Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:10]=[N+:11]=[N-:12].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.Cl>C1(C)C(C)=CC=CC=1.O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:12][N:11]=[N:10][N:5]=1
Reactant: N#Cc1ccccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: Brc1ccccc1-c1nnn[nH]1
Reaction time: 2 h
Yield: 76 %

Procedure:
A 64 g (350 mmol) sample of 2-bromobenzonitrile (Aldrich) was dissolved in 650 mL of xylene and treated with 22.75 g (350 mmol) of sodium azide and 95 mL (350 mmol) of tributyltin chloride at reflux for 48 h. The reaction was filtered; the filtrate was treated with 50 mL of anhydrous tetrahydrofuran (THF) and 20 g (550 mmol) of hydrogen chloride. The reaction was stirred for 2 h; filtration gave 59.6 g (76%) of 5-(2-bromophenyl)-1H-tetrazole: mp 178°-180° C.; NMR (DMSO-d6) δ7.50-7.64 (m, 2H), 7.67-7.74 (m, 1H), 7.83-7.91 (m, 1H). A 41.8 g (187 mmol) sample of this material was dissolved in 650 mL of methylene chloride and treated with 55.5 g (193 mmol) of triphenylmethyl chloride and 30 mL (220 mmol) of anhydrous triethylamine. The reaction was stirred overnight at reflux, cooled to ambient temperature, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization from toluene/hexane gave 80.7 g (92%) of N-triphenylmethyl-5-(2-bromophenyl)-1H-tetrazole: mp 160°-162° C.; NMR (CDCl3) δ7.14-7.21 (m, 6H), 7.26-7.45 (m, 11H), 7.70 (dd, J=8 and 1.5 Hz, 1H), 7.89 (dd, J=7.5 and 2 Hz, 1H). A 34.05 g (73.0 mmol) sample of this material was dissolved in 1700 mL of THF under a nitrogen atmosphere and treated with 73 mmol of n-butyllithium in hexane. The reaction was allowed to stir for 17 min and then was treated with 24.9 mL (220 mmol) of trimethyl borate. The reaction was allowed to come to ambient temperature overnight while stirring, quenched with 10 mL of methanol, and concentrated in vacuo. The residue was dissolved in 1M NaOH and extracted with toluene to remove any unreacted starting material. The pH was adjusted to 6 with 6M HCl and the product extracted with toluene and dried (MgSO4). Hexane was added and the solution was placed in the freezer overnight. Filtration provided 31.3 g (99%) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid: NMR (CDCl3) δ7.13-7.21 (m, 7H), 7.33-7.42 (m, 8H), 7.49-7.55 (m, 2H), 8.15-8.19 (m, 1H), 8.21-8.26 (m, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccn1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccccn2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 2-(bromomethyl)pyridine, except that Hunig's base (10 eq.) was used instead of cesium carbonate and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.75-8.91 (m, 1H) 8.14-8.27 (m, 1H) 7.85-8.01 (m, 1H) 7.62-7.75 (m, 1H) 7.30-7.42 (m, 1H) 6.68-6.80 (m, 1H) 6.38-6.47 (m, 2H) 5.80-6.03 (m, 2H) 5.25-5.54 (m, 1H) 4.15-4.28 (m, 2H) 3.68 (s, 3H) 2.61-2.74 (m, 2H) 2.06-2.16 (m, 2H) 1.89-2.02 (m, 3H) 1.04 (s, 9H); LCMS (m/z) ES+=516 (M+1).
Reaction SMILES: CO.[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15].[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][O:15][CH3:16]
Reactant: COC(=O)c1ccc(O)c(CO)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1cc(C(=O)OC)ccc1O
Temperature: 130 °C
Yield: 445.2 %

