Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34]Br)[CH3:28].O>CN(C=O)C>[CH2:27]([O:29][C:30](=[O:37])[CH2:31][NH:32][C:33](=[O:36])[CH2:34][O:20][N:19]=[C:18]1[C:5]2[C:6](=[N:7][C:8]([C:9](=[O:10])[NH2:11])=[C:3]([C:1]#[N:2])[N:4]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH3:28]
Reactant: CCOC(=O)CNC(=O)CBr
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
To a suspension of 33 (212 mg, 0.80), Cs2CO3 (260 mg, 0.80) in DMF (15 ml), 39 (200 mg, 0.89 mmol) was added portionwise and the mixture was stirred at room temperature for 2 days. H2O (30 ml) was added and the suspension was extracted with CH2Cl2 (70 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2Cl2/MeOH 9:1) affording 40 (56 mg, 17%) as yellow-brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.78 (m, 2H), 8.12 (bs, 1H), 8.05-7.78 (m, 3H), 7.67 (m, 1H), 4.72 and 4.69 (s, 2H), 4.10 (q, 2H), 3.92 and 3.90 (s, 2H), 1.19 (t, 3H). ESI+MS: calcd for C19H16N6O5: 408.38; found: 409.1 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1.F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CS(C)=O.CCOC(C)=O.O>[NH2:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[CH2:8]1
Reactant: N[C@H]1CCNC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
K2CO3 (7.71 g, 55.84 mmol) was added to a solution of (S)-pyrrolidin-3-amine (5.0 g, 58.04 mmol) and methyl 4-fluorobenzoate (8.6 g, 55.81 mmol) in DMSO (20 mL). The reaction mixture was stirred for 18 h at 130° C. in a sealed tube. The reaction mixture was cooled, diluted with AcOEt and H2O, and extracted with AcOEt (3 times). The extract was washed with water, NH4Cl and brine, dried over MgSO4, filtered and concentrated to give the title compound 323 (7.98 g, 65% yield) as a pink solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9](OCC)=[O:10])[CH:4]=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[CH:4]=[N:3]1
Reactant: CCOC(=O)CCc1cnn(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(CCCO)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of ethyl 3-(1-methyl-1H-pyrazol-4-yl)propionate (1.05 g) in tetrahydrofuran (10 ml) was added lithium aluminum hydride (0.22 g) under nitrogen atmosphere After the mixture was stirred for 30 minutes, water and 15% sodium hydroxide aqueous solution were added successively to the mixture. The resulting precipitates were filtered off through Celite® pad and the filtrate was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3-(1-methyl-1H-pyrazol-4-yl)-1-propanol.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2nnc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of benzotriazole (12 g) in DMF (150 mL) at r.t. was added a solution of 10N NaOH (11 mL). After stirring for 30 min., 4-fluorobenzyl bromide (3.9 mL) was added. The mixture was further stirred for 3 hrs, diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed water (2×), dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford the title compound as a white solid.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH3:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.O>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:4][CH2:5][CH3:6])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CCCBr
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C#N)c1cccc(OC)c1
Yield: 74 %

Procedure:
NaH (55-65%, 1.44 g, 36 mmoles) and, after 30 minutes under stirring, 1-bromo-propane (4.46 g, 36 mmoles) were added to a solution of 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles) in anhydrous DMF (30 ml) under N2 at room temperature. After 1.5 hours the mixture was poured into water (200 ml), extracted 3 times with ethyl ether, anhydrified and brought to dryness to give a residue which was chromatographed (eluent: petrolatum, then petrolatum/ethyl ether 95:5) to give 4.2 g of the title compound (yield: 74%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][CH2:25][N:26]2[C@H:31]3[CH2:32][CH2:33][C@@H:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:44]>[Pd].CO>[ClH:44].[ClH:44].[CH3:43][C:35]1[N:34]([CH:29]2[CH2:28][CH:27]3[N:26]([CH2:25][CH2:24][C:11]4([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=5)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 1-[(1R,5S)-8-(2-{1-benzyl-4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole (0.2 g, 0.34 mmol), 1N hydrochloric acid (0.34 mL) and 10% Palladium on carbon (50 mg) in methanol (10 mL) was hydrogenated overnight at rt and atmospheric pressure. The mixture was filtered through celite and concentrated to give 2-methyl-1-[8-(2-{4-[3-(trifluoromethyl)phenyl]piperidin-4-yl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-1H-benzimidazole dihydrochloride as a solid (0.15 g, 89%) that was used without further purification.
Reaction SMILES: C(O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[Cl-].[Na+]>CN(C)C=O>[OH:7][C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][C:8]=1[OH:9])[CH:3]=[CH2:2]
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(O)c(O)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
200 g (1.11 mol) of caffeic acid are dissolved in 1.2 l of dimethyl formamide dissolved and the solution is stirred for 3 h at 150° C. After cooling to room temperature, the solution is poured on to 3 kg of ice, saturated with sodium chloride and extracted twice with ethyl acetate. The organic phase is washed with 2% NaHCO3 solution and then with water, dried over Na2SO4 and concentrated by evaporation, giving 120 g (80% ) of a highly viscous liquid which can be recrystallised from toluene. The substance is, however, sufficiently pure and can be further processed without recrystallisation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][S:23][CH3:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[OH:31]O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][S:23]([CH3:24])=[O:31])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CSCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Reactant: OO
Solvent: O=CO
Product: CS(=O)Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.7 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (prepared as in Example 36, 514.3 mg, 1.099 mmol) in formic acid (11 mL) was treated with a 30% aqueous hydrogen peroxide solution (113 μL, 1.106 mmol). The reaction was stirred at 25° C. for 4 d. The reaction was then partitioned between ethyl acetate (250 mL) and water (250 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (250 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5% methanol/methylene chloride) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methanesulfinylmethyl-pyrazin-2-yl)-propionamide (269.9 mg, 51%) as a light yellow foam: mp 102–106° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O4S2 (M+H)+ 484.1126, found 484.1134.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2.Cl>C(COC)OC>[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:34][CH2:33]2
Reactant: CN(CCCl)c1ccc2c(c1)COC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of oxindole (0.739 g, 5.55 mmol) in anhydrous dimethoxyethane (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (14.0 ml, 14.0 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-one (1.0 g, 4.4 mmol) was added. The mixture was stirred at room temperature for 3 hours and was then poured into 1M HCl aqueous solution (300 ml) with stirring. The resulting mixture was heated at 40° C. for 30 minutes. The solid was filtered, washed with water and dried under vacuum to afford 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (1.20 g, 79%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]([O:26][CH2:27][C:28](OC)=[O:29])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]([O:26][CH2:27][CH2:28][OH:29])[CH:17]([OH:18])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)CO[C@H](O[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](OC(OCCO)C(O)c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h
Yield: 33.8 %

