Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
Using 4-nitro-benzoic acid (1 g) instead of 3-nitro-benzoic acid, and 1-methyl-piperazine (797 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained as a crude product.
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]([O:12][C:13]2([CH3:15])[CH3:14])[N:10]([CH3:17])[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[BH4-].Cl.[OH-].[Na+]>CO.C(O)(=O)C>[C:1]1([C:7]2([C:13]([CH3:15])([CH3:14])[OH:12])[CH2:8][CH2:9][N:10]([CH3:17])[CH2:11][CH2:16]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC2(c3ccccc3)CC1OC2(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC(c2ccccc2)(C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 1.47 g of the above product III in a mixture of 10 mL of methanol and 2 mL of acetic acid was cooled with ice and treated with 0.76 g of sodium cyanoborohydride. The mixture was stirred at room temperature for 2 h, and the excess borohydride was decomposed by addition, with ice cooling, of 8 mL of conc hydrochloric acid. After stirring at room temperature for 0.5 h the mixture was made basic with aqueous sodium hydroxide solution and extracted with methylene chloride. Removal of the solvent from the dried solution and crystallization of the residue from ethyl acetate gave 0.98 g of 4-phenyl-α,α,1-trimethyl-4-piperidinemethanol, m.p. 146°-147°. NMR (220 MHz in CDCl3): τ 2.7-2.8 (m, 5H); 7.0-8.2 (m, 9H); 8.0 (s, 3H) and 8.9 (s, 6H). Anal. Calcd. for C15H23NO: C, 77.21; N, 9.94; N, 6.00. Found: C, 77.12; H, 9.89; N, 6.00.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[CH3:17])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1nccn1-c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Cc1nccn1-c1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 10 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-(2-methylimidazol-1-yl)quinazoline was reacted with 3-chloro-4-fluoroaniline to give 4-(3-chloro-4-fluoroanilino)-6-(2-methylimidazol-1-yl)quinazoline in 10% yield: NMR Spectrum: (CD3SOCD3) 2.4 (s, 3H), 7.0 (d, 1H), 7.4 (m, 2H), 7.6 (m, 1H), 7.95 (d, 2H), 8.2 (m, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.7 (broad s, 1H).
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@:18]([CH3:42])([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH:41]=[N:40][CH:39]=[N:38]5)=[CH:33][CH:32]=4)[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:25]1[CH:26]=[C:21]([N:20]2[C:16]3=[N:15][CH:14]=[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])[N:17]3[C@:18]([CH3:42])([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[N:40][CH:39]=[N:38]4)=[CH:33][CH:32]=3)[C:19]2=[O:29])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(-n4cncn4)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(-n3cncn3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.8 %

Procedure:
To a solution of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (109 mg, 0.18 mmol) and morpholine (0.157 mL, 1.80 mmol) in 1 mL of THF was added Pd(Ph3P)4 (10 mg, 0.009 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with 30 mL of EtOAc and washed with 10 mL each of 10% HCl solution, water, and brine, dried over Na2SO4, filtered, and concentrated to afford 114 mg of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid as an orange oily solid that was carried to the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7](OCC)C.C[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[H-]>C(OCC)(=O)C>[CH3:13][CH:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[CH3:7])[OH:15]
Reactant: CCOCC
Reactant: CCC(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(C)O

Procedure:
In a dry flask under nitrogen atomosphere was suspended 3.25 g (0.086 mol) lithium aluminum hydride and 250 ml of dry diethyl ether. The suspension was cooled in an ice/water bath, then 24.5 g (0.184 mol) of 2-methylacetophenone was added dropwise. After 12 hours the excess hydride was decomposed with 100 ml of ethyl acetate. The reaction mixture was washed with ammonium chloride solution and water. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 25.0 g of a clear oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][C:27]5[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=5)=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)[C:6]([CH3:36])([CH3:35])[CH2:5]1)(=O)C.Cl>CCO>[CH3:35][C:6]1([CH3:36])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][C:27]5[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=5)=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc5c(c4)N(C(C)=O)CC5(C)C)cccc3c2)cn1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Oc2ccc3c(C(=O)Nc4ccc5c(c4)NCC5(C)C)cccc3c2)cn1
Temperature: 60 °C

