Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)(=[O:30])=[O:29])=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Yield: 41 %

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethyl ester (5.8 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.8 g (86%); Spongy brown solid; mp 98° C.; MS: 559.6 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(-c4ccc(F)cc4Cl)cccn3n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(-c2cccn3nc(NC4CCNCC4)nc23)c(Cl)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 101.5 %

Procedure:
To a solution of tert-butyl 4-(8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)piperidine-1-carboxylate (810 mg, 1.82 mmol) in tetrahydrofuran (8 mL) and methanol (6 mL) was added hydrogen chloride solution (4.0 M in dioxane, 2.3 mL, 9.1 mmol). The reaction mixture was stirred for 1.5 hours at 60° C. and then concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with aqueous sodium carbonate (1 M, 30 mL), water (30 mL) and brine (30 mL). The aqueous layers were extracted with further ethyl acetate (40 mL). The organic layers were combined, dried over magnesium sulfate and filtered off. Concentration afforded the title compound as yellow foam (639 mg, 98%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([P:17](=[O:24])([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][P:17](=[O:24])([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCP(=O)(CCC)Cc1ccccc1
Agent: N
Agent: O=S(=O)(O)O
Product: CCCP(=O)(CCC)Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of nitric acid (3.6 ml) and concentrated sulfuric acid (22 ml) was added benzyldipropylphosphine-oxide (10.75 g) at 0° C., and the mixture was stirred at 60° C. for 1.5 hours. The reaction mixture was added to ice-water, and ammonia solution was added to the mixture to neutralize the solution, which was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/ethanol=9:1→4:1) to give 4-nitrobenzyldipropylphosphine oxide (3.77 g) as pale yellow crystals.
Reaction SMILES: N[C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1O.N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O>>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Product: C1=Cc2ccccc2C1

Procedure:
The trans amide can be made from the epoxide either (1) by treating the indene oxide with ammonia or a primary amine to produce a trans-1-amino-2-indanol and reacting the trans-1-amino-2-indanol with an acylating agent, or (2) by treating the epoxide with an amide anion to produce the trans hydroxy amide directly. In one embodiment the indene is oxidized with aqueous hypochlorite in the presence of a chiral salen catalyst to produce a partially resolved epoxide, which is converted to the partially resolved trans-1-amino-2-indanol by treating with ammonia or a primary amine followed by acylating with benzoyl chloride. The resulting benzamide is recrystallized to yield substantially optically pure trans-1-benzamido-2-indanol. In two preferred embodiments, the cis-1-amino-2-indanols are (1S,2R)-1-amino-2-indanol and (1R,2S)-1-amino-2-indanol, produced by oxidation of indene in the presence of an R,R or S,S-salen catalyst respectively.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=[N:35][O:36][CH3:37])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:38][O:39]C(=O)C)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:37][O:36][N:35]=[CH:34][CH2:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:38][OH:39])[O:7]3)[CH:24]=[CH:23][C:22]=2[Cl:25])=[CH:32][CH:31]=1
Reactant: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CON=CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-(methoxyimino)ethyl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (80 mg, 0.132 mmol) in THF (0.5 mL), methanol (0.7 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (11 mg, 0.26 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 0.5:9.5 MeOH:DCM) to provide the title compound (44 mg, 77%).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:22])([CH3:21])[C@H:10]([NH2:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42].C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:22])([CH3:21])[C@H:10]([NH:20][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Yield: 74.1 %

