Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: CC(C)(C)CNS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2,2-dimethyl-propyl)-benzenesulfonamide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 580.3 [(M−H−]; mp 208° C.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C@:10]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[C@@H:9]1[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:19][C:15]1[C:14]([F:20])=[C:13]([C@H:11]2[CH2:12][N:8]([CH2:7][C:6]([OH:36])=[O:5])[C@@H:9]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C@@:10]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)C[C@@H]1N(CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N(CC(=O)O)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (2.1 g, 3.9 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 24 h. The mixture was concentrated, and water was added. The “pH” of the mixture was adjusted to 6-7 by saturated aqueous NaHCO3 solution, then extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried over MgSO4, then concentrated to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid as a off-white solid (1.6 g, 85%). HRMS (ES+) m/z Calcd for C24H24Cl2F2N2O2+H [(M+H): 481.1256; Found: 481.1254.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[CH:9][C:10]([O:18][CH3:19])=[C:11]([CH:13]2OCC[O:14]2)[CH:12]=1)[S:3]([CH3:6])(=[O:5])=[O:4].Cl>CC(C)=O>[CH3:1][N:2]([C:7]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:18][CH3:19])=[CH:9][CH:8]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: COc1ccc(N(C)S(C)(=O)=O)cc1C1OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(N(C)S(C)(=O)=O)cc1C=O
Yield: 81 %

Procedure:
A solution of 2-[5-(N-methyl-N-methylsulfonylamino)-2-methoxyphenyl]-1,3-dioxolane (4.0 g, 13.9 mmol) in 1N-HCl (4 ml)/acetone (80 ml) was stirred at room temperature for 2 hr. After removal of the solvent, water was added to the residue and the mixture was extracted with CH2Cl2. The extract was washed with brine, dried over MgSO4 and evaporated in vacuo to give crude 5-(N-5-methyl-N-methylsulfonylamino)-o-anisaldehyde (4.0 g, 118%). The resulted crude compound was recrystallized from ethyl acetate/hexane to give 5-(N-methyl-N-methylsulfonylamino)-o-anisaldehyde (2.64. g, 81%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:27])[CH3:26]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a mixture of NaH (60%, 4.92 g, 0.205 mol) in DMF (60 mL) is added 5-benzoxyindole at 0˜5° C., then stirred 30 min. ethyl 2-bromopropionate is added dropwise, the mixture is allowed to warm to room temperature and heated at 70° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate yields the title compound (29 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCC3=O)nc1
Yield: 30.3 %

Procedure:
Using a method similar to Intermediate 1, using 4-hydroxy-1-indanone (2.44 g, 16.5 mmol), 6-chloronicotinamide (234 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.22 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.29 (d, 1H), 8.03 (s, 1H), 7.55-7.46 (M, 4H), 7.19 (d, 1H), 2.81 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[C:7](=[O:13])[NH:8]2>[Pd].CCOC(C)=O>[CH2:3]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:14])[C:7](=[O:13])[NH:8]2)[CH:2]([CH3:15])[CH3:1]
Reactant: CC(C)=Cc1cccc2c1C(=O)C(=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Cc1cccc2c1C(=O)C(=O)N2
Reaction time: 1 h
Yield: 13.3 %

Procedure:
A mixture of 0.20 g (1.0 mmol) of 4-(2-methyl-propenyl)-1H-indole-2,3-dione and 0.05 g of 10% palladium on charcoal in 25 mL of EtOAc was subjected to hydrogenation on a Parr apparatus at 46 psi for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to dryness. The solid was purified by chromatography on silica gel, eluting with hexane:EtOAc (4:1), to furnish 0.027 g (13%) of 4-isobutyl-1H-indole-2,3-dione: 1H NMR (DMSO-d6): δ 0.89 (d, J=6.7 Hz, 6H), 1.86 (nonet, J=6.7 Hz, 1H), 2.72 (d, J=6.7 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.86 (d, J=7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 11.03 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O[Na])(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O.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].C1(C)C=CC=CC=1>[N:15]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(N2CCOCC2)cc1OC(F)(F)F
Temperature: 75 °C
Reaction time: 15 h
Yield: 9.8 %

