Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][N:25]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:26]=1[NH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:27][C:26]2[N:25]([CH2:28][CH:29]([CH3:30])[CH3:31])[N:24]=[CH:23][C:22]=2[CH3:21])=[N:3][CH:4]=1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1cnn(CC(C)C)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1cc(Nc2c(C)cnn2CC(C)C)ncc1Cl
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (300 mg, 0.96 mmol), 4-methyl-1-(2-methylpropyl)-1H-pyrazol-5-amine (309 mg, 2.01 mmol), cesium carbonate (939 mg, 2.88 mmol) and DMF (5 ml). The reaction mixture was degassed under nitrogen for 10 min, and palladium (II) acetate (10.8 mg, 0.05 mmol) and BINAP (59.8 mg, 0.096 mmol) were added. The reaction mixture was heated in an oil bath at 90° C. for 5 hrs and then in a microwave at 150° C. for 40 min. Solvent was evaporated and the residue was dissolved in MeOH, filtered thru celite and thru an Acrodisc an purified further using preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. The brown oil residue was diluted in DMF and water was added. A precipitate crashed out. It was filtered off and dried under vacuum at 40° C. for 5 hrs. LC-MS [M+H]+=429.1. 1H NMR (400 MHz, DMSO-d6) ppm 11.93 (s, 1 H) 9.48 (br. s., 1 H) 8.26 (s, 1 H) 7.94 (s, 1 H) 7.58 (d, J=7.33 Hz, 1 H) 7.44-7.51 (m, 2 H) 7.23 (s, 1 H) 7.08-7.16 (m, 1 H) 6.38 (s, 1 H) 3.70 (s, 3 H) 3.65 (d, J=7.33 Hz, 2 H) 2.03 (dt, J=13.71, 6.92 Hz, 1 H) 1.77 (s, 3 H) 0.75 (d, J=6.57 Hz, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([C:18]([O:20]C)=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([C:18]([OH:20])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(C)CCCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCCc2c(-c3ccc(Cl)cc3)noc2C1
Yield: 47.1 %

Procedure:
2 g of methyl 3-(4-chlorophenyl)-7-methyl-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate were treated with 0.5 g of potassium hydroxide in 2 ml of water and 20 ml of methanol at 20° C. for 16 hours. After working-up as described in Example 5 and crystallization from glacial acetic acid, there was obtained 0.9 g of 3-(4-chlorophenyl)-7-methyl-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 232°-235° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:19](=[O:23])(=[O:22])(N)N>COCCOCCOC>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][S:19]1(=[O:23])=[O:22]
Reactant: NS(N)(=O)=O
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: COCCOCCOC
Product: COC(=O)c1cccc2c1N(CC(OC)OC)S(=O)(=O)N2
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.5 g, 2.0 mmol) from Step C above and sulfuric diamide (0.2 g, 2.4 mmol) in diglyme (2 mL) was added to boiling diglyme (5 mL) dropwise and continued to reflux for 35 min. The flask was cooled to room temperature and the solvent was removed in vacuo. The crude reaction was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 3-(2,2-dimethoxyethyl)-1,3-dihydro-2,1,3-benzothiadiazole-4-carboxylate 2,2-dioxide (0.2 g, 27%): 1H NMR (500 MHz, DMSO-d6) δ 7.08 (br s, 1H), 6.59 (dd, J=8.0, 1.5 Hz, 1H), 6.52 (t, J=8.0 Hz, 1H), 6.46 (dd, J=6.0, 1.5 Hz, 1H), 4.41 (t, J=5.0 Hz, 1H), 3.82 (d, J=5.0 Hz, 2H), 3.74 (s, 3H), 3.14 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][CH2:14][C:15]([CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])=O)[CH2:10][N:9]=[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]=2[CH:35]=1.S(=O)(=O)(O)O>>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:15]([CH2:17][N:18]4[C:19](=[O:28])[C:20]5=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]5[C:22]4=[O:23])=[CH:14][N:13]=[C:11]3[CH2:10][N:9]=[C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]=2[CH:35]=1
Reactant: O=C(CNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1)CN1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 20, 7-trifluoromethyl-5-phenyl-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal is treated with concentrated sulfuric acid, then quenched to give after neutralization, 8-trifluoromethyl-1-(phthalimidomethyl)-6-phenyl-4H-imidazo-[1,2-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:13][C:4]1[CH:3]=[C:2]([C:14]#[N:15])[C:11]([F:12])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(F)c(Br)cc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: COC(=O)c1cc(F)c(C#N)cc1Cl
Temperature: 90 °C

