Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[N:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1.Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([O:17][CH2:16][C:13]3[N:12]=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:15][N:14]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2cnc(CO)nc2OCC(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2ncc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyrimidin-2-yl)methanol (111 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (92 mg) in THF (2.0 mL) was added 60% sodium hydride (17 mg) at room temperature, and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (111 mg) as a colorless oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:39])([F:38])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CS(C)=O.C(OCC)(=O)C.CCCCCC>[F:27][C:28]([F:38])([F:39])[O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(OC(F)(F)F)cc2)CO3)N1
Temperature: 90 °C
Yield: 46 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.0 g, 2.7 mmole) and 4-trifluoromethoxybenzylamine (2.0 g, 11 mmole) were combined in 30 ml of dry DMSO and heated to 90° C. for 4 hours under an argon atmosphere. After cooling to room temperature, the mixture was diluted with 400 ml of 1:1 ethyl acetate/hexane and washed with 400 ml of saturated sodium bicarbonate solution, with two 250 ml portions of water and with saturated brine. The mixture was dried over sodium sulfate, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 1% methanol/CHCl3 as eluant. The free base of the title compound (0.49 g) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.29 g of the (S) enantiomer of the title compound as a white solid fumarate, m.p. 201-202° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(COC)OC.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccn2)cc1
Temperature: 95 °C

Procedure:
2-Bromopyridine (650 μL), 4-nitrophenylboronic acid (1.479 g) and palladium tetrakistriphenylphosphine (391.5 mg) were added to a mixture of 40 mL of dimethoxyethane and 10 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 95° C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 1.40 g of 2-(4-nitrophenyl)pyridine.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[CH2:16][CH3:17])[C:6]([CH2:8][CH2:9][C:10](O)=O)=[O:7])[CH3:2].C(C1C=CC=CC=1CC)C.C1(=O)OC(=O)CC1.C(C1C=C(CCCC(O)=O)C=CC=1CC)C>>[CH2:16]([C:15]1[CH:14]=[C:13]2[C:5](=[CH:4][C:3]=1[CH2:1][CH3:2])[C:6](=[O:7])[CH2:8][CH2:9][CH2:10]2)[CH3:17]
Reactant: CCc1ccc(C(=O)CCC(=O)O)cc1CC
Agent: CCc1ccc(CCCC(=O)O)cc1CC
Agent: CCc1ccccc1CC
Agent: O=C1CCC(=O)O1
Product: CCc1cc2c(cc1CC)C(=O)CCC2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
3-(3',4'-Diethylbenzoyl) propanoic acid (m.p. 93° C, prepared by the acylation of 1,2-diethyl benzene with succinic anhydride) was catalytically reduced to 4-(3',4'-diethylphenyl) butanoic acid (b.p.0.7 143°-147° C). A mixture of this acid (59g; 0.27 mole) and 85% polyphosphoric acid (450g) was warmed to 80° C with stirring for 30 mins. and worked up as in example 8(a) to yield 48.30g (89%) of 6,7-diethyl-1-tetralone, b.p.0.7 118°-122° C. (Found; C, 82.95; H, 9.21; C14H18O requires; C, 83.12; H, 8.97%). Alternatively 4-(3',4'-diethylphenyl butanoic acid (23.3g; 0.106 mole) may be cyclized by stirring at 100° C with 80% sulphuric acid (115ml) for 1 1/2 hrs. After dilution, extraction into ether and distillation 15.53g (74%) of the tetralone was recovered.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:18]([F:19])([F:20])[F:21])[CH2:4][CH2:3]1
Reactant: CN1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1

