Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[C:7]1([CH:13]2[NH:17][N:16]=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+:26]>C(Cl)(Cl)Cl.C(O)C>[C:7]1([CH:13]2[N:17]([C:2]([O-:4])=[O:3])[N:16]=[CH:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:26]
Reactant: C1=NNC(c2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C([O-])N1N=CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl chloroformate (12 g) was added dropwise under ice cooling to a solution of 14.6 g 5-phenyl-2-pyrazoline and 12 g triethylamine in 100 ml chloroform, and the mixture was stirred at room temperature for three hours. The reaction mixture was washed with 3% hydrochloric acid and 3% aqueous solution of sodium bicarbonate in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off from the dried solution, and the oily residue thus obtained (20 g) was dissolved in 80 ml ethanol. To this ethanolic solution, was added 10 ml of 40% aqueous solution of caustic soda, the mixture was stirred at room temperature for one hour, and the crystals which precipitated out were collected by filtration and dried under reduced pressure, affording 12 g of pure product. M.p.: 210° C. (dec.); NMR (D2O): 2.6-3.4 (2H, m), 4.7 (1H, dd, J=12,5 Hz), 7.14 (1H, t, J=2 Hz), 7.40 (5H, s).
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[CH3:21].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:16][C:12]1[CH:11]=[C:10]([S:7]([N:6]2[C:2]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:3]([CH3:21])[C:4]([C:17]([O:19][CH3:20])=[O:18])=[CH:5]2)(=[O:9])=[O:8])[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cn(S(=O)(=O)c2cccc(Cl)c2)c(Br)c1C
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: COCCOC
Product: COC(=O)c1cn(S(=O)(=O)c2cccc(Cl)c2)c(-c2ccccc2)c1C
Yield: 72.9 %

Procedure:
Methyl 5-bromo-1-[(3-chlorophenyl)sulfonyl]-4-methyl-1H-pyrrole-3-carboxylate (1.0 g), phenylboronic acid (403 mg), sodium carbonate (405 mg) and tetrakis(triphenylphosphine)palladium (295 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and distilled water (10 mL), and the mixture was reacted in a microwave reactor (Emrys Optimizer, Personal Chemistry, 140° C., 4 min). The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-brown oil (yield 724 mg, 73%).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]([N:33]1[CH:37]=[CH:36]N=C1)(N1C=CN=C1)=[O:27].Cl.[Cl:39][C:40]1[CH:41]=C(C=[CH:45][C:46]=1[O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])N.Cl>CN(C=O)C.O>[Cl:39][C:40]1[CH:41]=[C:37]([NH:33][C:26]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:27])[CH:36]=[CH:45][C:46]=1[O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54]
Reactant: COCCOCCOc1ccc(N)cc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (1.11 g, 3.0 mmol) and 1,1′-Carbonyldiimidazole (535 mg, 3.3 mmol) were suspended in dry DMF (20 mL) and the mixture was stirred at rt for 24 h. While stirring, a portion of the reaction mixture (6.7 mL, ˜1 mmol) was transferred to a vial containing 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (310 mg, 1.1 mmol). The resulting mixture was stirred at rt overnight and the reaction progress was monitored by LCMS. After 48 h, additional 3-chloro-4-(2-(2-methoxyethoxy)ethoxy)aniline hydrochloride (56 mg, 0.2 mmol) was transferred to the reaction mixture and stirring continued for another 24 h. The reaction mixture was acidified with 1 N HCl and water was added with stirring until a precipitate formed. The solid was collected by filtration, suction dried, then dissolved in DMF and purified using C-18 preparatory HPLC to give 1-(3-chloro-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea as a white solid (390 mg, 72% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.40 min (99.8%); mp: 188-190° C.; 1H NMR (DMSO-d6) δ 1.92-2.10 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.60 (dd, J=2.2, 15.4 Hz, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 3.25 (s, 3H, CH3), 3.46 (dd, J=3.7, 5.6 Hz, 2H, CH2), 3.61 (dd, J=3.8, 5.7 Hz, 2H, CH2), 3.73 (d, J=4.7 Hz, 2H, CH2), 4.09 (t, J=4.9 Hz, 2H, CH2), 4.24-4.55 (m, 4H, CH2, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.77 (t, J=5.9 Hz, 1H, NH), 7.04 (d, J=9.1 Hz, 1H, Ar), 7.19 (dd, J=2.5, 9.0 Hz, 1H, Ar), 7.38-7.49 (m, 1H, Ar), 7.51 (s, 1H, Ar), 7.64 (d, 2.6 Hz, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.65 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.20, 42.80, 47.12, 51.56, 58.05, 68.80, 68.85, 69.84, 71.29, 114.66, 117.58, 119.49, 121.24, 121.88, 122.91, 126.89, 130.29, 134.53, 142.38, 144.84, 148.40, 155.25, 167.95, 171.01, 172.86; LCMS: MH=545, 547; Anal Calcd for C26H29ClN4O7+0.4 H2O: C, 56.55; H, 5.44; N, 10.15. Found: C, 56.64; H, 5.34; N, 10.15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:13][NH:14][C@H:15]([C:17]([C:19]1([NH2:38])[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH3:36])[C:20]1=[O:37])=[O:18])[CH3:16]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]([C:17]([C:19]2([NH2:38])[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH3:36])[C:20]2=[O:37])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CN[C@@H](C)C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@@H](C(=O)C1(N)N=C(c2ccccc2)c2ccccc2N(C)C1=O)N(C)C(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(N′-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-E), the title compound was prepared as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>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:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14]
Reactant: OB(O)c1ccccc1F
Reactant: O=c1oc(CO)c(Br)c2ccccc12
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: [Cs+]
Product: O=c1oc(CO)c(-c2ccccc2F)c2ccccc12
Yield: 33 %