Procedure:
Methyl 4-bromo-2-chloro-5-fluorobenzoate (2.10 g; 7.85 mmol; 1 eq.), zinc cyanide (553.15 mg; 4.71 mmol), tris(dibenzylideneacetone)dipalladium(0) (57.52 mg; 0.06 mmol), 1,1′-bis(diphenylphosphino)ferrocene (69.64 mg; 0.13 mmol; 0.02 eq.), zinc (20.54 mg; 0.31 mmol; 0.04 eq.) and zinc acetate (57.62 mg; 0.31 mmol; 0.04 eq.) were put in dry DMF (21 mL). The reaction mixture was purged with N2 and then heated to 90° C. for 12 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and concentrated affording the title compound as a brown solid. It was purified by washing with EtOH affording the title compound as a beige solid used without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.36-8.35 (m, 1H), 8-7.97 (m, 1H), 3.90 (s, 3H). HPLC (Method A) Rt 4.02 min (Purity: 92.5%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[CH:25]=1)=[C:22]=[O:23].Cl>C(#N)C>[CH3:31][C:26]1[CH:25]=[C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:23])[CH:29]=[C:28]([CH3:30])[CH:27]=1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: Cc1cc(C)cc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-isocyanato-3,5-dimethyl-benzene (0.17 mg, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture was stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3,5-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (280 mg, 67%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4 in H2O: tR=3.4 min (96%); mp. 289-291° C. 1H NMR (DMSO-d6) δ 1.92-2.06 (m, 1H, CHH), 2.19 (s, 6H, CH3+CH3), 2.38 (qd, J=4.4, 13.1 Hz, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.80-3.02 (m, 1H, CH—H), 4.17-4.58 (m, 4H, CH2+CHH), 5.11 (dd, J=5.2, 13.3 Hz, 1H, CHN), 6.54 (s, 1H, Ar), 6.69 (t, J=5.9 Hz, 1H, Ar), 7.03 (s, 2H, Ar), 7.44 (d, J=7.9 Hz, 1H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.45 (s, 1H, NH), 10.98 (s, 1H, NH). 13C NMR (DMSO-d6) δ 21.12, 22.49, 31.20, 42.76, 47.10, 51.56, 115.54, 121.88, 122.78, 122.93, 126.91, 130.27, 137.49, 140.19, 142.38, 144.93, 155.21, 167.95, 170.99, 172.85; LCMS MH=421. Anal Calcd for: C23H24N4O4+0.1H2O: C, 65.42, H, 5.78; N, 13.27. found: C, 65.15; H, 5.58; N, 13.18.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([OH:25])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:37][CH:38]1[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39]1)(=O)=O.O>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([O:25][CH2:37][CH:38]5[O:43][CH2:42][CH2:41][N:40]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:39]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCOc1ccn2c(-c3ccc4cccc(OCC5CN(C(=O)OC(C)(C)C)CCO5)c4n3)cnc2c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol [prepared as in Example 3, Step C; 50 mg, 0.15 mmol] in anhydrous DMA (2 mL) was added cesium carbonate (150 mg, 0.45 mmol) followed by tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (130 mg, 0.45 mmol). The heterogeneous mixture was stirred at 100° C. for 16 hours and allowed to cool. The mixture was treated with water (20 mL) and extracted with EtOAc. The combined organic phases were washed with water and brine, then dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography using gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 2% MeOH/CH2Cl2) to afford tert-butyl 2-((2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)methyl)morpholine-4-carboxylate as a gum. This was dissolved in CH2Cl2 (4 mL) and treated with TFA (1 mL). After stirring for 2 hours at ambient temperature the mixture was concentrated. The residue was triturated with ether, filtered and dried in vacuo to provide 29.1 mg (76%) of desired product as its di-TFA salt as a powder. MS ESI (+) m/z 435.3 (M+1) detected.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[CH2:22][C@H:21]([OH:23])[C@@H:20]([CH2:24][OH:25])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl[S:42]([NH:45]C(=O)OC(C)(C)C)(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:25][CH2:24][C@H:20]1[CH2:19][C@@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:22][C@@H:21]1[OH:23])[NH2:45]
Reactant: OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A neat mixture of (1S,2R,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol (100. mg, 0.294 mmol) and 2,6-di-tert-butyl-4-methylpyridine (181 mg, 0.881 mmol) was dissolved in ACN (5.00 mL) before tert-butyl (chlorosulfonyl)carbamate (95.0 mg, 0.441 mmol, as prepared in Example 21c) was added. The reaction was stirred for 2 h before being quenched via addition of MeOH (2 mL). The resulting mixture was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 10 to 20% MeOH in DCM to afford the title compound as an amorphous solid (50.0 mg, 33%). LC/MS: Rt=1.24 min, ES+ 520. (AA standard).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7](O)=[C:6]([NH:11][C:12](=[O:33])[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:20]([CH3:32])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:5]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:33][C:12]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:11][C:6]=2[CH:5]=1)=[O:34]
Reactant: CCC(CC)(C(=O)Nc1cc(C(=O)OC)ccc1O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(OCc2ccccc2)c(C)c1)c1nc2cc(C(=O)OC)ccc2o1
Yield: 90.9 %

