Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:14]4[O:22][CH:21]=[CH:20][C:15]=4[CH:16]=[N:17][C:18]=3[NH2:19])=[N:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:14]5[O:22][CH:21]=[CH:20][C:15]=5[CH:16]=[N:17][C:18]=4[NH2:19])=[N:9][N:10]=3)[N:7]=2)[CH:26]=[N:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc2ccoc2c1OCc1nnc2ccc(Cl)nn12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc3nnc(COc4c(N)ncc5ccoc45)n3n2)cn1

Procedure:
A mixture of 7-[(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy]furo[3,2-c]pyridin-6-amine (15.0 mg, 0.047 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.7 mg, 0.095 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (19.6 mg, 0.142 mmol) and 4:1 dioxane:water (2 mL) was microwaved at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 363.06 (100) [MH+]. HPLC: tR=1.89 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[S:20])[CH:15]=[CH:16][CH:17]=1.N1C=CN=C1.[N-]=C=S>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]([N:6]2[C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[S:3][CH:2]2[CH3:1])=[S:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc2ccccc2s1
Reactant: S=C=Nc1cccc(Cl)c1
Agent: [N-]=C=S
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC1Sc2ccccc2N1C(=S)Nc1cccc(Cl)c1

Procedure:
A mixture of 1.5 g. of 2-methylbenzothiazoline, 1.7 g. of 3-chlorophenyl isothiocyanate, about 100 ml. of chloroform, and a catalytic amount of imidazole was heated at reflux for several hours. Since thin layer chromatographic analysis showed that reaction was not complete and that some 3-chlorophenyl isothiocyanate had been lost, an additional 1.2 g. of the isothiocyanate was added to the reaction mixture which then was heated at reflux for about 16 hours. The solvent was distilled under reduced pressure and the residue was recrystallized from ethanol to give N-(3-chlorophenyl)-2-methylbenzothiazoline-3-carbothioamide, m.p. 120°-2°. The following elemental microanalysis was obtained:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:18][C:17]([O:21][CH3:22])=[O:20])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cc(F)cc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 96 h

Procedure:
To a solution of 1-(benzyloxy)-3-bromo-5-fluorobenzene (6.60 g) in acetonitrile (130 mL) were added methyl acrylate (13.7 g), triphenylphosphine (3.36 g) and triethylamine (14.5 g), and toluene (2.0 mL) and palladium acetate (480 mg) were further added. The reaction mixture was stirred at 100° C. for 96 hr, and the solvent was evaporated under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:16].C(OOC(=O)C1C=CC=CC=1)(=[O:24])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[OH:24][CH:5]1[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8](=[O:16])[CH2:7][CH2:6]1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC2=O
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c2c1C(O)CCC2=O
Temperature: 25 °C