Procedure:
To a solution of N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-6-((6-(methoxy)-3-pyridinyl)oxy)-1-naphthalenecarboxamide (482 mg, 0.48 mmol) in EtOH (5.5 mL) was added concentrated aqueous HCl solution (3.3 mL). The reaction mixture was heated at 55-65° C. for 4 h, cooled to RT. EtOH was removed in vacuo. The aqueous layer was basified to pH=7-8 by adding 6M aqueous NaOH solution. The title compound was isolated by filtration and dried under high vacuum. MS (ESI, pos. ion) m/z: 440.1 (M+1). Mass Calc'd for C27H25N3O3: 439.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:30][NH2:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=4)=[CH:15][CH:14]=3)=[CH:7][NH:31][N:30]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: CCOc1cccc(-c2ccc(-c3coc4cc(O)c(Cl)cc4c3=O)cc2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOc1cccc(-c2ccc(-c3c[nH]nc3-c3cc(Cl)c(O)cc3O)cc2)c1

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3′-ethoxy-biphenyl-4-yl)-7-hydroxy-chromen-4-on (0.2 g, 0.69 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][C@H:5]1[CH3:18])=[N+:2]=[N-:3].[ClH:19].C(OC)(C)(C)C>C1COCC1>[ClH:19].[N:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6][C@H:5]1[CH3:18])=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@H]1N=[N+]=[N-]
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](N)CC[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Yield: 94.4 %

Procedure:
tert-Butyl [(1R*,3R*,4R*)-4-azido-3-methylcyclohexyl]carbamate (example C10; 2.5 g; 10.0 mmol) is dissolved in THF (25.0 mL). After addition of HCl (4M solution in dioxane; 10.0 mL; 40.0 mmol) the reaction mixture is stirred at ambient temperature over night and gently refluxed for additional 6 hours. tert-BuOMe is added at ambient temperature, the precipitated product is collected by suction filtration, washed with several small portions of tert-BuOMe and dried under reduced pressure to yield 1.8 g of the title compound as colourless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N+:19]([O-])([O-:21])=[O:20].[Na+].[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O>CCOCC.Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Agent: Cl
Agent: [La+3]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cc(SC2CCCc3cccnc32)ccc1O
Reaction time: 24 h
Yield: 31.9 %

Procedure:
15.0 g (58 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 90 ml of ether were added dropwise to a stirred solution of 4.96 g (58 mmol) of sodium nitrate and 0.25 g (58 mmol) of lanthanum nitrate in 60 ml of 5.5N hydrochloric acid at 0° to 5° C. in an ice-bath. Stirring was then continued under nitrogen for 24 hours, after which water was added and the mixture was extracted with chloroform. Removal of solvent left a yellow oil which was purified by flash chromatography (Kieselgel 60; 10% ethyl acetate in dichloromethane) to obtain 5.6 g (20%) of 8-(4-hydroxy-3-nitrophenylthio)-5,6,7,8-tetrahydroquinoline as yellow crystals (from ethanol).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])[CH:14]=[N:13]2)[C:9]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 98 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 33) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (2.0 g, 98%); ES+-HRMS m/e calcd for C26H31N5O4F2 [M+H+] 516.2417 found 516.2417. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.26 (m, 6H) 1.03 (s, 3H) 1.04 (s, 3H) 1.45-1.70 (m, 5H) 1.73-1.91 (m, 1H) 2.01-2.24 (m, 1H) 3.87 (s, 2H) 4.66 (s, 1H) 5.52 (dd, J=11.0, 4.1 Hz, 1H) 6.02 (d, J=2.7 Hz, 1H) 6.37 (d, J=2.2 Hz, 1H) 7.24-7.49 (m, 3H) 7.51 (d, J=2.2 Hz, 1H) 8.27 (d, J=2.7 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[OH:25])[NH2:21]>C(#N)C>[NH2:21][C:20]1[CH:22]=[CH:23][C:24]([O:25][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=2[C:4]#[N:5])=[C:18]([Cl:17])[CH:19]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: Nc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(F)cccc1Oc1ccc(N)cc1Cl

Procedure:
1.00 g (7.19 mmol) of 2,6-difluorobenzonitrile is initially charged in 10 ml of acetonitrile. 1.99 g (14.4 mmol) of potassium carbonate and 1.03 g (7.19 mmol) of 3-chloro-4-hydroxyaniline are added, and the mixture is heated at reflux for 45 min. The mixture is filtered and the filtercake is washed with ethyl acetate and DCM. The solvent is removed under reduced pressure and the residue is by column chromatography (silica gel 60, gradient column: mobile phase: DCM:petroleum ether=2:1, then DCM).
Reaction SMILES: CC[CH2:3][CH2:4][O-:5].CC[CH2:8][CH2:9][O-:10].CC[CH2:13][CH2:14][O-:15].CC[CH2:18][CH2:19][O-:20].[Ti+4:21].C(O)CCC>C(O)C>[CH2:4]([O-:5])[CH3:3].[CH2:9]([O-:10])[CH3:8].[CH2:14]([O-:15])[CH3:13].[CH2:19]([O-:20])[CH3:18].[Ti+4:21]
Reactant: CCCC[O-]
Agent: [Ti+4]
Solvent: CCCCO
Solvent: CCO
Product: CC[O-]

