Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1.[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26]>>[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH3:26])[CH3:27]
Reactant: CCCCCCCCc1ccc(NCc2ccccc2OC)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccccc2OC)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 59.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (2-methoxyphenylmethyl)(4-octylphenyl)amine (1.4 g) and 2,6-diisopropylphenyl isocyanate (0.96 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(2-methoxyphenylmethyl)-N-(4-octylphenyl)urea (1.36 g) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][CH:14]([N:19]([C:24]1[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=1)[N:29](C1CCCCO1)[N:28]=[CH:27]3)[S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)[CH2:9][CH3:10].C(=O)([O-])O.[Na+]>ClCCl>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([N:19]([CH:14]3[CH2:15][CH:16]4[N:11]([CH2:8][CH2:9][CH3:10])[CH:12]([CH2:18][CH2:17]4)[CH2:13]3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: CCCN1C2CCC1CC(N(c1ccc3c(cnn3C3CCCCO3)c1)S(C)(=O)=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1C2CCC1CC(N(c1ccc3[nH]ncc3c1)S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-methanesulfonamide (19 mg, 0.0425 mmol) in dichloromethane (0.8 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a preparative thin-layer chromatography (200×200×0.5 mm, eluent: chloroform/methanol=9/1) to obtain N-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)methanesulfonamide (6 mg, 40%).
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](OC)=[O:6])#[N:2]>C(OCC)(=O)C>[C:9]1([CH:4]2[CH2:3][CH2:1][NH:2][C:5]2=[O:6])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(CC#N)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1NCCC1c1ccccc1

Procedure:
Prepare by the method of Example 2.2.2 using methyl 3-cyano-2-phenylpropionate to give the title compound Rf=0.20 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([NH:14][NH2:15])=[N:4][N:3]=1.[CH:16](O)=O>>[Cl:1][C:2]1[C:11]2[CH:10]3[CH2:9][CH2:8][CH:7]([CH2:13][CH2:12]3)[C:6]=2[C:5]2=[N:14][N:15]=[CH:16][N:4]2[N:3]=1
Reactant: O=CO
Reactant: NNc1nnc(Cl)c2c1C1CCC2CC1
Product: Clc1nn2cnnc2c2c1C1CCC2CC1
Yield: 88 %

Procedure:
1-Chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-ethanophthalazine (2.5 grams, 0.111 mol) was mixed with 150 milliliters of formic acid. The mixture was heated at the boiling temperature under reflux for 2 hours, then evaporated to dryness. The residue was triturated with saturated aqueous sodium bicarbonate. The resulting white solid was collected, washed with water and air dried to yield 23.0 grams (88% yield) of 6-chloro-7,8,9,10-tetrahydro-7,10-ethano(1,2,4)triazolo[3,4-a]phthalazine, melting at 137°-140° C. After recrystallization from a mixture of benzene and hexane the purified product melted at 140.5°-141° C. Infrared spectroscopy and elemental analysis confirmed the designated structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]1[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCC2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 69.9 %

Procedure:
The mixture of 2-bromo-5-hydroxypyridine (1 g, 5.75 mmol), bromocyclobutane (0.783 mL, 8.33 mmol) and potassium carbonate (1.589 g, 11.49 mmol) in DMF (11.5 mL) was stirred at 60° C. for 5 h, then at 80° C. for 14 h. The reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by ISCO (40 g), eluting with a gradient of EtOAc/hexane 0-10% to provide to give 2-bromo-5-cyclobutoxypyridine (0.916 g, 4.02 mmol, 69.9% yield) as white solid. MS: M+ 228, 230. C9H10BrNO, MW=228.09
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[N:23]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:23]1([CH2:29][CH2:30][CH2:31][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:12]=[C:11]([O:21][CH2:31][CH2:30][CH2:29][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:10]=4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc2c3c(ccc(OCCCN4CCCCC4)c3c1)-c1cc(OCCCN3CCCCC3)ccc1-2

