Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:37]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=Cc1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (110 mg, 0.22 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (15 ml). The stirred solution was then cooled to room temperature and treated with a solution of benzaldehyde (21 mg, 0.20 mmol) in dry tetrahydrofuran (2 ml) followed by addition of sodium triacetoxyborohydride (70 mg, 0.33 mmol). The resultant mixture was stirred at room temperature for 24 hr, diluted with ethyl acetate and then washed sequentially with saturated aqueous sodium hydrogen carbonate and brine. The organic solution was then dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol (92:8) to afford the title compound as a solid (67 mg). MS: 581 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][CH2:34][OH:35])=[C:27]([CH3:36])[CH:26]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[OH:35][CH2:34][CH2:33][O:32][C:28]1[C:27]([CH3:36])=[CH:26][C:25]([C:15]2[N:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:9][CH:10]=3)[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:30][C:29]=1[CH3:31]
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(N)cc2)cc(C)c1OCCO
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(NC(=O)C(C)C)cc2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
TEA (0.07 mL, 0.50 mmol) and isobutyryl chloride (0.25 mmol) were added to a solution of 3-(4-aminophenyl)-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.100 g, 0.25 mmol) in CH2Cl2 (5 mL), stirred at room temperature for 2 hours, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH in CH2Cl2, afforded the title compound as a white solid in 78% yield. 1H-NMR (300 MHz, DMSO-d6): δ 9.90 (s, 1H), 8.17 (dd, J=6.8, 1.2 Hz, 1H), 7.85-7.91 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.53-7.65 (m, 3H), 7.20 (d, J=8.9 Hz, 2H), 7.04 (s, 2H), 4.83 (t, J=5.4 Hz, 1H), 3.61-3.72 (m, 4H), 2.56-2.63 (m, 1H), 2.10 (s, 6H), 1.08 (d, J=6.9 Hz, 6H). MS (APCI) m/z: 472 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[Na+].[CH2:21]([OH:23])[CH3:22].NOS(O)(=O)=O>O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([N:1]=[CH:2][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:18]=[C:13]1[CH2:12][CH:11]3[CH:21]([C:22]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)[OH:23])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCO
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c2c(nc3ccccc13)C(C(O)c1ccccc1)Cc1cn(N=Cc3ccccc3)nc1-2
Temperature: 25 °C

Procedure:
To a warm suspension (50° C.) of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (26.77 g) and solid sodium hydroxide (24.9 g) in water (377 ml) was added ethanol (1133 ml). Hydroxylamine-o-sulfonic acid (34.27 g) was added in portions over 15 minutes and the reaction was cooled to room temperature. The resulting solid was filtered, washed with water, air dried, heated with excess benzaldehyde, filtered to remove insolubles, concentrated, and triturated (diethyl ether) to yield 10.32 g of a mixture of the target product and 11-amino-2-benzylideneamino-4,5-dihydro-2H-pyrazolo[3,4-a]acridine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:32]I.N1C=CN=C1>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][I:32])=[CH:2]1
Reactant: II
Reactant: OCCc1csc2ccccc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCc1csc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(1-benzothiophene-3-yl)ethanol (890 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(1-benzothiophene-3-yl)ethyl iodide, was obtained as brown liquid. Yield: 1.2 g (85%); 285 (M+H).
Reaction SMILES: FC1C=CC(C2(CCC3O[N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)CCCCC2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][CH:41]([C:44]([O:46]C)=O)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]2[CH2:39][CH2:40][CH:41]([C:44]3[O:46][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[CH2:30])=[CH:23][CH:22]=5)[CH2:42][CH2:43]2)=[CH:36][CH:37]=1
Reactant: COC(=O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1CCC1(c2ccc(F)cc2)CCCCC1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1

Procedure:
This compound was prepared according to the general procedure described for Preparation 26A, employing methyl 4-(4-chlorophenyl)cyclohexanecarboxylate as the starting material. LC/MS M+1=390.3.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1.[NH2:17][NH2:18]>>[NH:17]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4]([NH2:16])[N:3]=1)[NH2:18]
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Reactant: NN
Product: NNc1nc(N)c2ncn(COCCO)c2n1
Reaction time: 1 h

Procedure:
2-Chloro-9-(2-hydroxyethoxymethyl)adenine (0.83 g) was added with stirring to 95% hydrazine (11 ml) and the resulting solution stirred 1 hour under nitrogen. Excess hydrazine was removed by distillation in a rotary evaporator at a bath temperature of 30° C. followed by co-evaporation twice with ethyl acetate. The residue was thoroughly triturated with methanol to give a quantitative yield (0.8 g) of white to cream colored-2-hydrazino-9-(2-hydroxyethoxymethyl)adenine, m.p. 220°-222° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH2:12][CH2:11][NH2:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: NCCN
Product: NCCNc1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 95.3 %

