Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN([CH:24]=[O:25])C>>[F:18][C:7]([F:6])([F:17])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 75 %

Procedure:
Phosphorous oxychloride (7.6 mL, 83.0 mmol) was added dropwise to DMF (150 mL) at 0° C. A solution of 5 (4.5 g, 24.4 mmol) in DMF (30 mL) was added after 15 min. and the reaction mixture was allowed to warm to room temperature for 2 h. The mixture was poured on ice-water (300 g), made alkaline (pH 7-8) with 2 N aq. NaOH, extracted with EtOAc, the extracts were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography on silica gel using 10% MeOH/CHCl3 as eluent. Recrystallization by dissolving yellow solid in hot MeOH and pouring onto cold water afforded 1 (3.9 g, 75% yield) as a white solid. Mp 242-243° C. 1H NMR (300 MHz, MeOH-d4): δ 9.95 (s, 1H), 8.48 (bs, 1H), 8.22 (s, 1H), 7.63 (d, 8.5 Hz, 1H), 7.53 (dd, 8.5, 1.7 Hz, 1H). MS m/z: 212 (M−1). Analysis calcd. for C10H6NOF3; C, 56.35; H, 2.84, N, 6.57; found, C, 56.60; H, 2.92; N, 6.55.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](B(O)O)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=[N:25][CH:26]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Reactant: OB(O)c1cncc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cncc4ccccc34)sc2n1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 4-isoquinolinylboronic acid (40.1 mg, 0.232 mmol), bis(triphenylphosphine)palladium(II) chloride (16.26 mg, 0.023 mmol) and potassium carbonate (112 mg, 0.811 mmol) and the mixture heated at 100° C. for 1 h using a microwave reactor. The mixture was then filtered through celite, washing with ethyl acetate (30 mL) and the filtrate evaporated to dryness. The residue was then purified by MDAP (acidic conditions), to afford the title compound (41.45 mg). LCMS (A) m/z: 480 [M+1]+, Rt 1.13 min (acidic).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:17][CH:16]1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH:16]4[O:15][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[O:18][CH2:17]4)[CH2:27][CH2:28]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(CC2COc3ccccc3O2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 77% overall yield. FDMS m/e=423 (M+ of free base). α[D]589 =-10.21 (c=0.82, methanol).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7]>O.CC(C)=O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6](=[O:7])[CH:8]=1
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: CC(C)=O
Solvent: O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
A suspension of 25.6 g of ferric chloride in 50 ml of water was added at room temperature to a solution of 20 g of trimethylhydroquinone in 150 ml of acetone, and the resulting mixture was stirred for 1 hour, after which it was allowed to stand for 2 days. At the end of this time, it was concentrated to about one half of its original volume, and the concentrate was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 16.9 g of the title compound having an Rf value=0.48 (on thin layer chromatography on silica gel; developing solvent: a 1:6 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].C(N(CC)CC)C.[C:36](Br)(=[O:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([NH:26][C:36](=[O:38])[CH3:37])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CC(=O)Br
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(N)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(NC(C)=O)ccc1OC
Reaction time: 1 h

Procedure:
At 0° C., under an inert atmosphere, 1 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-amino-2-methoxyphenyl)-N-propylamino]thiazole is dissolved in 3.5 ml of dichloromethane. 0.4 ml of triethylamine is added followed by 0.14 ml of acetyl bromide. After 1 hour at room temperature, the reaction mixture is diluted with dichloromethane. The organic phase is washed with water and then dried over sodium sulphate. The evaporation residue is purified on silica gel; eluent cyclohexane/ethyl acetate 1/1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[CH2:15](N(CC)CC)[CH3:16].O.[OH-].[Na+]>C1(C)C=CC=CC=1.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>[F:9][C:8]([F:11])([F:10])[C:6]1[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=[C:2]([CH:15]=[CH2:16])[CH:7]=1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)n1
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.50 g, 1.8 mmol, Anichem), (2-Ethenyl)tri-n-butyltin (919 μL, 3.14 mmol, Aldrich) and tetrakis(triphenylphosphine)palladium(0) (428 mg, 0.370 mmol, Strem) in toluene (4.2 mL) was degassed by a stream of nitrogen through the solution for 15 minutes. Triethylamine (774 μL, 5.56 mmol) was added and the mixture was heated to 80° C. for 2 hours. After cooling to ambient temperature, water and 1N NaOH were added and the product was extracted with four portions of ethyl acetate. The aqueous layer was then treated with 1N HCl to achieve a pH between 4 and 5, and was extracted with six portions of 10% isopropanol in chloroform. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude product, which was used without further purification in Step B. H NMR (300 MHz, CDCl3) δ 8.40 (d, J=1.3 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 6.82 (dd, J=17.6, 10.9 Hz, 1H), 6.23 (d, J=17.4 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H); LCMS (M+H)+: 218.1.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:1]([CH:2]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(C(C)O)nn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccccc2)nn1
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of methyl 6-(1-hydroxyethyl)pyridazine-3-carboxylate (100 mg, 0.55 mmol), phenol (78 mg, 0.8 mmol), triphenylphosphine (216 mg, 0.8 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (166 mg, 0.8 mmol) at room temperature. The mixture solution was stirred for 18 hours. Then tetrahydrofuran was removed in vacuo. The residue was purified by column chromatography (silica-gel, petroleum/ethyl acetate=5:1) to give methyl 6-(1-phenoxyethyl)pyridazine-3-carboxylate as a colorless oil (100 mg, 70%). 1H NMR (300 MHz, DMSO-d6): δ 8.20 (d, J=9 Hz, 1H), 7.93 (d, J=9 Hz, 1H), 7.20-7.25 (m, 2H), 6.87-6.94 (m, 3H), 5.87-5.90 (m, 1H), 3.94 (s, 3H), 1.68 (d, J=6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([OH:8])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=1.CCN(CC)CC.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:8][C:5]1[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:25])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-n2nc(C)c(C)c2O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-n2nc(C)c(C)c2OS(=O)(=O)C(F)(F)F)n1
Temperature: -78 °C
Yield: 74.8 %

Procedure:
To the 500 mL round-bottomed flask with 3,4-dimethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-ol (6.68 g, 33 mmol) were added Et3N (5.5 mL, 39 mmol) and 35 mL CH2Cl2. the solution was cooled in dry ice acetone bath. Tf2O (6.1 mL, 36 mmol) was added slowly. The mixture was stirred at −78° C. and allowed to warm to room temperature. The mixture was then concentrated in vacuo. The crude product was purified using a Biotage Horizon System (0 to 25% EtOAc/hexane) to afford a colorless oil (8.28 g).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[Cl:35]C1C=C(Cl)C=CC=1[C:43](=O)[C:44](C1NC=C(C)N=1)=[CH:45][N:46](C)C>>[ClH:3].[ClH:35].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2[NH:46][CH:45]=[C:44]([CH3:43])[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: Cc1c[nH]c(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)n1
Agent: Cl
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(4-methylimidazolyl)prop-2-en-1-one (XI, 421 mg, 1.3 mmol) was used.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]([N:8]1[CH:14]([CH3:15])[CH2:13][C:12]2[CH:16]=[C:17]3[O:22][CH2:21][O:20][C:18]3=[CH:19][C:11]=2[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:9]1)=[S:7])=[O:4].BrBr.CO>C(Cl)(Cl)Cl>[CH3:15][CH:14]1[CH2:13][C:12]2[CH:16]=[C:17]3[O:22][CH2:21][O:20][C:18]3=[CH:19][C:11]=2[C:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:9][N:8]1[C:6]1[S:7][N:2]([CH3:1])[C:3](=[O:4])[N:5]=1
Reactant: CNC(=O)NC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Agent: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1nc(=O)n(C)s1)OCO3
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To an ice cooled stirred solution of 0.44 g (1.0 mmol) of the starting material XXVII in 8 ml of chloroform a solution of 0.19 g (1.2 mmol) of bromine in 3 ml of chloroform was added. After 0.5 h the reaction mixture was diluted with 15 ml of chloroform and washed with sodium hydrogen carbonate solution and water. The residue obtained on concentration was stirred with methanol and filtered to yield 0.36 g (82%) of the title compound. Mp.: 296° C. after recrystallization from ethyl acetate.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([C:21]([NH2:23])=[NH:22])[CH:15]=[CH:14]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24]1([CH3:30])[CH:29]=[CH:28]C=C[CH:25]=1>CO>[CH2:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]3[N:23]=[CH:30][C:24]([CH2:29][CH3:28])=[CH:25][N:22]=3)[CH:17]=2)[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccccc1
Reactant: CCCCCCCc1ccc2cc(C(=N)N)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCc1ccc2cc(-c3ncc(CC)cn3)ccc2c1
Temperature: 60 °C
Yield: 60 %

Procedure:
NaOH (1.1 g, 26 mmols) was added to anhydrous methanol (40 ml) and dissolved therein by heating to 60° C. with stirring. To the solution was added 6-heptyl-2-naphthalenecarboxamidine hydrochloride (4.0 g, 13 mmols) to prepare a suspension with stirring. To this suspension was dropwise added over one minute a solution obtained by dissolving α-ethyl-β-dimethylaminoacrolein (1.7 g, 13 mmols) in anhydrous methanol (5 ml), followed by gently refluxing the mixture with stirring for 2 hours, distilling off methanol under the atmospheric pressure after completion of the reaction, adding toluene (50 ml) to the residue to extract the resulting product, washing the extraction solution with a 2N-NaOH aqueous solution and then with water, drying over anhydrous sodium sulfate, and distilling off toluene under reduced pressure to obtain solids, which were then recrystallized from ethanol to obtain the objective 2-heptyl-6-(5-ethyl-2-pyrimidinyl)naphthalene (2.5 g, 7.8 mmols) (yield: 60%). M.P.: 62.3°-63.1° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[OH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][C:11]=1[O:19][CH3:20].[OH-].[K+]>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[C:13]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([O:19][CH3:20])[CH:12]=1
Reactant: Nc1ccccc1S
Reactant: COc1cc(C(=O)O)ccc1O
Agent: [K+]
Agent: [OH-]
Product: COc1cc(-c2nc3ccccc3s2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3 %

Procedure:
A slurry of 2-aminothiophenol (357 mg, 2.85 mmol) in polyphosphoric acid (14.0 g) was heated to 110° C. and 4-hydroxy-3-methoxybenzoic acid (480 mg, 2.85 mmol) was added. After 2 h, the reaction mixture was cooled to rt. The mixture was poured carefully into ice cold water, and the solution was neutralized with KOH (3 M aqueous solution). The aqueous phase was extracted with EtOAc (2×). The combined organic layers were washed with Na2CO3 (1 M aqueous solution), HCl (1 M aqueous solution) and water, dried, and concentrated under reduced pressure. Purification by silica gel chromatography gave 22 mg (3%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.55 (d, 1H), 7.48 (m, 1H), 7.36 (m, 1H), 7.00 (d, 1H), 5.92 (s, 1H), 4.03 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br.[Na]>O1CCOCC1.CO>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: OC1CCOC1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccccc1COC1CCOC1
Temperature: 50 °C
Yield: 80 %

