Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:4][N:5]([CH3:7])[CH:6]=1.[CH2:17]1COCC1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.CI.[NH4+].[Cl-]>>[Br:1][C:2]1[C:3]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12])=[N:4][N:5]([CH3:7])[C:6]=1[CH3:17]
Reactant: Cn1cc(Br)c(CO[Si](C)(C)C(C)(C)C)n1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CI
Solvent: C1CCCCC1
Product: Cc1c(Br)c(CO[Si](C)(C)C(C)(C)C)nn1C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-1H-pyrazole (130.0 mg, 0.4258 mmol) in THF (2 mL, 20 mmol) was cooled to −78° C., and 1.5 M of LDA in cyclohexane (0.85 mL, 1.3 mmol) was added. After stirring for 1 h, methyliodide (0.1 mL, 2 mmol) was added slowly, and the mixture was stirred at −78° C. for 1 h. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=0.07 (s, 6H), 0.86 (s, 9H), 2.21 (s, 3H), 3.73 (s, 3H), 4.50 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14]([N:16]1[CH2:36][CH2:35][CH2:34][C@H:17]1[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)=[O:19])=[O:15])[CH2:10][CH:11]1[CH2:13][CH2:12]1)=O)(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[CH:11]1([CH2:10][C@H:9]([C:14]([N:16]2[CH2:36][CH2:35][CH2:34][C@H:17]2[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[O:19])=[O:15])[NH2:8])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(F)ccc1-n1cncn1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@H](CC1CC1)C(=O)N1CCC[C@H]1C(=O)NCc1cc(F)ccc1-n1cncn1
Yield: 79.6 %

Procedure:
A solution of N-{tert-butoxycarbonyl}-3-cyclopropyl-D-alanyl-N-[5-fluoro-2-{1H-1,2,4-triazol-1-yl }benzyl]-L-prolinamide (35 mg, 0.069 mmol) in EtOAc (1 mL) was treated with 1 mL of 3.5N HCl/EtOAc at 0° C. for 1 h and at room temperature for 3 h. The solvent was removed under reduced pressure and the residue triturated with EtOAc to give 22 mg of the title compound as the hydrochloride salt. 1H NMR (400 MHz, CDCl3): d 8.9 (s, 1H), 8.73 (br s, 1H), 8.35 (br, 2H), 8.23 (s, 1H), 7.48–7.51 (m, 1H), 7.24–7.29 (m, 2H), 4.27–4.30 (d, J=8.52 Hz, 1H), 4.07–4.14 (m, 3H), 3.55 (m, 2H), 2.09 (m, 1H), 1.84–1.88 (m, 3H), 1.67–1.72 (m, 1H), 1.51–1.55 (m, 1H), 0.78 (m, 1H), 0.42 (m, 2H), 0.06–0.11 (m, 2H).
Reaction SMILES: C1C([N+]([O-])=O)=CC=C(Cl)C=1.C([O:13][CH:14](OCC)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])C.C(O)CCCCCCCC=C>>[CH:14](=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]
Reactant: C=CCCCCCCCC(OCC)OCC
Agent: C=CCCCCCCCCO
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Product: C=CCCCCCCCC=O

Procedure:
FIG. 40 shows a synthesis of PNCB which involves the cross-metathesis of vinyl borate pinacol ester (Matheson, D. S J Am Chem Soc (1960) 82, 4228-4233) with 9-decenal diethyl acetal (synthesized by the Swern oxidation of commercially available 9-decenol to yield 9-decenal, then protecting it as the acetal with ethanol and hydrochloric acid) with Catalyst 823 to yield the pinacol ester of 1-borodecenal diethyl acetal. This product was coupled with Z-1-iodohexene (Normant Org Syn VII, p 290-294) under Suzuki conditions as described by Miycuira Org Syn VIII p 532, to yield E-9,Z-11-hexadecadienal diethyl acetal. This material was purified by column chromatography, and the acetal was hydrolyzed in aqueous methanol and water with cat p-toluenesulfonic acid at 35° C. for 24 hours. E-9,Z-11-hexadecadienal was isolated by concentrating the reaction mixture and purified by column chromatography.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:32])[CH:12]=[CH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([CH3:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:18]=3[CH:31]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([S:7]([NH:10][C:11](=[O:32])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]3[N:21]=[C:20]([CH3:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:18]=3[CH:31]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: Cc1nc2ccc(C=CC(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2ccc(CCC(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Yield: 41 %