Procedure:
To MeOH (100 mL) was added methyl 4-hydroxy-3-(hydroxymethyl)benzoate (10 g; 54.89 mmol; 1 eq.) and PTSA (1.89 g; 10.98 mmol; 0.20 eq.). The resulting suspension was heated to 130° C. for 1 hour. The reaction mixture was concentrated giving a yellow solid. It was dissolved in EtOAc (400 mL), washed with a saturated aqueous solution of NaHCO3 (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (9.59 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 10.48 (br s, 1H), 7.87-7.86 (d, J=2.11 Hz, 1H), 7.76-7.28 (dd, J=8.44 Hz, 2.31 Hz, 1H), 6.91-6.88 (d, J=8.48 Hz, 1H), 4.39 (s, 2H), 3.79 (s, 3H), 3.33 (s, 3H). LC/MS (Method B): 195.2 (M−H)−.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([O:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:5]1[OH:30])=[N+:2]=[N-:3].N1C=CC=CC=1.[C:37](Cl)([CH3:39])=[O:38]>C(Cl)Cl>[C:37]([O:30][C@H:5]1[C@H:6]([O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:8][CH2:9][C@@H:4]1[N:1]=[N+:2]=[N-:3])(=[O:38])[CH3:39]
Reactant: [N-]=[N+]=N[C@H]1CCC[C@@H](OC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])CCC[C@H]1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
Compound 2 (625 mg, 1.57 mmol), pyridine (363 μL, 4.69 mmol) and AcCl (272 μL, 3.13 mmol) were dissolved in CH2Cl2 (15 mL) under nitrogen atmosphere at room temperature. After 2 h the mixture was diluted with CH2Cl2. The organic layer was washed (HCl(aq) 5%, sat NaHCO3, brine), dried (MgSO4), filtered and concentrated. No further purification was needed. The reaction yielded 100% of 3. 1H-NMR (CDCl3) 7.45 (m, 6 H), 7.20-7.35 (m, 9 H), 5.14 (t, J=9.49 Hz, 1 H), 2.99-3.10 (m, 2 H), 1.93 (s, 3 H), 1.86 (m, 1 H), 1.50 (m, 2 H), 1.25-1.40 (m, 2 H), 0.80 (m, 1 H).
Reaction SMILES: [CH2:1]([CH:8]([C:24]([O:26]CC)=[O:25])[C:9]([OH:23])([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([CH:8]([C:24]([OH:26])=[O:25])[C:9]([OH:23])([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)C(Cc1ccccc1)C(O)(CCc1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 48 h
Yield: 94.4 %

Procedure:
To a diethyl 3-benzyl-2-hydroxy-2-phenethylsuccinate (806 mg, 2.1 mmol) in 1,4-dioxane (8.0 mL) was added 1 M aqueous lithium hydroxide solution (8.4 mL, 8.4 mmol) at room temperature, and the mixture was stirred at 60° C. for 48 h. The reaction mixture was quenched and adjusted to pH 1 with 1 M hydrochloric acid with stirring under ice cooling. The solvent was evaporated under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, and washed with water and brine. The organic layer was concentrated under reduced pressure and dried in vacuum to give 651 mg (crude) of 3-benzyl-2-hydroxy-2-phenethylsuccinic acid
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].C[CH2:15][N:16]([CH:20](C)C)C(C)C.[C:23]([O:27][C:28](=[O:44])[N:29]([CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][CH2:41][OH:42])[CH:37]=[CH:36][C:35]=1[Cl:43])[CH:30]1[CH2:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24].CN>CC#N>[C:23]([O:27][C:28](=[O:44])[N:29]([CH2:33][C:34]1[CH:39]=[C:38]([CH2:40][CH2:41][O:42][C:15](=[O:3])[NH:16][CH3:20])[CH:37]=[CH:36][C:35]=1[Cl:43])[CH:30]1[CH2:31][CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN
Solvent: CC#N
Product: CNC(=O)OCCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 49.9 %

