Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([N:20]([CH2:22][C:23]1[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=1)[CH3:21])=[O:19])[CH:12]=[CH:11]2.S(=O)(=O)(O)O.O>O1CCCC1.CO>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]([N:20]([CH2:22][C:23]1[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[S:40][C:39](=[O:41])[NH:38][C:37]4=[O:42])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=1)[CH3:21])=[O:19])[CH:12]=[CH:11]2
Reactant: COCCOCOc1ccc2cc(C(=O)N(C)Cc3cccc(-c4ccc(CC5SC(=O)NC5=O)cc4)c3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
1.5 g (2.5 mmol) of 6-(2-methoxyethoxymethoxy)-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide (obtained in Example 16) in 10 ml of tetrahydrofuran and 10 ml of methanol are introduced into a round-bottomed flask. 500 μl of concentrated sulphuric acid are added and the medium is stirred for 2 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then evaporated off. The residue is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (30/70) mixture. 1.26 g (99%) of 6-hydroxy-N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnaphthalene-2-carboxamide are obtained in the form of a white powder having a melting point of 218° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CO[CH:16](OC)[CH2:17][CH:18](OC)OC.O.[NH4+].[OH-]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]3[N:13]=[CH:16][CH:17]=[CH:18][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: COC(CC(OC)OC)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc3ncccn3n2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-pyrazole-5-amine (5.0 g, 0.028 mol) in acetic acid (50 mL) is added 1,1,3,3-tetramethoxypropane (5.79 g, 0.035 mol). The mixture is stirred at 110° C. for 1 h. The reaction mixture is then poured into water, basified with NH4OH and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. 6.8 g (79%) of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine are obtained as a beige solid which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)([N:19]1[CH:23]=CN=C1)=O.C[NH:30][S:31](NC)(=[O:33])=[O:32].C1CCN2C(=NCCC2)CC1>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([NH:30][S:31]([N:19]([CH3:23])[CH3:17])(=[O:33])=[O:32])=[O:16])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNS(=O)(=O)NC
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Solvent: CC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.7 %

Procedure:
(1R,2S)-1-(tert-Butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid (1.3 g, 5.72 mmol, 1.0 eq.), dichloroethane (30 mL) and molecular sieves were charged into a 100 mL round bottom flask. The mixture was stirred at room temperature for 15 minutes. The molecular sieves were filtered off and washed with dichloroethane (2×5 mL). 1,1′-Carbonyldiimidazole (1.29 g, 8.01 mmol, 1.4 eq.) was added portionwise and the reaction mixture stirred vigorously at 50° C. for 1 hour until no more gas evolution was noticed. Dimethylsulfamide (1.70 g, 13.62 mmol, 1.7 eq.) was added portionwise followed by dropwise addition of DBU (3.2 mL, 21.63 mmol, 2.7 eq.). Stirring was continued at 50° C. for a further 15 hours by which time LCMS analysis of the reaction mixture showed full consumption of the starting material. The reaction mixture was washed with 0.5 M hydrochloric acid (3×50 mL) and brine (50 mL), dried over sodium sulfate and filtered. The residue was purified by flash column chromatography, using a methanol:dichloromethane gradient (from neat dichloromethane to 2% methanol in dichloromethane). After combining the relevant fractions and solvent removal, 1.5 g (78%) of (1R,2S)-1-(tert-Butoxycarbonylamino)-2-vinyl-cyclopropane-1-carbonyl-N,N-dimethylsulfamide was isolated as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.90-9.88 (m, 1 H) 5.46-5.73 (m, 2 H) 5.14 (d, J=10.38 Hz, 1 H) 2.90 (s, 6 H) 2.12 (q, J=8.70 Hz, 1 H) 1.87 (dd, J=7.93, 5.80 Hz, 1 H) 1.45 (br. s, 9 H) 1.23-1.38 (m, 1 H). LC-MS: purity 99% (UV), m/z [M+Na]+ 356.35.
