Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.Cl.[CH2:21]([NH:28][CH2:29][P:30]([O:35][CH2:36][CH3:37])(=[O:34])[O:31][CH2:32][CH3:33])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:21]([N:28]([CH2:29][P:30](=[O:34])([O:35][CH2:36][CH3:37])[O:31][CH2:32][CH3:33])[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCOP(=O)(CNCc1ccccc1)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(CN(Cc1ccccc1)Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)OCC
Yield: 46.1 %

Procedure:
1.0 g (3.05 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitroquinoxaline, 1.1 g (3.66 mmol) of diethyl benzylaminomethanephosphonate hydrochloride and 1.9 ml (10.98 mmol) of N-ethyldiisopropylamine are stirred at room temperature for about 18 hours and at 80° C. for a further 3 hours in 10 ml of dimethylformamide under argon. After addition of ethyl acetate, the mixture is extracted with water and brine, the aqueous phases are washed with ethyl acetate, and the organic phases are combined, dried using sodium sulfate, filtered on a suction filter and concentrated. The evaporation residue is chromatographed on silica gel using hexane-ethyl acetate (1:1). 0.71 g (46%) of diethyl N-benzyl-N-(2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl)aminomethylphosphonate is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:59])[CH3:58])[N:56]=4)[CH:40]=3)[CH2:35][NH:34]2)=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:20]([O:22][C:23]([C:25]1([NH:30][C:31]([CH:33]2[CH2:37][CH:36]([O:38][C:39]3[C:48]4[C:43](=[C:44]([Cl:51])[C:45]([O:49][CH3:50])=[CH:46][CH:47]=4)[N:42]=[C:41]([C:52]4[S:53][CH:54]=[C:55]([CH:57]([CH3:58])[CH3:59])[N:56]=4)[CH:40]=3)[CH2:35][N:34]2[C:3](=[O:5])[C:2]([CH3:1])([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:32])[CH2:27][CH:26]1[CH:28]=[CH2:29])=[O:24])[CH3:21]
Reactant: C=CCCCCCC(C)(C)C(=O)O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1)C(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCCCCCC(C)(C)C(=O)N1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of 2,2-dimethylnon-8-enoic acid (52, 239 mg, 1.3 mmol) in dry CH2Cl2 (10 mL) was added oxalyl chloride (165 mg, 2.6 mmol) and 2 drops of DMF. After 3 h at room temperature, the reaction mixture was concentrated and co-evaporated with toluene. This crude acid chloride was successively re-dissolved in CH2Cl2 and added to a stirred solution of 1-[[4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]pyrrolidine-2-carbonyl]amino]-2-vinylcyclopropanecarboxylic acid ethyl ester (50, 380 mg, 0.65 mmol) and triethylamine (264 μL, 1.95 mmol) in CH2Cl2 (30 mL). After 1.5 h, the resulting solution was successively washed with a saturated solution of NaHCO3 and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (gradient EtOAc/CH2Cl2 0:1 to 2:8) afforded the title product (53) as a colorless oil (490 mg, 100%): m/z=751 (M+H)+.
Reaction SMILES: [CH:1]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(Cl)Cl>[CH:1]1([O:9][C:19]([NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCCCC1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)OC1CCCCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A mixture of cyclooctanol (3.00 grams, 23 millimoles), 2-isocyanatoethyl methacrylate (3.63 grams, 23 millimoles), methylene chloride (10 milliliters), and one drop of dibutyltin dilaurate were stirred at 50° C. for three hours. The solvent was then removed under reduced pressure and the crude product was purified by column chromatography over silica gel using a mixture of ethyl acetate/hexane (20/80). The product was isolated as an oil (5.20 grams, 80% yield). Purity and structure verification of Comparative Example C5 were confirmed by 1H NMR.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:26]3[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Reactant: O[C@@H]1CCNC1
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CC[C@@H](O)C3)cc2n1C
Yield: 23 %