Procedure:
4-Nitrophenyl chloroformate (3.25 g, 15.7 mmol) and DIPEA (7.88 mL, 46.0 mmol) were added to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (3.00 g, 9.21 mmol) in CH3CN (46 mL). The mixture was stirred at 60° C. for 20 h, and was allowed to cool to rt. MeNH2 (2M in THF, 46.0 mL; 92.0 mmol) was added, and the mixture stirred at rt for 4 h. The mixture was partitioned between CH2Cl2, and water. The org. layer was washed with water and brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/Et2O 9:1) yielded the title compound (1.76 g, 50%). LC-MS: tR=1.02 min; ES+: 283.42.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21](C(Cl)=O)=[CH:20][CH:19]=1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:42][NH2:43])=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH2:42][NH:43][C:15]([C@@H:9]3[CH2:10][C:11](=[CH:13][Cl:14])[CH2:12][N:8]3[C:6]([C:30]3[CH:29]=[CH:28][C:27]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:32][CH:31]=3)=[O:7])=[O:17])=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: O=C(NCc1ccc2c(c1)OCO2)[C@@H]1CC(=CCl)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbo-nyl chloride, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=475.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20](Cl)=O>C(OCC)C>[CH3:16][O:17][C:18](=[O:23])[CH2:19][C:20]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
3.2 mL (30 mmol) 2-Amino-thiophenol are dissolved in 100 mL diethylether and treated with 4.17 mL (1 eq.) triethylamine to yield a suspension, to which 3.21 mL (1 eq.) chlorocarbonyl-acetic methyl ester in 10 mL diethylether is added dropwise within 20 min. The resulting suspension is stirred and additional 2 h at room temperature, and the precipitate removed by filtration. The filtrate is evaporated and column chromatographed (silica gel, ethyl acetate/petroleum ether 1:2) to yield the desired product as a yellowish liquid (5.1 g, 82%).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20](I)=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[N:42]1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([C:45]6[N:41]([CH3:40])[N:42]=[CH:43][CH:44]=6)=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([NH:36][CH3:37])=[O:35])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(I)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(-c3ccnn3C)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a degassed solution of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (100 mg, 0.16 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.48 mmol) and K3PO4.3H2O (60 mg, 0.45 mmol) in DMF (2 mL) was added Pd(dppf)Cl2 (20 mg) under N2 protection. The reaction mixture was stirred at 100° C. for 16 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=1:2) to provide the product of Compound 165 (15 mg, yield: 16%). 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.95 (dd, J=8.4, 6.0 Hz, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.15 (t, J=8.8 Hz, 5H), 7.02 (d, J=8.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.78 (t, J=8.8 Hz, 1H), 6.24 (s, 1H), 5.96 (s, 1H), 5.88 (s, 2H), 3.38 (s, 3H), 3.00 (d, J=5.2 Hz, 3H). MS (M+H)+: 588.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:7]1[C:6]([N:17]([C:16]2[CH:18]=[CH:19][C:13]([O:12][CH:11]([F:10])[F:20])=[CH:14][CH:15]=2)[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(OC(F)F)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A solution of 16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride in 70 ml of toluene is heated to boiling. A solution of 15.9 g (0.1 mole) of p-difluoromethoxyaniline in 30 ml of toluene is added dropwise to it over 20 minutes with stirring. Thereafter, the resulting solution is refluxed until water is no longer distilled. This requires about 2 hours. The mixture is cooled to room temperature to precipitate crystals. The precipitated crystals are filtered off and washed with hexane to obtain 29.2 g of 2,3-dichloro-N-(p-difluoromethoxyphenyl)maleimide melting at 217.5°-218° C. in the form of light yellow plate crystals.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:22]1[C:26]2=[N:27][CH:28]=[C:29]([NH2:31])[CH:30]=[C:25]2[CH:24]=[CH:23]1.[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43](O)=[O:44])[S:35](=[O:39])(=[O:38])[NH:36][CH3:37])[CH3:33]>CN(C=O)C.CCOC(C)=O>[CH2:32]([N:34]([C:40]1[C:41]([F:50])=[C:42]([C:46]([F:49])=[CH:47][CH:48]=1)[C:43]([NH:31][C:29]1[CH:30]=[C:25]2[CH:24]=[CH:23][NH:22][C:26]2=[N:27][CH:28]=1)=[O:44])[S:35](=[O:38])(=[O:39])[NH:36][CH3:37])[CH3:33]
Reactant: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(c1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F)S(=O)(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.1 %