Procedure:
Organic butyl titanate solution is mixed with a solvent (denatured ethanol) and graphite. The butyl titanate and solvent undergo a metathetical ligand exchange (room temperature decomposition) to form titanium tetraethanolate, butanol, and ethanol. The alcohols are then decanted, and the resulting slurry is then heated at 350° C. to completely decompose the remaining organic components, resulting in TiO2 being deposited on the basal plane surface of the graphite.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH3:23][C:24]1[CH:35]=[CH:34][C:27]([C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-].[Na+]>C(O)(C)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:34]=[CH:35][C:24]=3[CH3:23])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:3]=2[CH:13]=[CH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CCCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 80 °C

Procedure:
To 4-chloro-8-(2,6-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7 one (200 mg, 0.589 mmol, 1 eq) and 4-methyl-N-propyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (268 mg, 0.883 mmol, 1.5 eq) in isopropanol (6 mL) was added sodium bicarbonate (148 mg, 1.76 mmol, 3 eq) in water (1.5 mL). The reaction mixture was then purged with nitrogen followed by addition of tetrakis(triphenylphosphine)-palladium(0) (34 mg, 0.029 mmol, 5 mol %). The mixture was then heated to about 80° C. overnight. The mixture was then allowed to cool to room temperature before the solvent was removed in vacuo. The residue was then purified on the Flashmaster 2™: LC-MS m/z 481 (M+H)+, 3.34 min (ret time).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[K+]>O1CCCC1.CO>[C:12]1([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:25])=[O:2])=[CH:7][CH:8]=2)[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)COc1ccc(-c2cccc3sc4ccccc4c23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2cccc3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a solution of [4-(dibenzothiophen-1-yl)-phenoxy]-acetic acid methyl ester (0.911 g, 2.61 mmol) in tetrahydrofuran (15 mL) and methanol (5 mL) was added an aqueous solution of potassium hydroxide (1N, 3.10 mL, 3.10 mmol, 1.2 eq) dropwise at room temperature. After stirring 1 hour at room temperature the solvents were removed. The residue was dissolved in water (125 mL) and was acidified with 10% aqueous hydrochloric acid. The water was removed and the solid was triturated in petroleum ether. Recrystallization from boiling acetic acid with hot filtration to give the title compound as a white crystalline solid (0.458 g, 52%): mp 169.5-170.5° C.; NMR (CDCl3): δ 7.88-7.81 (m, 2H), 7.48-7.39 (m, 3H), 7.37-7.32 (m, 1H), 7.26-7.17 (m, 2H), 7.13-7.08 (m, 3H), 4.83 (s, 2H); MS (El): [M+] 334; Anal. Calc. for C20H14O3S: C, 71.84, H, 4.22, N, 0.00. Found: C, 71.04, H, 3.90, N, 0.09.
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[O:12])=[N:6][CH:5]=1.[OH-].[Li+].Cl.[C:35]1([NH2:42])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl.O.CO>[NH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:42][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:21]3[C:22](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:23]=2)=[O:12])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C(=O)Nc2ccc3ccccc3c2)N2CCN(C)CC2)nc1
Reactant: Nc1ccccc1N
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(C(=O)Nc2ccc3ccccc3c2)c2ccc(C(=O)Nc3ccccc3N)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound from Step A above was dissolved in 0.5 mL each of THF, methanol and water then 12.0 mg (0.5 mmol) of lithium hydroxide was added and the solution was stirred for 18 h at rt. The solution was allowed to cool to room temperature and 300 μL of 2 N HCl was added. The solvent was evaporated and the residue was dissolved in 500 μL of DMF. Phenylenediamine (104 mg, 0.500 mmol), EDC (96.7 mg, 0.500 mmol), and HOBt (67.2 mg, 0.500 mmol) were added and the solution was allowed to stir for 18 h. The solution was diluted with 50 mL of CH2Cl2 and washed with 50 mL each of NaHCO3 and brine. The solution was concentrated and purified by reverse phase HPLC to give the desired product. MS cal'd 495 (MH+), exp 495 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[NH2:9][C:10]1[N:17]=[C:16]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:15]([Br:1])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2ccco2)nc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(-c2ccco2)nc1N
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
N-Bromosuccinimide (3.5 g, 19.7 mmol) was added to a solution (60 ml) of 2-amino-6-(2-furyl)nicotinonitrile (4.0 g, 21.6 mmol) in N,N-dimethylformamide in a nitrogen atmosphere at 1 to 2° C., followed by stirring as it was. After 30 minutes, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of potassium carbonate. The organic layer was washed with an aqueous saturated solution of potassium carbonate and an aqueous saturated solution of ammonium chloride, then dried over anhydrous sodium sulfate and concentrated. Methanol was added to the residue, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.02 g, 53%) as a brown solid.
Reaction SMILES: [CH3:1][SiH:2]([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5].[CH2:9]([NH2:12])[CH:10]=[CH2:11]>[Rh]>[NH2:12][CH2:9][CH2:10][CH2:11][Si:2]([CH3:1])([O:6][CH2:7][CH3:8])[O:3][CH2:4][CH3:5]
Reactant: CCO[SiH](C)OCC
Reactant: C=CCN
Agent: [Rh]
Product: CCO[Si](C)(CCCN)OCC
Yield: 78 %

