Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:39]#[N:40])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Temperature: 120 °C

Procedure:
4-[5-(3-Bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 65, 0.44 mmol, 0.26 g), Zinc cyanide (0.44 mmol, 0.052 g) in DMF (5.0 mL), water (0.05 mL) were degassed with nitrogen for 10 min then Pd2dba3 (0.022 mmol, 0.02 g), dppf (0.053 mmol, 0.029 g) was added and then degassed for 10 more min. The reaction mixture was heated at 120° C. for 36 h under nitrogen. Cooled, water was added extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 20% ethyl acetate in hexanes to get 4-[6-butyl-5-(3-cyano-4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.17 g).
Reaction SMILES: O.O.[N+:3]([C:6]1[CH:13]=[CH:12][C:9]([O:10][Na])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19]Cl)[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1>[CH2:15]([N:17]([CH2:21][CH2:22][O:10][C:9]1[CH:12]=[CH:13][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(O[Na])cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Yield: 79.5 %

Procedure:
4-Nitrophenoxy sodium dihydrate (29.39 g), 2-(diethylamino)ethylchloride hydrochloride (25.60 g), potassium carbonate (30.17 g) and water (60 ml) were added into xylene (100 ml) and the mixture was heat-refluxed for 2 hours while mixing and continuously removing water by azeotropic distillation. After reaction, insolubles were removed by filtration. Filtrate was added with ethyl acetate (100 ml) and extracted 3 times with 1N HCl (100 ml). Aqueous layer was adjusted to pH 10 with 1N sodium hydroxide and oily substance separated was extracted 3 times with ethyl acetate (100 ml). Ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated to obtain N,N-diethyl-2-(4-nitrophenoxy)ethylamine (28.19 g) as color-less oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[N:18][CH:19]=2)[NH:14][N:13]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:30])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[N:18][CH:19]=2)[NH:14][N:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(-c2n[nH]c3nc(Oc4ccc(F)cc4F)ncc23)c1
Reactant: N
Solvent: CO
Product: NS(=O)(=O)c1ccc(Cl)c(-c2n[nH]c3nc(Oc4ccc(F)cc4F)ncc23)c1
Reaction time: 0.33 h

Procedure:
4-Chloro-3-[6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzenesulfonyl chloride (34 mg, 0.735 mmol) was added to a solution of 2M NH3 in MeOH (1 mL), and the reaction mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (40% EtOAc in hexanes) to give 15 mg of 4-chloro-3-[6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzenesulfonamide, MS (M+H)=418.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][NH:31][CH3:32])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][N:31]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:32])[CH3:27]
Reactant: CCN(CC)CCNC
Reactant: COC(=O)c1cc(C)cc(CO)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.19 mmol) and triethylamine (241 mg, 2.38 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (191 mg, 1.67 mmol). The reaction mixture is stirred for 15 min, the precipitate that formed is removed by filtration, and N,N-diethyl-N′-methylethylenediamine (465 mg, 3.57 mmol) was added. The reaction mixture is stirred at room temperature for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gives the title compound. 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 2H), 7.33 (s, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.95 (m, 4H), 2.75 (m, 4H), 2.41 (s, 3H), 2.31 (s, 3H), 1.21 (m, 6H).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:80].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:80])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCN(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCN(C)CC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.016 g, 0.033 mmol), 2,5-dimorpholinopyridin-3-amine (0.065 g, 0.25 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinoline (0.08 g, 0.21 mmol), Pd2dba3 (0.008 g, 0.008 mmol) and sodium tert-butoxide (0.049 g, 0.51 mmol) in toluene (2.1 mL) at 100° C. for 2 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (1H, d, J=2.3 Hz), 7.96 (1H, dd, J=9.2, 2.5 Hz), 7.83 (1H, d, J=2.7 Hz), 7.69 (2H, m), 7.21 (2H, m), 4.61 (2H, br. d), 3.73 (4H, m), 3.57 (3H, br. d.), 3.46 (4H, br. s.), 3.29 (3H, m), 3.15-3.06 (7H, m), 2.88 (4H, s), 2.04 (3H, s). Mass Spectrum (ESI) m/e=617.