Procedure:
2.0 gm of 5-methoxy-8-nitro-1-tetralone (described in Japanese Patent Laid-open (ko-kai) 279891/1989 and also in U.S. Pat. No. 4,939,255) and 2.05 gm of N-bromosuccinic imide were dissolved in 50 ml of carbon tetrachloride. After the addition of a catalytic amount of benzoyl peroxide, the mixture was heated under reflux for 4 hours and then cooled to room temperature, followed by the addition of 50 ml of chloroform. The mixture was washed with 10% aqueous solution of sodium hydroxide, water, and saturated brine in this order, and dried over anhydrous sodium sulfate. To the residue obtained by removing the solvent were added 5 ml of tetrahydrofuran, 5 ml of ethanol, 8 ml of water, and 250 mg of calcium carbonate, and the mixture was heated under reflux. A residue was obtained by removing the solvent from the reaction mixture, which, after the addition of 50 ml of water, was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography using chloroform-ethyl acetate (4:1) as an eluant~to obtain fractions containing the target compound. The fractions were concentrated to produce 1.49 gm of light yellow powder of-the title compound.
Reaction SMILES: [CH:1]1([CH2:5][NH2:6])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68](O)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:40]([C:44]1[N:48]([CH2:49][CH:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[C:47]2[CH:56]=[CH:57][C:58]([S:60]([N:63]3[CH:67]=[C:66]([C:68]([NH:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:69])[CH:65]=[N:64]3)(=[O:62])=[O:61])=[CH:59][C:46]=2[N:45]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: NCC1CCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NCC4CCC4)cn3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in example 53, step A, using (cyclobutylmethyl)amine (12 mg, 0.13 mmol), HATU (37 mg, 0.09 mmol), DIPEA (0.02 mL, 0.10 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (40 mg, 0.09 mmol) in DMF (5 mL). The crude product was purified by MPLC on silica gel using EtOAc/DCM (1:1) to provide the title compound as a white solid. The product was converted to its TFA salt. Yield: 27 mg (48%); 1H NMR (400 MHz, CD3OD) δ 1.43-1.51 (m, 3 H), 1.55 (dd, J=12.30, 3.91 Hz, 1 H), 1.61 (s, 9 H), 1.66-1.78 (m, 2 H), 1.81-1.93 (m, 2 H), 1.99-2.10 (m, 2 H), 2.26-2.37 (m, 1 H), 2.48-2.59 (m, 1 H), 3.26-3.36 (m, 4 H), 3.90 (dd, J=11.13, 3.71 Hz, 2 H), 4.45 (d, J=7.42 Hz, 2 H), 7.94-8.04 (m, 2 H), 8.05 (d, J=0.78 Hz, 1 H), 8.36 (d, J=1.37 Hz, 1 H), 8.76 (s, 1 H); MS (ESI) (M+H)+=513.7; Anal. Calcd for C26H35N5O4S+1.8 TFA+2.4H2O: C, 46.65; H, 5.50; N, 9.19. Found: C, 46.74; H, 5.61; N, 8.97.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32]([OH:34])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:30]3[CH2:37][CH2:36][CH2:35][C@H:31]3[C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CCC[C@H]5C(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), L-proline (28 mg) and acetic acid (0.1 mL) in DCM (10 mL) stirred at 20° C. was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-L-proline (E69) (12 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.71 (1H, m), 1.94 (2H, m), 2.16 (1H, m), 2.95 (1H, m), 3.05 (2H, m), 3.25 (2H, m), 3.60 (2H, m), 3.65 (3H, s), 4.88 (1H, m), 7.20 (1H, t), 7.31 (1H, s), 7.45 (2H, m), 7.86 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d). MS (ES): C27H29ClN4O4 requires 508; found 509.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.Cl.CO>C(Cl)(Cl)Cl>[NH:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC12CCCN(c1ncnc3[nH]ccc13)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: c1nc(N2CCCC3(CCCN3)C2)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.5 %

Procedure:
To a solution of 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester (60 mg) in chloroform (1.0 ml) were added 4M hydrochloric acid-ethyl acetate (1.5 ml) and 2M hydrochloric acid-methanol (0.5 ml), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and then azeotroped with toluene. The residue was neutralized by the addition of 4M aqueous sodium hydroxide solution, and thereto was added saturated aqueous sodium chloride solution. The mixture was extracted with chloroform. The separated organic solvent was concentrated under reduced pressure to give the titled compound (30 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14](O)([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc3c(c2)OCO3)cc1
Yield: 79 %

Procedure:
A mixture of 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole from Step 2 (1.26 g, 2.9 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (50 mL) was heated to reflux for 72 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (1.34 g) was purified by chromatography on silica gel using toluene/ethyl acetate 1/1 to give pure 5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-benzodioxole (940 mg, 80%) as a white solid: mp (DSC) 165° C. Anal Calc'd. for C18H13N2SO4F3: C, 52.68, H, 3.19, N, 6.83. Found: C, 53.05, H, 3.19, N, 6.65.
Reaction SMILES: F[C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].O.[NH3:28]>CN(C)C=O.CO>[NH2:28][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[F:12])[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)c(N)c([N+](=O)[O-])c2c1=O
Yield: 71 %