Procedure:
The title compound was prepared as a white solid in 23% yield (19 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2 of Example 11) and (R)-(−)-3-pyrrolidinol (77 mg, 0.63 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=1.[CH3:24][S:25]SC>C1COCC1.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:15]=1[S:25][CH3:24]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of inert gas, 32.8 ml (1.6 M in hexane, 52.5 mmol) of n-butyllithium were added dropwise to a solution, cooled to 0° C., of 7.77 ml (55 mmol) of diisopropylamine in 100 ml of anhydrous THF, and after 10 minutes of stirring the solution was cooled to −78° C. 8.21 g (50 mmol) of 3-fluorobenzotrifluoride were added at this temperature, and the reaction mixture was stirred at this temperature for 1 h. 4.21 ml (55 mmol) of dimethyl disulfide were then added dropwise. Within about 3 h, the reaction mixture had warmed to room temperature (RT), and it was then once more cooled to 0° C. At this temperature, 10 ml of water were added dropwise, and the reaction mixture was concentrated to about ¼ of its volume. The residue was taken up in water and dichloromethane, the phases were separated and the organic phase was washed successively with water, 10 percent strength hydrochloric acid, water, saturated aqueous NaHCO3 solution, water and saturated aqueous NaCl solution and dried over sodium sulfate and filtered. The solvent was removed and the residue was rectified under reduced pressure. This gave 8 g of 1-fluoro-2-methylthio-3-(trifluoromethyl)benzene of a boiling point of 68° C. at 6 mm Hg.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@@H:12]([CH3:26])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])(C(C)(C)C)(C)C.[ClH:27]>CO>[ClH:27].[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH3:26])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO
Reaction time: 4 h

Procedure:
Synthesis of 2-({(2S)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}amino)ethanol, hydrochloride salt (P4). To a solution of (2S)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C8) (460 mg, 1.16 mmol) in methanol (5 mL) was added a solution of hydrogen chloride (4N in dioxane, 2 mL). After 4 hours, the reaction mixture was concentrated in vacuo to afford the title compound as a clear gum. Yield: 398 mg, 100%. LCMS m/z 282.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.51 (d, J=6.8 Hz, 3H), 3.28-3.32 (m, 2H, assumed; largely obscured by solvent peak), 3.80-3.87 (m, 1H), 3.84 (dd, J=5.3, 5.2 Hz, 2H), 4.29 (dd, half of ABX pattern, J=10.6, 5.8 Hz, 1H), 4.38 (dd, half of ABX pattern, J=10.6, 4.0 Hz, 1H), 7.30 (dd, J=9.0, 4.2 Hz, 1H), 7.38-7.45 (m, 2H).
Reaction SMILES: O[CH:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][CH2:6]2.S(Cl)([Cl:22])=O>>[ClH:22].[Cl:22][CH:2]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][CH2:6]2
Reactant: O=C1NCc2cc(C(O)c3cccnc3)ccc2N1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C1NCc2cc(C(Cl)c3cccnc3)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
A mixture of 3 parts of intermediate 27, namely 3,4-dihydro-6-[hydroxy(3-pyridinyl)methyl]-2(1H)-quinazolinone, and 40.5 parts of thionyl chloride was stirred for 10 min. at room temperature and for 15 min. at reflux temperature. The reaction mixture was evaporated and the residue was co-evaporated with methylbenzene. The residue was dried in vacuo at 60° C. for 24 hours, yielding 3.1 parts (99.9%) of 6-[chloro(3-pyridinyl)methyl]-3,4-dihydro-2(1H)-quinazolinone monohydrochloride (intermediate 39).
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[CH3:17][C:18]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:18]=1[CH3:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: Cc1ccc(CNc2c(NC(C)(C)C)c(=O)c2=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A solution of 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1) and 2,4-dimethylbenzylamine (0.68 g, 5.0 mmol, a mixture of 2,4- and 2,6-dimethylbenzylamine isomers) in tetrahydrofuran (10 mL) was stirred at room temperature for approximately 16 hours. Removal of solvent, thorough trituration of the residue with diethyl ether and drying provided 1.07 g of crude product. Three recrystallizations of this material from acetonitrile gave 0.67 g (47%) of the title compound as a white solid: mp 228°-229° C.; 1H NMR (DMSO-d6) δ7.57 (m, 1H), 7.48 (s, br, 1H), 7.17 (d, 1H), 7.03 (s, br, 1H), 7.00 (d, br, 1H), 4.69 (d, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.35 (s, 9H) ppm. IR (KBr): 3310, 1785, 1670 cm-1 ; MS (m/z) 286 (M+). HPLC indicates a major component (98.7%).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23]O)[CH:20]=[CH:21][CH:22]=1>ClCCl>[ClH:3].[Cl:3][CH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClCCl
Product: Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reaction time: 18 h

