Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](Cl)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:21][CH2:22][CH2:23][CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: CCCCc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Product: CCCCc1cc2c(N3CCCC3)ccnc2cc1OCc1ccccc1
Reaction time: 24 h
Yield: 101.2 %

Procedure:
A solution of 1 g (3.07 mmol) of 7-benzyloxy-6-butyl-4-chloro-quinoline hydrochloride in 2.5 ml (30.7 mmol) of pyrrolidine was heated at 60° C. with stirring under an argon atmosphere for 24 h after which time the reaction was completed according to HPLC analysis. The excess pyrrolidine was evaporated off, and the residue was partitioned between EtOAc and water. The layers were separated and the aqueous layer once extracted with AcOEt. The combined organic layers were washed with water then saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo to give 1.12 g (97.4%) of the 7-benzyloxy-6-butyl-4-pyrrolidin-1-yl-quinoline as a brown oil. ISP mass spectrum, m/e: 361.3 (M+1 calculated for C24H28N2O: 361).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[F:14][C:15](F)([F:21])[C:16](OCC)=[O:17]>C(OCC)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:16](=[O:17])[CH:15]([F:21])[F:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1ccc(Br)cc1)C(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
n-Butyllithium (1.6 M in hexane) (165 mL, 0.264 mmol) was added dropwise to a −78° C. solution of 1,4-dibromobenzene (60.1 g) in diethyl ether (500 mL). After stirring at −78° C. for 2 h, ethyl trifluoroacetate (40 g) was added dropwise and the mixture was allowed to warm to ambient temperature overnight. The reaction mixture was cooled to −20° C., quenched with saturated aqueous ammonium chloride and extracted with ether. The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with petroleum ether/ethyl acetate (20:1) afforded the title compound.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
Boc-D-Cha-Pro-OBzl was prepared according a similar manner as described in example 1 using Boc-D-Cha and Pro-OBzl.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl.Cl.[CH3:49][Si:50]([CH3:77])([CH3:76])[CH2:51][CH2:52][O:53][CH2:54][N:55]1[C:59]2[N:60]=[CH:61][N:62]=[C:63]([C:64]3[CH:65]=[N:66][N:67]([C:69]4([CH2:73][C:74]#[N:75])[CH2:72][NH:71][CH2:70]4)[CH:68]=3)[C:58]=2[CH:57]=[CH:56]1.Cl[C:79]1[C:93]([F:94])=[CH:92][C:82]([C:83]([NH:85][C@H:86]([CH3:91])[C:87]([F:90])([F:89])[F:88])=[O:84])=[C:81]([F:95])[CH:80]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:74]([CH2:73][C:69]1([N:67]2[CH:68]=[C:64]([C:63]3[C:58]4[CH:57]=[CH:56][N:55]([CH2:54][O:53][CH2:52][CH2:51][Si:50]([CH3:76])([CH3:49])[CH3:77])[C:59]=4[N:60]=[CH:61][N:62]=3)[CH:65]=[N:66]2)[CH2:70][N:71]([C:79]2[C:93]([F:94])=[CH:92][C:82]([C:83]([NH:85][C@H:86]([CH3:91])[C:87]([F:90])([F:88])[F:89])=[O:84])=[C:81]([F:95])[CH:80]=2)[CH2:72]1)#[N:75]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: C[C@@H](NC(=O)c1cc(F)c(Cl)cc1F)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C(F)(F)F
Temperature: 130 °C
Reaction time: 5 h

Procedure:
(R)-(+)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (8.3 mg, 0.013 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (65 mg, 0.13 mmol), 4-chloro-2,5-difluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzamide (0.14 mmol), and cesium carbonate (0.13 g, 0.40 mmol) in toluene (4.0 mL) under N2, followed by palladium acetate (3.0 mg, 0.013 mmol). The reaction mixture was stirred at 130° C. for 5 h. After the reaction mixture was cooled to room temperature, the mixture was worked up with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=661.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH2:19][CH2:18][C:17](=[O:20])[C:16]=1[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29].[O:30]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31]1>C1COCC1.CCCCCC>[O:30]1[CH:34]=[CH:33][C:32]([CH:35]([OH:36])[CH:18]2[C:17](=[O:20])[C:16]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])=[C:15]([O:14][CH3:13])[CH2:19]2)=[CH:31]1
Reactant: O=Cc1ccoc1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)c2ccoc2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 80.1 %