Procedure:
Ethyl 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-carboxylate (10.04 g, 27.12 mmol) was dissolved in dimethylformamide (150 ml), and 28% ammonia water (32.1 ml) was added dropwise thereto while stirring and cooling with ice. While sealing the reaction solution in a sealed tube, it was stirred at room temperature for 4 hours. The reaction solution was then dissolved in methanol (200 ml) and concentrated under a reduced pressure. The residue obtained was purified by recrystallization from a mixed solvent of 2-propanol/chloroform/28% ammonia water, and after drying under a reduced pressure, 7.07 g (71%) of the title compound was obtained as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:9][CH2:8]2.[Br:21]Br>CCO.C(Cl)Cl>[Br:21][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:13][CH:14]([CH:18]1[CH2:20][CH2:19]1)[CH:15]1[CH2:17][CH2:16]1)[CH2:11]2
Reactant: COc1cccc2c1CC(NC(C1CC1)C1CC1)CC2
Reactant: BrBr
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Br)c2c1CC(NC(C1CC1)C1CC1)CC2

Procedure:
8-Methoxy-2-(di-cyclopropylmethylamino)tetralin (OSU427) (311 mg, 1.09 mmol) was brominated in EtOH with 1.5 ml of a solution containing 0.6 ml Br2 in 10 ml CH2Cl2). After night in room temperature, the solvent was evaporated and the raw product (HBr salt) was recrystallized from acetone/ether to give 311 mg of white crystals melting at 153°-154° C. αD20 =-51.2°. GC/MS shows M+/M+2 at m/e=363.10 (43.1%) and 365.00 (41.9%) and the base peak at m/e=160.05.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](Cl)(=[O:21])[O:19][CH3:20].CCN(C(C)C)C(C)C.ClCCl>C(OCC)C>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:19][CH3:20])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(CC2CCCCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1CCN(C(=O)OC)C(CC2CCCCC2)C1
Reaction time: 2 h

Procedure:
Methyl 2-(cyclohexylmethyl)piperidine-4-carboxylate (1.79 g, 7.48 mmol), methyl carbonochloridate (1.06 g, 11.2 mmol) and DIPEA (1.93 g, 15.0 mmol) were added to dichloromethane (60 mL) at room temperature and stirred for 2 h. The reaction mixture was diluted with diethylether and washed with water. The organic phase was dried over MgSO4, filtered through Celite® and the solvent was evaporated. Crude product 2.2 g. 1H NMR (400 MHz, cdcl3) δ 0.71-0.97 (m, 2H), 1.02-1.28 (m, 5H), 1.38 (dt, 1H), 1.69 (ddd, 6H), 1.98 (ddd, 3H), 2.52-2.61 (m, 1H), 3.01-3.16 (m, 1H), 3.67 (s, 3H), 3.69 (s, 3H), 3.81-3.94 (m, 1H), 4.13-4.31 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6](O)=[O:7])[C:3](O)=[O:4].S(Cl)([Cl:12])=O.[ClH:14].S(=O)=O>>[CH3:1][C:2]([CH3:9])([C:6]([Cl:12])=[O:7])[C:3]([Cl:14])=[O:4]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: O=S(Cl)Cl
Reactant: Cl
Agent: O=S=O
Product: CC(C)(C(=O)Cl)C(=O)Cl

Procedure:
To a 500 ml. one-necked flask equipped with reflux condenser with drying tube, is added 50 grams (0.38 mole) dimethylmalonic acid (Aldrich Chemical Co.) and 300 ml. thionyl chloride. The mixture is heated to reflux for about 1 hour during which time the dimethylmalonic acid is dissolved and hydrogen chloride and sulfur dioxide are evolved. The unreacted thionyl chloride is removed by distillation under reduced pressure. The residue is recrystallized twice from cyclohexane to yield a white solid, M.P. 186°-187° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)(O)=O.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1.FC(F)(F)C(O)=O>>[C:20]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][CH2:1][CH2:4][C:5]2[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=2)[CH:19]=1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2cccc(-c3ccccc3)c2)cs1)C(=O)O
Reaction time: 8 h