Procedure:
(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropylamine (5.85 g, 16.9 mmol) was dissolved in 200 mL of anhydrous CH2Cl2 and the mixture was stirred under N2. To this solution were added triethylamine (4.70 mL, 33.8 mmol) and 4-chloro-3-nitroquinoline (3.51 g, 16.9 mmol). The reaction mixture soon became bright yellow. After stirring for 3 days, the reaction mixture was concentrated under reduced pressure. The resulting yellow solid was partitioned between 200 mL H2O and 200 mL CH2Cl2. The layers were separated and the organic portion was washed with H2O and then brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting light brown oil was dissolved in about 200 mL of refluxing hexanes. A small amount of brown precipitate formed and was removed by filtration. The hexanes solution was concentrated to give a yellow solid. Chromatography (SiO2, 10% ethyl acetate/CH2Cl2) gave N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-3-nitroquinolin-4-amine (6.51 g) as a yellow solid.
Reaction SMILES: [CH3:1]N(C)P(=O)(N(C)C)N(C)C.[C:12]1(Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>CCOCC>[CH3:1][C:17]([CH3:12])=[CH:16][CH2:15][CH2:14][CH2:13][CH2:22][CH2:21][CH2:20][CH2:24][OH:23]
Reactant: C1CCOC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Brc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)=CCCCCCCCO
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 55.0 mL (~52 mmol) of 0.95M Grignard reagent prepared in Example 3, Part A in THF and 15.0 mL of hexamethylphosphoric triamide (HMPA) at 0° C. was treated dropwise with 1.95 g (13. 1 mmol) of phenyl bromide in 8 mL of THF over 10 minutes. After the addition the reaction was allowed to warm to room temperature and stir for 3.5 hours, at which point the reaction was diluted with ether and quenched with 100 mL (100 mmol) of 1M HCl solution. The organic layer was washed two times with NH4Cl solution, dried over MgSO4 and evaporated to provide a pale yellow oil. The oil was purified by flash chromatography performed on 200 g of silica gel eluted with 1:4 ethyl acetate/hexanes to provide 3.50 g of oil and hexanol. The hexanol was removed by distillation under reduced pressure (BP 75° C., ~20 mm Hg) to leave 1.50 g (67%) of title compound in the form of a colorless oil. This material contains ~2% of the Sn2' product, which could not be separated.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](/[NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8](\[C:12]#[N:13])/[C:9]([OH:11])=O.[CH:22]([NH2:25])([CH3:24])[CH3:23].OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:14][CH:15]([C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:16])=[C:8]([C:12]#[N:13])[C:9]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC(C)N
Reactant: CC(N/C(=C(/C#N)C(=O)O)c1sccc1Br)c1nccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)C(C#N)=C(NC(C)c1nccs1)c1sccc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of (2Z)-3-(3-bromo-2-thienyl)-2-cyano-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylic acid (0.18 g, 0.468 mmol, 1 eq.) in 5 ml of DCM (CH2Cl2) were added isopropylamine (0.083 g, 1.40 mmol, 3 eq.), hydroxybenzotriazole (HOBT) (0.066 g, 0.49 mmol, 1.05 eq.) and diisopropylethylamine (DIPEA) (0.090 g, 0.70 mmol, 1.5 eq.). The reaction was cooled to 0° C. and dicyclohexylcarbodiimide (DCC) (0.101 g, 0.49 mmol, 1.05 eq.) was added. Stirring was allowed overnight and the solid formed removed by filtration. The solvent was removed under reduced pressure and the residual oil submitted to chromatography on silica gel to give 2Z)-3-(3-bromo-2-thienyl)-2-cyano-N-isopropyl-3-{[1-(1,3-thiazol-2-yl)ethyl]amino}acrylamide (0.090 g, 43% yield) as a white solid and a mixture of atropoisomers.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].CI.[C:40](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:40][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)CN(C(=O)c1nc2ccccc2n1C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (205 mg) was dissolved in dimethylformamide (5 ml), methyl iodide (75 μl) and cesium carbonate (391 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (184 mg).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)cc2c1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)cc2c1
Yield: 14.5 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-methoxy-1-benzofuran (361 mg) synthesized in Example A22(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (325 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (87.0 mg, 14%) was obtained as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:16][C:15]=3[CH:25]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)Cl.CO>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])=[CH:16][C:15]=3[CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a solution of N-(1-{5-[2-(4-methoxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (922 mg, 2.73 mmol) obtained in Example 156 in methylene chloride (50 mL) was added 1M boron tribromide-methylene chloride solution (5.46 mL, 5.46 mmol) at −78° C., and the mixture was stirred at the same temperature for 4 hr. The reaction mixture was warmed to 0° C., and methanol was added thereto. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from hexane-ethyl acetate to give the title compound (774 mg, yield 88%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:15]=[C:16]1[O:20][CH2:19][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1.[CH3:32][Al](C)C>ClCCl>[CH2:24]([O:23][C:22]([NH:21][C@@H:18]([CH2:19][OH:20])[CH2:17][C:16]([NH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[C:4]([CH3:32])[CH:3]=1)=[O:15])=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: C[Al](C)C
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)CO1
Solvent: ClCCl
Product: Cc1cc(NC(=O)C[C@H](CO)NC(=O)OCc2ccccc2)ccc1C(=O)OC(C)(C)C

