Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(N(C(C)C)CC)(C)C.[CH3:28][Si:29]([CH3:50])([CH3:49])[CH2:30][CH2:31][O:32][CH2:33][N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:45]([SH:48])=[N:46][N:47]=3)[N:44]=2)[CH:36]=[N:35]1.C>CN(C=O)C>[CH3:28][Si:29]([CH3:50])([CH3:49])[CH2:30][CH2:31][O:32][CH2:33][N:34]1[CH:38]=[C:37]([C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:45]([S:48][C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[N:13]=[CH:12][CH:11]=[CH:10]5)=[N:46][N:47]=3)[N:44]=2)[CH:36]=[N:35]1
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(S)n3n2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Temperature: 70 °C
Yield: 37.1 %

Procedure:
A solution of 6-quinolinyl trifluoromethanesulfonate (436 mg, 1.57 mmol), diisopropylethylamine (0.746 mL, 4.29 mmol) in DMF (3.8 mL) under nitrogen was degassed by bubbling in nitrogen for 30 min. Tris(dibenzylideneacetone)dipalladium (33 mg, 2.5 mol %, Strem catalyst) and Xantphos (41 mg, 5 mol %) were added together in one portion, followed by 6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (498 mg, 1.43 mmol) under a stream of nitrogen. The reaction mixture was stirred at 100° C. for 3 h before 500 mg of activated decolorizing charcoal were added. The suspension was stirred at 70° C. for 20, then the warm mixture was directly filtered through a plug of celite, using DMF as eluent. The solvent was evaporated in vacuo and the residue taken up in dichloromethane and washed with 1N aqueous NaOH and concentrated onto silica gel and purified by flash column chromatography eluting with dichloromethane:methanol 100:0 to 92:8 to return title compound as a light yellow foam (250 mg, 0.53 mmol, 37% yield): 1H NMR (DMSO-d6) δ 0.00 (9H, s), 0.90 (2H, t), 3.62 (2H, t), 5.54 (2H, s), 7.62 (1H, dd), 7.83 (1H, dd), 7.91 (1H, d), 8.07 (1H, d), 8.18 (1H, s), 8.23 (1H, d), 8.43 (1H, dd), 8.57 (1H, d), 8.75 (1H, d), 8.96 (1H, dd); MS (m/z) 476 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OS(O)(=O)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:18])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3,5-dihydroxybenzoate (80 g, 0.52 mol) in CH3OH (600 ml), was added concentrated H2SO4 (40 ml) in portions at room temperature. The reaction mixture was heated to reflux temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. This solution was washed with a saturated aqueous Na2CO3 solution, brine, dried over Na2SO4 and concentrated under reduced pressure to give methyl 3-hydroxy-5-methoxybenzoate (73 g) as a white solid. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C12(NC3C(C(N)=O)=CN=C(S(C)(=O)=O)N=3)CC(C1)C2.Cl.[O:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=[C:9]([NH:45][CH:42]4[CH2:43][CH2:44][O:39][CH2:40][CH2:41]4)[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CS(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Reactant: NC1CCOCC1
Agent: CS(=O)(=O)c1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(NC2CCOCC2)nc1NC12CC(C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfinyl)pyrimidine-5-carboxamide, 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (300 mg) and tetrahydro-2H-pyran-4-amine hydrochloride (181.5 mg, 1.32 mmol) in NMP (10 mL) was added DIEA (426 mg, 3.3 mmol). The resulting mixture was stirred at 100° C. overnight. Then the reaction mixture was purified by preparative HPLC to give the desired product (221.3 mg, 0.73 mmol, yield 67%) as a yellow powder. 1H NMR (400 MHz, CD3OD) δ ppm 8.19 (s, 1H), 3.95-3.88 (m, 3H), 3.44-3.38 (m, 2H), 2.40 (s, 2.09 (s, 6H), 1.88-1.85 (m, 2H), 1.55-1.45 (m, 2H; MS (ESI) m/z=304.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].NC(N)=[S:14]>C(O)CCC>[SH:14][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Solvent: CCCCO