Procedure:
The title compound was made in a similar way as that of the intermediate B2 using 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.6 g, 2.352 mmol), 2-fluorophenylboronic acid (0.494 g, 3.53 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and Cs2CO3 (0.77 g, 2.35 mmol) to afford the title compound (0.21 g, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11]CC2C=CC(OC)=CC=2)[N:8]([CH2:21][C:22](=[O:38])[NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH2:21][C:22](=[O:38])[NH:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)n(CC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(O)n(CC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)n1
Temperature: 0 °C
Yield: 85.6 %

Procedure:
An ice cold sample of 100 mg (0.192 mmol) of 1-[((1S, 2S)2-Benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(4-methoxy-benzyloxy)-1H-pyrazole-3-carboxylic acid ethyl ester (2) was treated with 5 mL of 95:5 trifluoroacetic acid (TFA):H2O solution, and the resulting mixture was stirred for 1.5 h at rt, and then quenched by the addition of 5 mL of 1:1 acetonitrile:water solution. The mixture was concentrated to give 66 mg (86%) of crude 1-[((1S, 2S)2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (3) which was used without any further purification in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][CH2:11][CH:12]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:13][NH2:14].[CH2:23]([Br:26])[CH:24]=[CH2:25].C([O-])([O-])=O.[K+].[K+].O>O1CCCC1>[BrH:26].[CH2:25]([NH:14][CH2:13][CH:12]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH2:11][O:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Cc1cccc(C)c1C(CN)COCc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Br
Product: C=CCNCC(COCc1c(F)cccc1F)c1c(C)cccc1C