Procedure:
There is considerable prior art relating to the synthesis of poly(aminoalkylmethylsiloxanes). Generally, poly(aminoalkylmethylsiloxanes) have been produced by first preparing aminoalkylmethyldialkoxysilanes, followed by hydrolysis with or without an endblocking agent, such as a trimethylsilyl derivative, to form cyclic and linear poly(3-aminoalkylmethylsiloxanes). The isomeric purity of the poly(aminoalkylmethylsiloxane) fluids, prepared in the manner of the prior art, is dependent upon the isomeric purity of the aminoalkylmethyldialkoxysilane prepared in the first step of the synthesis. German Patent No. 2408480 describes the reaction of a silazane derivative from allylamine and an organohydrochlorosilane, in the presence of a proton acceptor to form an intermediate silazane which then undergoes a hydrosilylation reaction catalyzed by a platinum catalyst. Upon alcoholysis, the intermediate hydrosilylation product forms 3-aminopropylmethyldiethoxysilane in 70% overall yield. A molar excess of at least 50% of allylamine is used in this process. Identification of the beta-isomer in the product was not made. Japanese Patent No. 10017578 describes another method of synthesis by hydrosilylation of N,N-bis(trimethylsilyl)allylamine by methyldimethoxysilane. The product of that reaction is then heated with methanol to form 3-aminopropylmethyldimethoxysilane in at least 85% overall yield. The presence of the beta-isomer in the product was not made. Japanese Patent No. 11209384 describes the use of a rhodium:cyclooctadiene complex as a hydrosilylation catalyst for the addition of methyldiethoxysilane to allylamine to form 3-aminopropylmethyldiethoxysilane in 78% yield. 2-Aminopropylmethyldiethoxysilane is formed at very low levels in this process not exceeding 0.5%. U.S. Pat. No. 5,391,675 describes the formation of an aminopropylmethylsiloxy-containing polydimethylsiloxane by barium or strontium hydroxide catalyzed condensation of a silanol terminated polydimethylsiloxane with a 3-aminopropylalkoxysilane with elimination of an alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([CH3:43])=[N:22][O:23][C:24]=3[N:25](C(OCC(Cl)(Cl)Cl)=O)[C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OP([O-])(O)=O.[K+]>C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([CH3:43])=[N:22][O:23][C:24]=3[NH:25][C@H:26]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)Nc1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
To methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (688 mg, 1.04 mmol) in THF (20 mL) was added activated zinc powder (686 mg, 10.4 mmol) and an aqueous solution of KH2PO4 (1.0 M, 5.2 mL, 5.2 mmol) dropwise. After ½ hour additional aliquots of activated zinc powder (686 mg, 10.4 mmol) and aqueous KH2PO4 solution were added (1.0 M, 5.2 mL, 5.2 mmol) and the reaction mixture was stirred for 1 hour. The zinc powder was filtered off, rinsed with Et2O and water and the product extracted with ether (2×), dried over Na2SO4, concentrated iii vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 3/7) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucinate.