Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@H:7]2[CH2:10][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([C:20]5[CH:21]=[N:22][N:23](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:24]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O>[N:1]1([C@H:7]2[CH2:8][C@H:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([C:20]5[CH:24]=[N:23][NH:22][CH:21]=5)[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4nc([C@H]5C[C@H](N6CCCCC6)C5)sc4c3)cn2)cc1
Solvent: O=CO
Product: c1cc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2cc1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 51A (135.0 mg, 0.23 mmole) was dissolved in formic acid (88%, 2 ml) and stirred at room temperature for 2 hours. The reaction mixture concentrated was under reduced pressure. The solid residue was then treated with saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (1% ammonium hydroxide and 10% methanol in dichloromethane) to give 71.2 mg (90.5%) of title compound. MS: (M+H)+=339.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].Cl[C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19][N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:17]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19][N:18]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COCc1cc(Cl)ncn1
Reactant: COC(=O)c1cccc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cc(Oc2ccc3c(C(=O)OC)cccc3c2)ncn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A suspension of 3.4 g (16.8 mMol) 6-hydroxy-naphthalene-1-carboxylic acid methyl ester (see Step 3.1), 3.2 g (20.2 mMol) 4-chloro-6-(methoxymethyl)pyrimidine (preparation see: BE 64 1253, p. 38; or WO 2002/45652, p. 102) and 7.85 g (37 mMol) K3PO4 in 85 ml NMP is stirred for 4 h at 90° C. The cooled mixture is diluted with 0.4 l EtOAc and 0.4 l water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Chromatography (SiO2; CH2Cl2/EtOAc 19:1→9:1→4:1) gives the title compound: m.p.: 87-88° C.; MS: [M+1]+=325; TLC (CH2Cl2/EtOAc 4:1): Rf=0.28.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CCC(=O)CC(=O)OC
Agent: [Ru]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](O)CC(=O)OC
Yield: 98.1 %

Procedure:
Into a 200-ml autoclave (made of Hastelloy) were introduced 50 g of methyl 3-oxopentanoate (manufactured by Wacker Chemicals Co., Ltd.) and 75 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 325 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 3.8 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 30° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 50 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 49.8 g of methyl (R)-3-hydroxypentanoate. Yield, 98%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]2[CH:17]=1.Cl>CO.C1COCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]2[CH:17]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
5N aqueous solution of NaOH (2 mL) was added to stirred solution of ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 0.134 mmol) in a mixture of MeOH (4 mL) and THF (4 mL) and continued stirring at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with concentrated HCl solution to obtain a solid precipitate. This solid precipitate was filtered and dried well to afford 18 mg of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as off white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][NH:29][CH3:30])=[CH:24][CH:23]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:6][CH:5]=1.[CH3:31][C:32]([CH3:38])([CH3:37])[CH2:33][C:34](Cl)=[O:35].C(N(CC)CC)C.O1CCCC1>C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:29]([CH3:30])[C:34](=[O:35])[CH2:33][C:32]([CH3:38])([CH3:37])[CH3:31])=[CH:26][CH:27]=4)[CH:14]=[N:13][C:12]=3[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CNCc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)CC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A mixture of the compound (85 mg) obtained in Example 4, 3,3-dimethylbutanoyl chloride (31 mg), triethylamine (53 mg) and tetrahydrofuran (2 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (2:1, volume ratio) to give the title compound (70 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][C@H:24]([C:37](O)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:37](=[O:38])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[NH:23][C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
In 30 ml of N,N-dimethylformamide are dissolved 2.4 g of L-proline tert-butyl ester and 5.87 g of Nα -benzyloxycarbonyl-Nε -tert-butoxycarbonyl-L-lysine, and 3 g of diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling. After stirring for 30 minutes, a solution of 1.42 g of triethylamine in 5 ml of N,N-dimethylformamide is added to the mixture, followed by stirring under ice-cooling for 1 hour and then at room temperature for 2 hours. 500 ml of water is added to the reaction mixture, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with aqueous dilute phosphoric acid, 0.1N aqueous sodium hydroxide and water, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 5.5 of N-(Nα -benzyloxycarbonyl-Nε -tert-butoxycarbonyl-L-lysyl)-L-proline tert-butyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH:39]2[CH2:44][CH2:43]C[NH:41][CH2:40]2)[N:37]=[N:36][N:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1CCC(N2C(C3C=C(C4C=C(C(C)C)C=CC=4OC)C(OCC4C=CC=CC=4)=CC=3OCC3C=CC=CC=3)=NN=N2)C1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH:39]2[CH2:44][CH2:43][NH:41][CH2:40]2)[N:37]=[N:36][N:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2C2CCCNC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2C2CCN(C(=O)OC(C)(C)C)C2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2C2CCNC2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
This product was prepared using the same procedure as for compound 35 except 3-[5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-tetrazol-1-yl]-pyrrolidine-1-carboxylic tert-butyl ester was used as starting material. M.p.: 85-87° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.34-7.10 (m, 15H), 6.96 (d, J=7.6 Hz, 1H), 5.26 (s, 2H), 5.21 (s, 2H), 4.79 (br s, 1H), 3.67 (s, 3H), 3.01 (m, 2H), 2.81 (m, 2H), 2.07 (m, 2H), 1.92 (m, 1H), 1.16 (d, J=6.0 Hz, 6H); LCMS: 576 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH3:17])[C:12](I)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:55])[CH2:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:40]=2[F:54])=[CH:32][C:31]=1[C:56]([F:59])([F:58])[F:57])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([C:42]2[CH:43]=[CH:44][C:39]([CH2:38][C:37]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][O:26][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:31]([C:56]([F:57])([F:59])[F:58])[CH:32]=3)=[O:55])=[C:40]([F:54])[CH:41]=2)=[C:13]([O:15][CH2:16][CH3:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2)OC1(C)C
Reactant: CCOc1cc(OCc2ccccc2)ncc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(OCCOCc3ccccc3)c(C(F)(F)F)c2)c(F)c1
Temperature: 100 °C
Yield: 24 %