Procedure:
1 g (3.3 mmol) of 3-(2,6-difluorophenyl)methoxy-2-(2,6-dimethylphenyl)-propylamine are dissolved in 10 ml of tetrahydrofuran (THF) and stirred with 0.4 g (3.3 mmol) of allylbromide and 1.2 g of K2CO3 for 16 h at ambient temperature. Then the solvent is eliminated in vacuo, the residue is combined with 50 ml of water and extracted twice with 30 ml of ethyl acetate. The organic phase is dried, concentrated by evaporation in vacuo and the residue is chromatographed on silica gel (methanol/dichloromethane=2:98). The appropriate fractions are concentrated by evaporation, the residue is dissolved in ether and the hydrobromide is precipitated with HBr/glacial acetic acid. Yield: 1.0 g (71%), melting point: 105° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:5]([N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[Cl:26])(=[O:18])=[O:17])C(=O)OCC(C)C)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1)CCC.C(OCC)(=O)C.C(O)C>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>[Cl:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[S:16]([NH:8][C:5]1[C:4]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[N:3][C:2]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[CH:7][N:6]=1)(=[O:18])=[O:17]
Reactant: CC(C)COC(=O)N(c1ncc(Br)nc1OCc1cccnc1)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(Nc1ncc(-c2ccncc2)nc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl][(2,3-dichlorophenyl)sulphonyl]carbamic acid, 2-methylpropyl ester (Example 136a) (0.11 g), 4-tributylstannanylpyridine (0.067 g) and tetrakis(triphenylphosphine)palladium(0) (0.05 g) in toluene (3 mL) was heated at 95° C. for 16 h. Chromatography on silica gel eluting with ethyl acetate/ethanol mixtures gave the title compound protected with the 2-methylpropylcarbonyl group (0.09 g). The compound was heated at 60° C. in methanol (2 mL) and 1M sodium hydroxide (0.36 mL) for 1 h. The solution was evaporated. Purification was by reverse phase preparative high pressure liquid chromatography. Yield 0.015 g.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:43](OS(C(F)(F)F)(=O)=O)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[O:34][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of (2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-ol (1.0 g, 1.74 mmol, 1.0 equiv) in dry DCM (10 mL) under nitrogen atmosphere, was added 2,6-lutidine (0.41 mL, 3.5 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 5 minutes. The reaction was cooled to 0° C. and TBSOTf (0.6 mL, 2.6 mmol, 1.5 equiv) was added dropwise. The mixture was then slowly allowed to warm to room temperature. After 1 hour, the mixture was diluted with DCM (20 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4 and over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was then purified by silica gel chromatography, eluting with 5% EtOAc in petroleum ether to give (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane as a colorless oil (1.05 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 13H), 7.09-7.04 (m, 2H), 4.90-4.77 (m, 2H), 4.77-4.68 (m, 2H), 4.53 (d, J=12.1 Hz, 1H), 4.47 (d, J=10.7 Hz, 1H), 4.09 (ddd, J=12.2, 5.9, 3.4 Hz, 1H), 3.91 (dd, J=9.2, 5.9 Hz, 1H), 3.81 (dd, J=10.7, 3.2 Hz, 1H), 3.75 (dd, J=10.7, 2.1 Hz, 1H), 3.69 (dd, J=9.9, 8.7 Hz, 1H), 3.63-3.56 (m, 2H), 3.51 (dt, J=9.9, 2.6 Hz, 1H), 3.41 (t, J=11.8 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([NH:44][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 53 %

Procedure:
The title compound was prepared as described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from the previous step (0.139 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.116 g, 53%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 7.54-7.62 (m, 7H), 7.39 (m, 2H), 7.19 (d, 1H), 6.96 (d, 1H), 6.86 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 551 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Fc1ccc(CCl)cc1Oc1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 481.6 %