Procedure:
To a solution of 25 mg of (2-R)-2-((R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(methoxycarbonylmethoxy)-4′-fluoroacetophenone (higher Rf ester diastereomer) from Example 1 in 1 ml of methanol was added 4 mg of sodium borohydride at room temperature. The reaction was stirred for 16 h and was then quenched 18% aqueous citric acid. HPLC on a reverse phase phenyl column (gradient of 65% A: 35%B to 10% A: 90% B over 50 min, A=10 mM ammonium acetate in water: B=7.2 mM ammonium acetate in 92.8% acetonitrile/7.2% methanol) of the reaction mixture indicated a 4:1 ratio of diastereomeric diol products (Rt=23 and 24 min). The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were each washed with brine, dried over sodium sulfate, combined and evaporated. Prep TLC (60% ethyl acetate/hexanes) afforded 8 mg of title compound as a 4:1 mixture of diastereomers.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][C:7]([S:10]([N:12]=[C:13]1[CH2:16][O:15][CH2:14]1)=[O:11])([CH3:9])[CH3:8]>O1CCCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:13]1([NH:12][S:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:16][O:15][CH2:14]1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: c1cscn1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of n-butylithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7, 500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (ESI, m/z): 261.0 (M+H+).
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@@H:2]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.O>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)NCc1ccccc1

Procedure:
6 Grams of Z-D-Gln(Bzl)-OBzl are suspended in 100 ml of dioxane/water (4:1) and titrated with 1n-sodium hydroxide solution (thymolphthalein as indicator). Consumption: 13 ml of 1n-NaOH. Neutralisation with 2n-HCl and concentration are then carried out. The residue is distributed between ethyl acetate and 2n-HCl. Insoluble matter is filtered off with suction. The ethyl acetate phase is washed with water, dried with sodium sulphate and concentrated. The residue is triturated with ether and filtered off with suction. Yield: 3.05 grams melting at 80°-110°.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1)[C:4]1[C:5]2[CH2:26][NH:25][CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:33](O)(=[O:35])[CH3:34].C(O)C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1)[C:4]1[C:5]2[CH2:26][N:25]([CH2:34][CH2:33][OH:35])[CH2:24][CH2:23][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CNCC2
Reactant: CC(=O)O
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1CN(CCO)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.8 %

Procedure:
N4-Ethyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (95 mg, 0.22 mmol) was dissolved in methanol (3 mL). Acetic acid (0.013 mL, 0.22 mmol) was added followed by glycoaldehyde (13.16 mg, 0.22 mmol). The reaction was stirred at room temperature for 15 minutes and sodium cyanoborohydride (13.77 mg, 0.22 mmol) was added. The reaction was stirred for 1 h, the solvent was evaporated under reduced pressure, the crude redissolved in methanol, filtered and purified twice by preparative HPLC yielding 2-(4-(ethyl((tetrahydrofuran-2-yl)methyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (7.10 mg, 6.6%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1B(O)O>>[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1cccc(C)c1B(O)O
Product: Cc1cccc(C)c1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2,6-dimethylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=239.9 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:27]COC)([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[CH2:31][CH2:32][CH3:33])[CH2:7][CH2:6]1)=[O:4].[CH3:34][CH:35]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2([CH3:51])[NH:48][C:47](=[O:49])[NH:46][C:45]2=[O:50])=[N:42][CH:43]=1)[CH3:36]>>[F:22][C:19]([F:21])([F:20])[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:46]3[C:45](=[O:50])[C:44]([C:41]4[CH:40]=[CH:39][C:38]([O:37][CH:35]([CH3:34])[CH3:36])=[CH:43][N:42]=4)([CH3:51])[NH:48][C:47]3=[O:49])[CH2:6][CH2:7]2)=[C:13]([CH2:31][CH2:32][CH3:33])[CH:14]=1)([OH:27])[C:23]([F:24])([F:25])[F:26]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CBr)CC1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)CC1

