Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=2[N:10]=1)=[O:5])C.[OH-].[Na+:17]>C1COCC1>[Na+:17].[CH3:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([O-:5])=[O:3])=[N:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1nc2cc(C)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2oc(C(=O)[O-])nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-methyl-benzooxazole-2-carboxylic acid ethyl ester (170 mg) was added 2 mL of THF, and 0.83 mL (2 eq) of sodium hydroxide solution (2N in MeOH). The reaction mixture was stirred at room temperature overnight. The suspension was filtered and the solid was dried under vacuum to give 144 mg of 5-methyl-benzooxazole-2-carboxylic acid sodium salt as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH:12]=[CH2:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH2:18][CH2:19]Cl)[N:16]=[CH:17][C:3]=12.N12CCCN=C1CCCCC2.O>CN(C=O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH2:11][CH:12]=[CH2:13])[CH2:10][C:6]=2[N:5]=[C:4]2[N:15]([CH:18]=[CH2:19])[N:16]=[CH:17][C:3]=12
Reactant: C=CCN1Cc2nc3c(cnn3CCCl)c(N)c2C1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCN1Cc2nc3c(cnn3C=C)c(N)c2C1=O
Reaction time: 5 h
Yield: 80.8 %

Procedure:
A solution of 4-amino-1-(2-chloroethyl)-6,7-dihydro-6-(2-propenyl)pyrazolo[3.4-b]pyrrolo[3,4-e]pyridin-5(1H)-one (15.69 g.) in dry DMF (65 ml.) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (9.65 ml.). The mixture was heated to 110° under nitrogen with stirring for five hours. After cooling, the mixture was poured into water (400 ml.) and the product was extracted into dichloromethane. The extract was washed with brine, dried (Na2SO4) and evaporated at reduced pressure to afford a suspension of crude product in DMF. This was warmed to effect complete dissolution, and water (350 ml.) was added to precipitate the product. After cooling to 0° , the precipitated solid was collected by filtration, washed with water, and dried in vacuo at 50° . In this manner there was obtained 11.09 grams of 4-amino-6,7-dihydro6-(2-propenyl)-1-vinylpyrazolo[3,4-b]pyrrolo[3,4-e]pyridin-5(1H)-one as a light yellow solid: m.p. 190°-191°.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O[C@@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>ClCCl.C(OC(=O)C)C>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C@H:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16]
Reactant: Clc1cccc2c1CCN2
Reactant: O=C1OCC[C@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1OCC[C@@H]1N1CCc2c(Cl)cccc21
Temperature: -20 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., diisopropyl ethyl amine (7.59 g, 10.23 mL, 58.77 mmol) was added drop wise to a solution of solution of (R)-3-hydroxydihydrofuran-2(3H)-one (3 g, 29.38 mmol) in dichloromethane (50 mL). Then added trifluoromethanesulfonic anhydride (8.69 g, 5.18 mL, 30.81 mmol) drop wise by maintaining internal temperature of the reaction mixture <−20° C. Upon completion of addition, the mixture was stirred at −20° C. for 1 hour. Then added at −20° C., 4-chloro-indoline (6.74 gm, 44.07 mmol) drop wise. The reaction was allowed to warm to RT over a period of 30 minutes and continued to stir at RT for 16 hrs. The reaction mixture was diluted with 200 mL of ethylacetate and washed with saturated sodium bicarbonate (3×50 mL). The organic layer was washed with a saturated aqueous NaCl solution (2×50 mL). The solution was dried over magnesium sulfate, filtered, and concentrated. Purification via silica gel chromatography using 10-30% ethyl acetate in hexane gave (S)-3-(4-chloroindolin-1-yl)dihydrofuran-2(3H)-one as a white solid (5.47 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.03 (t, J=8.0 Hz, 1H), 6.63 (dd, J=0.6, 8.0 Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 4.91 (dd, J=9.2, 11.2 Hz, 1H), 4.45-4.40 (m, 1H), 4.30-4.23 (m, 1H), 3.55-3.48 (m, 1H), 3.28 (dd, J=8.5, 18.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.40-2.32 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=237.9; tR=1.51 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1COCC1>C(Cl)(Cl)Cl.C(O)(C)C.O.O.[Cu](Cl)Cl>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[N:7][CH:6]=1
Reactant: OCCO
Reactant: O=Cc1ccc(F)nc1
Agent: Cl[Cu]Cl
Solvent: CC(C)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C2OCCO2)cn1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
