Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4,6-Dichloronicotinic acid ethyl ester 16 (500 mg, 2.27 mmol) is dissolved in anhydrous dioxane (10 mL) and aniline (0.66 mL, 7.72 mmol) is added. The reaction is stirred at 100° C. overnight. The solvent is removed in vacuo and the crude product is purified using flash chromatography (hexane:ethyl acetate=10:1) to give 6-chloro-4-phenylamino-nicotinic acid ethyl ester 17. 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.70 (s, 1H), 7.33-7.37 (m, 2H), 7.15-7.21 (m, 3H), 6.80 (s, 1H), 4.31 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23]>CS(C)=O.O>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[CH:8][C:7]=1[F:23])#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 32.3 %

Procedure:
To a solution of sodium cyanide (99 mg) in dimethyl sulfoxide (5 ml), a solution of the compound (605 mg) obtained in Example 249 in dimethyl sulfoxide (10 ml) was added dropwise at 60° C. and stirred at 60° C. for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate-diethyl ether (1:1); thereafter, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 164 mg of the titled compound (yield, 32%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[F:15])[O:19][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccccc3F)nc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of 6.0 g (28.8 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 120 mL of nitrobenzene, 17.10 mL (144.0 mmol) of 2-fluorobenzoic acid chloride are added with protection from light. After 10 min of stirring at 80° C., 0.20 mL of concentrated sulfuric acid is added. The reaction mixture is heated to reflux for 18 h. After complete cooling, ether is added to produce a yellow precipitate, which is filtered through fritted glass and washed with ether. This solid is then purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40) to produce 2.5 g of 4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:50])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:49])[CH3:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39]C)=[O:38])=[CH:35][CH:34]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1>[O:50]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:46][CH2:45][C@@H:44]([CH:47]([CH3:48])[CH3:49])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:43])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C@@H:20]([C:33]3[CH:34]=[CH:35][C:36]([C:37]([OH:39])=[O:38])=[CH:41][CH:42]=3)[CH2:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NCCN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 80 °C
Yield: 77.1 %

Procedure:
A mixture of methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.056 mmol) and sodium hydroxide (0.564 mL, 0.564 mmol) in dioxane (1 mL) was heated up at 80° C. for 3 hours. The reaction mixture was filtered and purified by HPLC to provide the title compound as white solid (30 mg, 73%). LCMS: m/e 695.46 (M+H)+, 2.55 min (method 10). 1H NMR (500 MHz, Acetic) δ 8.02 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 3.44-3.36 (m, 1H), 3.35-3.21 (m, 6H), 3.19-2.99 (m, 5H), 2.50 (dd, J=13.0, 2.9 Hz, 1H), 2.34-1.01 (m, 26H), 1.28 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H), 0.93 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H), 0.84 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].CCN(CC)CC.Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([O:31][CH3:32])[N:23]=1>CCO>[CH3:32][O:31][C:24]1[N:23]=[C:22]([NH:1][C@@H:2]([CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][OH:4])[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=1
Reactant: N[C@H](CO)COCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(N[C@H](CO)COCc2ccccc2)n1
Temperature: 78 °C
Yield: 115.5 %

Procedure:
To a solution of (R)-2-amino-3-benzyloxy-1-propanol (698.4 g, 3.931 mol) in EtOH (3.6 L) was added Et3N (1.27 L, 9.11 mol) in portions over 10 min. Then a solution of 2-chloro-6-methoxy-3-nitropyridine (672.7 g, 3.567 mol) in EtOH (0.6 L) was added in portions over 10 min. The mixture was heated at 78° C. for 2 h. The reaction mixture was cooled to room temperature and added to stirred ice/H2O (8.4 L). The mixture was extracted with EtOAc (9+6+3 L). The extracts were washed with brine (6 L), dried over MgSO4 (˜900 g), filtered and evaporated to give (2R)-2-{[6-(methyloxy)-3-nitro-2-pyridinyl]amino}-3-[(phenylmethyl)oxy]-1-propanol (1373.1 g, 115%) as an orange oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]2[NH:8][C:9]3[C:14]([C:3]=2[CH:2]=1)=[C:13]1[C:15]([NH:17][C:18](=[O:19])[C:12]1=[C:11]1[C:20]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:21]=2[NH:22][C:10]=31)=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C)C=O>[CH2:34]([O:27][C:23]1[C:21]2[NH:22][C:10]3[C:9]4[NH:8][C:4]5[C:3](=[CH:2][CH:1]=[CH:6][C:5]=5[O:7][CH2:14][C:3]5[CH:4]=[CH:5][CH:6]=[CH:1][CH:2]=5)[C:14]=4[C:13]4[C:15](=[O:16])[NH:17][C:18](=[O:19])[C:12]=4[C:11]=3[C:20]=2[CH:26]=[CH:25][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)c2c1c1c3cccc(O)c3[nH]c1c1[nH]c3c(O)cccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c1c1c3cccc(OCc4ccccc4)c3[nH]c1c1[nH]c3c(OCc4ccccc4)cccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
180.5 mg of BE-13793C (12,13-dihydro-1,11-dihydroxy-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-(6H)-dione) was dissolved in 137 ml of N,N-dimethylformamide (DMF), 510 mg of potassium carbonate was added, and 170 μl of benzyl bromide was added under ice cooling. The reaction solution was stirred at room temperature for 2 hours and, after addition of 200 ml of water, extracted with 200 ml of ethyl acetate, and the extract was dried over sodium sulfate and concentrated under reduced pressure to give 1,11-dibenzyloxy-12,13-dihydro-5H-indolo[ 2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (yield: 93.7%).
Reaction SMILES: C([NH:4][CH:5]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])C(OCC)=O)(=O)C.[ClH:17]>>[ClH:17].[NH2:4][CH2:5][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Product: CCCCC(=O)CN