Procedure:
5% Palladium on carbon (0.500 g) was added to a solution of 0.607 g of N-benzenesulfonyl-1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylamide in 150 ml of ethanol, and the mixture was stirred in a hydrogen atmosphere at room temperature for 43 hours. The solid material was separated through filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solution of a 20% potassium hydrogencarbonate aqueous solution and methanol, and was adjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitated were separated through filtration, and was dried to give 0.250 g of N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]propionamide (266).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2C=[CH:2]1)C3.[Br:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[Br:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(F)(F)C(F)(F)Br
Agent: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(Br)C(F)(F)C1CC2C=CC1C2
Temperature: 170 °C
Reaction time: 5 h
Yield: 145.5 %

Procedure:
An autoclave was charged with 108.5 g of dicyclopentadiene and 322.4 g of 1-bromo-1,1,2,2-tetrafluoro-3-butene. A solution of 0.3 g of 4-methoxyphenol dissolved in 5 ml of toluene was added to the autoclave as a polymerization inhibitor and the mixture was stirred for 5 hours at 170° C. The reaction product was purified by distillation under reduced pressure at 85° C. and 25 mmHg to obtain 326 g of 1-bromo-1,1,2,2-tetrafluoro-2-(norborn-5-en-2-yl)ethane as a clear liquid (hereinafter referred to as “compound (1-a)”).
Reaction SMILES: [K].[CH:2]1([OH:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:12]I>O>[CH3:12][O:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:9])[CH2:3][CH2:4]1
Reactant: OC1CCC(O)CC1
Reactant: CI
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Product: COC1CCC(O)CC1

Procedure:
To mono-potassium salt of 1,4-cyclohexanediol which had been prepared from 17.5 g of 1,4-cyclohexanediol and 9.3 g of potassium hydroxide, 32 g of methyl iodide was added, and the resultant mixture was heated under reflux for 5 hours. After the reaction was completed, water was added and then the mixture was extracted with chloroform. The extract was subjected to distillation under reduced pressure to obtain 10.34 g of 4-methoxycyclohexanol. b15 : 100°-103° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].Cl.O>O1CCCC1.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:26][C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=O)Oc2ccc(Cl)c([N+](=O)[O-])c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 106.1 %

Procedure:
3,5-Di-t-butyl-4-hydroxybenzoyl chloride (56.2 g; 0.209 mole) in tetrahydrofuran (70 ml) was added with stirring to a solution of 4-chloro-3-nitrophenol (36.3 g; 0.209 mole) in pyridine (170 ml) at 0° C. over 20 minutes. The reaction mixture was stirred at room temperature for 22 hours and poured into an ice cold solution of 10M-hydrochloric acid (350 ml) and water (1400 ml). The mixture was extracted into ether (500 ml) and the ethereal extract washed successively with 2M-hydrochloric acid (150 ml), 2% sodium carbonate solution (4×150 ml) and water (2×100 ml). The extract was dried and the ether removed to give a dark orange oil (90 g). This material was chromatographed (silica) eluting with 4:1 hexane:ethyl acetate, to give the product (60.6 g; 72%) as a yellow viscous oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](Cl)=[O:50])[CH3:47]>>[CH2:46]([N:48]([CH2:52][CH3:53])[C:49](=[O:50])[NH:36][CH2:35][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:38])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12)[CH3:47]
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Product: CCN(CC)C(=O)NCCC[Si](C)(C)CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@@]3(CC)OC(C)=O