Procedure:
4-(N-methylpiperidin-4-yl)oxy-3-trifluoromethyl-1-nitrobenzene was dissolved in methanol in the presence of Pd/C. The solution was hydrogenated at 50 psi for 1 hour until hydrogen intake was completed. The catalyst was filtered off and the filtrate was concentrated to afford 4-(N-methylpiperidin-4-yl)oxy-3-trifluoromethylbenzenamine, >95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1>CN(C)C=O>[CH3:10][N:11]([CH2:12][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][C:6]=3[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1)[CH3:5]
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nncn1-2
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
To a suspension of this reagent in 10 ml. of dimethylformamide was added 3.00 mmol of 8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. The mixture was heated to 80° for a total of 24 hours, then quenched in cold water, neutralized with a 10% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil, which was chromatographed over 100 g. of silica gel by eluting with 3% methanol/97% chloroform mixtures. The product was collected and crystallized from ethyl acetate to yield 1-(dimethylamino)methyl-8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 163.5°- 165° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1.[H][H]>O>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C=NO)cc1
Temperature: 25 °C

Procedure:
8.3 g of 4-nitrobenzaldoxime together with 100 ml of tetrahydrofuran are initially introduced into a stirred autoclave. 50 mg of FeCl2.4 H2O and 0.2 g of the catalyst from Example A1 are added to the solution. Hydrogenation is carried out at 120° C. and a hydrogen pressure of 20×105 pascals. When hydrogenation is complete, the mixture is cooled to room temperature, the reactor is rendered inert with nitrogen and the catalyst is filtered off. The solvent is distilled off to give, after chromatographic purification, 3.5 g (51% of theory) of 4-aminobenzaldoxime.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][N:38]([CH3:40])[CH3:39]>>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH:13]2[C:11]([N:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=1)[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=1)=[O:12]
Reactant: CN(C)CCCl
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCN(C)C)cccc32)cc1
Yield: 70.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.32 g) as starting materials, 5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.54 g) was obtained. This compound was dissolved in ethyl acetate, and oxalic acid was added. The precipitated solid was subjected to recrystallization from ethyl acetate to give 5-[2-(dimethylamino)ethoxy]-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate ¼ hydrate (93.8 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
To a mixture of methyl 3,4,5-tribenzyloxybenzoate (15) (20.60 g, 45.30 mmol) in 2-propanol (200 mL) was added a solution of potassium hydroxide (3.50 g, 85%, 53.00 mmol) in 2-propanol (25 mL). The mixture was refluxed for 1 h, cooled, and water was added (250 mL). A white precipitate appeared, and the mixture was filtered. Recrystallisation from ethyl acetate afforded the desired compound as white crystals, m.p. 194-195° C. Yield: 17.2 g (86%). 1H NMR (300 MHz, DMSO-d6): δ=5.05 (2H, s), 5.18 (4H, s), 7.24-7.50 (17H, m), 13.4 (1H, s, broad); 13C NMR (75 MHz): δ=70.3, 74.3, 108.3, 126.1, 127.7, 128.0, 128.2, 128.3, 128.5, 136.9, 137.5, 141.0, 152.1, 167.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].Cl>O1CCOCC1>[O:14]=[C:13]1[C:12]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:11]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:10][N:9]1[CH2:8][C:7]1[CH:6]=[C:5]([CH:35]=[CH:34][CH:33]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C

