Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([Sn](C)(C)C)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([S:12](=[O:14])(=[O:13])[NH:15][CH3:16])[CH:3]=2)[N:31]=[C:30]([C:38]#[N:39])[N:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Sn](C)(C)c1cc(CCCOCc2ccccc2)nc(C#N)n1
Reactant: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cc(-c2cc(CCCOCc3ccccc3)nc(C#N)n2)cc(C(F)(F)F)c1
Yield: 35 %

Procedure:
3-Bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (37 mg), 4-(3-benzyloxy-propyl)-6-trimethylstannanyl-pyrimidine-2-carbonitrile (40 mg) and dichlorobis(triphenylphosphine)palladium(II) (7 mg) in DMF (1 mL) were heated in a microwave to 180° C. for five minutes. The mixture was diluted with ethyl acetate (20 mL) and washed with water (3×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield crude product. Purification by preparative-HPLC afforded 4-(3-benzyloxy-propyl)-6-(3-methylsulphamoyl-5-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (16.5 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)=[O:18]
Reactant: CCc1cc(-c2ccc(C(=O)O)s2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Product: CCc1cc(-c2ccc(C(=O)NCc3ccccn3)s2)c(C)[nH]c1=O
Yield: 97 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophene-2-carboxylic acid and pyridin-2-ylmethylamine to afford the title compound (97% yield). LC/MS: RT 2.07 min; m/e 354 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[OH:12].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: O=C([O-])O
Reactant: Cc1nccc2c1OCO2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c2c(cc[n+]1[O-])OCO2

Procedure:
To the methylene chloride solution of 2-methyl-3,4-methylenedioxypyridine from example I 21 sodium hydrogen carbonate (1M, 50 ml) and MCPBA (4 g, 70%) were added. The mixture was stirred at ambient temperature for 15 min whereupon the excess of MCPBA was destroyed with addition of sodium thiosulphate (1 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride (3×50 ml). The collected organic phases were concentrated under reduced pressure and chromatographed on silica (CH2Cl2 /MeOH, 90:10). Yield: 120 mg (7,8%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(C)Oc1ccc(F)cc1Br
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 15 gm (78.5 mMol) 2-bromo-4-fluorophenol, 11.2 mL (86.4 mMol) ethyl 2-bromopropionate, and 13 gm (94.2 mMol) potassium carbonate was heated at reflux for 3 hours. At this point 0.1 gm potassium iodide were added and reflux continued for another 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was extracted well with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 5% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 19.8 gm (87%) of the desired compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:37]1([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C=O)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][CH2:9][C:10]([N:45]2[CH2:46][CH2:47][N:42]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:43][CH2:44]2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: C1CCC(N2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCC(=O)N1CCN(C2CCCC2)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 107.6 %

Procedure:
To a mixture of 3-(4-chlorobenzoyl)propionic acid (31.9 g, 150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) was added a solution of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 1.5 hour, and a solution of 1-cyclopentylpiperazine (23.2 g, 150 mmol) in DCM (100 ml) was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was distributed between ethyl acetate (1.0 I) and a saturated, aqueous NaHCO3 solution (1.0 I). Phases were separated, the organic layer was dried (MgSO4), and concentrated, and the residue was redissolved in 1 molar aqueous hydrochloric acid (150 ml). The solution was concentrated, and the residue was dried by coevaporation with ethanol. Recrystallization of the residue from ethanol yielded 31.1 g (54%) of the title compound. Concentration of the mother liquor gave additional 19.4 g (34%) of product.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[SH3+].[I-].[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:26](=[O:43])[NH:27][C@H:28]1[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][C@H:29]1[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:21][CH2:22][S+](C)C)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[CH2:9]([O:16][C:17]([NH:19][C@H:20]1[CH2:21][CH2:22][N:27]([C@H:28]2[CH2:37][CH2:36][C:31]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:30][C@H:29]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:26]1=[O:43])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1NC(=O)[C@H](CC[S+](C)C)NC(=O)OCc1ccccc1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N1CC[C@H](NC(=O)OCc3ccccc3)C1=O)OCCO2
Reaction time: 20 h

