Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]#[CH:26])[CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:27]1([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35](I)=[C:36]([OH:38])[CH:37]=2)[CH2:29][CH2:28]1.CN(C)C(N(C)C)=N>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([Si:5]([O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]2[O:38][C:36]3[CH:37]=[C:32]([O:31][CH2:30][CH:27]4[CH2:28][CH2:29]4)[CH:33]=[CH:34][C:35]=3[CH:26]=2)[CH2:23][CH2:24]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Oc1cc(OCC2CC2)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(c2cc3ccc(OCC4CC4)cc3o2)CC1)(c1ccccc1)c1ccccc1
Yield: 66 %

Procedure:
A solution of tert-butyl [(4-ethynylcyclohexyl)oxy]diphenylsilane (3.52 g), 5-(cyclopropylmethoxy)-2-iodophenol (2.82 g), bis(triphenylphosphine)palladium(II) dichloride (0.34 g), copper iodide (0.09 g) and 1,1,3,3-tetramethylguanidine (3.65 mL) in DMF (30 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (3.36 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:4]2[C:5]([S:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Nc1cc(Cl)cnc1Sc1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Sc1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-chloro-2-(pyridin-4-ylsulfanyl)-pyridin-3-ylamine (100 mg, 0.42 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (117 mg, 0.42 mmol) in pyridine (0.25 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc and brine. The aqueous portion was separated and extracted with EtOAc. The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was treated with 0.3 M aqueous NaOH and washed with CH2Cl2. The aqueous portion was acidified with conc HCl to pH 3 and extracted with EtOAc. The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was separated by preparative HPLC (20→80% gradient of ACN-water) and pure product fractions were lyophilized to provide pure product as a solid. Mass spectrum m/z: 480.0 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+:37]>O.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:35])/[CH:11]=[CH:12]/[C:13]1[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][N:16]2[C:25]=1[CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]([O-:6])=[O:5].[Na+:37]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2c3ccccc3cnn2c1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccccc2)c2c3ccccc3cnn12
Yield: 81.8 %

Procedure:
A solution of a 3:2 mixture of the erythro- and threo-isomers of ethyl (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-hept -6-enoate (0.26 g; prepared as described in Example 1) and sodium hydroxide (22 mg) in water (1.0 ml) and methanol (10 ml) was stirred at the ambient temperature under an atmosphere of argon for 3 hours. The solution was then evaporated in vacuo and the residue was dried by treatment twice with methanol (2×10 ml) and once with diethyl ether (10 ml) followed each time by evaporation in vacuo, finally drying under high vacuum, to give sodium (E)-3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]phthalazin-2-yl)-hept-6-enoate (0.21 g) in the form of a yellow solid, m.p. 209°-215° C. [Elemental analysis: C, 65.8; H, 6.1; N, 5.4; H2O, 4.9%; calculated for C27H27N2O4Na:1.5H2O: C, 65.7; H, 6.13; N, 5.7; H2O, 5.5%; NMR (in a mixture of DMSO-d6 and D2O): 1.10-1.32 (2 H, m), 1.5 (6 H, d, J=7 Hz), 1.7-2.1 (2 H, m), 3.50-3.86 (2 H, m), 4.02-4.16 (1 H, m), 5.28 and 5.36 (1 H, two dd, J=16 Hz, 6 Hz), 6.46 (1 H, dd, J=16 Hz, 1 Hz), 7.16-7.60 (8 H, m), 7.78-7.88 (1 H, m), 8.57 (1 H, s)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.S1C2C=CC=CC=2C(N2CCNCC2)=N1.[Na+].[I-]>C(#N)C>[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]3[CH3:14])[CH2:29][CH2:30]2)=[N:17]1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 65 °C
Yield: 61.3 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.70 g), 1-(1,2-benzisothiazol-3-yl)piperazine 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.72 g), K2 CO3 (8.13 g) and NaI (300 mg) in acetonitrile (200 ml) was heated at 65° C. for 16 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.77 g of crystals, m.p. 209°-214° C.
Reaction SMILES: [O:1]=[V:2].[ClH:3].[ClH:4].[ClH:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[OH:14])=[CH:9][CH:8]=1>>[O-2:14].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[O:14][V+2:2]([O:14][Si:13]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[O:1][Si:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:5])=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][C:25]([Cl:4])=[CH:24][CH:23]=2)[C:10]2[CH:9]=[CH:8][C:7]([Cl:3])=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: Cl
Reactant: O=[V]
Reactant: O[Si](c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: Clc1ccc([Si](O[V+2](O[Si](c2ccc(Cl)cc2)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)O[Si](c2ccc(Cl)cc2)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Product: [O-2]