Procedure:
23.63 g (150 mmol) of 4-chloronitrobenzene are dissolved in 92.1 ml (1.38 mol) of ethylenediamine and heated to the boil under a nitrogen atmosphere. After 24 hours, the mixture is evaporated to dryness, and the crude product is suspended in 100 ml of 1 N sodium hydroxide solution and filtered off. Washing with water and drying under reduced pressure gives 25.9 g of N1-(4-nitrophenyl)ethane-1,2-diamine in the form of yellow crystals (ESI 182).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:15][CH2:16][C:17]2[C:25]3[C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=[N:21][C:20]=3[NH:19][CH:18]=2)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:11]1([N:15]2[CH2:16][C:17]3=[CH:18][NH:19][C:20]4[C:25]3=[C:24]([CH:23]=[CH:22][N:21]=4)[C:26]2=[O:27])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC1(NCc2c[nH]c3nccc(C(=O)O)c23)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid obtained in Example 4 was dissolved in DCM (3 mL) and TFA (1 mL) and allowed to stir at room temperature for 1 h. The solution was concentrated in vacuo and purified via preparative HPLC 5% to 20% B in A and gave 21 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.42 (m, 1H), 7.59 (m, 1H), 7.43 (m, 1H), 5.05 (s, 2H), 3.29-3.33 (m, 2H), 3.22-3.23 (m, 2H), 2.93-2.97 (m, 2H), 2.20-2.26 (m, 2H), 3.17 (s, 3H). [M+H] found 271.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20](OCC)=[O:21])=[CH:19][C:12]=2[N:11]=1.C[Al](C)C.[CH3:30][C:31]1[C:36]([CH3:37])=[CH:35][N:34]=[C:33]([NH2:38])[CH:32]=1>CCCCCC.C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([C:20]([NH:38][C:33]3[CH:32]=[C:31]([CH3:30])[C:36]([CH3:37])=[CH:35][N:34]=3)=[O:21])=[CH:19][C:12]=2[N:11]=1
Reactant: Cc1cnc(N)cc1C
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc3nc(Nc4c(Cl)cccc4Cl)n(C)c3cc2F)cc1C

Procedure:
Prepared analogously to example 131f from ethyl 2-(2,6-dichlorophenylamino)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxylate, 2 M trimethyl aluminium solution in hexane and 4,5-dimethylpyridin-2-amine in THF.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH2:10][CH2:9]1.[NH2:15][CH2:16][C:17]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]2[C:18]=1[N:19]=[C:20]([O:32][CH3:33])[C:21]([O:30][CH3:31])=[N:22]2>COC(C)(C)C>[CH3:31][O:30][C:21]1[C:20]([O:32][CH3:33])=[N:19][C:18]2[C:23](=[CH:24][C:25]([N+:27]([O-:29])=[O:28])=[CH:26][C:17]=2[CH2:16][NH:15][C:11](=[O:12])[CH2:10][CH2:9][C:8]([OH:13])=[O:14])[N:22]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(=O)CCC(=O)O)c2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
55 μl (0.397 mmol) of triethylamine and 40 mg (0.397 mmol) of succinic anhydride are added to a suspension of 100 mg (0.378 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline in 2 ml of tert-butyl methyl ether and the mixture is stirred for 3 hours at room temperature. The mixture is then filtered and the residue is washed twice with tert-butyl methyl ether. The filter residue is chromatographed on silica gel with dichloromethane/methanol/acetic acid (95:4.5:0.5). The title compound is obtained in the form of a beige powder.
Reaction SMILES: [CH3:1][O-:2].[K+].C[O-].[Li+].[Br:7][C:8]1[C:9](Cl)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.Cl>C1(C)C(C)=CC=CC=1.C(O)(C)(C)C>[Br:7][C:8]1[C:9]([O:2][CH3:1])=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: C[O-]
Agent: Cl
Agent: [K+]
Agent: [Li+]
Solvent: Cc1ccccc1C
Solvent: CC(C)(C)O
Product: COc1c(Br)cnc2[nH]ccc12
Temperature: 117 °C
Yield: 25.2 %