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C1COCC1>[C:10]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][NH2:30])[CH2:21][CH2:22]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C#N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
To a solution of (2-cyano-phenyl)-piperazine (2.4 g, 12.78 mmol) in THF and H2O (25 mL, 1:1) was added K2CO3 (3.9 g, 28.12 mmol). The solution was allowed to stir for about 10 minutes at r.t. Boc-anhydride (3.1 g, 14.06 mmol) was then added and reaction was allowed to stir for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 3.2 g of 1-Boc-4-(2-cyano-phenyl)-piperazine (88%). To a solution of sodium borohydride (2.1 g, 56.03 mmol) in THF (25 mL) at 0° C. was added TFA (4.3 mL, 56.03 mmol) dropwise. 1-Boc-4-(2-cyano-phenyl)-piperazine (3.2 g, 11.21 mmol) was then added slowly at r.t. The reaction was allowed to stir for about 12 hours at r.t. The reaction was quenched with H2O, diluted five-fold with EtOAc and washed with brine. The organic phase was concentrated to dryness yielding about 1.0 g of 1-Boc-4-(2-aminomethyl-phenyl)-piperazine (30%). MS (ESI+) 292.1 (M+1)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8]C(O)=O.[C:12]([O:16][C:17](=[O:36])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:22][CH2:21]1)([CH3:15])([CH3:14])[CH3:13].[C:37](N1C=CN=C1)([N:39]1C=CN=C1)=[O:38]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:36])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:37]([NH:39][CH2:8][CH2:7][CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:22][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: O=C(O)CCCc1cccs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCCCc3cccs3)cc2)CC1

Procedure:
A solution of 4-(2-thienyl)butanoic acid (1.35 g, 7.90 mmol), [1-(4-aminobenzen-esulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester (2.90 g, 7.90 mmol) and carbonyldiimidazole (1.27 g, 7.9 mmol) in methylene chloride was stirred overnight at ambient temperature. The reaction mixture was washed with 1N NaOH, 1N HCl, and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give near quantitative yield of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41]C(=NO)[CH:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C([N:53]1[CH:57]=[CH:56]N=C1)(N1C=CN=C1)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][C:56]([C:57]#[N:53])=[C:39]([F:45])[CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4=CC(F)C(=NO)C=C4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)c(F)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-fluoro-4-formylphenyl)-2-thienylmethyl)benzene (272 mg) obtained in Example 180-(1) was dissolved in N-methyl-2-pyrrolidone (10 ml) and added thereto was hydroxylamine hydrochloride (34 mg). The mixture was heated under stirring at 117° C. overnight. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (177 mg) as colorless caramel. APCI-Mass m/Z 693/695 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-hydroxyimino-3-fluorophenyl)-2-thienylmethyl)benzene (175 mg) was dissolved in chloroform (5 ml) and added thereto was 1,1′-carbonyldiimidazole (46 mg). The mixture was stirred at room temperature overnight. 1,1′-Carbonyldiimidazole (92 mg) was further added thereto, and the mixture was stirred at 40° C. for 6 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was separated and successively washed with brine. After drying over 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 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene (158 mg) as colorless caramel. APCI-Mass m/Z 675/677 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene was treated in a manner similar to Example 106-(3) to give desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyano-3-fluorophenyl)-2-thienylmethyl)benzene as pale yellow powder. APCI-Mass m/Z 507/509 (M+NH4).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]1([CH3:31])[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+].O>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[S:14][CH2:31][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:20]=1
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: Cc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 35.4 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (197 mg), 4-(4-toluoyl)benzyl bromide (336 mg) and 1N-sodium hydroxide/water (1 ml) in DMF (10 ml) was stirred at room temperature for 30 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=5:1:1) and crystallized from methanol to provide the title compound as colorless solid (140 mg).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>ClCCl.C(=O)([O-])O.[Na+]>[CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH:15][C:23](=[O:26])[CH2:24][CH3:25])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: CCC(=O)Cl
Reactant: NC/C=C1\CCc2ncc3c(c21)CCO3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC/C=C1\CCc2ncc3c(c21)CCO3