Procedure:
vanadium oxytrichloride is reacted with tri-(p-chlorophenyl)-silanol [m.p. 127°-128°C] to produce tris-[tri-(p-chlorophenyl)-siloxy]vanadium oxide [m.p. 181°C.]; vanadium oxytrichloride is reacted with tri-(p-bromophenyl)-silanol [m.p. 120°-121°C.] to produce the tris-[tri-(p-bromophenyl)-silox]-vanadium oxide [m.p. 175°C.]; and vanadium oxytrichloride is reacted with tri-4-biphenylyl-silanol [m.p. 199°-200°C.] to produce tris-[tri-(4-biphenylyl)-siloxy]-vanadium oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]=1[CH:6]=O)[CH3:2].[C:27]([O:33][CH:34]([CH3:36])[CH3:35])(=[O:32])[CH2:28][C:29]([CH3:31])=O.C(O)(=O)C.N1CCCCC1.[CH3:47][CH2:48][O:49][C:50](/[CH:52]=[C:53](\[NH2:55])/[CH3:54])=[O:51]>C(O)CCC>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:5]=1[CH:6]1[C:28]([C:27]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[C:29]([CH3:31])[NH:55][C:53]([CH3:54])=[C:52]1[C:50]([O:49][CH2:48][CH3:47])=[O:51])[CH3:2]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C=O
Reactant: CCOC(=O)/C=C(/C)N
Solvent: C1CCNCC1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C1C(C(=O)OCC)=C(C)NC(C)=C1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2-Ethoxy-6-pentadecyl benzaldehyde (3 g, 8.3 mmol) and isopropyl acetoacetate (1.19 g, 8.3 mmol) were dissolved in n-butanol (20 mL). Acetic acid (0.5 g, 8.3 mmol) and piperidine (0.7 g, 8.3 mmol) were added and stirred at room temperature for 3-4 hrs. Ethyl-3-amino crotonate (1.08 g, 8.3 mmol) was then added and refluxed for 10 hrs. n-Butanol was evaporated and reaction mixture was washed with distilled water and extracted with dichloromethane (10 mL). Organic layer was dried over sodium sulfate, evaporated and compound was purified by column chromatography using silica gel (100-200 mesh) with hexane:EtOAc (94:6) solvent system to give ethyl isopropyl 1,4-dihydro-4-(2′-ethoxy-6′-pentadecylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate as viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:17])[C:11](=O)[C:12]([F:15])([F:14])[F:13]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:17])=[C:11]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(Br)C(=O)C(F)(F)F
Solvent: COCCOC
Product: Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Temperature: 25 °C

Procedure:
A solution of 6-chloro-3-aminopyridazine x34 (3.16 g, 1 eq, 24.2 mmol) and 3-bromo-1,1,1-trifluorobutan-2-one (5 g, 1 eq, 24.4 mmol) in 1,2-dimethoxyethane (100 ml) is refluxed during 17 hours. After cooling to room temperature and filtration, the solvent is removed under reduced pressure and the crude mixture is purified by preparative chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/2/0.2 (v/v/v)) leading to 6-chloro-3-methyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x35.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=C([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)C#N)=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[OH-:34].[K+].[CH3:36][CH2:37][OH:38]>O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=[C:36]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:37]([OH:34])=[O:38])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Reactant: [OH-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: CC(C)(C)n1c(-c2cc(C(=O)O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 80 °C