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:28](Cl)(=[O:31])(=[O:30])[NH2:29]>ClCCl.Cl.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:14][NH:15][S:28](=[O:31])(=[O:30])[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](S)C[C@H]1CN
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](S)C[C@H]1CNS(N)(=O)=O
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a solution of crude (2S,4S)-1-t-butoxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (4.1 g) in dichloromethane (250 ml) at -70° C. under a stream of nitrogen, triethylamine (8.87 ml) and trimethylchlorosilane (6.73 ml) are added. The mixture is stirred for 1 hour and 40 minutes, mixed with triethylamine (8.87 ml) and a solution of 1M-sulfamoyl chloride in dichloromethane (64 ml), and stirred for 1 hour. The reaction mixture is acidified with dilute hydrochloric acid. The organic layer is taken, diluted with 1N-hydrochloric acid (21 ml) and methanol (50 ml), stirred for 35 minutes at room temperature, and poured into water. The organic layer is taken, washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4S)-1-t-butoxycarbonyl-2-sulfamoylaminomethyl-4-mercaptopyrrolidine (4.57 g). Yield: 69%. Colorless syrup. NMR δ(CDCl3) ppm: 1.46(s, 9H), 1.5 to 1.8(m, 1H), 1.71(d, J=6.6 Hz, 1H), 2.5 to 2.67(m, 1H), 3.0 to 3.46(m, 4H), 3.85 to 4.2(m, 2H), 4.6 (br s, 2H). IR ν (CHCl3) cm-1 : 3420, 3340, 3270, 1679.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[N+:21]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:48]2[N:52]([CH3:53])[C:51]3[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=3[S:49]2)[S:44][CH2+:43]1SC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([N:42]1[C:46](=[O:47])[C:45](=[C:48]2[N:52]([CH3:53])[C:51]3[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=3[S:49]2)[S:44][C:43]1=[N:21][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:18])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:19]=[CH:20][C:4]=1[NH:3][CH2:1][CH3:2])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCNc1ccc(NC(=O)CN2CCN(C)CC2)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN2CCN(C)CC2)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluene sulfonate to afford the title compound. MS(ESI): 628 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:15]
Reactant: COC(=O)CCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of methyl-9-hydroxy-nonanoate (1.1 g, 5.85 mmol, 1.0 equiv) in CH2Cl2 (30 mL, 0.2M) at 0° C. was treated successively with CBr4 (2.5 g, 7.54 mmol, 1.3 equiv) and PPh3 (2.15 g, 8.19 mmol. 1.4 equiv) and the reaction mixture was stirred at 4° C. for 10 h. The reaction mixture was then concenctrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, hexanes) afforded 13 as a clear, colorless oil (1.02 g, 1.47 g theorectical, 69.5%): 1H NMR (CDCl3, 250 MHz) d 3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J=6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, CH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 8H, alkyl protons).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([F:38])[CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[C:30]([F:38])[CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)c(F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-bromo-2-fluoro-benzotrifluoride.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc2ccccc2[nH]1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1c(C)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