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 29.8 (0.15 mole) of 3-piperidinopropyl chloride hydrochloride and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-piperidinopropoxy)fluoranthene, M.P. 92°-93°C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.O=[C:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[F:21][C:18]([F:20])([F:19])[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:8][CH2:7][C:6]([NH:5][CH:3]1[CH2:2][N:1]([CH:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)[CH2:4]1)=[O:22]
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: NC(=O)Cc1ccc(C2CCC(=O)CC2)cc1
Product: NC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 2-[4-(4-oxo-cyclohexyl)-phenyl]-acetamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:26]1[CH2:31][CH2:30][N:29]([S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH2:1]([NH:3][CH2:4][C:5]1[S:9][C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([C:23]([NH2:25])=[O:24])[CH:22]=2)[NH:19][CH:18]=[C:17]3[CH:26]2[CH2:27][CH2:28][N:29]([S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH2:30][CH2:31]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCNCc1ccc(B(O)O)s1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
To a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl}boronic acid (47 mg, 0.254 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. (This run was aborted prior to 30 min due to excessive pressure build-up). The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 60° C. to give 8.8 mg of the title compound (10%).
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:26])=[CH:19][C:20]4[O:24][CH2:23][CH2:22][C:21]=4[CH:25]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][CH2:36]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:24][CH2:23][CH2:22][C:21]=5[CH:25]=4)[O:26][CH2:36][CH2:35]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCBr
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12CCOc1cc3c(cc12)CCO3
Temperature: 50 °C
Reaction time: 7 h
Yield: 38.9 %

Procedure:
A suspension of 1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (5.1 g, 11.8 mmol), 1,2-dibromoethane (4.7 g, 25.0 mmol) and cesium carbonate (24.4 g, 75.0 mmol) in tetrahydrofuran (200 mL) was stirred under argon at ambient temperature for 16 h and at 50° C. for 7 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography with dichlromethane/methanol (100/1-20/1) to afford 1′-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one (2.11 g, 39%) as a colorless solid: MS (ES+) m/z 459.8 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([CH3:34])[CH:28]=4)[CH:24]=[C:23]([CH3:35])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH:24]=[C:23]([CH3:35])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)=[CH:28][C:29]=1[CH3:34]
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.5 %

Procedure:
To a cooled and stirred solution of 3′-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.45 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 ml), diethylether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.29 g, 65%). MS (ISP) 450.1 [(M+H)+]; mp 201° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(Cl)Cl>C1COCC1>[C:16]([NH:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
FMOC-(O-t-Butyl)tyr-val (1.0 gm, 1.8 mMole) and N-hydroxysuccinimide (210 mg, 1.8 mMole) were dissolved in 40 ml THF under nitrogen at 0° C. Dicyclohexylcarbodiimide (DCC) was added as a methylene chloride solution (0.5 M, 3.6 ml, I.8 mMole) and the reaction mixture was incubated for 2 hours with stirring, then stored overnight at 4° C. TLC showed incomplete reaction, so additional DCC was added (0.45 mMole), and the reaction mixture incubated at room temperature for one day. Dicyclohexylurea (DCU) formed was filtered and the filtrate concentrated to a solid, which was triturated with 4% sodium bicarbonate. The solid was filtered, washed with water dried, then crystallized from chloroform/petroleum ether. A white solid was obtained on filtration and air drying. Yield: 761 mg (65%); Rf: 0.75 [chloroform/methanol 9:1 (silica)]. Elemental analysis for C37H41N3O8.0.5 H2O calculated: C, 66.85; H, 6.37; observed C, 67.04; H, 6.85.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[S:25]1C=CC=C1CN>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[S:25][CH:22]=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCc1cccs1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2cccs2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (2-thienylmethyl)amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20-1.35 (m, 5H), 1.65-1.79 (m, 5H), 1.89 (s, 3H), 2.23 (s, 3H), 4.08 (bs, 1H), 4.71 (d, J=4.57 Hz, 2H), 6.96 (s, 1H), 7.05 (s, 1H), 7.40 (d, J=4.57 Hz, 1H), 7.70 (d, J=6.72 Hz, 1H), 8.07 (s, 1H); MS (ESI) m/z 317.7 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1Nc2ccc(F)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 8 h

Procedure:
5-fluoroisatin (0.082 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 8 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:24][CH2:25]3)=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 54.2 %