Procedure:
This is prepared analogously to Example 93d from tert.-butyl 4-amino-benzoate and benzyl(R)-(5-oxo-tetrahydrofuran-3-yl)-carbamate by reaction with trimethylaluminium in dichloromethane.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCCCC1>C1C=CC=CC=1.CS(O)(=O)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: CS(=O)(=O)O
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A solution of tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate (1.0 g., 0.00237 mole) in benzene (25 ml.) is treated with methanesulfonic acid (2 drops) and refluxed for 1/2 hour. The reaction mixture is treated with cyclohexane (20 ml.) and cooled affording (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which is filtered and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.OO.[C:18](=O)([O-])[O-:19].[K+].[K+].S(OC)(OC)(=O)=O>CO>[CH3:18][O:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc2c(C)ccc(C)c2n1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. After 15 ml of methanol was added and the reaction mixture was cooled to 0° C., 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Then 1.1 g of potassium carbonate and 0.68 g of dimethyl sulfate were added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to ice water and extracted with 15 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals thus obtained were purified by silica gel column chromatography to provide 400 mg of white crystals. Yield: 36% m.p.: 90°-91° C.; 1H-NMR (300 MHz, CDCl3 /TMS; δppm): 7.16 (s, 1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 2.68 (s, 3H), 2.48 (s,3H)
Reaction SMILES: [C:1]([C:5]1([SiH2:11][C:12]([O:27][C:28]([C:47]2[CH:48]=[N:49][C:50](Cl)=[CH:51][CH:52]=2)([SiH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[SiH2:29][C:30]2([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)([C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=2)[SiH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:54]1([Mg]Br)[CH2:56][CH2:55]1.[NH4+].[Cl-].O1[CH2:65][CH2:64][CH2:63]C1>>[C:1]([C:5]1([SiH2:11][C:12]([O:27][C:28]([C:47]2[CH:48]=[N:49][C:50]([CH:63]3[CH2:64][CH2:65]3)=[CH:51][CH:52]=2)([SiH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[SiH2:29][C:30]2([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]2)([C:20]2[CH:21]=[N:22][C:23]([CH:54]3[CH2:56][CH2:55]3)=[CH:24][CH:25]=2)[SiH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]C1CC1
Reactant: C1CCOC1
Reactant: CC(C)(C)C1([SiH2]C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(Cl)nc2)([SiH2]c2ccccc2)c2ccc(Cl)nc2)C=CC=CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)C1([SiH2]C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(C3CC3)nc2)([SiH2]c2ccccc2)c2ccc(C3CC3)nc2)C=CC=CC1
Reaction time: 5.5 h

Procedure:
NiCl2(dppf)2 (0.45 g, 0.66 mmol) was added to a solution of 1-(tert-butyl)-1,1-diphenylsilyl [(6-chloro-3-pyridyl)methyl]ether (5.0 g, 13 mmol) in tetrahydrofuran (26 ml) at room temperature, after which 1.0 M cyclopropylmagnesium bromide (16 ml) was slowly added dropwise and stirring was continued at room temperature for 5.5 hours. Next, 1.0 M cyclopropylmagnesium bromide (10 ml) was slowly added dropwise over a period of 1.5 hours and stirring was continued for 15 hours. Saturated aqueous NH4Cl was added, and then the mixture was stirred for 3 hours and filtered through celite and extraction was performed with ethyl acetate. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.3 g) as a mixture with impurities. This product was used without further purification for the following reaction.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([N:11]([CH3:24])[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[C:6]=2[N:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>>[CH3:24][N:11]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:8]1[C:6]2[N:7]=[C:2]([NH:37][C:34]3[CH:35]=[N:36][C:31]([N:28]4[CH2:27][CH2:26][O:25][CH2:30][CH2:29]4)=[CH:32][CH:33]=3)[N:3]=[CH:4][C:5]=2[S:10][CH:9]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: COc1cc(N(C)c2csc3cnc(Cl)nc23)cc(OC)c1OC
Product: COc1cc(N(C)c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)cc(OC)c1OC
Yield: 76.7 %

Procedure:
N7-Methyl-N2-(6-morpholinopyridin-3-yl)-N7-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-2,7-diamine (16 mg, 76% yield) was prepared in the same manner as Step of Example 1 using 2-chloro-N-methyl-N-(3,4,5-trimethoxyphenyl)thieno[3,2-d]pyrimidin-7-amine (15 mg, 0.041 mmol) and 6-morpholinopyridin-3-amine (9 mg, 0.049 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[CH3:39][N:40]([CH3:47])[CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:40]([CH3:47])[CH3:39])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)CCCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)CCCN(C)C)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 4-(dimethylamino)butanoic acid (2 equiv.) was added. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired product.