prepared from sodium (1.5 gm) in ethanol (60 mL) and the mixture stirred at room temperature overnight. The mixture was then concentrated in vacuo, and the residue partitioned between ethyl acetate and H2O, and the organic layer washed with H2O, brine, dried, filtered and evaporated. The residue was purified by column chromatography (2:1 hexanes/diethyl ether) to yield 4-cyano-2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran (2.7 gm, ir: 2250 cm-1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][OH:13])[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:35][CH2:36]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][O:13][CH2:36][O:35][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:7]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H](CCO)CCN1C(=O)OCC
Reactant: ClCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1[C@@H](CCOCOCc2ccccc2)CCN1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6 g of cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of methylene chloride containing 7.3 ml of diisopropylethylamine, to which is added 5.1 ml of 85% benzyloxymethyl chloride, is stirred 31/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:4) to yield cis ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:43])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[C:12]3[C:24]2[N:25]=[N:26][N:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)[CH:28]=2)[CH2:5]1>O1CCOCC1.C(Cl)Cl.CO>[CH3:2][N:3]([CH3:43])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[C:24]2[N:25]=[N:26][N:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])=[CH:31][CH:30]=3)[CH:28]=2)[CH2:5]1
Reactant: CN(C)C1CCN(c2ccc3c(c2)c(-c2cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn2)nn3C2CCCCO2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1CCN(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)C1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
Hydrogen chloride (0.72 mL of a 4 N solution in dioxane) was added to a solution of N,N-dimethyl-1-[3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl]pyrrolidin-3-amine (110 mg; 0.19 mmol; 1.0 eq.) in DCM (1.1 mL) and MeOH (0.55 mL). The reaction mixture was stirred at RT O/N. Solvents were then removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound as a yellow powder (65 mg, 69%). 1H NMR (300 MHz, MeOD): 8.98 (s, 1H), 8.14 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.1 Hz, 2.0 Hz, 1H), 3.80-3.68 (m, 9H), 3.63-3.43 (m, 4H), 2.84 (s, 6H), 2.61-2.51 (m, 1H), 2.30-2.21 (m, 1H). HPLC (max plot) 96.0%; Rt %2.12 min. UPLC/MS: (MS+) 487.4, (MS−) 485.3.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][O:13][C:23]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(OCCO)CC1
Reactant: NC(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCCOc2ccc(C(N)=O)cc2)CC1
Reaction time: 64 h
Yield: 45.2 %

Procedure:
N-Acetyl-4-(2-hydroxyethoxy)piperidine (5.0 g.), 3-hydroxybenzamide (4.4 g.), diethyl azodicarboxylate (5.6 g.) and triphenylphosphine (8.4 g.) in dry tetrahydrofuran (100 ml.) were stirred at 0° C. for 2 hours then at room temperature for 64 hours. The solvent was evaporated in vacuo, then the residue treated with refluxing ether (3×100 ml.) and the mother liquors decanted. The residual oil was taken up in chloroform and washed with dilute sodium hydroxide solution (40 ml.) and water (40 ml.). The chloroform layer was dried (MgSO4) then the solvent evaporated in vacuo. The residual oil was treated with ether (50 ml.) and set aside in the fridge. The resulting solid was collected, slurried with ether (30 ml.), filtered and the solid washed with ether (30 ml.) to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (3.7 g.) containing some triphenylphosphine oxide (approximately 25% by n.m.r.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17]([CH3:16])(=[O:18])=[O:19])[CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Reactant: NC[C@H]1CN(Cc2ccc(Cl)s2)CCO1
Product: CS(=O)(=O)Nc1cccc(CC(=O)NC[C@H]2CN(Cc3ccc(Cl)s3)CCO2)c1
Yield: 55 %

Procedure:
Example 49 was prepared in an analogous manner to Example 44 using a mixture of Intermediate 14 (0.1 g) and Intermediate 18 (0.1 g) to give the title compound (0.102 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12]CC(OCCCCCCCCCCCCCCCCCC)=O)=[CH:4][C:3]=1[C:35]([CH3:38])([CH3:37])[CH3:36].OC1C(C(C)(C)C)=CC(CC(C(OCCCCCCCCCCCCCCCCCC)=O)C(OCCCCCCCCCCCCCCCCCC)=O)=CC=1C.C(C1C=C(C)C=C(C(C)(C)C)C=1O)C1C=C(C)C=C(C(C)(C)C)C=1O.C(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.C(C1C(O)=C(C2(C)CCCCC2)C=C(C)C=1)C1C(O)=C(C2(C)CCCCC2)C=C(C)C=1.C(C1C(O)=C(C(C)(C)C)C=CC=1C)(C1C(O)=C(C(C)(C)C)C=CC=1C)CCC.CC1C=C(O)C(C(C)(C)C)=CC=1C(C1C=C(C(C)(C)C)C(O)=CC=1C)CC(C1C=C(C(C)(C)C)C(O)=CC=1C)C.C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C=1C)(C)(C)C.CC(C1OCC2(COC(C(C)(C)CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)OC2)CO1)(C)CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.C.C=C(CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C(O)=O.C=C(CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C(O)=O.C=C(CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C(O)=O.C=C(CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C(O)=O.C(C1C=C(CCC(NC(=O)C(=O)NC(=O)CCC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)=O)C=C(C(C)(C)C)C=1O)(C)(C)C>>[C:8]([C:7]1[C:2]([OH:1])=[C:3]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:4]=[C:5]([CH3:12])[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C
Agent: C=C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Agent: CC(C)(C)c1cc(CC(C)(C)C2OCC3(CO2)COC(C(C)(C)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC3)cc(C(C)(C)C)c1O
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
stearyl 3-(4-hydroxy-3,5-di-t-butylphenyl)propionate; distearyl (4-hydroxy-3-methyl-5-t-butylbenzyl)malonate; 2,2'-methyl enebis(4-methyl-6-t-butylphenol); 4,4'-methyl enebis(2,6-di-t-butylphenol); 2,2'-methyl enebis[6-(1-methylcyclohexyl)-p-cresol]; bis[3,3-bis (4-hydroxy-3-t-butylphenyl)butyric acid]glycol ester; 4,4', butylidenebis(6-t-butyl-m-cresol); 1,1,3-tris(2-methyl-4-hydroxy-5-t-butylphenyl)butane; 1,3,5-tris(3,5-di-t-butyl-4-hydroxy-benzyl)-2,4,6-trimethylbenzene; 3,9-bis[1,1-dimethyl-2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]-2,4,8,10-tetraoxaspiro[5.5]undecane; tetrakis[-methylene-3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]-methane;1,3,5-tris(3,5-di-t-butyl-4-hydroxybenzyl)isocyanurate and 1,3,5-tris[3,5-di-t-butyl-4-hydroxyphenyl)propionyloxyethyl]isocyanurate; bis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionyl]-oxamide.