Procedure:
Example 1, Alternative Step 9c: Cs2CO3 (61.5 g, 0.19M, 1.5 eq) was placed in an round bottom flask and anhydrous DMSO (2.4 L) was added. Sulfonium salt 3 (80.0 g, 0.13M, 1.0 eq) was then added portionwise. Once the addition was complete the reaction mass was left to stir in the dark for 20 h. The reaction mass was then split in half and each half worked up separately: the reaction mass was diluted with EtOAc (2.0 L) and washed with brine (2 L), the organic phase was washed with brine (500 mL). The combined aq. layers were then washed EtOAc (500 mL). The combined organic phases were then washed with brine (3×750 mL). The second half of the reaction mass was treated in an identical manner and the combined organics dried over MgSO4 and concentrated to give ethyl (7R,8S)-8-{(3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl}-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4 as a light colored oil (56.5 g, 0.13M, ˜100 area-% purity) pure by NMR analysis. 1H-NMR: (300 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.37 (br d, J 4.0 Hz, 1H), 5.11 (s, 2H), 4.27-4.18 (m, 1H), 4.17-3.82 (m, 8H), 3.32 (td, J 10.0Hz, 60.0 Hz, 1H), 3.23 (q, J 5.0 Hz, 1H), 2.63-2.57 (m, 1H), 2.42-2.25 (m, 2H), 1.94-1.68 (m, 5H), 1.25 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 8.99 min (Compound 5, produced on column, 4.2 AP), 9.48 (Compound 4, 74.3 AP). HRMS: m/z 447.2127 [Calc: C23H31N2O7 447.2131].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([C:15]1[CH:16]=[C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:12]([OH:17])=[CH:13][CH:14]=1)=[O:22]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)c(-c2ccccc2)c1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
At ambient temperature, to a stirred suspension of aluminum chloride (2.0 g, 15.0 mmol) in CH2Cl2 (20 mL) was added 2-phenylphenol (1.28 g, 7.53 mmol). After 30 min, the reaction was cooled to 0° C. To the reaction was added dropwise a solution of 2-chlorobenzoyl chloride (0.94 mL, 7.42 mmol) in CH2Cl2 (20 mL). The reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched into crushed ice (100 g) diluted with sat. aq. KH2PO4 (100 mL) and extracted with CH2Cl2. The organic extracts were dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with a 3 & 10% EtOAc/pet. ether step gradient to give 0.5g (21%) of the title compound as an off white solid, mp 194-198° C. 1H NMR (DMSO-d6) δ 7.07 (dd, 1H), 7.33 (tt, 1H), 7.40 (tt, 2H), 7.46-7.49 (m, 4H), 7.51-7.59 (m, 4H), 10.8 (s, 1H). mass spectrum (EI) m/z 308 (M+).
Reaction SMILES: [Br-].[Cl-].C([Al+]CC)C.[F:8][C:9]([F:33])([F:32])[C:10]1[CH:11]=[C:12]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH:26]=[O:27])[CH:13]=[CH:14][CH:15]=1.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCCC1.CCCCCC.[Zn]>[OH:27][CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][S:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:32])([F:8])[F:33])[CH:11]=1)[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Agent: CC[Al+]CC
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (0.25 g, 3 mmoles) and cooper (I) bromide (0.02 g, 0.129 mmoles) in distilled tetrahydrofuran (20 ml) was added a solution of diethylaluminum chloride (2.8 ml, 2.8 mmoles) in hexane while stirring under argon at 25° C. The resulting mixture was cooled to -20° C., and a solution of 2-[7-(3-trifluoromethylphenylthio)heptyl]benzaldehyde (1.08 g, 2.8 mmoles) and t-butyl bromoacetate (0.42 ml, 2.8 mmoles) in tetrahydrofuran (6 ml) was added slowly at -20° C. The reaction mixture was permitted to warm to room temperature. After 2 hours the zinc was filtered off and washed with ether. The solvents were evaporated and the residue flash chroma-tographed on silica gel, eluted with 10% ethyl acetate in hexane, to provide the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][CH:14]([NH2:16])[CH3:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11]C)C.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:16]([CH:14]([CH2:13][C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:1])[CH:5]=2)[CH3:15])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCOc1ccc(CC(C)N)cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(C)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(3,4-diethoxyphenyl)-2-aminopropane (1.95 grams, 10.0 mmol) and sodium carbonate (1.06 grams, 10.0 mmol) in 50 milliliters of water was added N-carbethoxyphthalimide (2.19 grams/10.0 mmol). After 10 minutes the reaction mixture was diluted with 40 milliliters of acetonitrile and the mixture stirred for 40 minutes. The reaction solution was partially concentrated in vacuo to remove the acetonitrile. The resulting mixture of an oil and aqueous layer was extracted with methylene chloride (25 milliliters). The organic extract was dried over sodium sulfate and concentrated in vacuo to afford a crude product which was purified by flash chromatography to afford 1.73 grams (53%) of product as a thick oil which slowly solidified to a white wax: 1H NMR (dmso-d6, 250 MHz) δ 7.7 (m, 4 H, Ar), 6.7 (m, 3 H, Ar), 4.63 (m, 1 H, CH), 3.79 (s, 3 H, Ome), 3.73 (s, 3 H, OMe), 3.28 (dd, 1 H, J=13.8, 9.8 Hz) 3.03 (dd, J=13.8, 6.5 Hz, 1 H), 1.54 (d, J=6.9 Hz, 3 H); 13C NMR (dmso-d6) δ 168.4, 148.6, 147.4, 133.7, 131.8, 130.9, 122.9, 120.9, 111.1, 55.7, 55.6, 48.6, 39.3, 18.3 Anal. Calcd for C19H19NO2. Theoretical C, 70.14; H, 5.89; N, 4.30. Found C, 70.08; H, 5.83; N, 4.30.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]([CH3:18])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.C(O)(C(F)(F)F)=O>>[CH3:18][N:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(CCN(C)C(=O)OCc1ccccc1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CN(CCC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of phenylmethyl [3,3-bis(ethyloxy)propyl]methylcarbamate (2.982 g, 10.1 mmol) and TFA (15 mL) was stirred at ambient temperature for 30 min. The reaction was evaporated in vacuo and the residue was purified on silica gel eluting with 30% EtOAc in hexanes to provide the product as an oil: 1H NMR (d6-DMSO) δ 9.63 (1H, s), 7.26-7.36 (5H, m), 5.02 (2H, b), 3.48 (2H, b), 2.75-2.85 (3H, m), 2.64 (2H, b); ES+ MS: 244 (M+Na+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:16]([O:23][C:24]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]([Br:40])=[CH:28][C:25]=1[CH:26]=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][NH:12][C:13]([N:15]=[CH:26][C:25]3[CH:28]=[C:29]([Br:40])[C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:31][C:24]=3[O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(NNC(N)=O)ccc21
Reactant: O=Cc1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CCO
Product: Cn1ccc2cc(NNC(=O)N=Cc3cc(Br)c(OCc4ccccc4)cc3OCc3ccccc3)ccc21

