Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](O[C:13](=O)[CH3:14])(=O)[CH3:10].[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44](Cl)=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si](C(C)(C)C)(C)C)[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:9][CH3:10].[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44]([N:4]([CH2:13][CH3:14])[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]
Reactant: Nc1ccccc1F
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC)c3ccccc3F)c2)C[C@H]1C
Product: CCNc1ccccc1F

Procedure:
2-Fluoro-N-ethylaniline [NMR (DMSO-d6, 200 MHz): δ 1.16 (t, J=7.1 Hz, 3H); 3.11 (dq, J1 =7.2 Hz, J2 =6.5 Hz, 2H); 5.30 (br m, 1H); 6.48-6.59 (m, 1H); 6.70 (t, J=8.5 Hz, 1H); 6.92-7.06 (m, 2H)] was prepared from 2-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(2-fluorophenyl)benzamide as a light yellow wax. NMR (DMSO-d6, 200 MHz): δ 0.9 (d, J=6 Hz, 3H); 0.95 (d, J=6 Hz, 3H); 1.1 (t, J=7 Hz, 1H); 2.1 (m, 1H); 2.3 (m, 1H); 2.5 (m, 2H); 2.7 (m, 1H); 2.85 (m, 1H); 3.8 (br m, 2H); 4.8 (br s, 1H); 5.1 (d, J=10 Hz, 1H); 5.2 (d, J=17 Hz, 1H); 5.8 (m, 1H); 6.45 (m, 1H); 6.5 (s, 1H); 6.65 (m, 1H); 7.0-7.4 (m, 9H); 9.35 (s, 1H). [α]D20 =+3.4° (abs ethanol, c=2.04). Calc. for C31H36FN3O2HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.61; H, 7.14; N, 7.53; Cl, 6.40. Mass spectrum (CI--CH4) m/e: 502 (M+1, 89%), 501 (M, 17%), 348 (36%), 153 (100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:12])=[CH:4][N:3]=1.[CH3:13][NH2:14]>O1CCCC1.CO>[I:12][C:5]1[C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[N:7][C:2]([NH:14][CH3:13])=[N:3][CH:4]=1
Reactant: CCCNc1nc(Cl)ncc1I
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CCCNc1nc(NC)ncc1I
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-iodo-N-propylpyrimidin-4-amine (F1, 46.3 mg) in tetrahydrofuran (0.5 mL), a 9.8 mol/L solution of methylamine in methanol (0.5 mL) was added at room temperature, the reaction vessel was sealed, and then by using a microwave reaction system, the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 27% hexane in ethyl acetate) to obtain 5-iodo-N2-methyl-N4-propylpyrimidine-2,4-diamine (F222, 32.4 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 95%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:19]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A solution of 4-hydroxy-3-nitrobenzaldehyde (6.9 g) and ethyl bromoacetate (5.0 mL) in dimethylformamide (250 mL) was treated with anhydrous potassium carbonate (10 g) and the mixture was heated at 60° C. for 18 hours and evaporated to dryness. The residue was partitioned between water and diethyl ether, and the diethyl ether layer was washed with 0.5M sodium hydroxide. It was then dried over anhydrous sodium sulfate and evaporated to give an oil that was chromatographed on silica gel (ethyl acetate/dichloromethane) to afford an oil (1.9 g). MS (+ve ion electrospray) m/e 253 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:18]=3)=[CH:11][N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:18]=3)=[CH:11][N:10]=2)=[CH:7][N:6]=[C:5]([N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[N:4]=1
Reactant: C1CCNC1
Reactant: COc1nc(SC)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(N2CCCC2)ncc1-c1cc(C)c(Oc2ccnc(-c3cnn(C)c3)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
A solution of 4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyri-dine-2-yl)-2-(methylthio)pyrimidine (0.28 g, 0.67 mmol) in DCM (10 mL) was treated with mCPBA (0.20 g, 0.80 mmol), stirred at RT for 3 h, treated with pyrrolidine (0.50 mL, 6.1 mmol) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over MgSO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(pyrrolidin-1-yl)pyrimidine (0.19 g, 64%). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.37 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.5 Hz, 1H), 4.00 (s, 3H), 3.84 (s, 3H), 3.55 (s, 5H), 2.18 (s, 3H), 1.93-1.92 (m, 4H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([CH3:19])=[CH2:18])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1>CCOC(C)=O.C(O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][C:14]([OH:20])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Reaction time: 3 h
Yield: 89.7 %