Procedure:
A 500 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with 4-bromo-2-(trifluoromethoxy)benzaldehyde (8.00 g, 29.7 mmol, 1.00 equiv), morpholine (2.59 g, 29.7 mmol, 1.00 equiv), t-BuONa (4.28 g, 44.5 mmol, 1.50 equiv), Pd2(dba)3 (1.36 g, 1.49 mmol, 0.05 equiv), BINAP (1.85 g, 2.97 mmol, 0.10 equiv), toluene (150 mL). The resulting solution was stirred for 15 h at 75° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/4) to provide 0.800 g (10% yield) of 4-(morpholin-4-yl)-2-(trifluoromethoxy)benzaldehyde as a yellow solid. LCMS (ESI, m/z): 276 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1.[H-].[Na+].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])=[CH:8][C:9]=2[CH3:11])[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)cn(C)c12

Procedure:
By a method similar to Example 56, using 1,7-dimethyl-3-(1-methylpiperdin-4-yl)-5-hydroxy-1H-indol (1.98 mmol, 0.511 g) in THF (5.0 mL), sodium hydride (2.37 mmol, 0.095 g, 60% dispersion in mineral oil), and benzenesulfonyl chloride (2.18 mmol, 0.384 g), afforded 0.501 g (64%): ms (ion spray): m/z=399 (M+1); 1H NMR (DMSOd6): 7.85-7.77 (m, 3H), 7.67-7.62 (m, 2H), 7.01 (s, 1H), 6.64 (d, J=2.56 Hz, 1H), 6.55 (d, J=1.83 Hz, 1H), 3.94 (s, 3H), 2.82-2.72 (bd, 2H), 2.60 (s, 3H), 2.39 (tt, J=3.72 Hz, 1H), 2.18 (s, 3H), 1.91 (m, 2H), 1.67-1.54 (m, 2H), 1.47 (m, 2H); Calculated for C22H26N2O3S: C, 66.31; H, 6.58; N, 7.03. Found: C, 66.18; H, 6.58; N, 7.08.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:28]=[CH:27][C:21]2[CH2:22][CH2:23][S:24](=[O:26])(=[O:25])[C:20]=2[CH:19]=1)(C)(C)C>C(Cl)Cl.CCCCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:29])=[O:5])=[C:10]([C:16]#[C:17][C:18]2[CH:28]=[CH:27][C:21]3[CH2:22][CH2:23][S:24](=[O:26])(=[O:25])[C:20]=3[CH:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2
Solvent: ClCCl
Solvent: CCCCC
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2
Yield: 93 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{4-chloro-2-[(1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate (Intermediate 235), the title compound was obtained as a beige solid in 93% yield after trituration in DCM/pentane.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:22][N:21]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CN(C=O)C.O>[CH:17]([C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][C:27]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])[N:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Cc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.077 g) and cesium carbonate (0.203 g) were added to a solution of compound (6c) (0.150 g) in DMF (1.73 mL), followed by stirring at 80° C. for 18 hr. The reaction solution was distributed between ethyl acetate and water. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile (0.154 g, 73%). This 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-3-methylbenzonitrile was dissolved in DMSO (5.0 mL) and ethanol (5.0 mL). A 4 N aqueous sodium hydroxide solution (0.195 mL) and a 30% hydrogen peroxide solution (0.088 mL) were added to the resulting solution, followed by stirring at room temperature for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain compound (80) (0.135 g, 83%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (Lancaster Synthesis GmbH; 11.75 g, 50 mmol) in ethanol (300 mL) is hydrogenated at atmospheric pressure over Raney nickel (1 g) at 40° C. The calculated amount of hydrogen is taken up after 8 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 134-139° C.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]([C:11]2[C:12]3[C:26]([CH3:27])=[N:25][N:24](C4CCCCO4)[C:13]=3[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl>C1COCC1>[CH3:1][C:2]1([NH:8][C:9]([C:11]2[C:12]3[C:26]([CH3:27])=[N:25][NH:24][C:13]=3[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCNCC3)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCNCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.1 %

