Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.Cl>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(Cl)cc4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.5 g, 1.4 mmol) and 4-chlorobenzoyl chloride (0.25 g, 1.4 mmol) in DMF (30 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then, 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.22 g, 40% yield); mp 278-280° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.10 (95.66%); 1H NMR (DMSO-d6) δ 1.97-2.03 (m, 1H), 2.31-2.45 (m, 1H), 2.57-2.62 (m, 1H), 2.85-2.97 (m, 1H), 4.30 (d, 1H, J=17.3 Hz), 4.45 (d, 1H, J=17.3 Hz), 4.59 (d, 2H, J=5.7 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.54-7.58 (m, 3H), 7.70 (d, 1H, J=7.8 Hz), 7.91-7.96 (m, 2H), 9.23 (t, 1H, J=6.0 Hz). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 122.1, 122.9, 127.1, 128.4, 129.2, 130.4, 132.9, 136.1, 142.4, 143.7, 165.2, 167.9, 170.9, 172.8; LCMS: MH=412, 414; Anal. Calcd for C21H18ClN3O4+0.5 CH2Cl2: C, 56.84; H, 4.22; N, 9.25. Found: C, 56.79; H, 4.30; N, 9.33.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.[NH2:21][CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[N:25]([CH3:30])[C:24]([CH3:32])([CH3:31])[CH2:23]1>>[S:9]1[C:13]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH:22]3[CH2:23][C:24]([CH3:31])([CH3:32])[N:25]([CH3:30])[C:26]([CH3:29])([CH3:28])[CH2:27]3)[N:7]=2)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cc2ccccc2s1
Product: CN1C(C)(C)CC(Nc2nccc(-c3cc4ccccc4s3)n2)CC1(C)C

Procedure:
The title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and 4-amino-1,2,2,6,6-pentamethylpiperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(C(C)C)C(C)C)C.[C:26]1([S:32][N:33]([CH2:39][CH2:40]OS(C)(=O)=O)[C:34](=[O:38])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(C=CC(O)=CC=1)O>CS(C)=O.N1C=CC=CC=1>[C:26]1([S:32][N:33]([CH2:39][CH2:40][O:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=3)=[CH:11][CH:10]=2)[C:34](=[O:38])[O:35][CH2:36][CH3:37])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)N(CCOS(C)(=O)=O)Sc1ccccc1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: Oc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 4.3 g of 4-(3,5-difluorophenoxy)phenol and 1.58 g of pyridine or 2.58 g of ethyl diisopropylamine in 35 ml of dry dimethyl sulfoxide is metered at a constant rate at +25° C. in the course of 5 hours to a solution of 6.4 g of ethyl N-phenylthio-2-methylsulfonyloxyethylcarbamate and 0.2 g of hydroquinone in 20 ml of anhydrous dimethyl sulfoxide, with stirring. The mixture is stirred for 5 more hours at room temperature. After this, the reaction mixture is poured into ice-water and extracted three times with an ether/hexane mixture (1:4), and the combined organic phases are washed with water and dried over sodium sulfate. After the solvents have been distilled off in vacuo, the crude product is purified by chromatography, by which process ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate is isolated, nD20 1.5700.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.O>[OH:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:12]([S:13]([C:16]1[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])=[O:14])[C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(N(Cc2cccc(O)c2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)(=O)N(Cc2cccc(O)c2)c2ccc(CCC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid methyl ester (0.017 g, 0.04 mmol) in 0.5 mL tetrahydrofuran was added sodium hydroxide (0.004 g, 0.11 mmol) in 0.1 mL water. The reaction was stirred at room temperature for 24 hr. The reaction mixture was adjusted to a pH of 4 with 1N HCl and water was added. The aqueous solution was washed with methylene chloride and the organic layer was concentrated to afford 0.015 g of 3-{4-[(3-hydroxy-benzyl)-(2,4,6-trimethyl-benzenesulfonyl)-amino]-phenyl}-propionic acid. 1H NMR (CDCl3) δ 7.05 (t, 1H, J=7.6 Hz), 7.00–6.93 (m, 2H), 6.90–6.80 (m, 4H), 6.70–6.62 (m, 2H), 6.43 (bs, 1H), 4.69 (s, 2H), 2.83 (t, 2H, J=7.2 Hz), 2.56 (t, 2H, J=7.2 Hz), 2.42 (s, 6H), 2.24 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C@H:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23])[S:3]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=2)[CH:7]=1)(=[O:5])=[O:4].[Li]N([Si](C)(C)C)[Si](C)(C)C.Br[CH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[CH:41][N:40]=[C:39]2[Cl:46]>C1COCC1>[Cl:46][C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([CH2:35][N:20]3[CH2:21][CH2:22][C@H:18]([N:2]([CH3:1])[S:3]([C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][C:10]([O:16][CH3:17])=[CH:11][CH:12]=5)[CH:7]=4)(=[O:5])=[O:4])[C:19]3=[O:23])[CH:37]=2)[N:42]=[CH:41][N:40]=1
Reactant: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCNC3=O)cc2c1
Reactant: Clc1ncnc2ccc(CBr)cc12
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2ccc(S(=O)(=O)N(C)[C@H]3CCN(Cc4ccc5ncnc(Cl)c5c4)C3=O)cc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 52.1 %

Procedure:
To a solution of 7-methoxynaphthalene-2-sulfonic acid methyl-(2-oxopyrrolidin-3-(S)-yl)-amide (0.35 g, 1.04 mmol) in THF (7 mL) at 0° C. is added LiN(SiMe3)2 (1 mL, 1 mmol, 1 M solution in THF). The solution is stirred at 0° C. for 40 minutes. After this time, 6-bromomethyl-4-chloro-quinazoline (0.24 g, 0.94 mmol) is added. The resulting solution is stirred for 4 hours. The reaction is quenched by the addition of a saturated NH4Cl solution. The solution is diluted with EtOAc and water. The layers are separated. The organic layer is washed with water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to give the title compound (0.25 g, 0.49 mmol) as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1.CCOCC>[C:1]([C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2ccoc12
Temperature: 25 °C
Yield: 116.3 %

Procedure:
A solution of 0.31 g (1.22 mmol) of 7-Carbomethoxy dihydrobenzofuran and 1.66 g (3.3 mmol) of DDQ in 25 mL of toluene was heated at reflux for 7 h. The reaction mixture was then cooled to rt, diluted with ether, and washed with 3×30 mL of sat'd NaHCO3 solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 9:1) to give 0.25 g of the title compound.
Reaction SMILES: CN[C:3](=O)[CH2:4]CC1C=CC2C(=CC=CC=2)C=1.[CH3:17][N:18]([C@@H:29]([C:41](=[O:55])[N:42]([CH3:54])[C@@H:43]([C:50](=[O:53])[NH:51][CH3:52])[CH2:44][C:45]1S[CH:47]=[CH:48][CH:49]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:19](=[O:28])/[CH:20]=[C:21](\[CH3:27])/[CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24].NC(C)(C)CC=CC(N(C)[C@@H](C(=O)N(C)[C@@H](C(=O)NCC(F)(F)F)CC1C=CC=CC=1)CC1C=CC2C(=CC=CC=2)C=1)=O>>[CH3:17][N:18]([C@@H:29]([C:41](=[O:55])[N:42]([CH3:54])[C@@H:43]([C:50](=[O:53])[NH:51][CH3:52])[CH2:44][C:45]1[CH:4]=[CH:3][CH:47]=[CH:48][CH:49]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:19](=[O:28])/[CH:20]=[C:21](/[CH3:27])\[CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24]
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(\C)CC(C)(C)N
Reactant: CNC(=O)CCc1ccc2ccccc2c1
Agent: CN(C(=O)C=CCC(C)(C)N)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C(/C)CC(C)(C)N