Procedure:
A suspension of 2-(benzyloxy)-4-ethoxy-5-iodopyridine (80 mg, 0.225 mmol), N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (129 mg, 0.225 mmol), PdCl2(dppf) (16.48 mg, 0.023 mmol), Cs2CO3 (73.4 mg, 0.225 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was heated to 100° C. for 20 min under a N2 atmosphere in a microwave. Then the mixture was concentrated to give the residue which was extracted with DCM (20 mL×2). The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (EA/PE=1:1, Rf=0.5) to yield 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide (60 mg, 0.054 mmol, 24.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.95 (s., 1H), 7.85-7.84 (d, J=2.4 Hz, 1H), 7.74-7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.44-7.42 (m, 2H), 7.38-7.24 (m, 10H), 7.16-7.14 (d, J=8.8 Hz, 1H), 6.48 (s, 1H), 5.35 (s, 2H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 4.15-4.10 (m, 3H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H), 3.66-3.65 (m, 1H), 3.55-3.54 (m, 1H), 1.36 (t, J=7.2 Hz, 3H); ES-LCMS m/z 721 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18](O)=O>Cl>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18]1[NH:1][C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: COCCCC(=O)O
Reactant: COC(=O)c1cccc(N)c1N
Agent: Cl
Product: COCCCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C

Procedure:
A solution of 4 g of methyl 2,3-diaminobenzoate and 8.53 g of 4-methoxybutyric acid in 70 ml of 4N HCl is stirred at reflux over 21 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase is concentrated by evaporation—the residue is diluted with 100 ml of methanol and 2 ml of conc. H2SO4 and stirred at reflux over 45 hours. The reaction mixture is cooled to room temperature, neutralized with saturated aqueous sodium bicarbonate solution and concentrated by evaporation. The residue is diluted with water and extracted with ethyl acetate (2×)—the combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a red solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (95:5 dichloromethane-methanol); Rt=2.53.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][CH3:16])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][CH3:16])=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: CNCc1c(C)noc1-c1ccc(Br)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-methyl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N:1]1([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl>[C:15]([N:4]1[CH2:3][CH2:2][N:1]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-piperazinyl)-tert-butoxycarboxamide (15 g) in dichloromethane (200 ml) was added acetic anhydride (7.74 ml) and pyridine (6.63 ml). The mixture was stirred at ambient temperature for 1 hour. The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was triturated with n-hexane to give N-(4-acetyl-1-piperazinyl)-tert-butoxycarboxamide (16.4 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>CO>[OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Solvent: NCCN
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(O)C1