Procedure:
To a solution of diisopropylamine (527 μl) in THF (5 ml) under nitrogen at −78° C. is added, dropwise, butyl lithium, 2.5M solution in hexane (1.32 ml) and the reaction allowed to stir at −78° C. for 20 minutes. This solution is then added dropwise to a solution of 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (691 mg) in THF (5 ml) under nitrogen at −78° C. and the resulting solution allowed to stir for a further 30 minutes. A solution of 3-furaldehyde (377 mg) in THF (1 ml) is then added in one portion and the reaction is allowed to warm to room temperature and stirred for a further 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (50 ml) and extracted with ethyl acetate (50 ml). The organic layer is removed and purified by automated flash chromatography to give 5-(furan-3-yl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (784 mg)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COC1C=CC(N2CCOCC2)=CC=1[N+]([O-])=O>>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Agent: COc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cc(N2CCOCC2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared using morpholine and 1-benzyloxy-4-bromo-2-nitro-benzene (prepared from 4-bromo-2-nitro-anisol and benzyl bromide) using the general method of example “4-(4-methoxy-3-nitro-phenyl)-morpholine” as yellow solid (58%), MS: m/e=315(M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-:3])=[O:2].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)([O:9][CH2:8][CH2:7][C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Product: Cc1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Yield: 96 %

Procedure:
3-Nitrophenethyl tosylate was prepared according to the general method as outlined in Preparation 1 starting from 3-nitrophenethyl alcohol (15 g, 89.7 mmol) and tosyl chloride (20.52 g, 110 mmol). The product was isolated as an off white powder (21.5 g). Yield 96%; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H), 7.87 (t, 1H), 7.63 (d, 2H), 7.46 (m, 2H), 7.25 (m, 2H), 4.26 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.40 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:57])[C@H:4]([CH2:53][CH2:54][S:55][CH3:56])[NH:5][C:6](=[O:52])[C@:7]([CH2:14][C@@H:15]([N:20]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:21][CH2:22][CH:23]([SH:43])[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:16]([CH3:19])[CH2:17][CH3:18])([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][CH3:9].[OH-].[Na+].Cl>CO>[C:48]([O:47][C:45]([NH:44][N:20]([CH2:21][CH2:22][CH:23]([SH:43])[C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:15]([C@@H:16]([CH3:19])[CH2:17][CH3:18])[CH2:14][C@@:7]([C:6]([NH:5][C@H:4]([C:3]([OH:57])=[O:2])[CH2:53][CH2:54][S:55][CH3:56])=[O:52])([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][CH3:9])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC[C@H](C)[C@@H](C[C@@](NC)(C(=O)N[C@@H](CCSC)C(=O)OC)[C@@H](C)CC)N(CCC(S)C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)[C@@H](C[C@@](NC)(C(=O)N[C@@H](CCSC)C(=O)O)[C@@H](C)CC)N(CCC(S)C(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
N-[2(S)-(2(R)-(t-butoxycarbonylamino-3-triphenylmethyl mercaptopropylamino)-3(S)-methylpentyl]-N-methyl-isoleucyl-methionine methyl ester (0.19 g, 0.232 mmol, prepared as an intermediate in Example 5) was dissolved in MeOH (4 mL), treated with 1N NaOH soln (0.927 mL, 0.927 mmol), and stirred for 3.5 h at ambient temperature. The reaction mixture was concentrated, the residue dissolved in H2O (20 mL), neutralized with 1N HCl (0.927 mL, 0.927 mmol), and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, and dried (Na2SO4). Filtration and concentration to dryness gave 0.18g (96%) of the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[CH3:10][C:11]1([CH3:27])[C:20]2[CH:21]=[C:22]([C:24](Cl)=[O:25])[S:23][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12]1>N1C=CC=CC=1.C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[C:24]([C:22]1[S:23][C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([CH3:27])([CH3:10])[C:20]=2[CH:21]=1)=[O:25]
Reactant: CNc1ccccc1Cl
Reactant: CC1(C)Oc2ccccc2-c2sc(C(=O)Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OC2(C)C)c1ccccc1Cl
Temperature: 25 °C
Yield: 31 %