Procedure:
To tert-butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.23 g, 0.48 mmol) was added 4M solution of HCl in dioxane (5 mL). After stirring at room temperature for an hour, the reaction mixture was concentrated in vacuo to obtain methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.CO[N:12]=[C:13]1[CH2:16][C@@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:14]1[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O1CCCC1>[CH3:34][C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][C@@H:14]1[C@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][C@H:13]1[NH2:12])([CH3:32])[CH3:33]
Reactant: CON=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
To 4.74 g (125 mmol) of sodium borohydride in 125 mL of tetrahydrofuran (THF) was added (slowly) 14.25 g (9.63 mL, 125 mmol) of trifluoroacetic acid (TFA), followed by 10.228 g (26.4 mmol) of [2R,3R]-2,3-Bis(((1,1-dimethylethyl)di-methylsilyl)oxymethyl)cyclobutanone-O-methyl oxime, from Step F, in 25 mL of THF. After stirring the reaction mixture at ambient temperature for 1.5 h, it was concentrated, diluted with methylene chloride and washed with brine. An emulsion developed which cleared up after filtration. The methylene chloride solution was dried overnight over anhydrous magnesium sulfate, filtered and concentrated to give 10.98 g of crude title compound which was taken on to the next step without purification; MS DCI-NH3M/Z: 360 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.CC1(C)C(C)(C)OB([C:53]2[CH:54]=[N:55][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:57]=2)O1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:29]([C:31]2[C:32](=[O:44])[N:33]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:34]=[CH:35][CH:36]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:53]3[CH:54]=[N:55][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:57]=3)[C:10]=12
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc(Cn2nc(-c3cnn(C(=O)OC(C)(C)C)c3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (40.0 mg, 0.0566 mmol, prepared in Example 63, step A), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (50.0 mg, 0.170 mmol), Pd(OAc)2 (2.54 mg, 0.0113 mmol), tricyclohexylphosphine (4.76 mg, 0.0170 mmol), cesium fluoride (77.4 mg, 0.510 mmol) and CH3CN (10 mL). The reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to room temperature and then the reaction was partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude material was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (29.7 mg, 70.2%). LRMS (APCI neg): >96% purity, 254 nm, m/e 745 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Cn1cc(N)cn1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 125 °C
Yield: 17.9 %

Procedure:
A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ 10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)[CH3:24].O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:34]([NH:33][C:29]5[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=5)[C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:35])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.208 g, 0.707 mmol) in anhydrous dichloromethane (10 mL) was added 3-isocyanato-benzoic acid ethyl ester (0.135 g, 0.707 mmol). The reaction was then shaken at room temperature for 30 minutes. On completion of the reaction water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The organic extracts were combined, washed with brine (2×20 mL), dried using sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexanes to 66% EtOAc in hexane) to give the pure desired product, ethyl 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.265 g, 77%) as a white solid. M.p.=>80° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.41 (s, 1H), 8.2 (s, 1H), 8.14-8.1 (m, 1H), 7.85-7.8 (m, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.81 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.84 (t, J=6 Hz, 2H), 3.69 (s, 3H), 3.15 (t, J=6 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); LCMS [M+H]: 486.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([C:18]2[CH:19]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=4)[NH:25]3)[CH:21]=[CH:22][CH:23]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([C:18]2[CH:19]=[C:20]([CH:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:37])[CH:30]=4)[NH:25]3)[CH:21]=[CH:22][CH:23]=2)[CH2:12]1
Reactant: CC1CN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)CC(C)O1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
To a suspension of 60% sodium hydride (149 mg, 3.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (460 mg, 3.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.38 mmol) and 1,1′-carbonyldiimidazole (125 mg, 0.76 mmol) in N,N-dimethylformamide (1.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(2,6-dimethyl-morpholin-4-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (56 mg, 30%) as a white solid: LC/MS m/e calcd for C27H35N3O4S (M+H)+: 498.66, observed: 498.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]([C:27]3[O:28][C:29](=[O:43])[C:30]4[C:35]([C:36]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:26])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([O:17][Si](C(C)(C)C)(C)C)[CH:16]=3)[C:3]=12.[ClH:44]>CCO>[ClH:44].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]([C:27]3[O:28][C:29](=[O:43])[C:30]4[C:35]([C:36]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:26])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
3-(1-(4-amino-3-(5-((tert-butyldimethylsilyl)oxy)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one single enantiomer (intermediate S.2, first eluted enantiomer under the conditions described above, 0.070 g, 0.118 mmol) was dissolved in a solution of 1M HCl in EtOH (0.38 mL) and the mixture was stirred at RT for 5 h. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford title compound as a white solid (0.059 g, 0.115 mmol, 97%). This compound proved to be the second eluted enantiomer under Chiral HPLC conditions of Method A9: Rt=15.4 min, ee>99%.