Procedure:
To a mixture of 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-benzonitrile (Example 7) (400 mg, 0.92 mmol) in EtOH (10 mL) is added KOH (103 mg, 1.8 mmol) in H2O (1 mL) at room temperature. The mixture is heated to 80° C. for 48 hours. The solution is cooled down and is concentrated under vacuum. The residue is dissolved in H2O (10 mL) and the pH of the solution is adjusted to 6 with 2M HCl solution. The white solid that precipitates out from the solution is collected by filtration. The white solid is dried under vacuum providing the title compound. LCMS (ESMS): m/z 455.20 (M++1)
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].NCC#CC1C=CC([Cl:31])=CC=1C(=O)C1C=CC=CC=1>>[NH2:1][CH2:2][C:3]#[C:4][C:5]1([Cl:31])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Product: NCC#CC1(Cl)C=CC=CC1C(=O)c1ccccc1Cl

Procedure:
The preparation of 3-amino-1-[4-chloro-2-(2-chlorobenzoyl)phenyl]propyne was conducted in the same manner as the preparation of 3-amino-1-[4-chloro-2-benzoylphenyl]propyne [Method A] to give pale yellow prisms, mp 81°-82° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])C.C1COCC1.[OH-].[K+].Cl>C(O)C>[Cl:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:21])[N:8]=3)[S:19][C:18]=12
Reactant: CCOC(=O)c1sc(-c2cc3nccc(Cl)c3s2)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)O
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a solution of 15.2 g (46.2 mmol) 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 80 mL of THF and 20 mL of absolute ethanol was added (13 g, 231 mmol) freshly ground potassium hydroxide. The reaction was stirred at room temperature for sixteen hours. The reaction was cooled to 0° C. and the pH was adjusted to pH 3 with conc HCl. The resulting yellow precipitate was filtered and dried to give 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylic acid (10.3 g) in 72% yield. C12H7N2O2S2: APCI m/z 310.2/312.2 (pos.); 1H NMR (d6-DMSO): δ 8.67 (d, 1H, J=5.0 Hz), 8.42 (s, 1H), 7.65 (d, 1H, J=5.0 Hz), 2.65 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(C)c(-c3ccccc3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2)sc2c(Cl)c(Cl)c(O)cc12
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A mixture of 2.5 g of 6,7-dichloro-5-methoxy-3-methyl-2-phenylbenzo[b]thiophene and 20 g of pyridine hydrochloride is stirred at 185°-190° for 3 hours. The cooled mixture is triturated with water and extracted 3 times with ether. The combined ether extracts is washed with dilute hydrochloric acid, water and dried. Removal of solvent leaves a brownish solid which is purified by passing it though a silica gel column packed in hexane. Elution with 50:50 ether-hexane gave 1.8 g of 6,7-dichloro-5-hydroxy-3-methyl-2-phenylbenzo[b]thiophene as colorless crystals, mp 146°-147°. For analysis, a sample is recrystallized twice from ether-hexane (10% of ether) and dried at 100°.
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO>[O:37]1[CH2:38][CH2:39][N:34]([C:3]([C:5]2[N:10]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:17]=3)[N:8]=[C:7]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[CH:6]=2)=[O:4])[CH2:35][CH2:36]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)N3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (200 mg, 0.45 mmol) and morpholine (0.5 ml, 5.73 mmol) in anhydrous methanol (5.0 ml) was heated at 120° C. for 18 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was triturated with diethylether. The resulting solid was collected by filtration to give the title compound (120 mg, 52%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([CH2:12][NH:13][C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])=[CH:16][CH:15]=1)=[O:11].C(Cl)[Cl:30]>>[ClH:30].[CH3:8][O:9][C:10]([CH2:12][NH:13][C:14]1[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[O:11]
Reactant: ClCCl
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNc1ccc(/C=C/C(=O)O)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution of 50% TFA in CH2Cl2 (75 mL) was added to tert-butyl (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]acrylate (5.20 g, 17.8 mmole). The reaction was stirred at room temperature for 45 min then was concentrated under vacuum. The residue was taken up in 4.0 N HCl in dioxane (75 mL), stirred for 5 min, then concentrated to dryness under vacuum. The remaining solid was triturated with 1:1 Et2O/petroleum ether, filtered and dried under vacuum to give the title compound (4.87 g, 100%) as a white solid: MS (ES) m/e 237.2 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[C:26]([O:30][C:31]([NH:33][C:34]1[CH:35]=[C:36](O)[CH:37]=[CH:38][CH:39]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:38]3[CH:39]=[C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:35]=[CH:36][CH:37]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: OC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(OC2CCN(c3ccncc3)CC2)c1
Temperature: 4 °C
Yield: 66.2 %