Procedure:
2-(4-Hydroxyphenyl)-7-isopropenyl-1,3-benzoxazol-5-ol (64 mg, 0.24 mmol) was dissolved in a mixture of EtOAc (5 mL) and absolute ethanol (5 mL) and placed under an inert atmosphere with argon. To this mixture was added 10% Pd—C (25 mg). The solution was hydrogenated on a Parr apparatus at 25 psi for 3 h. The solution was filtered through celite and rinsed with ethanol. The filtrate was concentrated and the residue purified by flash chromatography (50% EtOAc/petroleum ether) to give (58 mg, 90% yield) of the product as a tan solid, m.p. 200° C.; MS m/e 270 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC#N>[Br-:30].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCOc1ccccc1
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-3-thienyl)methanol (0.0787 g, 0.258 mmol) and 2-bromoethyl phenyl ether (0.0839 g, 0.417 mmol) in 2MeOH/3CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0709 g, 54.5%). EI-MS m/z 426(M+) Rt (1.85 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccc(F)cc4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(-c3ccc(F)cc3)c(Cl)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
5-Chloro-4-(6-chloro-4′-fluoro-4-(pyridazin-4-yl)biphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 101, 100 mg, 0.13 mmol) was dissolved in a 4M solution of HCl in dioxane (10 mL). The reaction mixture was stirred for 18 hours at room temperature. Methanol (50 mL) was added to the reaction mixture and the suspension was concentrated in vacuo. The crude residue was purified by reverse phase semi preparative HPLC (solvent A: 0.05% formic acid in acetonitrile, solvent B: 0.05% formic acid in water; flow rate: 12.5 ml/min; gradient: 0 min 10% A, 2.5 min 10% A, 32.5 min 95% A, 37.5 min 95% A then return to initial conditions) to afford the title compound (46 mg, 60%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccccc1-c1ccccc1
Yield: 165.7 %

Procedure:
40.0 g (235 mmol) of 2-phenylphenol from Tokyo Chemical Industry Co., Ltd. and 51.06 g (282 mmol) of 6-bromo-1-hexanol from Tokyo Chemical Industry Co., Ltd. were dissolved in 600 mL of methyl ethyl ketone from Kanto Chemical Co., Inc. to prepare a solution. 97.4 g of sodium carbonate were added to the solution, and refluxed for 8 hrs. After the solution was cooled to have room temperature, it was filtered and condensed. The resultant light brown liquid was dissolved in methylene chloride and washed with water. The isolated organic layer was dried with magnesium sulfide and a solvent was removed therefrom. The residue was refined by silica gel column chromatography using methylene chloride as an eluent to obtain 105.3 g of 6-(2-phenyl-phenoxy)hexane-1-ol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(O)=[O:2].[BH4-].[Na+].Cl>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([CH2:1][OH:2])[CH:9]=[CH:8][N:7]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Yield: 86.7 %

Procedure:
4-Carboxy-2-chloropyridine (78.7 g) is added slowly to a suspension of sodium borohydride (28.4 g) in tetrahydrofuran (750 ml) under nitrogen atmosphere, and thereto is added dropwise boron trifluoride-ether complex (123 ml). The mixture is reacted at room temperature for six hours. To the mixture is added a 6 M hydrochloric acid (960 ml), and the mixture is concentrated under reduced pressure to remove the solvent. The resultant is basified with sodium hydroxide, and extracted with chloroform, The chloroform layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried and concentrated under reduced pressure to remove the solvent to give 2-chloro-4-hydroxymethylpyridine (62.2 g).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[C:3]#N.C[CH2:14][O:15]C(C)=O.[OH2:19]>Cl.CO>[CH3:14][O:15][C:3](=[O:19])[C:2]([NH2:1])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH3:5]
Reactant: CC(N)(C#N)c1cccc(Br)c1
Reactant: CCOC(C)=O
Reactant: O
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(N)c1cccc(Br)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
rac-2-Amino-2-(3-bromo-phenyl)-propionitrile (20 g, 88.9 mmol) was dissolved in HCl/MeOH (500 mL) and the mixture was refluxed for 4 days. After cooling to room temperature, AcOEt (100 mL) and water (100 mL) were added and the mixture was extracted with AcOEt (2×100 mL). The combined aqueous layers were basified with aqueous ammonia solution until pH 8 and extracted with AcOEt (5×100 mL). The combined organic layers were dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield rac-2-amino-2-(3-bromo-phenyl)-propionic acid methyl ester (10.6 g, 46% yield) as an oil.
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[CH2:1]([C:5]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][O:7][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:8][O:9][CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CO)(CCCC)COC
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CCCCC(CCCC)(COC)CO[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure as described in Example 8,2,2-di-n-butyl-1-methoxy-3-[(tert-butyldimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-n-butyl-3-methoxy-1-propanol and reagent tert-butyidimethylsilyl chloride.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:26][C:27]1[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 105 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A suspension of tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoropyridin-3-yl)boronic acid (221 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was stirred at 105° C. for 1 hr. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture 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=6:1→1:1) to give the title compound as a pale-yellow oil (yield 310 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH2:11]>>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:11])[C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 2 h
Yield: 28.5 %