Procedure:
3-[2-(4-Benzyloxy-3-methyl-phenyl)-2-ethyl-butyrylamino]-4-hydroxy-benzoic acid methyl ester (5.80 g, 12.6 mmol), TsOH—H2O (478 mg, 2.51 mmol) in toluene (100 mL) are reacted analogous to Example 1, step E to give the title product (5.08 g, 91%). MS (ES) m/e: 444.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[C:26]([O:30][C:31]([NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:26]([O:30][C:31]([NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([CH3:12])=[CH:5][N:6]=[CH:7]3)[CH2:38][CH2:39]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cncc2cccc(Br)c12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cncc2cccc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Temperature: 120 °C

Procedure:
According to the method of Example 15, Step A, the title compound was synthesized from Intermediate 93. That is, under nitrogen atmosphere, a suspension of Intermediate 93 (1.13 g), tris(dibenzylideneacetone)dipalladium(0) (0.71 g), tri(tert-butyl)phosphine (0.5 ml), trans-N-(tert-butoxycarbonyl)-1,4-cyclohexanediamine (1.04 g) and sodium tert-butoxide (0.73 g) in toluene was stirred with heating at 120° C. for 1 hour. The reaction mixture was cooled to room temperature and added with ethyl acetate (50 ml), and the insoluble matters were removed by filtration through Celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (456 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])=[O:14].O>CS(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)c(Cl)c1
Temperature: 60 °C
Yield: 82.1 %

Procedure:
To a solution of 9.09 g (0.0558 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 2.23 g (0.0558 mole) of NaOH. The mixture was heated to 60° C. and 11.3 g (0.0502 mole) of 3,4-dichlorophenyl methyl sulfone was added and the mixture heated at 150° C. for 3.75 hrs. The mixture was cooled and poured into water. The crystalline product was collected by filtration, washed with water and dried, which gave 14.5 g (82.4% yield) of product. Recrystallization from ethanol afforded purified 4-(2-chloro-4-(methylsulfonyl)phenoxy)-1,2-dichlorobenzene, mp 102°-104° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1OC=C)(=[O:3])[CH3:2].O>CO.C1COCC1>[C:1]([O:4][C:5]1[C:6]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: C=COc1ccc2ccccc2c1-c1c(OC(C)=O)ccc2ccccc12
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccc2ccccc2c1-c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 10 h
Yield: 34 %