Procedure:
(2R)-2-(N-[{2-Amino-2-methylpropoxy}acetyl]-N-methylamino)-N-((1R)-1-dimethylcarbamoyl)-2-phenylethyl)-N-methyl-3-(2-naphthyl)propionamide: ##STR93## 2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide, and its acetate salt;
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]2=[CH:17][C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][CH:14]2[C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:25][C:19]1[C:18]2[CH2:17][C:15]3[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]4[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[C:3]([OH:27])=[O:2])[C:13](=[O:26])[C:14]=3[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC2=Cc3c(Cl)cccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 79.8 %

Procedure:
A solution of (S)-2-(8-chloro-3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid methyl ester (1.5 g, 4.0 mmol) and lithium hydroxide monohydrate (0.22 g, 5.22 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (50 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (1.2 g, 83.3%).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: Fc1cccc(CCl)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(F)c2)CCCC1=O
Reaction time: 0.08 h
Yield: 37.4 %

Procedure:
40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at 0° C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 mM) was added and the resultant mixture stirred at 0° C. for 3 h, then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HCl, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 502.3 mg (37%) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow foam. 1H NMR (CDCl3) δ 7.4-7.2 (m, 4H), 6.9 (m, 1H), 6.7 (m, 2H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C.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:13][C:5]1[CH:4]=[C:3]([CH2:2][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: OB(O)c1cccc(F)c1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(Cc2cccc(F)c2)cc1F
Temperature: 130 °C
Yield: 51.7 %

Procedure:
Methyl 4-(bromomethyl)-2-fluorobenzoate (0.300 g; 1.21 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.193 g; 1.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g; 0.0061 mmol) and sodium carbonate (0.259 g; 2.43 mmol) were successively added. The resulting suspension was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.164 g (52%) of methyl 2-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: COCCOCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: COCCOCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 77.9 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0665 g, 0.227 mmol) and 1-bromo-2-{[2-(methyloxy)ethyl]oxy}ethane (0.055 mL, 0.405 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0843 g, 78.8%). EI-MS m/z 396 (M+) Rt (1.64 min).
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.FC1C=CC(C2N(C(C)C)N=C3C=2CC(C)NCC3)=CC=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:12]2[N:13]([CH:19]([CH3:20])[CH3:21])[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH:17]([CH3:18])[CH2:16]3)=[CH:33][CH:32]=1
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)cc1
Agent: CC1Cc2c(nn(C(C)C)c2-c2ccc(F)cc2)CCN1
Product: CC1Cc2nn(C(C)C)c(-c3ccc(F)cc3)c2CCN1

Procedure:
The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 115 of 4-fluorophenylboronic acid. The reaction sequence also yielded 3-(4-fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C17H22FN3, 287.18; found, m/z 288.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.32-7.28 (m, 2H), 4.36 (m, 1H), 3.61-3.56 (m, 1H), 3.50-3.47 (m, 1H), 3.20-3.08 (m, 3H), 2.85-2.80 (m, 1H), 2.73-2.69 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.41-1.38 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12](O)=[O:13])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])=[CH:6][CH:5]=1
Reactant: N
Reactant: O=C(O)C=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.90 g (21.1 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 2.70 ml (32.0 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 10 min. Stirring was continued at 0-5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 75 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 4.48 g (92%) 3-(4-Trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.ClC1C=C(C(F)(F)F)C=CC=1C1C=CC=C2C=1C=CC(S(NC1C=CN=CN=1)(=O)=O)=C2.C(C1C=C(C(F)(F)F)C=C[C:66]=1[C:75]1[C:84]2[C:79](=[CH:80][C:81](S(N(CC3C=CC(OC)=CC=3OC)C3SC=CN=3)(=O)=O)=[CH:82][CH:83]=2)[CH:78]=[CH:77][N:76]=1)#N>>[C:84]1([CH:75]2[CH2:66][CH2:78][CH2:77][N:76]2[C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Agent: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCCC3c3ccccc3)nccc2c1