Procedure:
Potassium methoxide (103 mg), lithium methoxide (27 mg) and tert-butanol (40 μl) were added to a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (81 mg) in xylene (3.5 ml), and the mixture was heated under reflux at 117° C. for 16 hours. The reaction solution was brought to pH 4 by adding concentrated hydrochloric acid in small portions and separated by adding ethyl acetate and distilled water. The resulting aqueous layer was brought to pH 8 by adding a 5 N aqueous sodium hydroxide solution and separated by adding ethyl acetate. All the resulting organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developed with ethyl acetate-hexane) to give the title compound (20 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)(=[O:3])[CH3:2].[CH3:36][Mg]Br.C(=O)(O)[O-].[Na+].O>ClCCl>[OH:3][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)([CH3:36])[CH3:2]
Reactant: CC(=O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: C[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)c1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-(2-acetylphenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 532, 77 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL) and cooled to −78° C. Methylmagnesium bromide (0.056 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added dropwise and the mixture was stirred for 30 minutes at −78° C. Additional methylmagnesium bromide (0.057 mL, 3 M diethyl ether solution, 0.17 mmol, 1 equiv) was added and the mixture was stirred for an additional 30 minutes at −78° C. The mixture was treated with sodium bicarbonate (3 mL, aqueous saturated), warmed to ambient temperature, poured into water and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (100:0 to 0:100 hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.12 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.15 (1H, dd, J=8.0, 1.1 Hz), 7.90 (1H, dd, J=7.9, 1.3 Hz), 7.84 (2H, d, J=8.7 Hz), 7.78 (1H, d, J=8.6 Hz), 7.73 (1H, d, J=1.4 Hz), 7.64-7.60 (1H, m), 7.53 (1H, t, J=7.6 Hz), 7.48 (2H, d, J=8.7 Hz), 7.46-7.43 (1H, m), 7.35 (1H, td, J=7.5, 1.3 Hz), 7.17 (1H, dd, J=7.5, 1.1 Hz), 6.53 (1H, dd, J=2.3, 1.9 Hz), 5.77 (2H, s), 5.28 (1H, s), 1.37 (6H, s) ppm; high resolution mass spectrometry (ES+) m/z 476.2069 [(M+H)+; calculated for C29H26N5O2: 476.2081].
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>C(Cl)Cl>[Si:10]([O:29][CH2:28][CH2:27][NH:26][CH2:24][CH3:25])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Imidazole (1.53 g, 22.44 mmol) and a solution of tert-butylchlorodiphenylsilane (4.63 g, 16.83 mmol) in DCM (10 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (1.099 ml, 11.22 mmol) in DCM (30 ml) and the resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 1N aq. NaHSO4 and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), concentrated under reduced pressure to give a residue which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (2.95 g, yield: 80) %).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@@H:12]([O:14][CH2:15][C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:10][CH2:11][C@@H:12]([O:14][CH2:15][C@H:16]([O:21][C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][N:33]=3)[N:30]=[CH:31][C:24]=12)[C:17]([O:19][CH3:20])=[O:18])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@@H](O)CO[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CO[C@@H](C)CO[Si](C)(C)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
Sodium hydride (0.219 g, 5.48 mmol) was added to (S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-hydroxypropanoate (Intermediate AO1) (1.336 g, 4.57 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (1.216 g, 4.57 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 60% EtOAc in isohexane to give (2S)-methyl 3-((S)-1-(tert-butyldimethylsilyloxy)propan-2-yloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (1.658 g, 69.5%). m/z (ES+), (M+H)+=522.50; HPLC tR=3.35 min
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH:13]=O)=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[C:11]([CH3:13])[CH:10]=[N:8]2
Reactant: Nc1cccc(O)c1N
Reactant: CC(=O)C=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc2cccc(O)c2n1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 2,3-diaminophenol (2.93 g) in 2M aqueous acetic acid solution (47 ml) and 4M aqueous sodium acetate solution (29 ml) was added 40% aqueous pyruvic aldehyde solution (3.79 ml) at 60° C. The reaction mixture was stirred at 60° C. for 40 minutes. After cooling the reaction mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate and extracted with dichloromethane (50 ml) twice. The organic layer was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the solution was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 450 ml) eluting with n-hexane/ethyl acetate (5/1, V/V) to give 8-hydroxy-2-methylquinoxaline (the less polar product) as crystals and with n-hexane/ethyl acetate (3/1, V/V) to give 8-hydroxy-3-methylquinoxaline (the more polar product) as crystals. The former was washed with n-hexane to afford pale yellow crystals (1.27 g). The latter was washed with isopropyl ether to afford pale yellow crystals (1.30 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[S:39][C:38]([CH:40]=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]2[S:39][C:38]([C:40]3[NH:25][C:24]4[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]5[CH:14]=[CH:13][C:12]([N:15]6[CH2:20][CH2:19][O:18][CH2:17][CH2:16]6)=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1ccc(N2CCC(O)CC2)s1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC(O)CC4)s3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 417 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 5-(4-hydroxypiperidinyl)thiophene-2-carboxaldehyde. [M+H]+ calcd for C27H29N5O3S: 504.20; found: 503.99.
Reaction SMILES: CC1N=C([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[O:10])ON=1.[N:32]1(C2C=CC=CC=2C(O)=O)[CH:36]=[CH:35][CH:34]=[N:33]1.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[N:32]1([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=2)=[O:10])[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: O=C(O)c1ccccc1-n1cccn1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 2-(1H-pyrazol-1-yl)benzoic acid (CAS number 55317-53-8; 53 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:23]3[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the previous step, 1.45 g, 4.61 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (782 mg, 5.08 mmol) and dichloro(1,1-bisdiphenylphosphino-ferrocene palladium (II) (Pd(dppf)Cl2) dichloromethane adduct (337 mg, 0.461 mmol) in 40 mL of DMF was added K3PO4 (3.91 g, 18.4 mmol). The resulting mixture was stirred at 70° C. for 18 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc, washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-2% EtOAc/DCM) to afford 1.14 g (72%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H29NO3, 344.2 (M+H). found 344.4.