Procedure:
The required product was prepared according to Procedure E, above, using Compound 21 and diethylcarbamyl chloride. The required product was obtained in 70% yield.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:17]([O:21][C:22](=[O:43])[NH:23][C:24]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:17]([O:21][C:22](=[O:43])[NH:23][C:24]1([C:28]2[CH:29]=[CH:30][C:31]([C:2]3[C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:4][C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Reactant: Clc1nn2ccnc2cc1-c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nn4ccnc4cc3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
100 mg (0.44 mmol) 6-Chloro-7-phenyl-imidazo[1,2-b]pyridazine (intermediate example Int-1-0) in 1.5 mL DME, 178.8 mg (0.48 mmol) {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, 0.85 mL aqueous sodium carbonate (10%) and 16 mg (0.02 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) were put in a microwave vial (no complete dissolution). The reaction mixture was degassed with argon, the vial closed with a cap and put in a heating block. The reaction mixture was stirred for 18 h at 90° C. (complete dissolution). Due to the still presence of starting material additional 86 mg boronic ester, 0.42 mL aqueous base and 8 mg palladium catalyst were added and stirring was continued for 6 hours at 90° C. 20 mL water and 100 mL dichloromethane were added and the reaction mixture was vigorously stirred for one hour. After separation of the organic phase the aqueous phase was extracted once more with dichloromethane. The combined organic extracts were washed with water and dried over sodium sulfate. After removal of the drying agent the solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) yielding 109 mg (56.8%) of the desired compound which was yet slightly contaminated.
Reaction SMILES: C(OC[N:9]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[N:11]=[N:10]1)(=O)C(C)(C)C.[OH-].[Na+].Cl>CO.C1COCC1.O>[N:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[N:18][CH:17]=2)[CH:13]=1
Reactant: CC(C)(C)C(=O)OCn1cc(COc2ccc(-n3cnnn3)nc2)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Reaction time: 0.5 h

Procedure:
To a solution of (4-((6-(1H-tetrazol-1-yl)pyridin-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl pivalate (10 g, 27.9 mmol) in MeOH (60 mL) and THF (6 mL) was added sodium hydroxide (61.5 mL of a 1M solution in water). The mixture was stirred for 30 minutes and hydrochloric acid was added (61.5 mL of a 1M solution in water). The resulting solution was extracted with ethyl acetate, separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford the expected product which was used in subsequent steps without further purification. 1H NMR (DMSO-d6): δ 10.07 (1H, s), 8.43-8.41 (2H, m), 8.00 (1H, d, J=8.8 Hz), 7.88 (1H, dd, J=3.2, 8.8 Hz), 6.32 (2H, s), 5.38 (2H, s), 1.08 (9H, s).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C1COCC1>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)(=[O:39])=[O:38])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: Cc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a stirred solution of 2-bromo-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridin-4-amine (Description 59) (487 mg, 1.461 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added LiHMDS (1M solution in THF) (1.608 mL, 1.608 mmol) and 3-chlorobenzenesulfonyl chloride (0.226 mL, 1.608 mmol). The reaction mixture was warmed to RT under a nitrogen atmosphere for ca. 1 h and was then partitioned between ethyl acetate and water (ca. 30 mL each). The aqueous layer was separated and re-extracted with ethyl acetate (ca. 30 mL) and the combined organic layer passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (320 mg). LCMS (A) m/z: 508/510 [M+1]+, Rt 1.60 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19](Cl)[N:18]=3)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:35]2[C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=[C:34]2[CH2:32][CH3:33])[N:18]=3)([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)n(C)c2n1
Temperature: 100 °C
Yield: 83.7 %

Procedure:
A mixture of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.52 mmol), 2-ethylbenzimidazole (968 mg, 6.62 mmol), tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol), XPhos (263 mg, 0.55 mmol) and K3PO4 (2.34 g, 11.04 mmol) in dioxane (50 mL) was purged with N2 then heated at 100° C. for 6 h before further tris(dibenzylideneacetone)dipalladium (126 mg, 0.14 mmol) and XPhos (263 mg, 0.55 mmol) were added. The resulting mixture was heated at 100° C. for 18 h then diluted with 2-methyl THF and filtered through Celite®. The filtrate was washed with H2O and brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 40-100%) affording 4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.6 g, 84%). LCMS (method H): RT 2.99 min, [M+H]+ 563.4
Reaction SMILES: O.NN.C1(=O)[N:8](C(N)=O)[C:7](=O)[C:6]2=CC=CC=C12.O=C1C2C(=CC=CC=2)C(=O)N1CC[C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([C:40]([NH2:42])=[O:41])=[CH:35][CH:34]=2.CN1C(N)=NC(=O)C1.S([O-])([O-])(=O)=O>C(O)C.O>[NH2:8][CH2:7][CH2:6][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:40]([NH2:42])=[O:41])[CH:37]=2)[NH:32][CH:31]=1
Reactant: NC(=O)c1ccc2[nH]c(CCN3C(=O)c4ccccc4C3=O)cc2c1
Reactant: NC(=O)N1C(=O)c2ccccc2C1=O
Agent: CN1CC(=O)N=C1N
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: NCCc1c[nH]c2ccc(C(N)=O)cc12