Procedure:
A flask was charged with N-(1-methyl-1H-indol-5-yl)-semicarbazide (3.83 g; 18.77 mmol), 2,4-bis-benzyloxy-5-bromobenzaldehyde (7.46 g; 18.77 mmol) and ethanol (100 mL). The reaction was stirred at reflux for one hour, cooled, filtered, washed with ethanol (2×20 mL), and dried under vacuum to give N-(1-methyl-1H-indol-5-yl)-N″-(2,4-bis-benzyloxy-5-bromo-benzylidene)-semicarbazide, which was used crude in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.CO[Na]>O1CCCC1.CO>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:13](=[O:21])[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:7]2=[O:9]
Reactant: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Agent: CO[Na]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Nc2ccc(Br)cc2C(=O)C1c1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask were placed a solution of methyl 5-bromo-2-[2-(pyridin-2-yl)acetamido]benzoate (3 g, 7.73 mmol, 1.00 equivalent, 90%, Intermediate 61, step a) in tetrahydrofuran (30 mL). A 2.38 M solution of MeONa in MeOH (freshly prepared from dissolving 2.74 g of Na in 50 mL of anhydrous MeOH solution, 11.7 mL, 27.85 mmol, 4.00 equivalents) was then added. The resulting solution was stirred overnight at 20° C., and the precipitate was collected by filtration to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:17]O)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=[C:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1.O=S(Cl)[Cl:25]>C1COCC1>[C:19]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[C:9]([CH2:17][Cl:25])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:16]=2)[N:5]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CO)c3ccccc3c2)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cc(CCl)c3ccccc3c2)n1
Yield: 88.5 %

Procedure:
To [3-(5-amino-3-t-butyl-pyrazol-1-yl)naphthalen-1-yl]methanol (1.6 g, 5.4 mmol) in THF (20 mL) was added SOCl2 (3.0 g, 25 mmol). The mixture was heated at reflux for 3 h and then concentrated under pressure to yield crude 3-t-butyl-1-[4-(chloromethyl)naphthalen-2-yl]-1H-pyrazol-5-amine (1.5 g), which was used for the next reaction without further purification. MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C.O>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[N:20][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)nc3)c2cc1OC
Yield: 73 %

