Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([CH2:20][C:11]2[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:10]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Yield: 85.5 %

Procedure:
Following the procedure of Example 1(10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 85.5%).
Reaction SMILES: [FH:1].[Sb](Cl)(Cl)(Cl)(Cl)Cl.Cl[C:9]1([F:21])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][C:10]1([F:20])[F:19]>C(Cl)Cl>[F:1][C:9]1([F:21])[O:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][C:10]1([F:20])[F:19]
Reactant: FC1(F)Oc2ccccc2OC1(F)Cl
Reactant: F
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: FC1(F)Oc2ccccc2OC1(F)F

Procedure:
500 ml of hydrogen fluoride, 5 ml of antimony pentachloride and 150 g of 2-chloro-2,3,3-trifluorobenzodioxane were heated in a closed vessel for 6 hours at 40° C., excess hydrogen fluoride was then drawn off, and the residue was taken up in methylene chloride, rendered alkaline and stem-distilled. The re-distillation gave 27 g of 2,2,3,3-tetrafluorobenzodioxane having a boiling point from 142° to 146° C. at 1020 mbar.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH:20]=[CH:19][C:18]4C(OC(=O)[C:16]5[C:17]=4[C:12]=3[C:13](=[CH:14][CH:15]=5)[C:8]3[C:9]=2[C:4]2[C:5](C(OC(=O)[C:3]=2[CH:2]=1)=O)=[CH:6][CH:7]=3)=O.[C:31]1([NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>C(O)(=O)C>[CH:14]1[C:13]2=[C:12]3[C:11]([C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][C:8]2=5)[CH:3]=[CH:2][CH:1]=4)=[CH:20][CH:19]=[CH:18][C:17]3=[CH:16][CH:15]=1.[N:37]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:38][CH:1]=1
Reactant: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Product: c1ccc2[nH]cnc2c1
Temperature: 210 °C
Reaction time: 8 h

Procedure:
There was mixed in a three-liter flask 5.85 grams of 3,4,9,10-perylenetetracarboxylic dianhydride, 26.77 grams of o-phenylene diamine and 7 milliliters of glacial acetic acid. The mixture resulting was then heated with stirring for 8 hours at 210° C., followed by cooling to room temperature. A solid product was then obtained by filtering the mixture throught a sintered glass funnel; followed by washing with 1,000 milliliters of methanol. Thereafter, the solid was slurried with 500 milliliters of 1 percent sodium hydroxide solution. After filtration, the solid was washed with 600 milliliters of water, and then was dried in an oven at 80° C. overnight yielding 7.62 grams, of the above product III.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][C@H:13]1[O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-hydroxypiperidine-1-carboxylate (5.0 g, 14.3 mmol) and triethylamine (4.5 g, 43.0 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.9 g, 43.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The solution was washed with water (150 mL×3) and brine, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure to give the title compound (6.0 g, crude) as a yellow oil. MS (ES+) C19H28H2O7S requires: 428, found: 329 [M+H−100]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.C([Li])CCC.[B:43]([O:48]C)(OC)[O:44]C.Cl>C1(C)C=CC=CC=1.CCOCC>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:43]([OH:48])[OH:44])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:17][CH:18]=1
Reactant: COB(OC)OC
Reactant: Brc1c2ccccc2c(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OB(O)c1c2ccccc2c(-c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
9-Bromo-10-(4-naphthalene-2-yl-phenyl)anthracene 13.8 g was dispersed in dehydrated toluene 80 ml and dehydrated ether 80 ml, and the mixture was cooled down to −30° C. A 1.58M n-butyllithium hexane solution 21. 0 ml was dropwise added thereto, and after the solution was stirred at −40° C. for 30 minutes, the temperature was elevated up to −10° C. The solution was cooled again down to −70° C., and a dehydrated ether solution of trimethyl borate 10.0 ml was gradually added thereto. The solution was stirred at −70° C. for 2 hours and then gradually heated up to room temperature. After left standing for a night, a 10% hydrochloric acid aqueous solution 100 ml was added thereto and stirred, and then it was extracted twice with toluene. The organic layer was washed with saturated brine and dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from toluene/hexane, filtered and dried, whereby targeted 10-(4-naphthalene-2-yl-phenyl)anthracene-9-boronic acid 8.48 g was obtained in the form of yellow crystal (yield: 67%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:23]([N:22]([CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])([CH3:25])[CH3:24]
Reactant: CNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Yield: 194 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (10 mg, 35 μmol), N,2-dimethylpropan-2-amine (CAN 94896-77-2, 3.68 mg, 42.2 μmol), 1-hydroxybenzotriazole hydrate (11 mg, 70 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12 mg, 70 μmol) and DIEA (18.2 mg, 24 μl, 141 μmol) in DMF (157 μL) was stirred for 2 d at ambient temperature. The reaction mixture was poured onto ice-water/1N HCl (20 mL), extracted with EtOAc (2×30 mL) and washed with ice-water/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give 24 mg of a yellow oil which was purified by TLC (silica gel, Heptane/EtOAc 1:1, elution with DCM/EtOAc 1:1) to give the title compound (11 mg, 89%) as light yellow oil; MS (EI): m/e=354.5 [MH+].
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](SC1C=C(C=C(S(=O)(=O)N)C=1OC1C=CC=CC=1)C(O)=O)CCC>>[O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH3:28])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][C:23]1[CH:27]=[CH:26][S:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccsc2)c1Oc1ccccc1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Product: COC(=O)c1cc(SCc2ccsc2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 47 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoic acid for 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid and following the procedure described, methyl 4-phenoxy-5-sulfamyl-3-(3-thienylmethylthio)benzoate is obtained with a melting point of 148°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH:13]([NH:16][CH2:17][C:18]2[CH:34]=[CH:33][C:21]([O:22][C:23]([CH3:32])([CH3:31])[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH3:15])=[O:12])=[C:5]([CH3:35])[CH:4]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH:13]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]([CH3:32])([CH3:31])[C:24]([OH:26])=[O:25])=[CH:33][CH:34]=2)[CH2:14][CH3:15])=[O:12])=[C:5]([CH3:35])[CH:4]=1
Reactant: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)Nc1cc(C)c(OC)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1cc(C)c(OC)cc1C
Yield: 98.5 %

Procedure:
Similarly to the procedure of Example 1-9, 115 mg (0.237 mmol) of tert-butyl 2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}-phenoxy)-2-methylpropionate (Example 1-8) are reacted with 0.46 ml (5.93 mmol) of trifluoroacetic acid in 3 ml of dichloromethane to give 100 mg (93%) of 2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionic acid.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].CCCCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1.[C:22]1(=[O:28])[CH2:27]CCC[CH2:23]1>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[C:18]([C:14]1[CH:13]=[C:12]([C:22]2([OH:28])[CH2:27][CH2:3][C:1](=[CH2:4])[CH2:2][CH2:23]2)[CH:17]=[CH:16][CH:15]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)c1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C1CCC(O)(c2cccc(C(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 1.7 M tert-butyllithium in pentane (32.0 mL, 54.4 mmol) was added to a solution of 1-bromo-3-tert-butyl-benzene (5.54 g, 26.0 mmol) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, cyclohexanone (2.00 g, 18.2 mmol) in tetrahydrofuran (15 mL) was added. After stirring for 18 h, during which time the solution warmed to ambient temperature, the solution was diluted with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was flash chromatographed with 49:1, 24:1, 23:2 hexanes:ethyl acetate as the eluant to yield 3.61 g (81% yield) of 1-(3-tert-butyl-phenyl)-4-methylene-cyclohexanol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:17])=[O:11])[CH:3]=1
Reactant: Nc1cc(C(=O)O)nc(Cl)c1F
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 50 °C
Yield: 86 %

Procedure:
To a solution of 4-amino-6-chloro-5-fluoropicolinic acid (23.8 g, 125 mmol) in MeOH (400 ml), cooled in an ice water bath, thionyl chloride (11.78 ml, 162 mmol) was added. The reaction mixture was heated to an internal temperature of 50° C., for 8 hours. The reaction mixture was then diluted with H2O, and extracted with EtOAC (3×100 mL). The combined organics were washed with Sat. NaCl, dried over Mg Sulfate, filtered and concentrated under vacuum to give methyl 4-amino-6-chloro-5-fluoropicolinate (21.9 g, 107 mmol, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:17])[C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:52]1[CH2:62][CH2:61][N:60]2[C:55](=NC[CH2:58][CH2:59]2)[CH2:54][CH2:53]1.OC1C=C2C(=CC=1)NC=C2>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:62]3[CH:52]=[C:53]4[C:59](=[CH:58][CH:61]=3)[NH:60][CH:55]=[CH:54]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1c2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1ccc2[nH]ccc2c1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Product: CC1c2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-methyl-4-oxo-3,4,5,7-tetrahydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (1 g, 3.98 mmol) in acetonitrile (40 ml), PyBOP (2.69 g, 5.17 mmol) is added, followed by DBU (1.200 ml, 7.96 mmol). After 20 min, 5-hydroxyindole (1.060 g, 7.96 mmol) is added. The reaction is left stirring at rt overnight. The reaction mixture is then evaporated, the crude product is added to a silica gel column and is eluted with heptane/ethyl acetate (100:0 to 60:40) to give the title compound. MS (ESI) m/z 367.05 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].N1C=C[CH:13]=[CH:12][CH:11]=1.C([OH:19])CC>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:8][CH2:11][CH2:12][CH3:13])=[O:19]
Reactant: O=C(Cl)c1cnccn1
Reactant: c1ccncc1
Reactant: CCCO
Solvent: ClCCl
Product: CCCOC(=O)c1cnccn1