Procedure:
8.8 g (0.1 mole) of 3-hydroxy-tetrahydrofurane were added dropwise, whilst stirring, to a mixture of 2.8 g (0.12 mole) of sodium hydride (3.5 g of 80% strength sodium hydride in paraffin oil) in 100 ml of absolute dioxan at room temperature. The mixture was then heated for 30 minutes under reflux. After cooling to 50° C., 19 g (0.1 mol) of 2-fluorobenzyl bromide were added dropwise to the sodium salt thus obtained. The mixture was then heated for 3 hours under reflux and was allowed to cool to room temperature, 10 ml of methanol were added to destroy the excess sodium hydride, and the mixture was concentrated by distilling off the solvent in vacuo. The residue was taken up in 100 ml of water and extracted with methylene chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo. 15.7 g (80% of theory) of 3-(2-fluorobenzyloxy)-tetrahydrofurane of boiling point 89° C./0.1 mm Hg were obtained.
Reaction SMILES: Cl.[S:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18]([C:20](Cl)=[O:21])=[CH:17][C:16]=2[CH:23]=1.[CH2:24]([NH:31][CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(CC)CC>C(Cl)Cl>[CH2:24]([N:31]([CH3:32])[C:20]([C:18]1[O:19][C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[S:2][C:10]4[C:5]([N:4]=3)=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:23][C:16]=2[CH:17]=1)=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Yield: 15.1 %

Procedure:
To a solution of 5-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carbonyl chloride hydrochloride (150 mg, 0.43 mmol) in CH2Cl2 (4.3 mL) was added N-benzyl-N-methylamine (55 μL, 0.43 mmol) and Et3N (0.12 mL, 0.86 mmol). The reaction mixture was stirred (rt, 2 h) before additional N-benzyl-N-methylamine (55 μL, 0.43 mmol) was added. The mixture was concentrated and purified by reverse phase chromatography to provide the title product as an orange oil (27 mg, 15%). MS (ESI): mass calcd. for C23H17N3O3S, 415.10; m/z found, 416.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.60 (d, J=3.7, 1H), 8.09 (dd, J=7.9, 1.5, 1H), 7.75 (br s, 1H), 7.66-7.49 (m, 1H), 7.46-7.28 (m, 8H), 5.05-4.62 (m, 2H), 3.45-2.94 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]2=[O:41])[CH:17]=[CH:18][CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:28]=3)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:21]2=[O:41])[CH:17]=[CH:18][CH:19]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Yield: 51.7 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.1 mL, 1.28 mmol), triethylamine (0.18 mL, 1.28 mmol), and 1-(3-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example G-1, 0.17 g, 0.43 mmol) provided 0.1 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(OC)c1
Solvent: Cc1ccccc1
Product: COc1cc(NC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90486 %

Procedure:
To a solution of 3,5-dimethoxy-phenylamine (20 g, 0.131 mol) in toluene (110 mL) was added acetic anhydride (14 g, 0.137 mmol) at room temperature. The resulting mixture was stirred for 18 hours at room temperature. PE (55 mL) was added, the precipitate was filtered and washed with PE (100 mL) to obtain the title compound (24.2 g, yield: 95%). 1H-NMR (400 MHz, CDCl3) δ 2.16 (s, 3H), 3.77 (s, 6H), 6.23 (s, 1H), 6.75 (s, 2H), 7.20 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Fc1ccc(Oc2ccc(COC3CCCNC3)cc2)cc1
Product: COC(=O)c1cccc(N2CCCC(OCc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Yield: 41.8 %

Procedure:
Using 3-[4-(4-fluorophenoxy)benzyloxy]piperidine (157 mg, 0.521 mmol) and 3-(methoxycarbonyl)phenylboric acid (187 mg, 1.04 mmol), the same procedure was followed as in Example 2 to give 94.8 mg (42%) of the desired compound as a colorless oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30]([OH:32])[CH:31]=1>C1COCC1>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[O:33][CH3:34]
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(C)=O)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A small screw cap test tube was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 29, 70 mg, 0.217 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (26.0 mg, 0.258 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 72% yield (0.069 g, 0.1555 mmol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:21]([CH2:23][NH2:24])[OH:22]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:24][CH2:23][CH2:21][OH:22])=[O:13])[CH2:8]2
Reactant: NCCO
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1NCCO

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 59 mg; 0.20 mmol) and ethanolamine (0.20 mL; 3.3 mmol) under microwave irradiation according to the procedure described in Example 14 Step 2 provided after purification by reverse phase HPLC, 5-(2-hydroxy-ethylamino)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (26 mg, 41%) as a white powder. ES-HRMS m/e calcd for C17H27N4O2 (M+H+) 319.2129, found 319.2127.