Procedure:
Example 237 was synthesized in a similar manner to Example 236, except that 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO) was used instead of 1-chloro-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (Intermediate X). Isolated 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.87 (br. s., 1H), 8.51 (br. s., 1H), 8.29 (br. s., 1H), 7.84 (br. s., 1H), 7.78 (d, J=9.1 Hz, 1H), 7.36 (d, J=7.4 Hz, 3H), 7.32-7.22 (m, 2H), 7.18 (d, J=5.9 Hz, 1H), 6.87 (d, J=4.4 Hz, 1H), 5.59 (br. s., 1H), 4.36 (br. s., 1H), 3.92 (br. s., 1H), 2.02 (br. s., 2H), 1.90 (br. s., 2H). m/z (ESI) 437.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:19][S:20]SC>N1C=CC=CC=1>[CH3:19][S:20][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: CSSC
Reactant: O=Cc1cc(Br)c(O)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Product: CSc1cc(C=O)cc(OCc2ccccc2)c1O
Temperature: 90 °C

Procedure:
A five liter flask equipped with a mechanical stirrer was charged with 100 g of 3-bromo-4-hydroxy-5-benzyloxybenzaldehyde, 80 g Cu powder, 80 mL methyldisulfide and 1.7 L pyridine, and the mixture was heated at 90° C. overnight with gentle stirring. The following day, the reaction mixture was filtered and most of the pyridine (1.3 L) was distilled off. The remaining solid residue was washed with about 2 L of methylene chloride and combined with the residue left after pyridine evaporation. The combined organic fraction was washed with 1.5N HCl until the dark methylene chloride layer turned light brown and the aqueous layer was clear. The resulting light brown methylene chloride layer was dried over MgSO4 and filtered through a bed of silica gel. Evaporation and crystallization from methylene chloride-hexane gave the title compound: NMR (200 MHz, CDCl3) 2.50 (s, SCH3), 5.20 (s, OCH2Ar), 6.72 (s, OH), 7.34-7.46 (m, ArH), 9.78 (s, ArCHO).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)C2=O
Reactant: NNC(=O)c1ccccc1
Product: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1- benzyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. 1H NMR (CDCl3): δ 3.77 (s, 3H), 4.94 (s, 2H), 6.35 9d, 1H), 6.62 (dd, 1H), 7.29-7.36 (m, 4H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.95 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([O:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolve 3,5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide and cool to 0° C. Add imidazole (918.74 g, 6.75 mol), followed by tertbutyldimethylsilyl chloride (1017.13 g, 6.75 mol). Warm the mixture to room temperature and stir for 15 min. Pour into water (6 L) and extract with ether (4 L). Wash the organic layer with water 2 times, 10% aqueous lithium chloride solution then brine before drying over sodium sulfate. Filter and concentrate under vacuum to 135 g of an oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11]>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:11])=[O:5].[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:11])=[O:5].[CH3:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11]
Reactant: O=C1C=CC(=O)O1
Agent: CC(CO)CO
Product: O=C(O)/C=C\C(=O)O

Procedure:
A three-liter resin kettle equipped with mechanical stirrer, nitrogen sparge tube, and addition funnel is charged with maleic anhydride (1713 g, 17.3 mol). The anhydride is heated to 60° C. to melt it. 2-Methyl-1,3-propanediol (787 g, 8.73 mol) is added at a rate effective to keep the exothermic reaction mixture at a temperature less than about 100° C. Following diol addition, the mixture is heated at 85° C. for another 2 h. The product (2475 g, 99% yield) is a clear, viscous liquid. Analysis by 1H and 13C NMR spectroscopy indicates that the product is the desired 2:1 adduct of maleic anhydride and 2-methyl-1,3-propanediol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CC(Cl)C(=O)O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 (or Example A above), N-(3,5-dichlorophenyl)-D,L-alanine was prepared using 3,5-dichloroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).