In a pressure vessel, combine 6-fluoro-pyridine-3-carbaldehyde (4 g, 32 mmol), ethylene glycol (3 g, 48 mmol), copper (II) chloride di-hydrate (0.56 g, 3.2 mmol) and THF (10 mL). Heat the mixture at 100° C. for 1 hour. Dilute the mixture with chloroform-isopropanol (3:1, 100 mL). Wash the organic phase with saturated aqueous sodium chloride and water. Dry the organic layer over sodium sulfate. Concentrate the solution in vacuo to brown oil. Purify by column chromatography (20% ethyl acetate in hexane) to afford the title compound (2.1 g, 39%) as a pale yellow oil. MS (ES) m/z 170 [M+1]+.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>ClCCl>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: Nc1ccccc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of benzene-1,2-diamine (100 g, 0.93 mol) in dichloromethane (1 L) at 0° C. was added acetic anhydride (87 mL, 0.92 mol). After stirring at 0° C. for 2 hours, the mixture was stand at 0° C. for 12 hours and the precipitate was collected by filtration, washed by dichloromethane and ether, dried in air to afford the product N-(2-aminophenyl)acetamide (25 g, yield 18%). 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.26 (m, 2H), 7.04-7.08 (m, 1H), 6.78-6.81 (m, 2H), 3.86 (br s, 2H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].[CH3:16][N:17]=[C:18]=[S:19].CN(C)C=O.CC(C)([O-])C.[K+]>C(O)(=O)C>[CH3:16][NH:17][C:18]([C:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C:9]=1[OH:14])=[S:19]
Reactant: CN=C=S
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CNC(=S)C1=C(O)C(C)(C)Oc2ccc(C#N)cc21
Temperature: 0 °C
Yield: 68.5 %

Procedure:
To a mixture of 1.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.6 g of methyl isothio-cyanate, and 15 ml of dried N,N-dimethylformamide was added 0.93 g of potassium t-butoxide with stirring under ice-cooling, followed by stirring for 4 hours under ice-cooling. Ice-water was added to the reaction mixture, and the mixture was made acidic with acetic acid and then extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. The ether layer was removed by distillation, and the residue was recrystallized from ethanol to yield 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH:22]=O)=[CH:20][C:15]=2[O:14][N:13]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[N+:21]([C:19]1[CH:18]=[CH:17][C:16]2[C:12]([N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[N:13][O:14][C:15]=2[CH:20]=1)#[C-:22]
Reactant: O=CNc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]c1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
1-5 (150 mg, 0.480 mmol) was suspended in CH2Cl2 (10 mL) and cooled to 0° C. To the mixture were added triphosgene (87.0 mg, 0.290 mmol) followed by Et3N (0.140 mL, 0.980 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine and dried over Na2SO4. The residue was triturated with hexane to give 115 mg (82%) of 1-6 as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (1H, br s), 8.09 (2H, m), 8.04 (1H, dd, J=8.4, 0.8 Hz), 8.00 (2H, m), 7.68 (1H, dd, J=8.4, 1.6 Hz); ESI-MS m/z 290 [C16H7N3O3]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][C:24](O)=[O:25])=[O:21])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][CH:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>CN(C=O)C.O>[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][CH:58]1[CH2:63][CH2:62][N:61]([C:24](=[O:25])[CH2:23][NH:22][C:20]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[NH:19][N:18]=2)=[O:21])[CH2:60][CH2:59]1
Reactant: O=C(O)CNC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Reactant: Clc1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2cccc(OCc3ccccc3)c2)[nH]n1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a stirred solution of {[5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (0.15 g, 0.00039 mol) in DMF (2 mL) was added DIPEA (0.224 g, 0.00174 mol) HOBt (0.065 g, 0.000482 mol) and EDCI.HCl (0.0925 g, 0.00048 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00041 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration. Purification by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) afforded 0.19 g (91%) of 5-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 544.2 (M+1)+, 96.18%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To an oven-dried flask under N2 was added N-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (750 mg, 2.62 mmol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (230 mg, 0.33 mmol), copper(I) iodide (38 mg, 0.20 mmol), and trimethylsilylacetylene (640 mg, 6.53 mmol). Next, triethylamine (2.64 g, 26 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.67 g, 84%) as an off white solid. ESIMS (M−H)−=302.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][N:7]=1.Cl.[C:24](=N)(OCC)[CH3:25]>CO>[CH3:24][C:25]1[NH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]([N:4]3[CH:5]=[CH:6][N:7]=[C:3]3[S:2][CH3:1])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]=2[N:16]=1
Reactant: CCOC(C)=N
Reactant: CSc1nccn1C(c1ccccc1)c1ccc(N)c(N)c1
Agent: Cl
Solvent: CO
Product: CSc1nccn1C(c1ccccc1)c1ccc2[nH]c(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
(a-6) A mixture of 5.6 parts of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]-phenylmethyl]-1,2-benzendiamine, 2.8 parts of ethyl ethanimidate hydrochloride and 60 parts of methanol was stirred first overnight at room temperature and then for 2 hours at reflux temperature. After cooling, the reaction mixture was evaporated. The residue was treated with alkaline water and the product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.2 parts (79.3%) of (+)-2-methyl-5-[[2-(methylthio)-1H-imidazol-1-yl]phenylmethyl]-1H-benzimidazole as a residue (int. 144).