Procedure:
5-(6,7-Dimethoxyquinolin-4-yloxy)pyridin-2-ylamine (29.7 mg, 0.100 mmol) and phenyl isocyanate (13.1 mg, 0.110 mmol) were stirred in dimethylformamide (1 ml) at room temperature for 18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:methanol=20:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (30.4 mg, 0.073 mmol, 73%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[CH:13][N:14](C)C>CC(O)=O.O.O.[Zn]>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: Cc1ccc([N+](=O)[O-])c(C=CN(C)C)c1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2[nH]ccc2c1Br
Temperature: 0 °C
Yield: 19 %

Procedure:
[2-(2-Bromo-3-methyl-6-nitro-phenyl)vinyl]-dimethyl-amine (10 g) was dissolved in AcOH/H2O (100 mL:25 mL), cooled to 0° C. and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20%)
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH:20]([CH3:25])[C:21]2=O)=[CH:17][CH:16]=1.ClCCl.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>C1(C)C=CC=CC=1.O>[CH2:33]([O:32][C:29](=[O:31])[CH2:30][C:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH2:13][C:4]3[CH:5]=[CH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:3]=3)[CH:23]=2)[CH2:19][C:20]=1[CH3:25])[CH3:34]
Reactant: CCOC(C)=O
Reactant: CC1Cc2ccc(OCc3ccc4ccccc4n3)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CC1=C(C)Cc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 1 h

Procedure:
Triethylphosphonoacetate (22.42 g, 100 mmole) is added dropwise under nitrogen to a stirred and cooled (0° C.) slurry of NaH (57% in oil, 4.27 g, 100 mmole) in dry toluene (250 mL). The cooling bath is removed and stirring continued at room temperature for 60 minutes whereby an almost homogeneous solution is obtained. A solution of the indanone (15.15 g, 50 mmole) of Step E, in toluene (50 mL) is then added dropwise. The flask is placed in an oil bath heated at 95° C. for 19 hours (TLC, traces of starting material present, dichloromethane-ethyl acetate 9:1, UV, Vaughn's). The reddish solution is cooled, diluted with water and extracted with ethyl acetate (3 times). The combined extracts are washed with brine, dried (anhydrous K2CO3) and evaporated to dryness. The residue (heavy brown oil) is flash chromatographed (on silica Merck-60, eluted using a gradient dichloromethane→dichloromethane:ethyl acetate 84:16) to provide the title compound as a mixture of endo and exo isomers (16.3 g, 87.4%, oil that solidifies upon standing) together with unreacted, more polar starting material (1.84 g, 12% recovery).
Reaction SMILES: [CH3:1][C@:2]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][C:5](=O)[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.B.O1CCCC1.C(O)C.C(N(CC)CC)C>O1CCCC1.O>[CH3:1][C@:2]1([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:6][CH2:5][N:4]([C@@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:3]1
Reactant: C[C@H](c1ccccc1)N1C[C@@](C)(NC(=O)OC(C)(C)C)CC1=O
Agent: B
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: C[C@H](c1ccccc1)N1CC[C@](C)(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.9 %

Procedure:
tert-Butyl {(3S)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl}carbamate (I-343) (500 mg, 1.57 mmol) was dissolved in tetrahydrofuran (15 ml), and with cooling with ice, borane/tetrahydrofuran complex (1.2 mol/l tetrahydrofuran solution) (3.93 ml, 4.71 mmol) was added, followed by stirring at room temperature for 17 hours. Ethanol (12 ml), triethylamine (4 ml) and water (4 ml) were added to the reaction liquid, followed by stirring in an oil bath at 90° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1→1:2, v/v) to obtain the entitled compound (406 mg, 85%) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([O:9]C)=[O:8])[S:5][CH:6]=1.[OH-].[K+]>CO.O>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(Br)csc1C(=O)O
Yield: 95.6 %

Procedure:
A solution of 37.5 g (0.15 mole) of methyl 4-bromo-3-methoxy-2-thiophenecarboxylate and 12 g of KOH (0.18 mole) in a mixture of 250 mL of methanol and 100 mL of water was refluxed for 2 hr. The reaction mixture was cooled and most of the methanol was removed in vacuo. The solution was partitioned with ether and dilute aqueous HCl. The organic phase was separated dried over MgSO4, filtered and concentrated and dried under a vacuum to give 34 g (94%) of a colorless solid. mp 191-192° C. 1H NMR (300 MHz, CDCl3): δ 7.5 (s, 1H); 4.1 (s, 3H). Anal. Calc'd for C6H5BrO3S: C, 30.04; H, 2.23; S, 13.52. Found: C, 29.89; H, 2.06; S, 13.14.