Procedure:
To 4.0 g (28 mmol) of pyrazinoyl chloride dissolved in methylene chloride (20 mL) and pyridine (2 mL) cooled to 0° C. in a 50 mL round bottom flask was added n-propyl alcohol (4.0 g, 66 mmol). Completion of the reaction and separation as described above, followed by distillation, led to isolation of the title compound as a water white oil; b.p: 68°-73° C. at 0.20 mm Hg.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][C:20]([C:23]1[CH:24]=[C:25]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([NH2:37])[N:31]=2)[C:26](F)=[N:27][CH:28]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[F:38][C:39]1[CH:40]=[C:41]([NH2:47])[CH:42]=[N:43][C:44]=1[O:45][CH3:46]>C1COCC1>[Si:11]([O:18][CH2:19][C:20]([C:23]1[CH:24]=[C:25]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([NH2:37])[N:31]=2)[C:26]([NH:47][C:41]2[CH:42]=[N:43][C:44]([O:45][CH3:46])=[C:39]([F:38])[CH:40]=2)=[N:27][CH:28]=1)([CH3:21])[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(N)nc(-c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.447 mL, 0.447 mmol) was added to an orange-brown solution of 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (73.0 mg, 0.186 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 31.8 mg, 0.224 mmol) in THF (2.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1 h. Excess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL), and the resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) furnished 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (88.8 mg, 0.173 mmol, 93% yield) as a yellow-orange solid. m/z (ESI, +ve) 514.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:13](I)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 632.5 %

Procedure:
0.25 g of methyl 2-chloro-4-hydroxybenzoate was dissolved in 10 ml dimethylformamide, and 0.23 g of ethyl iodide and 0.21 g of potassium carbonate were added, and the mixture was stirred for 8 hours. After diluting the reaction mixture, it was extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in 6 ml methanol, and 3 ml of 1 N sodium hydroxide was added, and the solution was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 1.7 g of 2-chloro-4-ethoxybenzoic acid.
Reaction SMILES: C([C:5]([CH3:10])([CH3:9])[C:6]([NH2:8])=[O:7])CCC.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].C(S([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)=O)C.O>C(OCC)C>[CH2:11]([N:8]([C:20]1[O:21][CH:22]=[CH:23][N:24]=1)[C:6](=[O:7])[CH:5]([CH3:9])[CH3:10])[CH2:12][CH2:13][CH3:14]
Reactant: CCS(=O)c1ncco1
Reactant: [Li]CCCC
Reactant: CCCCC(C)(C)C(N)=O
Solvent: CCOCC
Solvent: O
Product: CCCCN(C(=O)C(C)C)c1ncco1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyl-isobutyramide(4.93 g, 0.0344 m) in dry diethyl ether (25 ml) was stirred at room temperature under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium (23.8 ml, 0.0344 m). The mixture was stirred for 15 minutes at room temperature and then 2-ethylsulphinyloxazole (5.0 g, 0.0344 m) in dry diethyl ether (25 ml) was added rapidly. The mixture was stirred at room temperature for 3 hours and then hydrolysed with water. The organic phase was washed several times with water, dried over magnesium sulphate and evaporated in vacuo to give a yellow oil. Distillation gave the title product as a colourless oil, b.p. (airbath) 120° C./0.5 mm.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 389.15 g/mol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13](N2[C@H](C3C=CC=CC=3)[C@H](C)N(C)C2=O)=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:29][C:30]1[CH:31]=[C:32]([Mg]Br)[CH:33]=[C:34]([F:36])[CH:35]=1.C1([C@@H](C2C=CC(S(C)(=O)=O)=CC=2)CC=O)C=CC=CC=1>>[F:29][C:30]1[CH:31]=[C:32]([C@@H:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[CH2:12][CH:13]=[O:14])[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C=Cc2ccc(S(C)(=O)=O)cc2)C(=O)N1C
Agent: CS(=O)(=O)c1ccc([C@@H](CC=O)c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc([C@@H](CC=O)c2cc(F)cc(F)c2)cc1