Reaction SMILES: O.[O:2]=[C:3]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:12][CH:13]([OH:15])[CH3:14])[CH:6]=[CH:5][C:4]1=2>COCCOCCOC.[Pd]>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(O)Cn1ccc2c1CCCC2=O
Agent: [Pd]
Solvent: COCCOCCOC
Solvent: O
Product: CC(O)Cn1ccc2c(O)cccc21
Yield: 78.5 %

Procedure:
10 g of 5% by weight palladium-on-charcoal, containing 50% of water, were added to a solution of 19.3 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β-hydroxypropyl)indole, obtained in the preceding stage, in 300 cm3 of diglyme. The temperature of the reaction mixture was brought to the reflux temperature of the diglyme for 5 hours, after removal of the water by azeotropic distillation. The catalyst was then filtered off on Celite and the diglyme was then evaporated. 17 g of crude product were obtained. After chromatography on silica gel (heptane/ethyl acetate=1/4), 15 g of a viscous product were obtained, which product crystallized on addition of 15 cm3 of dichloromethane.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)[CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][CH:23]2[C:28]([N:30]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:36]=1)[C:37]1[CH:38]=[N:39][C:40]([CH:43]([CH3:45])[CH3:44])=[CH:41][CH:42]=1)=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOCCOCCO
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Product: CCOCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monoethyl ether (1.5 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.72 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-ethoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.89 g) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([OH:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:18][C:15]1[S:14][C:13]([C:10]([OH:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[N:17][CH:16]=1
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(Br)s1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
The product of Step 1 (364 mg, 1.331 mmol) was dissolved in DMF (2 ml). N-bromosuccinimide (284 mg, 1.597 mmol) was added, and the solution was maintained 2 h at rt. Water was added and the mixture extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel column chromatography (0%-10% EtOAc:hexanes) afforded 2-(5-bromo-1,3-thiazol-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (104 mg, 22%) as a white solid. MS ESI: [M+H]+ m/z 352, 354.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH-:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][CH:3]=1.[O:11]=[C:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:25](O)=O)[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[F:9][C:6]1[C:7]2[N:8]=[C:25]([C:20]3[C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:12](=[O:11])[C:24]=4[CH:23]=[CH:22][CH:21]=3)[NH:1][C:2]=2[CH:3]=[CH:4][C:5]=1[F:10]
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Reactant: [NH-]c1c(N)ccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2c(F)c(F)ccc2[nH]1
Temperature: 115 °C

Procedure:
The procedure used in Example 68 is followed. In a 100 ml round-bottomed flask under an argon atmosphere, heat, at 115° C. for 6 hours, a suspension of 1.7 g of (6-amino-2,3-difluorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 35 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in water and bring to pH=8 by adding a 10% saturated aqueous solution of sodium hydrogen carbonate, with water. The precipitate that formed is filtered off, washed with water, and rinsed with diisopropyl ether. In this way, we obtain 1.5 g of 4-(4,5-difluoro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]>CN(C=O)C>[CH3:1][N:2]([CH3:34])[C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]5[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=5)[CH:23]=4)=[N:20][CH:21]=3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)C1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H]1CC[C@H](n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1

Procedure:
4-(4-{2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-pyrimidin-5-yl}-pyrazol-1-yl)-cyclohexanecarboxylic acid dimethylamide (example 121; 165 mg; 0.33 mmol) was suspended in DMF and filtered to give the title compound as a white solid (50 mg; 20%). 1H NMR (300 MHz, DMSO) δ 9.16 (s, 2H), 8.53 (t, J=1.6 Hz, 1H), 8.49 (s, 1H), 8.26 (s, 1H), 8.24-8.18 (m, 1H), 8.13 (s, 1H), 7.92 (d, J=0.7 Hz, 1H), 7.74-7.67 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.32-4.16 (m, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.83 (s, 3H), 2.77-2.63 (m, 1H), 2.20-2.06 (m, 2H), 1.97-1.77 (m, 4H), 1.67-1.48 (m, 2H). HPLC (Chiralpak IC, EtOH:THF 90:10): Rt 6.91 min (purity 98.4%); MS (ESI+): 456.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:38])[NH:34][CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>C1COCC1.CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([NH:37][CH2:36][CH2:35][NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:38])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CC)c2nc(NCCNC(=O)OC(C)(C)C)c(F)cc2c1=O
Temperature: 70 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
7-Chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (2.20 g, 7.37 mmol) in THF (20 mL) and MeCN (20 mL) was treated with triethylamine (3.07 mL, 22.0 mmol), followed by (2-amino-ethyl)-carbamic acid tert-butyl ester (1.41 g, 8.80 mmol) and the mixture heated to 70° C. After 26 h (2-amino-ethyl)-carbamic acid tert-butyl ester (300 mg, 1.87 mmol) was added. After a further 15 h the heating was stopped and the solvent removed in vacuo. The residue was taken up in ethyl acetate, washed with water, dried filtered, and concentrated in vacuo to give a residue which was purified by chromatography (silica gel, 30-100% ethyl acetate in petroleum ether (b.p. 40-60° C.)) to give the title compound (2.89 g); ESMS m/z 423 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:21]([OH:22])=[N:20][C:11]2[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CN1CCCC1=O.C(OCC)(=O)C>[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:13]2[N:14]=[CH:15][C:10]3[CH:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:21]([OH:22])=[N:20][C:11]=3[N:12]=2)[CH2:26][CH2:25]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1ncc2cc(-c3ccccc3Cl)c(O)nc2n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2ncc3cc(-c4ccccc4Cl)c(O)nc3n2)CC1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a solution of sulfone 2 (1.27 g, 3.78 mmol) in 15 mL of 1-methyl-2-pyrrolidinone was added trans-1,4-diaminocyclohexane (3.75 g, 32.8 mmol). The reaction mixture was stirred at 65° C. for 1.5 hours, cooled, and diluted with 80 mL of ethyl acetate. The resulting suspension was filtered and washed several times with ethyl acetate and methanol. The solid was dried to yield 1.31 g (94%) of 2-(trans-4-aminocyclohexylamino)-6-(2-chlorophenyl)-pyrido[2,3-d]pyrimidin-7-ol as an off-white powder (mass spec. M+H+=370). The free base was taken up in ethyl acetate and treated with a 1 M solution of HCl/Et2O to form the dihydrochloride salt of the title compound as a white powder with a melting point of >300° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[Br:8]
Reactant: O=c1[nH]ncc(Br)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]nc([N+](=O)[O-])c(Br)c1Br
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To 4,5-dibromopyridazin-3(2H)-one (2 g, 7.87 mmol) in concentrated sulfuric acid (12 mL), fuming nitric acid (978 μL, 23.8 mmol) was gradually added at 100° C. with stirring, and the resulting reaction solution was stirred at 100° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and poured onto ice-cold water. The precipitated crystals were collected by filtration and dried under reduced pressure to give the desired product (2.2 g, 93%).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH3:42])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:22]([CH3:34])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:15]([C:17]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([CH3:42])[CH:36]=1)([C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:22]([CH3:34])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCCC2)c(C)c1
Reaction time: 4 h
Yield: 92.8 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (3.33 M solution in toluene, 6.7 mL, 22.3 mmol) was added to a solution of 4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 32-(1); 2.8 g, 7.4 mmol) in tetrahydrofuran (37 mL) at 0° C., and the mixture was stirred at the same temperature for four hours. The reaction mixture was diluted with ethyl acetate. Brine and celite were added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=3/1) to give the title compound (2.6 g, 92%).