Procedure:
Ethyl 2-acetamido-3-oxoheptanoate (10.4g) was hydrolysed by heating under reflux with 50% hydrochloric acid (80 ml) for 9 hours. The mixture was evaporated to dryness to give 1-amino-2-hexanone hydrochloride (5.8g) as a dark red oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[OH:41][CH:42]([C@@H:67]1[CH2:71][C@H:70]([SH:72])[CH2:69][N:68]1[C:73]([O:75][CH2:76][C:77]1[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=1)=[O:74])[CH2:43][C:44]([N:46]1[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH3:66])[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:47]1)=[O:45]>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:72][C@@H:70]3[CH2:69][N:68]([C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][C:80]([N+:83]([O-:85])=[O:84])=[CH:81][CH:82]=4)=[O:74])[C@H:67]([CH:42]([OH:41])[CH2:43][C:44]([N:46]4[CH2:50][CH2:49][C@H:48]([CH2:51][N:52]([CH3:66])[C:53]([O:55][CH2:56][C:57]5[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=5)=[O:54])[CH2:47]4)=[O:45])[CH2:71]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C[C@H]1CCN(C(=O)CC(O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(O)CC(=O)N4CC[C@H](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 80.3 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (660.8 mg) and (2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl)ethyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (683.5 mg), reaction and purification were carried out in a similar manner to that described in Example 40-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(2S,4S)-2-[1-hydroxy-2-[(3S)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]ethyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate (841.4 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][C@@H:18]([CH3:20])[O:17][C@@H:16]([CH3:21])[CH2:15]2)[N:11]=[C:10]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=3[N:24]=[C:23]2[CH:33]([F:35])[F:34])[N:9]=1>O>[F:34][CH:33]([F:35])[C:23]1[N:22]([C:10]2[N:11]=[C:12]([N:14]3[CH2:19][C@@H:18]([CH3:20])[O:17][C@@H:16]([CH3:21])[CH2:15]3)[CH:13]=[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:9]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:25]=2[N:24]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)cc(N2C[C@@H](C)O[C@@H](C)C2)n1
Reactant: C1COCCN1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Morpholine (275 ml, 3.15 mol) was added to 4-chloro-2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-6-(cis-2,6-dimethylmorpholino)pyrimidine (14.4 g, 34 mmol) thus obtained, and stirred at room temperature for 30 minutes and further at 80° C. for 30 minutes. Water was added to the reaction solution, and the precipitated crystals were filtered, and washed well successively with hexane, ether and ethyl acetate, then air-dried to afford 2-(2-difluoromethyl-4-methoxybenzimidazol-1-yl)-4-(cis-2,6-dimethylmorpholino)-6-morpholinopyrimidine (13.7 g, yield 86%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[CH:12]=[CH:13][C:14]1[CH:19]=[C:18]([O:20]C)[C:17]([CH2:22][CH2:23][CH3:24])=[C:16]([O:25]C)[CH:15]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([OH:25])[C:17]([CH2:22][CH2:23][CH3:24])=[C:18]([OH:20])[CH:19]=1
Reactant: CCCc1c(OC)cc(C=Cc2c(F)c(F)c(F)c(F)c2F)cc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(O)cc(C=Cc2c(F)c(F)c(F)c(F)c2F)cc1O
Yield: 21 %