Procedure:
HOBt (0.011 g, 0.085 mmol), EDCI (0.036 g, 0.19 mmol), and 1H-pyrrolo[2,3-b]pyridin-5-amine (0.025 g, 0.19 mmol) was added to 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (0.050 g, 0.17 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (6 mL) and washed with brine (3×5 mL). The organic layers were dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 5% MeOH-DCM to afford 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluoro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.005 g, 0.012 mmol, 7.2% yield). m/z (APCI-neg) M−1=408.0.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22]>O.C1(C)C=CC=CC=1>[C:19]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
18.19 g of tyrosine was suspended in a solution of 9.8 g of concentrated sulfuric acid, 40 mL water, 40 mL of butanol, and 200 mL of toluene in a 500 mL round bottom flask equipped with a condenser and a Dean-Stark apparatus. The resulting solution was heated at reflux temperature until no more water could be distilled. The resulting solution was cooled in an ice bath, which caused the solution to separate into two phases. The upper phase was discarded and the lower phase, an oily syrup, was retained. The syrup was mixed with sufficient 5% aqueous sodium bicarbonate solution to neutralize acidic impurities to provide a solid that was collected by filtration and washed with cold water. The resulting solid was re-crystallized in ethyl acetate.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([N:18]2[C:22]([SH:23])=[N:21][N:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[O:1]([CH2:8][CH2:9][CH2:10][S:23][C:22]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[N:20][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: Sc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: c1ccc(OCCCSc2nnnn2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
3-phenoxypropyl bromide (1.53 g) was dissolved in acetone (9 mL), 1-phenyl-5-mercapto-1H-tetrazole (1.27 g) and potassium carbonate (985 mg) were added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added water, and the extract obtained by extraction with ethyl acetate was washed with water and a saturated saline, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a titled compound (2.23 g) having the following physical property values.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]1=[O:29])[CH3:14].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[Cl-].[NH4+]>O1CCCC1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C:15]1([CH2:13][CH3:14])[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:16]1=[O:29])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: CCC1CCN(Cc2ccc(OC)cc2)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(CC)CCN(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (3.4 mL) in tetrahydrofuran (10 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 15 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 3-ethyl-1-(4-methoxybenzyl)pyrrolidin-2-one (2.8 g) obtained in Step B in tetrahydrofuran (10 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Ethyl bromoacetate (4.0 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.5 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:20])=[O:19]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](COS(C)(=O)=O)O1

Procedure:
The (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich, 0.38 mL, 3.1 mmol), triethylamine (0.85 mL, 6.1 mmol), and methanesulfonyl chloride (0.31 mL, 4.1 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].I.C[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[CH:52](N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(#N)C.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:46]3[CH2:45][CH2:44][C:43]([C:38]4[CH:37]=[CH:42][C:41]([CH3:52])=[CH:40][CH:39]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccccc1C1(C(N)=O)CCNCC1
Agent: I
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccc(C)cc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 20 h

Procedure:
Combine 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.37 g, 0.7 mmol), 4-(methyl-phenyl)-piperidine-4-carboxylic acid amide hydriodide (0.7 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.07 mmol) in acetonitrile (10 mL). Heat to reflux. After 20 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate and then 10% methanol/ethyl acetate to give the title compound: Rf =0.23 (silica gel, 10% methanol/ethyl acetate).