Procedure:
To a solution of 2-chloro-N-methylaniline (32.10 uL, 0.2750 mmol) in 1.2 M of Pyridine in methylene chloride (0.8333 mL) was added a pinch of DMAP, followed by the addition of 4,4-dimethyl-4H-thieno[3,2-c]chromene-2-carbonyl chloride (70.2 mg, 0.250 mmol). The reaction was stirred at room temperature under N2 with LC/MS monitor. The crude product was purified on silica to give 30 mg 141bp. Yield=31% of theoretical. MS: (ESI+)=385
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:14][CH2:13]1.[H][H]>[Ni].C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[NH2:26])[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1

Procedure:
20 g of 1-[(benzo-1,4-dioxan-2-yl)-methyl]-4-(5-chloro-2-nitroanilino)-piperidine were hydrogenated under normal pressure and at room temperature, using 4 g of Raney nickel as a catalyst in 200 ml of ethanol. When the uptake of hydrogen had ended, the mixture was filtered, the material on the filter was rinsed with ethanol and the filtrate was concentrated.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCCN
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1

Procedure:
1-Cyclohexyl-6-[(5-(methoxycarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is reacted according to general operating instructions 7 with 3-methoxypropylamine. 1-Cyclohexyl-6-[(5-((3-methoxy-propyl)aminocarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is obtained as a solid.
Reaction SMILES: N.[CH:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[CH:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])([CH3:4])[CH3:3].[Li].C(O)C>O1CCCC1.O>[CH:2]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22][CH3:23])[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])([CH3:4])[CH3:3]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]12
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]32)C1
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
Add liquid ammonia (100 cc.) to 13β-isopropyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in tetrahydrofuran (50 cc.) followed by lithium metal (0.5 g.), and stir the solution for 10 minutes. Then add ethanol (6 cc.) dropwise. When the blue color is discharged, add water and extract the product with ether. Evaporate the washed and dried extracts to give crude 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.5 g.) as colorless gum.
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]2([C:25]3[CH:34]=[C:33]([O:35][CH2:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH:32]=[CH:31][C:26]=3[C:27]([NH:29][NH2:30])=[O:28])[CH2:23][CH:22]3[CH2:24][CH:19]2[CH2:20][CH2:21]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.C(=O)(O)[O-].[Na+]>C(OC(OCC)OCC)C>[O:28]1[CH:1]=[N:30][N:29]=[C:27]1[C:26]1[CH:31]=[CH:32][C:33]([O:35][CH2:36][C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)=[CH:34][C:25]=1[C:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][CH2:21]2
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: c1ccc(C2(c3cc(OCc4ccc5ccccc5n4)ccc3-c3nnco3)CC3CCC2C3)cc1
Reaction time: 0.5 h