Procedure:
Operations similar to Example 520-1 and Example 488-2 were performed using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and 3-aminobiphenyl as starting materials. To the obtained resin was added trifluoroacetic acid and the mixture was left standing overnight. The resin was filtered off and the filtrate was concentrated by blowing nitrogen gas thereto, and purified by preparative HPLC to give the title compound (0.015 g) as a pale-brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-])=[O:16])=[CH:13][CH:12]=1)=[O:8])([O-:3])=[O:2].O.[NH2:24][NH2:25]>CCO>[NH:24]([C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:20]=[CH:21][CH:22]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:12][CH:13]=1)=[O:16])[NH2:25]
Reactant: O=C([O-])c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a suspension of 4-{[(3-nitrobenzoyl)amino]methyl}benzoate (500 mg, 1.59 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.16 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×2 mL), EtOH/water (2×2 mL)and water (2×2 mL), and drying under vacuo at 70° C. for 5 hrs gave 379 mg of the title compound (76%) as a pale yellow solid in 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])([CH3:36])[CH3:35])[C:31]([CH2:44][O:45][CH2:46][CH3:47])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39])([CH3:35])[CH3:36])[C:31]([CH2:44][O:45][CH2:46][CH3:47])=[N:30][C:25]=3[CH:26]=[N+:27]([O-:9])[C:28]=2[CH:29]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reaction time: 3 h
Yield: 108.8 %

Procedure:
mCPBA (60% pure, 1.18 g) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea (1.96 g, 4.0 mmol) in chloroform (50 mL). The reaction was stirred for 3 hours and then an additional 0.53 g of mCPBA was added. The reaction was stirred for 2 more hours and then quenched with aqueous 1% sodium carbonate. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 2.2 g of crude N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as an orange foam.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:28][O-:29].[Na+]>>[F:27][C:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[O:29][CH3:28])(=[O:11])=[O:12])=[CH:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: C[O-]
Reactant: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1F
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-1-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)-3-methoxybenzene (Example 192, 45 mg, 0.116 mmol) and sodium methoxide (0.5M in methanol, 1 mL) was heated to 150° C. for 10 minutes in a microwave reactor. A further 0.5 mL sodium methoxide was added and heating continued at 150° C. for 30 minutes. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20% ethyl acetate/isohexane, to give the title compound. δH (500 MHz, d6 DMSO): 7.91 (2H, d, J=8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.7 Hz), 7.52 (1H, dd, J=2.2, 8.5 Hz), 7.39 (2H, d, J=2.3 Hz), 7.28 (1H, s), 7.25-7.19 (2H, m), 7.14 (1H, d, J=8.6 Hz), 3.82 (3H, s), 3.80 (3H, s).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:1]1([C@@H:7]([CH3:10])[CH2:8][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](CO)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 112.4 %

Procedure:
An oven dried 250.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with (2R)-2-phenylpropan-1-ol (2.0 mL, 14.32 mmol), phthalimide (2.1 g, 14.32 mmol), triphenylphosphine (5.63 g, 21.48 mmol) and THF (70.0 mL). To this solution at room temperature was then added a solution of diethylazodicarboxylate (3.38 mL, 21.48 mmol) dissolved in THF (10.0 mL) over a period of 15-20 minutes (reaction exothermed slightly to 50° C. by the end of addition went from clear to reddish color). Stirred reaction to room temperature overnight). To the red solution was added water (50.0 mL) and the organic extracted with chloroform (140.0 mL). Dried the organic solution with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. To the oil was added heptane (150.0 mL) with stirring. Filtered of precipitates, then concentrated filtrate to an oil. Plug filtration of the oil over silica gel with 1:1 ethylacetate/hexane and concentrating product fractions afforded the intermediate title compound, 2-((2R)-2-phenylpropyl)isoindoline-1,3-dione, (4.27 g, 96%) as an oil which solidified on equilibrating to room temperature; 1H nmr (CDCl3, 300 MHz) δ 1.3 (d, 3H), 3.3-4.0(m, 1H), 3.7-3.9 (m, 2H), 7.1-7.3 (aromat. m, 2H), 7.63-7.7 (aromat. m, 2H), 7.8-7.85 (aromat. m, 4H).