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a mixture of (2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethanamine (220 mg, 0.999 mmol) and triethylamine (167 μL, 1.20 mmol) in dichloromethane (10 mL) was added propionyl chloride (104 μL, 1.20 mmol) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→10/90) and recrystallization (chloroform/hexane) to give the title compound (195 mg, yield 75%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[O:13][CH2:14][CH2:15][OH:16])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[OH:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C:2](=[O:22])[NH:1]3)[CH:19]=[CH:18][CH:17]=1
Reactant: CCO
Reactant: OCCOc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2c(cccc2-c2cccc(OCCO)c2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To the suspension of 2-[3-(1H-indol-4-yl)phenoxy)-ethanol (5.4 g, 21 mmol) in t-BuOH: ethanol: acetic acid (139.5 mL: 84 mL: 100.5 mL) was added pyridinium tribromide (21.21 g, 63 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (90 mL) and water (3 mL). Zinc dust (21 g) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with 1N HCl (3×), water (1×), brine (2×), dried over Na2SO4, concentrated. The residue was recrystallized to give 1.82 g (32%) of 4-[3-(2-hydroxy-ethoxy)phenyl]-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C[CH2:22][N:23](C(C)C)[CH:24](C)C.[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[C:18]([CH2:17][C@H:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:34](=[O:33])[C:30]2[CH:31]=[CH:32][CH:24]=[N:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:20])#[N:19]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Reactant: C1CCOC1
Product: COc1ccc(N(C(=O)c2cccnc2)C2CCN([C@H](C)CC#N)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
The residue was suspended in THF (30 mL) and cooled to 0° C. A solution of (R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyronitrile (1.09 g, 1 eq.) and DIPEA (1.5 mL, 2 eq.) in THF (10 mL) was added drop-wise and the mixture was stirred at 0° C. for 30 min. The reaction was quenched with saturated NaHCO3 (50 mL) and extracted with DCM (150 mL in 3 extracts). The organic layer was washed once with saturated NaHCO3 (20 mL), dried with Na2SO4 and filtered through a silica plug (35 mL glass frit, 1 cm). The plug was washed with 50 mL 5:1 Et2O-MeOH, and the filtrate was concentrated. The residue was purified by flash chromatography on 150 mL silica using 10:1 Et2O-MeOH as the eluent to give N-[(R)-1-(2-cyano-1-methyl-ethyl)piperidin-4-yl]-N-(4-methoxy-phenyl)-nicotinamide (1.23 g, 81%) as light brown thick oil. 1H NMR (δ, CDCl3): 8.44 (1H, s), 8.39 (1H, d, J=4.8 Hz), 7.53 (1 H, d, J=7.5 Hz), 7.08 (1 H, dd, J=7.5, 4.8 Hz), 6.90 (2 H, d, J=8.7 Hz), 6.72 (2 H, d, J=8.7 Hz), 4.69 (1 H, t, br, J=12.9 Hz), 3.73 (3 H, s, and an overlapping 1 H, m), 3.05-2.95 (1 H, m), 2.95-2.75 (2 H, dd, J=20, 11), 2.53-2.25 (4 H, m), 1.96-1.80 (3 H, m), 1.50 (2 H, qd, J=11.4, 2.4 Hz), 1.77(3 H, d, J=6.9 Hz), 1.01 (2 H, d, J=6.3 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][C:4]#[C:5][NH2:6].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH3:1][Si:2]([CH3:8])([CH3:7])[C:3]#[C:4][CH2:5][NH:6][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)CC#CN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#CCNC(=O)c1ccccc1

Procedure:
To 8.2 g (0.07 M) of 3-trimethylsilylprop-1-ynylamine in 150 ml of diethyl ether containing 6.6 g (9.1 ml) of triethylamine at 0° C is added 9.1 g (0.07 M) of benzoyl chloride in 30 ml of ether. After 1 hour at 25° C the solution is washed well with brine and the ether extract dried over magnesium sulfate, filtered and the filtrate concentrated. The residue is recrystallized from methanol to give N-(3-trimethylsilylprop-2-ynyl)benzamide.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][CH:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:10][CH:8]([CH3:9])[CH3:7])[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 26 step 1 using a solution of chloromethyl chloroformate (10 g, 78.2 mmol) in DCM (200 mL), a mixture of i-PrOH (6.6 mL, 86.2 mmol) and pyridine (7.5 mL, 93.2 mmol) in DCM (50 mL). The title compound was obtained as colorless oil (9.63 g, 81.0%) and was used in the next step without further purification. The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](CCl)=[CH:7][C:6]=1C)[CH:2]=[CH2:3].N[C:15](N)=[S:16].O.N.[CH2:20](O)C>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:15][SH:16])=[C:9]([CH3:20])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: NC(N)=S
Reactant: CCO
Reactant: C=CCOc1ccc(CCl)cc1C
Agent: N
Solvent: O
Product: C=CCOc1ccc(CS)c(C)c1
Yield: 59 %

Procedure:
A mixture of 3.40 g (17.3 mmol) 1-allyloxy-4-chloromethyl-2-methyl-benzene and 1.45 g (19.0 mmol) thiourea in 5.0 ml ethanol was heated to reflux for 7 h. Solvents were distilled off and the crystalline residue was washed with cold ethanol and isolated by filtration. After addition of 5.0 ml ethanol, 2.0 ml water and 1.4 ml 25% aqueous ammonia, the mixture was heated to reflux for 2 h. Ethanol was distilled off, then acidified with 0.5 ml half conc. HCl and extracted with ethyl acetate. The solution was dried over MgSO4 and solvents were removed in vacuum to yield 1.99 g (59%) (4-allyloxy-2-methyl-phenyl)-methanethiol as nearly colourless oil, which was used immediately.