Procedure:
A catalytic amount of p-TSA (˜3 mg) was added to a stirred suspension of 4d HCl salt (54.6 mg, 0.10 mmol) in triethylorthoformate (600 μL) at room temperature. After 30 min, 1N hydrochloric acid (600 μL) was added, and the resulting solution was aged for an additional 45 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TFA as modifier). Lyophilization of the purified fractions afforded the title compound Sc, m/z (ES) 474 (MH)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1.[CH3:36][NH:37][C:38]1[N:43]=[C:42]([CH:44](O)[CH3:45])[CH:41]=[CH:40][CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:36][NH:37][C:38]1[N:43]=[C:42]([CH2:44][CH2:45][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C@H:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)C[C@H](Cc1ccc(O)cc1)c1cccnc1
Reactant: CNc1cccc(C(C)O)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](Cc1ccc(OCCc2cccc(NC)n2)cc1)c1cccnc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Diisopropyl azodicarboxylate (7.8 mL, 39.8 mmole) was added dropwise to a solution of ethyl (S)-4-(4-hydroxyphenyl)-3-(pyridin-3-yl)butanoate (9.455 g, 33.1 mmole), 6-(methylamino)-2-pyridylethanol (6.06 g, 39.8 mmole), and triphenylphosphine (10.44 g, 39.8 mmole) in anhydrous THF (150 mL) at 0° C. The mixture was allowed to warm to RT as the bath warmed. After 18 hr the reaction was concentrated and the residue was flash chromatographed on silica gel (3% MeOH in 1:1 EtOAc/CHCl3) to afford the title compound (9.2 g, 66%) as a viscous yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=4.8, 1.6 Hz, 1 H). 8.39 (d, J=1.9 Hz, 1 H), 7.31-7.45 (m, 2 H), 7.13-7.21 (m, 1 H), 6.91 (d, J=8.6 Hz, 2 H), 6.77 (d, 3=8.6 Hz, 2 H), 6.53 (d, J=7.3 Hz, 1 H), 6.24 (d, J=8.2 Hz, 1 H), 4.43-4.58 (m, 1 H), 4.26 (t, J=7.0 Hz, 2 H), 3.92-4.05 (m, 2 H), 3.32-3.45 (m, 1 H), 3.04 (t, J=7.0 Hz, 2 H), 2.89 (d, J=5.3 Hz, 3 H), 2.88 (dd, J=13.7, 7.2 Hz, 1 H), 2.82 (dd, J=13.7, 7.8 Hz, 1 H), 2.70 (dd, J=15.6, 6.3 Hz, 1 H), 2.59 (dd, J=15.6, 9.0 Hz, 1 H), 1.11 (t, J=7.1 Hz, 3 H); MS (ES) m/e 420 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:15][C:16]1(C)[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]1)[NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[CH3:24]O.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:24][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:23])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)[C@H](CC1(C)C=CC=CC1)NC(=O)OC1CCCCC1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(OC(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
Saponification of the above ester is accomplished by dissolving the oil in 10 ml. of methanol; 10 ml. of water is added and the pH of the mixture adjusted to 12 by addition of 1 N sodium hydroxide. The reaction is allowed to stir for 46 hours at 25°C. The pH of the reaction is adjusted to 7 by addition of 2 N sulfuric acid. The methanol solvent is removed in vacuo, saturated sodium bicarbonate is added to the residual aqueous solution, and then washed twice with ether. The reaction mixture is acidified by dropwise addition of concentrated sulfuric acid to pH 3.0, extracted three times with ethyl acetate, wash the combined organic layers twice with sodium chloride solution and dry over sodium sulfate. After removing the solvent in vacuo, 758 mg. of substantially pure N-(1-methylcyclohexyloxycarbonyl)-phenylalanine is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Cl)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.71 g (4.6 mmol) of p-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The precipitated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(4-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 154°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3].[Cl:25][CH:26]([CH3:30])[C:27](Cl)=[O:28]>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:27](=[O:28])[CH:26]([Cl:25])[CH3:30])=[C:16]([Br:21])[CH:15]=2)=[C:8]([Cl:22])[C:7]=1[CH2:23][CH3:24])(=[O:4])[CH2:2][CH3:3]
Reactant: CC(Cl)C(=O)Cl
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)c(Br)c2)c(Cl)c1CC
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)Cl)c(Br)c2)c(Cl)c1CC
Yield: 93.1 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (80 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 90 mg of ethyl(3,5-dichloro-4-[3-bromo-4-(2-chloropropionamido)phenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 30 mg of 3,5-dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylpropionic acid.