Product: Cc1cc(C)c(C#N)c(S)n1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A mixture of 2-chloro-4,6-dimethylnicotinonitrile (800 mg, 4.83 mmol) and thiourea (1.2 kg, 15.76 mmol) was heated at reflux (118° C.) in n-butanol for 4 h. After cooling to room temperature, the yellow solution turned to a suspension containing light yellow solids. The solids were collected by filtration, rinsed with n-butanol, and dried in vacuo to give 2-mercapto-4,6-dimethylnicotinonitrile (778 mg, 98% yield). C8H8N2S; light yellow powder; mp 219-221° C.; 1H NMR (400 MHz, CDCl3) δ 6.40 (1H, s), 2.45 (3H, s), 2.43 (3H, s); ESI-HRMS (negative mode) calcd for C8H7N2S: 163.0330. found: m/z 163.0332 [M−H]−.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[O:4]
Reactant: CCOC(=O)NCCO
Reactant: CC(Br)C(=O)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)NCCOC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 32.4 g of 2-bromopropionyl bromide in 70 ml of diethyl ether is added dropwise within one hour while cooling with ice to a solution, cooled to 0° C., of ethyl 2-hyroxyethylcarbamate and 13.1 g of pyridine in 80 ml of diethyl ether. The reaction mixture is then stirred at room temperature for 45 minutes. For the working-up, the mxture is filtered under suction through Celite and the filtrate is poured into water. The aqeuous phase is extracted twice with diethyl ether, and the combined organic phases are washed twice with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated to dryness. There is obtained ethyl 2-(2-bromopropionyloxy)-ethylcarbamate as a colourless oil which either can be used in the reaction without further purification or can be purified further by chromatography on silica gel with n-hexane/diethyl ether (1:1); nD20 1.4770.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=C[C:11]([F:17])=[C:12]([CH:16]=1)C(O)=O>ClCCl.CN(C)C=O>[Br:7][C:8]1[CH:16]=[CH:12][C:11]([F:17])=[C:1]([CH:9]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)ccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a well stirred suspension of 5-bromo-2-fluoro-benzoic acid (25.0 g, 114 mmol) in dichloromethane (150 mL) and N,N-dimethylformamide (1.5 mL) at 0° C. The resulting mixture was allowed to gradually warm to room temperature. After 18 hours, the solid had gone into solution. The resulting light orange solution was concentrated under reduced pressure and was chased two times with diethyl ether to afford 5-bromo-2-fluoro-benzoyl chloride (27.0 g, quantitative yield) as a pale orange oil.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:13][CH2:14]1
Reactant: O=C1CCCC(=O)O1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: O=C(O)CCCC(=O)NCCN1CCOCC1
Reaction time: 0.75 h

Procedure:
There are added to 10 cm3 of dioxane, 1.517 g of glutaric anhydride and then, dropwise, 1.75 cm3 of N-(2-aminoethyl)morpholine. Stirring is continued at 20° C. for 0.75 hours. The white solid formed is filtered, washed successively with dioxane and diethyl ether, and then dried at 20° C. (90 Pa) to give 1.94 g of 5-(2-morpholinoethylamino)-5-oxopentanoic acid in the form of a white solid melting at 96° C.