Procedure:
Thionyl chloride (0.95 mL, 13 mmol) is added to a solution of [3-(quinolin-2-ylmethoxy)-phenyl]-methanol (2.9 g, 11 mmol, example 48) in dichloromethane (30 mL) and allowed to stir 18 h. The reaction is concentrated in vacuo and azeotroped twice from chloroform to yield the title compound which is used without further purification.
Reaction SMILES: ClC1C=CC(C[C:7]2[C:16]([C:17]([NH2:19])=[O:18])=[C:15]([OH:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[ClH:33].Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C=O)C>[Cl:33][C:9]1[CH:14]=[CH:13][C:12]([CH2:21][NH:19][C:17]([C:16]2[C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]#[C:22][CH2:23][OH:24])[CH:13]=3)[N:8]([CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:7]=2)=[O:18])=[CH:11][CH:10]=1
Reactant: ClCCN1CCCC1
Reactant: Cl
Reactant: NC(=O)c1c(Cc2ccc(Cl)cc2)nc2ccc(C#CCO)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 1-(2-chloroethyl)pyrrolidine hydrochloride (0.425 g) are added. The reaction mixture is heated to 90° C. for 3 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.17 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.153 g of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][C:15](C(OC)=O)([C:16]([O:18]C)=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.FC1C=CC(C(C2N3CCC(C(OC)=O)C3=CC=2)=O)=CC=1.[OH-].[K+]>CO.O>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH:15]([C:16]([OH:18])=[O:17])[C:11]3=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(=O)OC)CCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: COC(=O)C1CCn2c(C(=O)c3ccc(F)cc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc(F)cc1)c1ccc2n1CCC2C(=O)O
Yield: 80 %

Procedure:
A solution of the mixture of dimethyl 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate and methyl 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (0.200 g) in methanol (5 ml) and water (3 ml) containing potassium hydroxide (0.5 g) was heated at reflux temperature for 1 hour. The solvent was removed in vacuo, water was added to the residue and the solution was made acidic with 10% hydrochloric acid solution. The product was extracted into ethyl acetate, the extract was dried and evaporated. The solid residue on crystallization from ethyl acetate-hexane gave 5-(4-fluorobenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (0.124 g, 80%) m.p. 163°. A mixed m.p. with an authentic specimen (m.p. 170°) had m.p. 165°. The IR spectrum was identical to that of the authentic sample.
Reaction SMILES: [CH3:1][PH:2](=[O:5])[O:3][CH3:4].[C:6]([O:9][CH:10]=[CH2:11])(=[O:8])[CH3:7]>>[C:6]([O:9][CH2:10][CH2:11][P:2]([O:3][CH3:4])([CH3:1])=[O:5])(=[O:8])[CH3:7]
Reactant: C=COC(C)=O
Reactant: CO[PH](C)=O
Product: COP(C)(=O)CCOC(C)=O