Procedure:
Following General Procedure I, tert-butyl (1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)cyclopropyl)methylcarbamate (750 mg, 1.57 mmol) was reacted with NBS (280 mg, 1.57 mmol)) to afford the desired product (473 mg, 54%) as a yellow solid: ESI MS m/z 555 [C27H27BrN2O4S+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14](F)=[CH:15][CH:16]=3)[CH:8]=[N:7][C:6]=12.[NH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])=[N:13][CH:12]=3)[CH:8]=[N:7][C:6]=12
Reactant: Fc1ccc(-c2cnc3c(Br)cnn3c2)cn1
Reactant: CC(C)(O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)CNc1ccc(-c2cnc3c(Br)cnn3c2)cn1

Procedure:
A solution of 3-bromo-6-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyrimidine (0.1 g, 0.34 mmol), 1-amino-2-methylpropan-2-ol (0.06 g, 0.68 mmol) and potassium carbonate (0.9 g, 0.68 mmol) in DMF (3 mL) was heated to 80° C. for 72 hours. The reaction was directly purified by reverse phase LC to give 1-{[5-(3-bromopyrazolo[1,5-a]pyrimidin-6-yl)pyridin-2-yl]amino}-2-methylpropan-2-ol. LC-MS EIMS: m/z 364.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1.[ClH:39]>C(Cl)Cl>[ClH:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH:23][C:24]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[O:25])=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-tert-butyl 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperazine-1-carboxylate (Example 15; 10 mg, 0.019 mmol) was dissolved in 0.2 mL DCM, followed by addition of 0.5 mL 4 N HCl (dioxane) solution in one portion. After stirring at ambient temperature overnight, the reaction was concentrated to yield the final product salt form as a light yellowish solid. MS (apci) m/z=428.2 (M+H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3F)[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>O>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:3][CH2:2][CH2:1][OH:4])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 120 °C
Yield: 95 %

Procedure:
Ethylene glycol (150 ml) was treated with sodium hydride (60% in oil, 3.15 g) and the exotherm controlled to about 10° C. with an ice-bath. N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 12 g) was added in small portions and the mixture heated at 120° C. for 1 hour. The slurry was cooled, poured into water/saturated ammonium chloride (1.5 litres) and the solid collected and dried to give 2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethanol (12.6 g, 95%); NMR spectrum (DMSO-d6) 3.89-3.98 (m, 2H), 4.33 (t, 2H), 5.27 (s, 2H), 5.37 (t, 1H), 7.13 (d, 1H), 7.23 (d, 1H), 7.31-7.38 (m, 2H), 7.57 (d, 1H), 7.68-7.75 (m, 2H), 7.83-7.90 (m, 1H), 8.26 (d, 1H), 8.54 (s, 1H), 8.58 (d, 1H), 10.41 (s, 11H); Mass spectrum MH+ 422.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]([O:31][C:32](=O)[CH:33](C1C=CC=CC=1)[OH:34])(=[O:30])[CH3:29].C(N(CC)CC)C>O1CCOCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:33]([CH2:32][O:31][C:28](=[O:30])[CH3:29])=[O:34])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Reactant: CC(=O)OC(=O)C(O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
This material was prepared according to the procedure described in Example 78(a) using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.36 g, 0.9 mmol), O-acetyl mandelic acid (0.41 mL, 1.8 mmol, Heico Chemicals, Inc.) and triethylamine (0.25 mL, 1.8 mmol) in dioxane (3 mL). Purification by silica gel chromatography (3:1 hexanes: EtOAc) provided the title compound as a light-yellow foam. MS (ESI, pos. ion) m/z: 565 (M+1). Mp: 118.6–138.4° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1[CH2:8][C:9]([OH:11])=[O:10].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[H][H]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=C1C=CC=CC1CC(=O)O
Reactant: [H][H]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: Cc1ccccc1CC(=O)O
Yield: 99.9 %

Procedure:
In a 100 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 0.3 g (2 mmoles) of 2-methylenephenylacetic acid and 20 ml of methanol. Then, 8.4 mg (0.01 mmole) of Ru((+)-BINAP)(O2CCH3)2 prepared according to the same manner as in Referential Example 3 except using (+)-BINAP in place of (-)-BINAP was added to the mixture to perform hydrogenation for 24 hours at a hydrogen pressure of 100 kg/cm2 and at a reaction temperature of 30° C. to provide 0.3 g of 2-methylphenylacetic acid. The yield was 100%.