Procedure:
This material was prepared from 1-(2,3,4,5,6-pentafluorophenyl)-2-(−3,5-dimethoxy-4-1-propylphenyl)ethene and pyridine hydrochloride in 21% yield in the same way as described in Example 34. 1HNMR (CDCl3, ppm): δ 1.40 (d, J=7.2 Hz, 6H), 3.53 (d, J=7.2 Hz, 6H), 4.91 (s, 2H), 6.55 (s, 2H), 6.86 (d, J=17 Hz, 1H), 7.28 (d, J=17 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:33]([OH:37])(=[O:36])[CH:34]=[CH2:35].ClC1C=CC(N(C(=O)CC)C2C3C(=CC=C(C=CC(O)=O)C=3)N(C(=O)C3C=CC(F)=CC=3)C(C)C2)=CC=1.C(N(C1C=CC(Cl)=CC=1)[C@H]1C2C(=CC=CC=2)N(C(C2C=CC(CCC(O)=O)=CC=2)=O)[C@@H](C)C1)(=O)C>>[C:9]([N:8]([C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:14]([CH3:32])[CH2:13]1)[C:5]1[CH:6]=[CH:7][C:2]([CH2:35][CH2:34][C:33]([OH:37])=[O:36])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Br)cc3)C[C@@H]2C)cc1
Reactant: C=CC(=O)O
Agent: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Agent: CCC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(CCC(=O)O)cc3)C[C@@H]2C)cc1

Procedure:
(2S,4R)-3-(4-{Acetyl-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-amino}-phenyl)-propionic acid was prepared from (2S,4R)-N-(4-bromo-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide. (2S,4R)-N-(4-Bromo-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was converted to the acrylic acid using the same procedure described in the synthesis of (±)-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid. The reduction and saponification were carried out as in the procedure describing the preparation of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-propionic acid.
Reaction SMILES: C(C1CN(CC(NC2C=CC=C([N+]([O-])=O)C=2)=O)CCN1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])C1C=CC=CC=1.[CH2:37]([CH:44]1[CH2:49][NH:48][CH2:47][CH2:46][N:45]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl>[CH2:37]([CH:44]1[CH2:49][N:48]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:47][CH2:46][N:45]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(CN1CCN(C(=O)OCc2ccccc2)C(Cc2ccccc2)C1)Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1Cc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl 2-benzyl-4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazine-1-carboxylate. To a solution of 3.0 g (10.9 mmol) of (RS)-tert-butyl 2-benzylpiperazine-1-carboxylate in 30 mL of methylene chloride at 0° C. was added 2.3 mL (16.5 mmol) of triethylamine and 1.7 mL (11.9 mmol) of benzyl chloroformate. The resultant mixture was stirred at ambient temperature for 16 h and an additional 0.4 mL (2.8 mmol) of benzyl chloroformate was added. After stirring for a further 2 h, the reaction was partitioned between methylene chloride and water. The organic layer was washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated in vacuo to give 4-benzyl 1-tert-butyl 2-benzylpiperazine-1,4-dicarboxylate. The tert butyl carbamate was deprotected as described in Example 1, Step A to give 2.9 g of the free amine. A portion (1.5 g, 4.8 mmol), of this material was coupled with 1.6 g (7.5 mmol) of alpha-chloro-3-nitroacetanilide as described in Example 1, Step A, to give 1.3 g of the title compound as an off-white foamy solid. 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 7.99 (d, 1H, J=8 Hz), 7.96 (d, 1H, J=8 Hz), 5.58 (t, 1H, J=8 Hz), 7.36–7.05 (m, 10H), 5.00 (bs, 2H), 4.38–4.31 (m, 1H), 3.99 (d, 1H, J=16 Hz), 3.48 (td, 1H, J=16,2 Hz), 3.22–2.95 (m, 5H), 2.80 (d, 1H, J=14 Hz), 2.33–2.20 (m, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1>CN1CCCC1=O.O>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([NH:2][NH2:3])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4.5 ml of hydrazine hydrate were added dropwise to the solution of 3.2 g of 4-fluoro-2-methoxynitrobenzene in 15 ml of N-methylpyrolidone and the mixture was stirred for 2 hours, which initially resulted in gentle heating. The mixture was then diluted with 50 ml of water and stirred, and a precipitate formed which was filtered off with suction and dried under reduced pressure.
Reaction SMILES: C(NC(=O)/C=C(\O[C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1)/C)(C)(C)C.[CH3:32][N:33]([NH2:35])[CH3:34]>C(#N)C>[CH3:32][N:33]([CH3:34])[NH:35][C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Reactant: CN(C)N
Solvent: CC#N
Product: CN(C)NC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Reaction time: 24 h