Procedure:
Various multistep processes to prepare phosphinothricin are known in the art. For example, some routes utilize phosphorus trichloride to produce a phosphinate precursor, which is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis to produce phosphinothricin. In particular, one process for producing phosphinothricin generally comprises converting phosphorus trichloride to methylphosphonous dichloride or a derivative thereof. The methylphosphonous dichloride or derivative thereof is then reacted with methanol to form methyl methylphosphinate. Methyl methylphosphinate is then reacted with vinylic compounds (e.g., vinyl acetate) to form an intermediate (e.g., 2-(methoxy(methyl)phosphoryl)ethyl acetate). The resulting intermediate is pyrolyzed to prepare a vinylphosphinate precursor. The vinylphosphinate precursor is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis of the hydroformylation-aminocarbonylation product in the presence of hydrochloric acid to produce phosphinothricin.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 71.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with 4-methoxyphenylboronic acid (62 mg, 0.41 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (13.2 mg, 0.0166 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-(4-methoxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.2 mg, yield 71%).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([S:20]([NH:23][C:24]2[C:29]([O:30][CH3:31])=[N:28][C:27]([CH3:32])=[CH:26][N:25]=2)(=[O:22])=[O:21])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)=[CH:9][CH:10]=1)C(C)C>CO.O.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[C:7]([S:20]([NH:23][C:24]3[C:29]([O:30][CH3:31])=[N:28][C:27]([CH3:32])=[CH:26][N:25]=3)(=[O:21])=[O:22])=[CH:6][CH:5]=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[CH2:7][CH:8]([CH3:11])[CH3:9]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cc(CC(C)C)ccc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1-c1ccc(CC(C)C)c(N)c1
Yield: 65.7 %

Procedure:
4-Isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-3'-nitro-2-biphenylsulphonamide (0.456 g) was dissolved in methanol/water (1:9 v/v; 10 ml) and the solution was catalytically hydrogenated over 10% Pd-C (0.046 g). The catalyst was removed by filtration through diatomaceous earth and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column. The resulting foam was recrystallised from ether to give 3'-amino-4'-isobutyl-N-(3-methoxy-5-methyl-2-pyrazinyl)-2-biphenylsulphonamide (0.14 g), m.p. 160°-162° C.; mass spectrum (+ve FAB, DMSO/methanol/NBA): 427 (M+H)+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[N-:20]=[N+]=[N-].[Na+].CS(C)=O>O>[NH2:20][C:2]1[CH:19]=[CH:18][C:5]([CH:6]([C:8]2[C:13]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:11]=[CH:10][N:9]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOc1cccnc1C(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cccnc1C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-propoxypyridine (4.46 g) and sodium azide (3.34 g) in. DMSO (50 ml) was stirred for 22 hours at 90° C. To the reaction mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and a solution of the residue (4.8 g) in THF (50 ml) was added dropwise to a suspension of aluminum lithium hydride (1.3 g) in. THF (40 ml) at 0° C. The mixture was stirred at room temperature for 30 minutes, water (1.3 ml), 15% aqueous solution of sodium hydroxide (1.3 ml) and water (3.9 ml) were sequentially and slowly added dropwise to the solution at 0° C. The mixture was stirred at room temperature for 2 hours, magnesium sulfate was added to the mixture, and the precipitates were removed by filtration (Celite). The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give (4-aminophenyl)(3-propoxypyridin-2-yl)methanol (2.82 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Sc2cccc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Sc2cccc(Cl)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 30c (320 mg, 1.15 mmol), LiOH (110 mg, 4.59 mmol) in THF/MeOH/H2O (3/3/3 mL) was stirred for 4 h. A 15% aqueous citric acid solution (10 mL) was added. The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine, filtered, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue (compound 30d, 290 mg) was dried under reduced pressure for 18 h and was used without further purification.
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:39]1([C:45](=[O:53])[CH2:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[ClH:25].[C:1]([C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14]2[N:15]([C:33]([N:50]3[CH2:51][CH2:52][N:47]([CH2:46][C:45]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[O:53])[CH2:48][CH2:49]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:18]=2)=[C:7]([O:36][CH2:37][CH3:38])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C)c(OCC)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12f) and 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 750.4 [(M+H)+]