Procedure:
30.4 mg (0.086 mmol) of 2-acetyloxy-2′-vinyloxy1,1′-binaphthyl and 2.8 mg (0.004 mmol) of Co (OAc) (L3) were dissolved in 90 μl of a mixed solvent (2:1) of methanol and THF under the atmosphere and 8 μl (0.44 mmol) of water was added to the mixture, and the mixture was then stirred at 0° C. After 10 hours, the reaction solution was analyzed by HPLC, to find that 66% of the 2-acetyloxy-2′-vinyloxy1,1′-binaphthyl was left with an optical purity of 44% ee. Further, the reaction solution was purified by silica gel column chromatography to obtain the reaction product O-acetylbinaphthol in a yield of 34%. Also, the kre1 value showing the selectivity of reactions at this time was 20.7.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>CS(C)=O.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:6][C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27]
Reactant: COC(=O)CCl
Reactant: Cn1c(NCCNCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN(CCCNc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Yield: 100.7 %

Procedure:
1.5 g of 1,3-dimethyl-6-{2-[3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound b) obtained in the above procedure (3) were dissolved in 12 ml of DMSO, followed by the addition of 1.2 g of methyl chloroacetate and 1.5 ml of triethylamine. The resultant mixture was stirred at 50° C. for 2 hours, dissolved in chloroform, washed with water and then dried over anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=30/1, by volume), thereby obtaining 1.8 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])(=[O:5])=[O:4].C1COCC1.[OH-].[Li+]>O>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[S:3]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])(=[O:5])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)N(C)CCN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCN1CCOCC1)S(=O)(=O)c1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of methyl 3-(N-methyl-N-(2-morpholinoethyl)sulfamoyl)-thiophene-2-carboxylate (Int. 47) (510 mg, 1.464 mmol) in a 1:1 mixture of THF and H2O, lithium hydroxide (351 mg, 14.64 mmol) was added, and the mixture was stirred at RT overnight. The organic solvent was evaporated and the aqueous residue was acidified with 2N HCl (pH=7); the precipitate was collected by filtration affording 3-(N-methyl-N-(2-morpholinoethyl)-sulfamoyl)thiophene-2-carboxylic acid (Int. 48) (410 mg, 1.226 mmol, MS/ESI+334.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.Br[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: COC(=O)CCBr
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: COC(=O)CCn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with methyl 3-bromopropanoate in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium iodide to give the title compound as a light yellow solid, MS (ESI+): m/z=518.4 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1cccc(Br)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Br)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-bromobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[CH:23][C:22](I)=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].B(OC(C)C)(OC(C)C)[O:42]C(C)C.C(OO)(=O)C>C1COCC1.O>[CH2:1]([O:8][C:9]1[N:24]=[CH:23][C:22]([OH:42])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(I)c1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(=O)OO
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(O)c1OCc1ccccc1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 36.5 %

Procedure:
Into a solution of benzyl 2,4-bis(benzyloxy)-5-iodonicotinate (1.0 g, 1.8 mmol) in THF (8.0 mL) at −45° C. was added a solution of i-PrMgCl—LiCl (1.3 M×2.8 mL, 3.6 mmol) dropwise. The mixture was stirred at −45° C. for 30 min, into which triisopropyl borate (0.87 mL, 3.78 mmol) was added dropwise. After stirring at −45° C. for 15 min, the temperature was allowed to rise to room temperature slowly. The mixture was stirred at room temperature for 1.5 h then cooled to −20° C., into which peracetic acid (32%, 0.79 mL, 3.78 mmol) was added. The mixture was stirred at room temperature for another 30 min before it was treated with water (50 mL). The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 36%).