Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)=[CH2:2].[H][H]>CO.[Pd]>[CH2:1]([C:3]1[S:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:7]=1)[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ncc(C(=O)OCC)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc(CC)s1
Yield: 100 %

Procedure:
To a solution of ethyl 2-vinylthiazole-5-carboxylate (400 mg, 2.18 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (267 mg, 0.25 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is concentrated to give ethyl 2-ethylthiazole-5-carboxylate (404 mg). HPLC retention time=0.60 minutes (condition B); MS (m+1)=186.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.35 (t, J=7.3 Hz, 2 H) 1.39 (t, J=7.20 Hz, 2 H) 3.07 (q, J=7.58 Hz, 2 H) 4.35 (q, J=7.16 Hz, 2 H) 8.22 (s, 1 H)
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O.CC(C)=O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: OCCCl
Reactant: CC(C)(O)C#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
Additional procedure. ZnCl2 (352.3 g 2.59 moles) was added to a 2 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Acetone cyanohydrin (110.0 g 1.29 moles) was slowly added to the stirred solid over 30 minutes keeping the temperature below 32° C. with external cooling. To the slurry, 2-chloroethanol (124.9 g 1.55 moles) was slowly added over 20 minutes keeping the temperature below 32° C. with external cooling. Acetone (3.75 g, 64.6 mmoles) was added and the mixture was heated to 60° C. After stirring for 4 h at 60° C., the reaction mixture was cooled to 30-35° C., diluted with water (1.10 L) and extracted with CH2Cl2 (1×440 mL and 1×220 mL). The combined CH2Cl2 extracts were washed with 0.5M sodium bicarbonate (330 mL), followed by water (3×330 mL). The dichloromethane solution was concentrated under vacuum to afford crude product (109 g). The crude product was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling at 60-80° C. was collected to afford 2-(2-chloroethoxy)-2-methylpropanenitrile as colorless oil (88.7 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.BrC(OC)=O.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Na+].[Cl-]>O1CCCC1.N1C=CC=CC=1>[CH3:24][N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: COC(=O)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.8 ml of pyridine are added to 50 ml of tetrahydrofuran, and then 1.0 ml of methyl bromoformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 5°-15° C. after addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.2 g of N-methylcyclohexylamine, followed by additional 3-hour agitation. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain 2.3 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with m.p. of 184.5°-186° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=[C:8]2[C:7]([CH:15]=[O:16])=[CH:6]1)=[O:4].S([CH2:28][N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1>COCCOC>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=[C:8]2[C:7]([C:15]2[O:16][CH:30]=[N:29][CH:28]=2)=[CH:6]1)=[O:4]
Reactant: CN(C)C(=O)n1cc(C=O)c2cc(Br)cnc21
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN(C)C(=O)n1cc(-c2cnco2)c2cc(Br)cnc21
Temperature: 90 °C
Yield: 29.5 %