Procedure:
2-Bromo-1-(4-{4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}-1,4-diazepan-1-yl)ethanone and 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione were used for a similar reaction and treatment as Examples 14-1 and 15-1, and the title compound was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:20][C:21]3[C:28]([CH3:29])=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[CH3:30])[C:13]3[N:18]([CH3:19])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:20][C:21]3[C:22]([CH3:30])=[CH:23][C:24]([C:25]#[N:26])=[CH:27][C:28]=3[CH3:29])[C:13]=2[N:18]([CH3:19])[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccn(C)c12
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Br)cn(C)c12
Yield: 56.3 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (58 mg, 0.15 mmol) in CH2Cl2 (8 mL) was added NBS (29 mg, 0.16 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC, eluting with hexanes:ethyl acetate (2:1), to give the product as a yellow solid (40 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:23])(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:23])=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: Oc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 6-bromo-naphthalen-2-ol (5 g, 22.4 mmol, Aldrich) in dry DMF (50 mL, Aldrich) was added N-fluorobenzene sulfonimide (21.9 g, 67.2 mmol, Aldrich). The reaction was stirred at RT for 48 h. The volatile portion was removed in vacuo and the residue was purified by silica gel chromatography (CHCl3) to give title compound as a yellow solid. MS (ESI, neg. ion) m/z: 240.0 (M−1). Mass Calc'd for C10H6BrFO: 239.96.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu]I.C1(C)C=CC=CC=1>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ncc2c1
Reactant: COc1cccc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cccc(-n2ncc3ccccc32)c1
Temperature: 110 °C
Reaction time: 72 h
Yield: 98.4 %

Procedure:
To a dry pressure tube equipped with a magnetic stir bar was added 1H-indazole (3.54 g, 30 mmol, 1.0 eq), 1-iodo-3-methoxybenzene (8.07 g, 36 mmol, 1.2 eq), CuI (0.29 g, 1.5 mmol, 0.05 eq), K2CO3 (13.37 g, 63 mmol, 2.1 eq) and trans-1,2-cyclohexanediamine (0.65 g, 6 mmol, 0.2 eq). Then the tube was taken into a glove box and solvent toluene (40 mL) was added. The mixture was bubbled with nitrogen for 5 minutes and then the tube was sealed. The tube was taken out of the glove box and the mixture was stirred in an oil bath at 105-115° C. for 3 days. The mixture was cooled down to ambient temperature, diluted with ethyl acetate, and then filtered and washed with ethyl acetate. The filtrate was concentrated and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (20:1-10:1) as eluent to obtain the desired product as a colorless liquid 6.62 g in 98% yield. 1H NMR (DMSO-d6, 400 MHz): δ 3.85 (s, 3H), 6.98 (dd, J=8.0, 2.0 Hz, 1H), 7.25-7.30 (m, 2H), 7.35 (dd, J=8.0, 1.6 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.86 (d, J=8.4 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 8.37 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 55.40, 107.75, 110.59, 112.42, 114.12, 121.49, 121.70, 125.10, 127.55, 130.48, 135.69, 138.13, 140.83, 160.13.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21]([OH:23])=O)=[CH:8][C:7]2=[O:24].[N:25]1([C:31]([C:33]2[CH:38]=[CH:37][C:36]([NH:39]C(C3OC4C(C(=O)C=3)=CC=CC=4N3CCN(C)CC3)=O)=[CH:35]C=2)=O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([C:31]2[CH:35]=[C:36]([NH:39][C:21]([C:9]3[O:10][C:11]4[C:6]([C:7](=[O:24])[CH:8]=3)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=4[N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:23])[CH:37]=[CH:38][CH:33]=2)[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(C(=O)N5CCOCC5)cc4)oc23)CC1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3cccc(N4CCOCC4)c3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and 3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in Example 12, yielding a yellow solid. (80 mg=60%), LCMS-m/z=479.5.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1>O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][CH3:1])[CH2:12]1
Reactant: CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Product: CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
21-Methyl-5α-pregnane-3,11,20-trione (0.4 g.) was added to "stock" chloroiridic acid solution (75 ml.) and the resulting mixture was refluxed for 2 hr. The solution was then cooled and partitioned between water and ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and evaporated.