Reaction SMILES: Cl.[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19](I)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>>[CH:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([C:38]4[O:39][C:35]([CH:31]5[O:32][CH2:33][CH2:34][O:30]5)=[CH:36][CH:37]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(I)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Product: O=S(=O)(c1ccccc1)N(c1ccccc1)c1ncnc2cc(F)c(-c3ccc(C4OCCO4)o3)cc12

Procedure:
Prepared according to Procedure B from (4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ1H NMR (400 MHz, DMSO-d6) 10.49(s, 1H), 8.88(d, 1H), 8.63(s,1H), 8.1 (d, 2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m,1H), 6.75(d, 1H), 6.01 (s,1H), 4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M−1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][C:2](=[O:3])[N:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH3:6])[CH:8]=[CH:9]2)[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1
Reactant: Cn1ccc2cc(Nc3ccncc3)ccc21
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(c1ccncc1)c1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of methyl chloroformate (1.3 g) in 5 ml DCM was added to a solution of 1-methyl-5-(4-pyridinylamino)-1H-indole (2.5 g) in 120 ml DCM and 6 ml triethylamine (4.4 g). After stirring one hour at ambient temperature the reaction mixture was washed with water and saturated sodium chloride, dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 50% ethyl acetate in dichloromethane via flash column chromatography yielded 3.1 g of a solid. Recrystallization from methanol yielded 2.4 g of crystals, mp 157°-159° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:14][CH2:13][Br:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCCCBr
Reactant: CC(=O)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
A mixture of 1.52 g (10 mmol) of 4-acetoxyphenol, 2.22 g (11 mmol) 1,3-dibromopropane, and 2.98 g (21 mmol) of anhydrous potassium carbonate in dimethylformamide was stirred rapidly at room temperature for 4 hours. Ethyl acetate was added, and the salts present were removed by filtration. The solvent was removed under reduced pressure, and the residue chromatographed over silica gel. Elution with 15% ethyl acetate-hexane gave 270 mg of the title compound, which was homogeneous by thin layer chromatography (15% by volume of ethyl acetate/hexane on silica gel plates).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C:31](=[O:36])[CH2:30][N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)C(C)(C)C)c2ncnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1 g), 1-bromo-3,3-dimethylbutan-2-one (0.4 mL), potassium carbonate (0.75 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with 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 to give the title compound as a colorless solid (0.4 g, 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C.C(OC1C(C)=C2C(=C(C)C=1C)O[C@](C)(CCO)CC2)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:26][S:27]([O:23][CH2:22][CH2:21][C@:14]1([CH3:24])[CH2:13][CH2:12][C:11]2[C:16](=[C:17]([CH3:20])[C:18]([CH3:19])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH3:25])[O:15]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCO)O2
Agent: C
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCOS(C)(=O)=O)O2
Temperature: 0 °C

Procedure:
A solution of 0.5 g. (1.47 mmoles) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol and 0.25 ml. (0.37 g.; 3.2 mmoles) of methanesulfonyl chloride in 5 ml. of anhydrous pyridine was kept at 0° C. for 45 hours then poured into 100 ml. of ice-water and the resulting mixture was stirred for 15 minutes. The mixture was then extracted three times with ether and the combined ether extracts were washed with cold 1 N aqueous HCl followed by water and saturated brine. After drying and filtration, the ether extracts were concentrated in vacuo giving 0.587 g. (95.6%) of (S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol methane as a colorless solid, m.p. 81°-83° C.; [α]25D-0.36° (c 0.82, C6H6).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12](Cl)[N:13]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[C:9]([C:25]([NH2:27])=[O:26])=[N:10][C:11]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[C:12]([C:29]2[S:28][CH:32]=[CH:31][CH:30]=2)[N:13]=1
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2cccs2)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 73.6 %

Procedure:
Under nitrogen atmosphere, a solution of Na2CO3 (138 mg) in water (0.8 ml) was added to a suspension of 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarboxamide (100 mg), 2-thienylboronic acid (104 mg) and tetrakis(triphenylphosphine)palladium (11.3 mg) in dioxane (2 ml) and the mixture was stirred at 100-105° C. for 4 hours. After addition of water (10 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-(2-thienyl)-2-pyrazinecarboxamide as a solid (85 mg).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[C:42]1(=O)[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[O:43]1>O1CCOCC1>[O:43]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:1]1[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N1C(=O)c3ccccc3C1=O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 110 °C

Procedure:
(R)-1-(3-Amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 47, Step 1; 503 mg, 0.934 mmol) and isobenzofuran-1,3-dione (159 mg, 1.074 mmol) were added to a 1.5 mL microwave vial, charged with dioxane (4 mL), and heated to 110° C. for 4.5 h. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (2-10% EtOAc/DCM) to give (R)-1-(3-(1,3-dioxoisoindolin-2-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C42H32N6O3 [M+1]+ 669. found 669.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([OH:39])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([OH:39])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: O[C@]12C[C@H]1CN(CCCCl)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1C[C@@H]2C[C@]2(O)C1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hexan-1-ol (92 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at rt. The mixture was heated at 80° C. for 7 h, then cooled to room temperature and quenched with H2O (10 mL). The mixture was diluted with EtOAc (20 mL). The water layer was then extracted with EtOAc (5 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (10:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (90 mg, 46.70%), HPLC:91.67%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.83 (2H, m), 1.09 (1H, t, J=4.8 Hz), 1.36 (1H, m), 2.57 (2H, m), 2.72 (1H, d, J=8.8 Hz), 3.05 (1H, d, J=8.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][O:10][CH3:16]
Reactant: CC(C)(C)[O-]
Reactant: OCC#CCOCc1cc(Br)ccc1F
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCC#CCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (1.07 g, 3.92 mmol) in tetrahydrofuran (26 ml) was cooled to −40° C. and then treated with potassium t-butoxide (4.31 ml of a 1 M solution in tetrahydrofuran, 4.31 mmol). The resulting dark orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.49 ml, 7.84 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 790 mg (70%) as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:12]([O:13][CH2:14][CH2:15]Cl)[C@H:11]([F:21])[C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:12]([O:13][CH2:14][CH2:15][N:23]=[N+:24]=[N-:25])[C@H:11]([F:21])[C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@@H](OCCCl)[C@H](F)[C@@H](O)[C@@H]1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCO[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloroethyl 4-O-benzyl-2-deoxy-2-fluoro-β-D-glucopyranoside (1.53 g, 4.57 mmol) in DMF (45 mL) at rt was added sodium azide (360 mg, 5.54 mmol). After stirring at 70° C. for 16 hr, the reaction mixture was cooled down to rt and poured onto ice water (200 mL) and extracted with CH2Cl2 (3×100 mL). The organic layers were combined and washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (120 g), eluting with 0-100% EtOAc in hexanes to give the title compound. TLC: silica gel, hexane/EtOAc: 1/1, Rf=0.55. 1H NMR (CDCl3) δ 7.37-7.28 (5 H, m), 4.84-4.71 (2H, m), 4.55-4.52 (1 H, m), 4.22-4.07 (1H, m), 4.03-3.98 (1H, m), 3.94-3.86 (2H, m), 3.79-3.71 (2H, m), 3.56-3.51 (1H, m), 3.48-3.36 (3H, m).
Reaction SMILES: [CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH:21]C(=O)[O-])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH:7]2[CH:16]3[CH2:17][CH2:18][CH2:19][O:20][CH:15]3[C:14]3[CH:13]=[C:12]([NH2:21])[CH:11]=[CH:10][C:9]=3[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)C1OCCCC1C(C1CCCCC1)N2
Temperature: 0 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To an ice-cooled solution of tert-butyl (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-ylcarbamate (prepared according to the method described in example 1) (227 mg, 0.587 mmol) in CH2Cl2 (5 mL) under argon atmosphere was added TFA (1.5 mL) dropwise. The reaction solution was allowed to reach r.t. and stirred overnight. The mixture was cooled down and 0.5 N NaOH solution was added until basic pH. The product was extracted with CH2Cl2 three times. The combined organic fractions were washed with sat. NaCl solution, dried over Na2SO4, and the solvent removed under reduced pressure after filtration giving (4aSR*,5SR*,10bSR*)-5-cyclohexyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-9-amine (145 mg, 86%) as orange viscous solid. The product was used without further purification.