Procedure:
This was prepared from (4S,5R)-1-(3-[4-methanesulfonylphenyl]acryloyl)-3,4-dimethyl-5-phenyl-imidazolidin-2-one and 3,5-difluorophenylmagnesium bromide using a method similar to that used to prepare (S)-3-phenyl-3-(4-methanesulfonyl-phenyl)propionaldehyde from phenylmagnesium bromide (Method N).
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[C:16](OC)=[CH:15][C:14]([F:19])=[C:13]([F:20])[C:12]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.C[N+]1([O-])CC[O:34][CH2:33]C1.CC[O:40]C(C)=O>C1COCC1.O.[Os](=O)(=O)(=O)=O>[F:20][C:13]1[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:11]([NH:10][S:7]([C:4]2([CH2:1][CH:2]([OH:40])[CH2:33][OH:34])[CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:16]=[CH:15][C:14]=1[F:19]
Reactant: CCOC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1(S(=O)(=O)Nc2c(OC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1(CC(O)CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
1-Allyl-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)cyclopropane-1-sulfonamide (97 mg, 0.18 mmol) and 4-methylmorpholine N-oxide (21 mg, 0.18 mmol) were dissolved in THF (8 mL). Osmium tetroxide was added at room temperature (0.018 mmol, 0.13 mL, 4% in H2O) and the reaction mixture was stirred at room temperature for 16 hours. EtOAc was added, the organic phase was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel chromatography (eluants: EtOAc/MeOH) to obtain the titled product (0.80 g, 78%). 1H NMR (CDCl3, 300 MHz): δ 7.38 (dd, J=1.7 & 10.3 Hz, 1H), 7.26 (m, 1H), 7.14 (s, 1H), 6.87 (s, 1H), 6.53 (dd, J=6.8 & 11.4 Hz, 1H), 6.43 (m, 1H), 4.06 (m, 1H), 3.89 (s, 3H), 3.63 (dd, J=3.7 & 11.1 Hz, 1H), 3.49 (dd, J=6.4 & 11.1 Hz, 1H), 2.3 (dd, J=9.7 & 16.1 Hz, 1H), 1.77 (dd, J=1.9 & 16.0 Hz, 1H), 1.37 (m, 1H), 1.25 (m, 1H), 1.21 (m, 2H), 0.86 (m, 2H); m/z=571 [M−1]−.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][N:3]12.[Cl:16]N1C(=O)CCC1=O>O1CCCC1>[Cl:16][C:15]1[N:3]2[N:2]([CH3:1])[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c2ccccc2c(=O)c2cccn21
Solvent: C1CCOC1
Product: Cn1c2ccccc2c(=O)c2ccc(Cl)n21
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (5.0 g) in 180 mL of tetrahydrofuran at 0° C. was treated with N-chlorosuccinimide (3.4 g) all at once and the mixture was stirred at ambient temperature. After 36 h the solution was concentrated and the residue taken up in chloroform. This solution was washed with two 100 ml portions of water, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, dichloromethane) to give 2.83 g of an off-white powder, mp 88.5°-90.5° C.
Reaction SMILES: [CH3:1][N:2]([Si](C)(C)C)[CH3:3].[CH3:8][O:9][S:10]([O-:13])(=[O:12])=[O:11].[CH3:14][N:15]([C+:17]([N:19]([CH3:21])[CH3:20])Cl)[CH3:16]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:3])[C:17](=[N+:15]([CH3:16])[CH3:14])[N:19]([CH3:21])[CH3:20].[CH3:8][O:9][S:10]([O-:13])(=[O:12])=[O:11]
Reactant: CN(C)[Si](C)(C)C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: COS(=O)(=O)[O-]
Solvent: ClC(Cl)Cl
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
10 ml of dry chloroform and 1.29 g (11.00 mmol) of N,N-dimethyltrimethylsilylamine are added to 2.45 g (9.93 mmol) of bis(dimethylamino)chlorocarbenium methylsulfate. The reaction mixture is stirred for 1 hour at room temperature, and all volatile compounds are subsequently removed under reduced pressure. The residue is dried for a further 1 hour under reduced pressure at 7.0 Pa and an oil-bath temperature of 50° C., giving 2.42 g of hexamethylguanidinium methylsulfate, corresponding to a yield of 95.5%.