Procedure:
N-tert-butyl-3-(2-furfurylamino-4-chloro-5-methylsulfonylbenzoyloxy)crotonamide (4.69 g.; 0.01 mole) and unsymmetrical-dimethylhydrazine (1.20 g.; 0.02 mole) are added to acetonitrile. The reaction mixture is refluxed with stirring for 24 hours. Additional unsymmetrical-dimethylhyrazine (1.20 g.; 0.02 mole) is added, and refluxing is continued for an additional 24 hours. The acetonitrile is removed under reduced pressure, and the dark residue is triturated with isopropyl alcohol. The tan colored solid which crystallizes is collected and dried, yield 2.4 g. (64%), m.p. 90° -104° C. Several recrystallizations from butyl chloride followed by a recrystallization from benzene yields 2-furfurylamino-4-chloro-5-methylsulfonylbenzoic acid 2,2-dimethylhydrazide in the form of a white solid, m.p. 169.5°-171° C.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([O:35][C@H:36](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Cl:59]C1C=CC(C=C)=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(OC)(OC)(OC)C.Cl[Si](C)(C)C>CC(O)(C)C.O.C(Cl)Cl>[Cl:59][C:32]1[CH:31]=[CH:30][C:29]([C@H:28]2[CH2:36][O:35]2)=[CH:34][CH:33]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1ccc(Cl)cc1
Agent: COC(C)(OC)OC
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClCCl
Product: Clc1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of AD-mix-alpha (7.0 g) in tBuOH (23 mL) and water (23 mL) was stirred at r.t. during 15 min. The mixture was then cooled down to 0° C. and 4-chlorostyrene (0.64 mL, 5.0 mmol, 1.0 eq.) was added. The resulting heterogeneous slurry was stirred vigorously at 0° C. for 3 hours. Sodium sulfite (7.5 g, 59.5 mmol, 11.9 eq.) was added and the reaction mixture was allowed to warm to r.t. and stirred at that temperature for 1 hour. DCM (45 mL) was added and the layers were separated. The aq. phase was extracted with DCM (3×20 mL). The combined org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in DCM (12 mL). Trimethyl orthoacetate (0.85 ml, 6.5 mmol, 1.3 eq.) was added and the mixture was cooled down to 0° C. Chlorotrimethylsilane (0.83 mL, 6.5 mmol, 1.3 eq.) was added dropwise and the reaction mixture was stirred for 1.5 hour. The solvent was removed in vacuo and the residue was dissolved in MeOH, treated with K2CO3 (0.86 g) and stirred vigorously at r.t. for 18 hours. The suspension was filtered and the filter cake was washed with DCM. The filtrate was concentrated in vacuo. The resulting residue was dissolved in DCM and water was added. The layers were separated and the aq. phase was extracted once with DCM. The combined org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 28 fractions of 45 mL, Heptane 100% to Heptane+10% AcOEt) to yield (S)-2-(4-chloro-phenyl)-oxirane as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[CH3:24][N:25]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:26](N1C=C[N+](C)=C1)=[O:27]>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:26](=[O:27])[N:25]([CH3:24])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:9]=2
Reactant: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(O)ccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)ccc12

Procedure:
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide by applying procedure 3. HPLC-MS m/z=452 (M+1), Rt: 5.15 min.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][SH:11])=[CH:6][CH:5]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:15]>C(O)C>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11][CH2:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: SCc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CSCc1ccncc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.52 g., 9.6 mmoles) was dissolved in 15 ml. of absolute ethanol and cooled to 0°-5° C. 4-Picolyl mercaptan (1.2 g., 9.6 mmoles) in 15 ml. of ethanol was added over 5 minutes time. Alpha-bromo-p-nitro-acetophenone (2.3 g., 9.6 mmoles) in 20 ml. of warm ethanol was then added over 5 minutes, the mixture was warmed to room temperature and left to stir for approximately 16 hours. The reaction mixture was filtered and the filtrate concentrated to an oil (4.3 g.). The oil was chromatographed on 175 g. of silica gel with 1:1 hexane:ethyl acetate as eluant. Product-containing fractions were combined and evaporated to yield alpha-(4-picolylthio)-p-nitro-acetophenone [1.40 g.; oil; pnmr/CDCl3 /TMS/delta: 6.5 (3, 4H), 2.7 (d, 2H), 1.9 (d, 4H), 1.5 (d, 2H); mass spectra: m/e calcd.: 288; found: 288, 242, 165, 150, 138, 124, 104, 92, 76, 65, 39; ir (film): 3-3.5, 5.95, 6.25, 6.55, 7.35, 7.85, 11.70,μ].