Procedure:
To aldehyde 20 (2.00 g, 6.75 mmol) in 1,2-dimethoxyethane (70 mL) was added tosylmethyl isocyanide (1.58 g, 8.10 mmol) followed by DBU (1.44 g, 9.46 mmol), and the reaction mixture heated at 90° C. overnight. After cooling, sorbent (HM-N, Jones Chromatography) was added and the solvent evaporated. The product was purified by silicagel chromatography using ethyl acetate:hexane (4:6) (gradient elution) to give product 21 as a light orange solid (667 mg, 29%); 1H NMR (400 MHz, CDCl3) δ 3.40-2.90 (bs, 6H), 7.32 (s, 1H), 7.86 (s, 1H), 7.96 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[CH2:16]([Sn:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])/[CH:21]=[CH:22]/[CH:23]=[O:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1.CCCCCC>[CH3:10][O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH:23]([OH:24])/[CH:22]=[CH:21]/[Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](/C=C/C=O)(CCCC)CCCC
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/C(O)CC(=O)CC(=O)OC)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of sodium hydride (1.28 g) in tetrahydrofuran (70 ml) is cooled to 0° C. and methyl acetoacetate (3.2 ml) added over about 1 minute. The mixture is stirred for about 15 minutes at 0° C., 2.5M n-butyllithium in hexane (12.3 ml) added, stirred for about 20 minutes, E-3-tributylstannylacrolein (10.0 g) in tetrahydrofuran (25 ml) added over five minutes and stirred for about 15 minutes. The mixture is quenched by slow addition of 1M hydrochloric acid, diluted with ether. The aqueous layer is back-extracted with ether and the combined organic solutions washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography in 25% ethyl acetate in hexane to give the desired product.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.[CH3:14][C:15]1([CH3:42])[NH:27][CH:26]([C:28]2[C:33]([F:34])=[CH:32][C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])=[CH:30][C:29]=2[F:41])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:34][C:33]1[CH:32]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[CH:30]=[C:29]([F:41])[C:28]=1[CH:26]1[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][C:15]([CH3:14])([CH3:42])[N:27]1[CH2:7][C:8]([F:11])([CH3:9])[CH3:10])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2CC(C)(C)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
2-Fluoro-2-methylpropyl trifluoromethanesulfonate (obtained as described in Example 1, preparation of starting materials) (679 mg, 3.03 mmol) was added to a solution of (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (obtained as described in Example 5, preparation of starting materials) (600 mg, 1.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.915 ml, 5.30 mmol) in 1,4-dioxane (2.5 ml). The reaction was stirred at room temperature for 1 h. The reaction was then heated to 105° C. for 88 hours. The volatiles were removed under vacuum and the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (430 mg, 60.4%) as a white solid. The racemic product was purified by preparative HPLC (Chiralpak AD column, 20 μm silica, 50 mm diameter, 250 mm length), Heptane:Ethanol 90:10 90 ml/min. Fractions containing the desired compounds were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1, first eluted, 149 mg, 34.6%) and (E)-methyl 3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 2, second eluted, 143 mg, 33.3%) as cream coloured solids. 1H NMR (400 MHz, CDCl3, 30° C.) δ 1.01 (3H, d), 1.08 (3H, s), 1.15 (3H, d), 1.34 (3H, s), 2.55 (1H, dd), 2.66 (1H, d), 2.98-3.06 (1H, m), 3.17 (1H, dd), 3.80 (3H, s), 5.23 (1H, s), 6.38 (1H, d), 6.97 (2H, d), 7.07-7.12 (2H, m), 7.17-7.22 (1H, m), 7.32 (1H, s), 7.46-7.5 (1H, m), 7.52 (1H, d). m/z ES− [M−H]− 469.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([S:18][CH3:19])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([S:18]([CH3:19])=[O:28])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2cnc(SC)nn2)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cnc(S(C)=O)nn2)cc1F

Procedure:
To a cooled (0° C.) solution of methyl 2-fluoro-4-[3-(methylthio)-1,2,4-triazin-6-yl]benzoate (0.180 g, 0.000644 mol) in methylene chloride (10 mL) was added m-chloroperbenzoic acid (0.32 g, 0.0014 mol) in DCM (3 ml) with stirring. The mixture was stirred at 0° C. for 1.5 h, and diluted with DCM. The resulting solution was quenched with saturated Na2S2O3 solution. After separation the organic layer was washed with saturated NaHCO3 solution, brine; and dried over Na2SO4. After filtration the filtrate was concentrated to yield nearly quantitative product which was directly used in the next step without further purification. Analytical LCMS: (M+H)+=296.0.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.Cl.[NH2:17][OH:18]>CCO.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:5](=[N:17]/[OH:18])/[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2-c2ccc(Br)cc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: O/N=C1/c2ccccc2-c2ccc(Br)cc21