Procedure:
13.6 g (0.1 mole) of 2,3,6-trimethylphenol was pulverized and dispersed in 40 g of water. Then, oxidation reaction was conducted in the same manner as in Example 4. The reaction proceeded so late that 2 hours were required at a room temperature. After conducting stream distillation, the same treatment as in Example 1 (B) was effected to obtain 4.28 g (28.6 percent in yield) of 2,3,6-trimethyl-p-benzoquinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])C)[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.[O-]Cl.[Na+].[OH-].[Na+].S(S([O-])=O)([O-])(=O)=[O:20].[Na+].[Na+]>C(COC)OC.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:20])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(=O)c1cc(Br)c2c(c1)CCC2
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: O=C(O)c1cc(Br)c2c(c1)CCC2
Temperature: 50 °C
Yield: 98.2 %

Procedure:
1-(7-bromo-2,3-dihydro-1H-inden-5-yl)ethanone (8.6 g, 36 mmol) was dissolved in dimethoxyethane (100 mL) and to the solution were added NaClO aq (200 mL 1M, 200 mmol) and NaOH aq (20 mL 10 M, 200 mmol). The mixture was heated to 50° C. for 1 h and then diluted with water (200 mL). Sodium pyrosulfite (5.7 g, 30 mmol) was added. The mixture was washed with ether, acidified with concentrated HCl and then extracted twice with ether (150 mL). The organic solution was washed with brine, dried and then the solvent was evaporated. The solid residue was treated with cold CH2Cl2 (−40° C.), then filtered off and dried. There was obtained 7.1 g (82%) of 7-bromoindane-5-carboxylic acid as a solid material. 1H NMR (300 MHz, CD3OD): 2.0-2.2 (q, 2H), 2.9 (t, 2H), 3.1 (t, 2H), 7.8 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH3:13])[C@:10]([CH:16]3[CH2:18][CH2:17]3)([C:14]#[N:15])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.ClC1N=C(N2CC(C)C(C3CC3)(C#N)C2=O)C=CN=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH:16]3[CH2:17][CH2:18]3)([C:14]#[N:15])[C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@]1(C#N)C1CC1
Agent: CC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CC(C)O
Solvent: CCCCCC
Product: C[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 100 %

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (2.6 g) obtained in Step C of Example 357 was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (820 mg) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (1.3 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (810 mg) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=900/100) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=900/100) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-methyl-2-oxopyrrolidine-3-carbonitrile (400 mg) having a longer retention time.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11](OC)=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:14]=O)=[CH:6][NH:7]2.[C:16]([O-:19])(=O)C.[NH4+].[N+:21]([CH3:24])([O-:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:14]=[CH:24][N+:21]([O-:23])=[O:22])=[C:6]([O:19][CH3:16])[NH:7]2
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc2[nH]cc(C=O)c2c1OC
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: COc1[nH]c2cccc(OC)c2c1C=C[N+](=O)[O-]
Yield: 99 %

Procedure:
A solution of 4,5-dimethoxyindole-3-carbaldehyde (0.21 g, 1.02 mmol) and ammonium acetate (0.1268 g, 1.60 mmol) in nitromethane (10 cm3) was stirred at 70-75° C. under nitrogen for 11 hours using the method of Macor et al. The mixture was concentrated under vacuum and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgS04, and evaporated under vacuum to afford dimethoxy-3-(2-nitroethenyl)indole (0.25 g, 99%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][N:54]1[NH:58][CH:57]=[CH:56][S:55]1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][N:54]2[NH:58][CH:57]=[CH:56][S:55]2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NN1NC=CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous was extracted with ethylacetate (2×250 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95 g). LCMS: retention time 3.34 min, MH+ 346. NMR: δH [2H6]-DMSO 13.08,(1H, b), 9.22,(1H, s), 8.35,(1H, d), 8.11,(1H, dd), 7.38,(1H, d), 2.55,(3H, s), 1.34, (12H, s).