A solution of ethyl chlorooxoacetate (22.53 g, 0.165 mol) in diethyl ether (100 mL) was added over a period of 15 minutes to a cooled (0° C.) solution of 2-methylindole (19.7 g, 0.15 mol) and pyridine (14.2 g, 0.18 mol) in diethyl ether (200 mL). The reaction was stirred for two hours at 0° C. under a nitrogen atmosphere. Most of the diethyl ether had evaporated by the end of the two-hour reaction time, and a solid was present. Water (100 mL) was added, and the solid was isolated by filtration and washed with 1:1 diethyl ether/hexane. The solid (27.9 g) was then dissolved in boiling toluene (250 mL) and recrystallized upon cooling to 6° C. The crystals were isolated by filtration, washed with toluene, dried for two hours on the vacuum filter funnel, triturated with water at 75° C. for five minutes, isolated by filtration, and dried for three hours on the filter funnel to provide 17.8 g ethyl (2-methyl-1H-indol-3-yl)(oxo)acetate of as a rust-colored powder.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:44](=[O:45])[N:14]2[CH:15]([C:38]([O:40]CC=C)=[O:39])[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:36][C:35](=[O:37])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CCCC)C([O-])=O)C.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(O)=O>C(Cl)Cl.C(OCC)(=O)C.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:1]([CH2:8][C:9]([NH:11][C@@H:12]1[C:44](=[O:45])[N:14]2[CH:15]([C:38]([OH:40])=[O:39])[C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:36][C:35](=[O:37])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)C1C(COc2ccccc2-c2nc3ccccc3c(=O)[nH]2)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(COc3ccccc3-c3nc4ccccc4c(=O)[nH]3)=CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 135 %

Procedure:
Compound 9 and 10 (0.071 g, 0.114 mmol) were dissolved in 5 mL of dry methylene chloride. Sodium 2-ethylhexanoate (0.019 g, 0.11 mmol) was dissolved in 2 mL of ethyl acetate. After these two solutions were mixed together, PPh3 (0.01 g, 0.04 mmol) and Pd(PPh3)4 (0.01 g, 0.009 mmol) were added. The combined reaction mixture was stirred for 1.5 h at rt. AcOH (0.5 mL) was added to the solution and the reaction mixture was evaporated in vacuo. The residue was re-evaporated from toluene to yield two separable isomers, 23 and 24 (0.09 g). The crude product was used for the next step without any purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1F.[F:15]C1C=C(CO)C=C(OC)C=1[N+]([O-])=O>>[Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([F:15])[CH:4]=1
Reactant: COc1cc(CCl)c(F)cc1[N+](=O)[O-]
Reactant: COc1cc(CO)cc(F)c1[N+](=O)[O-]
Product: COc1cc(CCl)cc(F)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using the procedure from Compound 130C (1-(chloromethyl)-2-fluoro-5-methoxy-4-nitrobenzene) with (3-fluoro-5-methoxy-4-nitrophenyl)methanol (Compound 146D). 1H NMR (CDCl3, 400 MHz): δ=3.96 (s, 3 H), 4.55 (s, 2 H), 6.87-6.90 (m, 2 H).
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=CC=1)(O)=O.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH2:11]([N:12]([CH2:29][C:30]1[CH:31]=[CH:32][C:23]([CH2:14][CH2:13][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:24][CH:25]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=1[C@@H:23]1[CH2:32][CH2:31][C:30]2[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=2[CH2:24]1)[CH3:10]
Reactant: C1CCNC1
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 43.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and pyrrolidine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.8 mg) was obtained.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[C:15]([NH2:22])(=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:21][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=3[C:3]=2[N:22]=1)=[O:17])[CH3:20]
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.4 g, 11 mmol) and ethyl thioamidooxalate (4.2 g, 32 mmol) was added ethanol (81 mL) and heated at reflux (at 80° C.) for 4 days. The reaction mixture was cooled to room temperature and cooled in an ice bath. The precipitate was collected by filtration to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (2.59 g, 69%). LC/MS (ESI+): m/z 355 (M+H).