Procedure:
To a solution of 2-bromo-9H-fluoren-9-one (100 mg, 0.39 mmol) in EtOH (10 mL) and water (3 mL) was added hydroxylamine hydrochloride (54 mg, 0.77 mmol). The mixture was then heated to reflux for 1 h. The solvent was then removed in vacuo, and to the residue was added aqueous NaHCO3. The solid was then filtered and dried to give the title product. LRMS (M+H)+ 274.2.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=5)[C:28]([O:30]C)=[O:29])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1.O.[OH-].[Li+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=5)[C:28]([OH:30])=[O:29])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)c1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a precooled (0° C.) stirred solution of methyl 3-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoate 10 (20 mg, 0.034 mmol) in a 2 mL-mixed solvent of THF-H2O (3:1) was added lithium hydroxide monohydrate (4.3 mg, 0.1 mmol). The resulting mixture was stirred for 2 hours at 0° C. before being buffered with saturated sodium bicarbonate solution. The reaction mixture was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford 3-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid 11 as white powder solid (18 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.91 (s, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.40-7.36 (m, 7H), 7.26-7.24 (m, 2H), 7.14-7.08 (m, 2H), 4.55-4.49 (m, 1H), 3.92 (br, 1H), 3.34 (br, 1H), 4.24 (br, 2H), 2.45 (s, 3H), 2.39-2.32 (m, 3H), 2.14 (br, 3H), 1.86-1.73 (m, 10H), 1.59 (d, J=7.3 Hz, 2H). HRMS m/z (M+H)+ calcd 577.3179; obsd 577.3192.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+].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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[N:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCCCC2)C1
Yield: 64.2 %

Procedure:
A solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), piperidine (0.522 ml, 6.13 mmol), X-phos (17.4 mg, 0.0365 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.0 mg, 0.0120 mmol), sodium tert-butoxide (87.5 mg, 0.912 mmol) and dioxane (4 ml) was stirred at 80° C. for 3 hr under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (130 mg, 64.3%) as an oil.
Reaction SMILES: [Na][Na].[P:3]([CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11])([OH:6])([OH:5])=[O:4].Cl[C:14]([O:16][CH2:17][C:18]#[C:19][CH2:20][Cl:21])=[O:15].[OH-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1>O>[Cl:21][CH2:20][C:19]#[C:18][CH2:17][O:16][C:14]([N:8]([CH2:7][P:3]([OH:6])([OH:5])=[O:4])[CH2:9][C:10]([OH:12])=[O:11])=[O:15]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: O=C(Cl)OCC#CCCl
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [Na][Na]
Solvent: O
Product: O=C(O)CN(CP(=O)(O)O)C(=O)OCC#CCCl
Yield: 38 %

Procedure:
To a stirred solution containing 21.3 (0.1 mol) of disodium-N-phosphonomethylglycine in water at a temperature of 10°-15° C. was slowly added 17.5 g (0.105 mol) of 4-chloro-2-butynyl chloroformate. A 50% sodium hydroxide solution was slowly added to the reaction mixture to a phenolphthalein endpoint. The addition of the sodium hydroxide solution was repeated until the phenolphthalein endpoint was stable. The resulting mixture was extracted with diethyl ether. The layers were separated and the aqueous layer was acidified with hydrochloric acid, then passed over acid Dowex-50 ion exchange resin. The eluate was concentrated in vacuo yielding a residual gum which was dried over potassium hydroxide pellets (at 1 mm Hg) to yield N-[(4-chloro-2-butynyl)oxy]carbonyl-N-phosphonomethylglycine (11.3 g; 38% yield) as a tan glass having the following analysis: Calculated: Cl, 11.83; P, 10.34. Found: Cl, 12.82; P, 11.03.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[NH:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:18]2[CH:19]=[C:20]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[N:22][CH:23]=2)[CH:9]=1.[NH2:34][C:35]([NH2:37])=[O:36]>C(Cl)Cl>[N:8]1[C:17]2[NH:16][CH2:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([C:18]2[CH:19]=[C:20]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[N:22][CH:23]=2)[CH:9]=1.[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:20]2[CH:19]=[C:18]([C:10]3[CH:11]=[C:12]4[C:17](=[N:8][CH:9]=3)[N:34]([C:35]([NH2:37])=[O:36])[CH2:15][CH2:14][CH2:13]4)[CH:23]=[N:22][CH:21]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: NC(N)=O
Agent: CC(=O)N1CCC(Oc2cncc(-c3cnc4c(c3)CCCN4)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(Oc2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2)CC1