Procedure:
A solution of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo-[3,4-b]pyridine-4-carboxylic acid (4-methyl-piperidin-4-yl)-amide (75 mg) in THF (1 mL) was added to a stirred solution of HCl (4N in dioxane). The mixture was stirred at r.t. overnight, the precipitate formed was filtered off and washed with ethyl acetate and acetone and dried in air to give 72 mg (99%) of the title compound as hydrochloride
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]#N)=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CC(O)=[O:34].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:21])[N:7]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=[O:34])=[CH:16][CH:17]=2)[O:12][CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C#N)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCOc2cc(C=O)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of (7-cyano-chroman-4-yl)-methyl-carbamic acid tert-butyl ester (299 mg, 1.04 mmol, 1.0 eq) in anhydrous toluene (5 mL) under N2 at −20° C. was added diisobutylaluminum hydride (Aldrich, 1.50 M in toluene, 1.38 mL, 2.08 mmol, 2.0 eq) slowly. The reaction was stirred at −20° C. for 1 h. Glacial HOAc (1 mL) and H2O (5 mL) was added sequentially. The reaction was warmed to RT spontaneously and stirred at this temperature for an additional 1.5 h. A solution of saturated sodium potassium tartrate (50 mL) was added and the mixture was extracted with EtOAc (60 mL). The aqueous layer was adjusted to pH-10 with 2N NaOH, and extracted with EtOAc (60 mL×2). Combined organic phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-8% EtOAc-Hexane) afforded the title compound as a colorless sticky solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH2:23])[C:17](=[CH:21][CH:22]=1)[C:18](O)=[O:19])[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]2[C:17]([C:18](=[O:19])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:23]2)=[CH:21][CH:22]=1)[CH3:12]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOc1ccc(C(=O)O)c(N)c1
Product: CCOc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13