Procedure:
3-Hydroxy-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.020 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and evaporated to dry. The resultant residue was mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) for 2 h. The reaction was concentrated and purified on prep. LCMS (pH=10) to give 2 isomers of the desired products. First peak retention time 0.714 min, LCMS calculated for C15H15N6O(M+H)+: 295.1; Found: 295.3. Second peak retention time 0.750 min, LCMS calculated for C15H15N6O(M+H)+: 295.1; Found: 295.3. 1H NMR (400 MHz, CD3OD): δ 8.67 (1H, s), 8.66 (1H, s), 8.38 (1H, s), 7.51 (1H, d, J=3.6 Hz), 6.98 (1H, d, J=3.6 Hz), 4.37 (1H, s), 3.34 (2H, s), 3.22 (2H, m), 2.48 (2H, m) ppm.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[I-:20].[Na+].CCCCCC>COCCOC>[OH:15][C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][I:20])=[CH:6][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)CI)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 6.54 g (20 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-tert-butylphenyl)-ethanone in 25 ml of 1,2-dimethoxyethane, a solution of 3.14 g (21 mmol) of sodium iodide in 25 ml of 1,2-dimethoxyethane is added dropwise at room temperature. After the addition, stirring is continued for 16 hours at room temperature. Then 10 ml of hexane is added and, after stirring for additional 15 minutes, the precipitated salts are removed by filtration. The obtained solution is evaporated and the resulting residue is purified by recrystallization from hexane to give 5.21 g (70%) of compound 202, m.p. 88-89° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[C:8]([CH3:19])([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:35])[F:36])[C:8]([CH3:19])([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OCC(C)(c1ccncc1)C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(c2ccncc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of (3RS,4RS)-7-methoxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-3-(4-pyridyl)chroman (15.2 mg, 0.0265 mmol) in methylene chloride (1 ml) was added at −78° C. BBr3 (1.0 mol/l, 0.080 ml), which was then slowly warmed, and stirred for 2 hours under ice-cooling. After the reaction was completed saturated aqueous NaHCO3, solution was added under ice-cooling, the resulting mixture was then extracted with chloroform and washed with saturated saline solution. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give (3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-3-(4-pyridyl)chroman (6.3 mg, yield 43%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](Cl)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C(O)C.[Pd]>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:18]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CNC(=O)C2CCNCC2)c(OC)c1

Procedure:
1-Benzyloxycarbonyl-4-[N-2,4-dimethoxybenzylcarbamoyl]piperidine was prepared similarly to Preparation C starting from 1-benzyloxycarbonylpiperidine-4-carboxylic acid chloride and 2,4-dimethoxybenzylamine. The product was identified by n.m.r. spectroscopy. This product (7.6 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal at 50°/50 p.s.i. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give 4-[N-(2,4-dimethoxybenzyl)carbamoyl]piperidine (5.0 g) as a solid. A sample in chloroform was converted to the hydrochloride salt by treatment with ethereal hydrogen chloride and recrystallised from isopropanol, m.p. 222°-224°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=O)[CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:15](Br)(Br)([Br:17])[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Zn].ClCCl>[Br:16][C:15]([Br:17])=[CH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[S:5][CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C=C(Br)Br)cc21
Reaction time: 2 h

Procedure:
5 g (24.2 mmol) of 4,4-dimethyl-6-thiochromancarboxaldehyde, prepared in Example 11(a), and 50 ml of dichloromethane were introduced into a round-bottomed flask. 16.1 g (48.4 mmol) of carbon tetrabromide, 12.7 g (48.4 mmol) of triphenylphosphine and 3.16 g (48.4 mmol) of zinc powder were successively added and stirring was carried out at room temperature for two hours. The reaction mixture was evaporated and the residue obtained purified by chromatography on a silica column eluted with hexane. 7.75 g (88%) of the expected compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][CH:17]=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].CC(=CC)C.[O-:24]Cl=O.[Na+].[NH4+].[Cl-]>C(O)(C)(C)C.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([OH:24])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7]
Reactant: [O-][Cl+][O-]
Reactant: Cc1c(Br)cnn1CC1(OCC=O)CCCCC1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)cnn1CC1(OCC(=O)O)CCCCC1

Procedure:
To a solution of EXAMPLE 174A (3.15 g) in t-butanol (200 mL) and tetrahydrofuran (50 mL) was added 2-methyl-2-butene (8 mL). The mixture was allowed to stir in an ice bath. NaClO2 (1.2 g) and NaH2PO4 (3 g) were dissolved into water (75 mL), and the solution was added to the mixture. The mixture was allowed to stir in an ice bath for 15 minutes, and then stirred at room temperature for 12 hours. NH4Cl was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to provide the title compound.