Reaction SMILES: O[C:2]([C:24]([F:27])([F:26])[F:25])([CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:3][O:4]S(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+]>CN(C)C=O.O>[C:18]1([CH:16]([CH3:17])[CH2:15][C:2]2([C:24]([F:27])([F:26])[F:25])[CH2:3][O:4]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)(CC(C)c2ccccc2)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CC1(C(F)(F)F)CO1)c1ccccc1
Reaction time: 1 h
Yield: 87.4 %

Procedure:
400 mg of 4-toluenesulfonic acid-(2-hydroxy-4-phenyl-2-trifluoromethyl-pentyl)ester in 5 ml of dimethylformamide is mixed at 0° C. with 35 mg of sodium hydride (80% in mineral oil). After one hour at 0° C., it is diluted with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried (Na2SO4) and concentrated by evaporation. The residue is distilled. 200 mg of 2-(2-phenylpropyl)-2-trifluoromethyl-oxiran, boiling point 110° C./1 hPa, is obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C:13](=[O:22])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:10]([OH:23])[C@H:9]([OH:24])[C@H:7]2[N:8]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([C@@H:13]([OH:22])[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:10]([OH:23])[C@H:9]([OH:24])[C@H:7]2[N:8]=1)[CH3:2]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(=O)CCc3ccccc3)O[C@@H]2S1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@@H](O)CCc3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude 1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one (200.00 mg; 0.57 mmol; 1.00 eq.) in MeOH (3.00 ml) was added sodium borohydride (21.59 mg; 0.57 mmol; 1.00 eq.). Reaction was stirred at room temperature for 30 min. The desired product was isolated by prep HPLC (0% B for 10 min, then up to 30% B for 10 min, 0.1% TFA, 220 nm) to afford (3aR,5R,6S,7R,7aR)-2-Ethylamino-5-((S)-1-hydroxy-3-phenyl-propyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1.9 mg, 1%) as a white solid (once lyophilized).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[I-:30].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][I:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: ICCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-benzyloxy-phenyl)-ethanol (78.72 g, 0.34 mol) in methylene chloride (400 ml) is added triethylamine (67.3 ml, 0.44 mol, 1.4 eq), then at 0° C. is added mesylchloride (34.8 ml, 0.44 mol, 1.3 eq). The reaction mixture is stirred at 0° C. for 30 minutes and allowed to rise to room temperature. The reaction mixture is extracted with methylene chloride (2×300 ml), the combined organic layers are then washed with brine (2×300 ml) and concentrated under vacuum. To the crude product in solution in ethyl acetate (600 ml) is added sodium iodide (67.2 g, 0.44 mol, 1.3 eq) and the reaction mixture is stirred under reflux for 6 hours. After filtration, the organic layer is washed with brine (3×400 ml), dried with Na2SO4, filtered and concentrated under vacuum. 1-Benzyloxy-4-(2-iodo-ethyl)-benzene is isolated after crystallization with diethyl ether (116.5 g, 86%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH2:24])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9].N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:29])[C:13]2[O:19][C:18]3[C:20]([Cl:25])=[CH:21][C:22]([NH:24][C:3](=[O:4])[CH2:2][Cl:1])=[CH:23][C:17]=3[CH2:16][S:15](=[O:27])(=[O:26])[C:14]=2[CH:28]=1)=[O:9]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Reaction time: 2 h

Procedure:
Chloroacetylchloride (3.3 mL, 40.8 mmol) was added to the solution of compound of Example 1 (5 g, 13.6 mmol) in dichloromethane (100 mL) at 20° C. Pyridine (6.6 mL, 81.6 mmol) was added and the reaction mixture was stirred for 2 h. The solvent was removed under vacuum and water (200 mL) was added. The solid obtained was filtered, washed with water and purified by stirring in ethyl acetate (200 mL) at reflux condition for 30 min. The solid was filtered and dried to obtain the title compound. Yield: 4.86 g (80.1%); mp 292-293° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.27 (s, 2H, CH2), 5.34 (s, 2H, CH2), 7.67 (s, 1H, Ar), 7.88 (s, 1H, Ar), 8.11 (s, 1H, Ar), 8.15 (s, 1H, Ar), 10.70 (s, 1H, NH); MS: m/e (ES+) 445 (M+1); analysis: C18H15Cl2NO6S requires C, 48.66; H, 3.40; N, 3.15; Cl, 15.96; S, 7.22. found: C, 48.09; H, 3.37; N, 3.38; Cl, 16.37; S, 7.72%.