Procedure:
3-Ethoxybenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-ethoxyanthranilic acid.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:19][NH2:20]>CN(C=O)C.O>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:19][NH:20][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)N=C=O
Reactant: COCCOCOc1ccc(CN)cc1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(CNC(=O)NC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
tert-Butylisocyanate (2.9 mL, 25.5 mmol) followed by triethylamine (9.8 mL, 68 mmol) was added to a magnetically stirred solution of 3-bromo-4-(2-methoxyethoxymethoxy)benzyl-amine (5 g, 17 mmol) in DMF (50 mL) and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with water (10 mL) and the dilution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatographic (silica gel) employing 100% ethyl acetate as eluent to give 1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-tert-butylurea (5.3 g).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]#[C:13]Br.C(N(CC)CC)C>CC(C)=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[C:13]#[N:12]
Reactant: N#CBr
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#CN1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a 25 mL round-bottomed flask was added phthalimide (1.47 g, 10.0 mmol), cyanogen bromide (1.27 g, 12.0 mmol), and 10 mL of reagent grade acetone. The resulting mixture was cooled using an ice/salt bath while triethylamine (1.8 mL, 12.8 mmol) was added dropwise over a 2 minute period. After 15 minutes, the mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and filtered. The solution was decolorized with activated charcoal, and concentrated to give a brown solid. This material was recrystallized from ethyl acetate to give 1.32 g (77%) of a brown crystalline solid, mp 189°-191° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 190° C.): IR (nujol) 2258 (nitrile), 1755 (carbonyl) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.05-8.15 (m, 4); 13C NMR (50 MHz, DMSO) δ 162.61, 136.35, 130.76, 125.03, 102.86.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#N)[CH:7]=[CH:6]2.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[CH:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([NH:2][CH3:1])[CH:12]=[CH:11]2)=[O:28]
Reactant: O=S(=O)(O)O
Reactant: CNc1ccc2cc(C#N)ccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CNc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A solution of 6-methylamino-2-naphthonitrile (0.84 g, 4.6 mmol) prepared above in toluene (50 ml) was mixed with diisobutylaluminum hydride (9 ml, 1.0M (in toluene)) under a nitrogen atmosphere at −70° C. The mixture was stirred at −78° C. for 30 minutes and at room temperature for 4 hours. The mixture was added to a saturated solution of ammonium chloride, and then an aqueous solution of sulfuric acid was added thereto. The reaction mixture was extracted with ether, washed with brine, dried over MgSO4, and concentrated to give the title compound (0.76 g, yield: 89%).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:31][C:32]([CH3:34])=O>O>[OH:1][CH2:2][C@@H:3]1[O:4][C@@H:9]2[C@@H:7]([O:8][C:32]([CH3:34])([CH3:31])[O:10]2)[C@@H:5]1[OH:6]
Reactant: CC(C)=O
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)O[C@@H]2O[C@@H](CO)[C@@H](O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a suspension of L-(−)-xylose (133, 19.15 g, 127.5 mmol) and MgSO4 (30.72 g, 255.0 mmol) in acetone (190 mL) was added conc. H2SO4 (1.9 mL) at room temperature. After 12 h, the reaction mixture (all L-(−)-xylose had been consumed) was filtered and the collected solids were washed with acetone (twice, 20 mL per wash). The stirring yellow filtrate was neutralized with NH4OH solution to pH≈9. The suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as yellow oil. The yellow oil was suspended in water (5 mL), and then the pH was adjusted from 9 to 2 with 1N HCl in water solution. The reaction mixture was stirred for 12 h at room temperature. The resulting mixture was neutralized by the addition of 25% (w/w) K3PO4 in water until pH≈7. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide the title compound (12.63 g, 52%) as yellow oil.
Reaction SMILES: C([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29]C(=O)OC(C)(C)C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].Br.Br[CH:41]([C:43]1[O:44][C:45](=[O:65])[C:46]2[C:51]([C:52]=1[C:53]1[S:54][C:55]([CH2:58][N:59]3[CH2:64][CH2:63][O:62][CH2:61][CH2:60]3)=[CH:56][CH:57]=1)=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH3:42]>CN(C)C=O.[Cl-].[Na+].O>[N:24]1[C:25]([NH:29][CH:41]([C:43]2[O:44][C:45](=[O:65])[C:46]3[C:51]([C:52]=2[C:53]2[S:54][C:55]([CH2:58][N:59]4[CH2:60][CH2:61][O:62][CH2:63][CH2:64]4)=[CH:56][CH:57]=2)=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH3:42])=[C:26]2[C:21]([NH:20][CH:28]=[N:27]2)=[N:22][CH:23]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2[nH]cnc12)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCOCC2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
tert-Butyl 9-trityl-9H-purin-6-ylcarbamate (102 mg, 0.213 mmol) was added to a solution of 50% dispersion in mineral oil NaH (5.12 mg, 0.213 mmol) in N,N-dimethylformamide (0.5 ml) and the mixture was stirred at RT for 30 min. 3-(1-Bromoethyl)-4-(5-(morpholinomethyl)thiophen-2-yl)-1H-isochromen-1-one hydrobromide (intermediate C16, 100 mg, 0.194 mmol) was suspended in DMF (0.5 ml, 0.194 mmol) and reacted with 50% dispersion in mineral oil NaH (5.1 mg, 0.213 mmol) at RT for 15 min. The resulting solution was added to the previous prepared mixture and left on stirring at 60° C. for 1 hrs, at RT for 3 hrs and then at 80° C. for 3 hrs. The reaction mixture was poured into brine and extracted with EtOAc. The collected organic phases were dried and concentrated. The resulting crude material was purified under reverse phase chromatography using a Biotage C18 60 g SNAP cartridge. The collected fractions were added with 37% HClaqueous (1 ml) and concentrated. The resulting material was further purified under reverse phase chromatography using a Biotage C18 30 g SNAP cartridge. The resulting material was finally purified on silica with a gradient of DCM and 2-propanol, modified with 0.5% TEA, to give the title compound (9 mg, 9.5%).