Procedure:
Diethyl azodicarboxylate (3 ml) was added over 15 minutes to a stirred mixture of 1-(4-pyridyl)piperidin-4-ol (3.39 g), 3-(N-tert-butoxycarbonylamino)phenol (Chemical Abstracts, vol. 119, abstract 139113; PCT Patent Application WO 9306085; 3.98 g), triphenylphosphine (4.99 g) and THF (150 ml) which had been cooled to 4° C. The resultant mixture was stirred for 48 hours at ambient temperature. The solvent was evaporated and the residue was purified by column chromatography using a 9:1 mixture of methylene chloride and methanol as eluent. The resultant foam was crystallised from diethyl ether to give tert-butyl N-{3-[1-(4-pyridyl)piperidin-4-yloxy]phenyl}carbamate (4.65 g), m.p. 165-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36]([OH:38])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCC[N:47]([CH3:49])C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:61][O:62]CN>CN(C=O)C.O.C(N(CC)CC)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36](=[O:38])[N:47]([O:62][CH3:61])[CH3:49])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13]1)=[O:20]
Reactant: CCN=C=NCCCN(C)C
Reactant: COCN
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (7.5 g), WSC.HCL (4.06 g) and HOBt (3.25 g) were dissolved in DMF (50 ml), N-methoxymethylamine hydrochloride (1.38 g) and triethylamine (7.88 ml) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:4-9:1) was concentrated under reduced pressure to give the object product (4.76 g).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3](O)[CH:2]=1.[OH-:9].[Na+].CS(C)=O.Cl[CH2:16][CH2:17][CH2:18][Si:19]([CH3:24])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[CH:1]=[C:2]([CH:3]=[CH:4][CH:5]=1)[O:9][CH2:16][CH2:17][CH2:18][Si:19]([CH3:24])([O:22][CH3:23])[O:20][CH3:21]
Reactant: Nc1ccc(O)cc1
Reactant: [OH-]
Reactant: CO[Si](C)(CCCCl)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CO[Si](C)(CCCOc1cccc(N)c1)OC
Temperature: 115 °C
Yield: 80 %

Procedure:
Using the general procedure described in Example 1 a reactor was charged with 60 g (0.55 mole) of p-aminophenol, 43.28 g of a 50% by weight aqueous solution of sodium hydroxide (0.54 mole NaOH), 112 cc dimethylsulfoxide and 120 cc toluene. The resultant mixture was heated to the boiling point for six hours under a nitrogen atmosphere to remove all of the water present by azeotropic distillation. The reaction mixture was then allowed to cool to about 75° C., at which time 100.4 g (0.56 mole) of 3-chloropropyl methyldimethoxysilane was added dropwise while the reaction mixture was stirred. Following completion of the addition the reaction mixture was heated at 115° C. for about 16 hours, following which the mixture was allowed to cool and was filtered to remove any solid material. The solvents were then removed under a pressure of about 15 mm of mercury at a temperature of about 60° C. The pressure was then reduced to from 3 to 4 mm of mercury and the material boiling from 230° to 235° C. was removed. This fraction weighed 112 g, equivalent to a yield of 80% based on starting materials. Analysis by vapor phase chromatography indicated that the purity of the product was greater than 98%. The infrared and nuclear magnetic resonance spectra of the product were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1ccc(F)c(Oc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C=O)COCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A solution of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan- 1-ol (5.0 g) in dichloromethane (30 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (6.77 g) in dichloromethane (20 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete the mixture was allowed to warm to the ambient temperature over a period of 2 hours. The solvent was removed and the residual oil (3.0 g) purified by column chromatography using a silica gel column and eluting with a 10:1 (by volume) mixture mixture of petroleum ether (boiling range 40°-60°) and diethyl ether to yield 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-al (1.5 g) as a yellow oil.