Reaction SMILES: C(B(CC)CC)C.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[O:18][CH:17]=[N:16][CH:15]=2)[CH:10]=1.[Li]CCCC.[C:24]([O:28][C:29](=[O:31])[NH2:30])([CH3:27])([CH3:26])[CH3:25].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[C:24]([O:28][C:29](=[O:31])[NH:30][C@H:34]([CH:33]([OH:32])[C:17]1[O:18][C:14]([C:11]2[CH:10]=[C:9]([CH3:8])[O:13][N:12]=2)=[CH:15][N:16]=1)[CH2:35][CH3:36])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1cc(-c2cnco2)no1
Reactant: C1CCOC1
Agent: CCB(CC)CC
Agent: [Li]CCCC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1ncc(-c2cc(C)on2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylborane (1M in THF, 12 mL, 12 mmol) is added to a solution of 5-Methyl-3-oxazol-5-yl-isoxazole (1.8 g, 12 mmol) in 40 mL of dry Tetrahydrofuran and the mixture is stirred at room temperature for 15 minutes. The mixture is cooled to −78° C., nBuLi (2.5M in Hexanes, 4.8 mL, 12 mmol) is added drop wise and the mixture is stirred at −78° C. for 15 minutes. A solution of (S)-1-Formyl-propyl)-carbamic acid tert-butyl ester (898.7 mg, 4.8 mmol) in 15 mL of dry tetrahydrofuran is added drop wise and the reaction mixture is stirred at −78° C. for 3 hours, then let warm to −30° C. and quenched with acetic acid in ethanol (4%, 250 mL), stirring continued for 2 hours, while warming to room temperature. The reaction is concentrated under reduced pressure; the residue is dissolved in diethyl ether (250 mL) and stirred for 1.5 hours at room temperature. The precipitate is filtered; the filtrate is concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives the title compound as a solid (830 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Si:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:22](=[O:23])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N2C(=O)c3ccccc3C2=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 2-nitro-4-(tert-butyldimethylsilyloxy)aniline (10.3 g, 38.5 mmol) and phthalic anhydride (6.50 g, 41.5 mmol) in toluene (30 mL) was refluxed for 18 h. A Dean-Stark apparatus was fitted to the flask, diisopropylethylamine (0.1 mL) was added and water was removed azeotropically over the next 24 h. About 20 mL of solvent was removed by distillation and the resultant solution allowed to cool to room temperature. The residue was diluted with methylene chloride and passed through a plug of silica gel eluting with methylene chloride. The desired fractions were combined and concentrated in vacuo. Recrystallization from methylene chloride-hexane provided 12.2 g (80%) of the title compound in two crops.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([I:13])=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: II
Reactant: Clc1ccc2[nH]ncc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc2[nH]nc(I)c2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (100 mg, 0.65 mmol) in DMF (5 mL), was added KOH (91 mg, 1.63 mmol), I2 (247 mg, 0.98 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water. The organic phase was washed by sat. NaHSO3, dried over MgSO4, filtered, concentrated, and purified by silica gel column, eluting by 0-70% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C6H3ClIN3: 279.9 (M+H+); Found: 279.3 (M+H+).