Procedure:
To a stirred solution of 12.6 grams (0.106 mole) of thionyl chloride and one drop (catalyst) of pyridine in 25 mL of toluene was added dropwise a solution of 19.5 grams (0.088 mole) of 4-fluoro-3-phenoxyphenylmethanol in 30 mL of toluene at such a rate as to maintain the reaction mixture temperature at 25°-35° C. Upon completion of the 45 minute addition time, the reaction mixture was warmed to 45° C. where it was stirred during a one hour period. After this time the reaction mixture was cooled, and the excess thionyl chloride was removed under reduced pressure. The residue, 23.5 grams of a semi-solid mixture, was combined with 114.2 grams of the same material from a previous reaction. The combination was distilled under reduced pressure yielding 100.3 grams of 4-fluoro-3-phenoxyphenylmethyl chloride; b.p. 98°-105° C./0.025-0.055 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.C(O[C:20](=[O:28])[NH:21][C@@H:22]([CH2:26][CH3:27])[C:23](=[O:25])[CH3:24])(C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:26]([C@@H:22]1[NH:21][C:20](=[O:28])[CH2:1][C@@:23]1([OH:25])[CH3:24])[CH3:27]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC[C@@H]1NC(=O)C[C@]1(C)O
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A solution of diisopropylamine (7.50 g) in tetrahydrofuran (110 mL) was ice-cooled under a nitrogen atmosphere, and 1.6 mol/L n-butyllithium-hexane solution (45.4 mL) was added. The mixture was stirred at the same temperature for 30 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (7.17 mL) was added to the reaction solution, and the mixture was stirred at the same temperature for 1 hr. A solution of tert-butyl[(1S)-1-ethyl-2-oxopropyl]carbamate (9.75 g) in tetrahydrofuran (60 mL) was added, and the mixture was stirred at the same temperature for 5.5 hr. A saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→30%) and the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (285 mL), and diisopropylethylamine (22.2 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=3→13%), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (yield: 4.69 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.[I:15]I.[I-].[K+].[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][N:22]=[C:21]1[SH:26]>CO.O>[IH:15].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[C:6]2[S:26][C:21]1[N:20]([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]=1
Reactant: II
Reactant: CN1CCCN=C1S
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2[nH]c(C(=O)O)c(SC3=NCCCN3C)c2c1
Product: I

Procedure:
A solution of 3.45 g of 5-methoxy-indole-2-carboxylic acid in 50 ml methanol is added to a solution of 4.57 g of iodine and 9 g of potassium iodide in 27 ml of water. This is treated with a solution of 2.34 g of 1-methyl-1,4,5,6-tetrahydro-2-pyrimidinethiol in 30 ml of water. The reaction is carried out and worked up as described under Example 1 to yield 5-methoxy-3-(1-methyl-1,4,5,6-tetrahydro-2-pyrimidinylthio)-indole-2-carboxylic acid hydriodide which melts at 256° (with decomposition) after recrystallization from a mixture of methanol and ethyl acetate.
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.Cl>>[Cl:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Fc1ccc(Cl)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(Cl)c(C(Cl)(Cl)Cl)cc1F
Temperature: 25 °C
Yield: 65.4 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 14.9 g (0.1 mol) of 1-chloro-3,4-difluorobenzene was gradually dropwise added over a period of 1.5 hours under reflux so that hydrochloride gas was slowly generated. The generated hydrochloride gas was absorbed by an aqueous sodium hydroxide solution. After completion of the dropwise addition, the mixture was reacted for 10 minutes. After cooling to room temperature, the reaction mixture was poured into 300 ml of ice water. The organic layer was separated and washed with 100 ml of water, then with 100 ml of 5% of sodium hydrogen carbonate aqueous solution and further with 100 ml of water. After distilling off carbon tetrachloride, the residue was distilled under reduced pressure to obtain 17.4 g (yield: 65.4%) of 2-chloro-4,5-difluorobenzotrichloride. Boiling point: 104°-106° C./8 mmHg, nD20 1.540; purity: 98.2%
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(F)(F)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a mixture of 2-chloro-5-(2,2-difluoropropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (466 mg, 1.46 mmol) and iodomethane (0.365 ml, 5.84 mmol) in DMSO (8 ml) at 0° C. was added sodium 2-methylpropan-2-olate (211 mg, 2.19 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude solid. The solid was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 2:1) to afford 2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (264 mg, 0.793 mmol, 54% yield) as a white solid. MS [M+H] found 333.