Procedure:
Hydrazine hydrate (30 ml) was added to the crude phthalimido carboxamide prepared in (ii) above (1.5 g) in ethanol (60 ml). The mixture was refluxed for 2.5 hours and cooled. The solvent was evaporated off and the residue stirred with 2 N sodium carbonate solution (60 ml) and the resulting solution was evaporated to dryness. The residue was extracted with ethanol and the combined extracts were evaporated to give a yellow solid that was dissolved in hot ethanol (45 ml) and treated with a solution of creatinine sulphate (1.6 g) in water (20 ml) and ethanol (10 ml). The solution obtained was diluted with ethanol to 85 ml. The title compound (1.8 g) precipitated as an off-white solid m.p. 205°-210° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[C:39](N1C=CN=C1)([N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1)=[O:40].P([O-])([O-])([O-])=O>ClCCl.[H-].[Na+]>[N:41]1([C:39]([O:38][C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@H:10]([S:12][C@@H:13]2[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=3[F:31])[O:15][CH2:14]2)[CH3:11])=[O:40])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)n1ccnc1)c1ccc(F)cc1F
Yield: 69.6 %

Procedure:
4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (4.90 g, 9.03 mmol) described in Reference example 1 and 1,1′-carbonyldiimidazole (1.53 g, 9.44 mmol) were dissolved in dichloromethane (20 ml). To the mixture was added sodium hydride (55% dispersion in mineral oil; 10 mg, 2.3×10−4 mol), and the reaction mixture was heated under reflux for 3 hours with stirring. After cooling, a phosphate buffer solution (pH 7.4) was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:1˜1:0) to afford the title compound (4.00 g, 70% yield) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[NH:20][CH:21]=2)[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][O:27][CH3:28].BrCC1CC1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[CH:17]=[C:18]([CH3:23])[C:19](=[O:22])[N:20]([CH2:25][CH2:26][O:27][CH3:28])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: COCCBr
Reactant: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Agent: BrCC1CC1
Product: COCCn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cc(C)c1=O

Procedure:
The title compound from Example 242, step 1 was reacted in a manner similar to Example 242, step 2 except that 1-bromo-2-methoxyethane was substituted for bromomethylcyclopropane to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.86-7.83 (m, 2H), 7.65 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.22 (t, J=4.8 Hz, 1H), 3.96 (d, J=6.8 Hz, 1H), 3.74 (t, J=4.8 Hz, 1H), 3.34 (s, 3H), 3.07 (s, 3H), 2.23 (s, 3H), 1.30-1.27 (m, 1H), 0.70-0.66 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 392.2 (M+1)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)ccc1SCC(=O)OC(C)(C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 20A], (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid tert-butyl ester (example 20C]), was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give {2-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenylsulfanyl}-acetic acid tert-butyl ester, which was subsequently saponified in analogy to the procedure described in example 20B] to yield the title compound as white solid of mp. 168–169° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOCCn1ccnc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 68.0 g of imidazole, 318 g of 2-[2-(2-methoxyethoxy)ethoxy]ethyl p-toluenesulfonate, 276 g of potassium carbonate, and 1,000 g of N,N-dimethylformamide was heated and stirred at 100° C. for 16 hours. To the reaction solution was added ethyl acetate. The precipitate was filtered off, after which the solvent was distilled off in vacuo. The residue was purified by distillation in vacuo, obtaining 163 g of 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-1H-imidazole (boiling point 121° C./16 Pa, yield 76%).