Procedure:
1-{4-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-piperidin-1-yl}-ethanone is synthesized according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent. 1-{4-[5-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yloxy]-piperidin-1-yl}-ethanone (200 mg, 0.57 mmol) is converted to 34 mg of the titled product according to the procedure of Urea Formation Method I.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=O)=[C:7]([Cl:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[C:7]([Cl:24])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2ccc(Cl)c(Cl)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)c(Cl)c1
Yield: 89.2 %

Procedure:
1.95 ml (1.95 mmol) of a 1M borane-THF complex solution in THF were added under nitrogen at rt to 250 mg (0.65 mmol) of 4-tert-butyl-2-chloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-benzamide dissolved in 3.2 ml THF. The reaction mixture was heated to reflux for 4 h. At rt 6 ml 2N aqueous HCl solution were added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was basified with 7 ml 2N aqueous NaOH solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; DCM/methanol 19:1) to yield 215 mg (89%) of (4-tert-butyl-2-chloro-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.46-7.43 (m, 2H), 7.30 (d, 1H), 7.28 (s, 1H), 7.23 (d, 1H), 7.15 (d, 1H), 3.67 (s, 2H), 2.67 (s, 4H), 1.19 (s, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:16][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:24]1([C:30]2[C:31]([C:39]3[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=3)=[N:32][C:33]3[N:34]([CH:36]=[CH:37][N:38]=3)[CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CN(C=O)C>[C:24]1([C:30]2[C:31]([C:39]3[CH:40]=[CH:41][C:42]([CH2:43][N:2]4[CH2:3][CH2:4][CH:5]([C:8]5[NH:16][C:11]6[CH:12]=[N:13][CH:14]=[CH:15][C:10]=6[N:9]=5)[CH2:6][CH2:7]4)=[CH:45][CH:46]=3)=[N:32][C:33]3[N:34]([CH:36]=[CH:37][N:38]=3)[CH:35]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: c1cc2nc(C3CCNCC3)[nH]c2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4nc5ccncc5[nH]4)CC3)cc2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
121 mg (0.6 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine hydrochloride salt was dissolved in 3 mL methanol. 0.2 mL (1.2 mmol) Triethylamine in 3 mL DMF, 150 mg (0.5 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde, 0.08 mL (1.3 mmol) acetic acid and 200 mg (1 mmol) NaBH(OAc)3 were added. The reaction mixture was stirred at room temperature and after 1 and 2 hours two additional portions of 2 equivalents NaBH(OAc)3 each were added. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel (dichloromethane/methanol) to yield 126 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[F:23])[C:9]=2[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:14]=3[F:23])[C:9]=2[CH:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[OH:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccnc1)c1c(-c2cc(C(F)(F)F)ccc2F)noc1-c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC(c1cccnc1)c1c(-c2cc(C(F)(F)F)ccc2F)noc1-c1cccc(Cl)c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 56 mg (0.13 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethyl-phenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 2 mL of ethanol was added 24 mg (0.63 mmol) of sodium borohydride. After 2 hrs at room temperature, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated sodium chloride and was dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The residue was purified by prepTLC to give 44 mg (0.098 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 6.01 (s, 1), 7.01 (m, 1), 7.83 (m, 1), 8.27 (m, 1), and 8.35 ppm (br s, 1). MS m/z: 449.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Oc2ccc(Cl)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4ccc(Cl)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((6-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Si:1](Cl)([C:4](C)(C)C)([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])[N:16]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[NH2:9][C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH2:22][CH2:23][CH2:24][O:25][Si:1]([CH3:2])([CH3:3])[CH3:4])[N:16]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OCCCNc1nccc(Oc2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
1.99 ml (1.99 mmol) of 1M t-butyl-dimethylsilyl chloride in dichloromethane were added at 0° C. to a solution of 470 mg (1.81 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol and 256 mg (2.53 mmol) triethylamine in 5 ml dichloromethane. The reaction mixture was stirred for 12 h at r.t. and extracted with water. The organic phase was dried (sodium sulphate) and evaporated. The obtained material was purified by chromatography on silica (ethyl acetate/n-heptane 1:1) to give 520 mg (77%) oily [4-(4-Amino-phenoxy)-pyrimidin-2-yl]-(3-trimethylsilanyloxy-propyl)-amine.