Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8](Cl)=[O:9])=[O:4].[NH2:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12>C(OCC)(=O)C.C1OC1C>[Cl:1][CH:2]([Cl:16])[C:3]([O:5][N:6]=[C:7]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH:17][C@@H:18]1[C:49](=[O:50])[N:20]2[C:21]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][S:24][C@H:19]12)=[O:9])=[O:4]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)s1
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1cccs1
Agent: CC1CO1
Solvent: CCOC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c4cccs4)[C@H]3SC2)s1

Procedure:
A solution of 2-dichloroacetoxyimino-2-(thien-2-yl)acetyl chloride 0.585 g.) in ethyl acetate (5 ml.) was added to a stirred suspension of diphenylmethyl 7β-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (1 g.) in ethyl acetate (10 ml.) and propylene oxide (1 ml.) at 20°. After 30 minutes all the solid had dissolved. The solution was washed with 2 N-hydrochloric acid, saturated sodium bicarbonate solution, water and brine, dried and concentrated to give crude diphenylmethyl 7β-[2-dichloroacetoxyimino-2-(thien-2-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethylceph-3-em-4-carboxylate (syn-isomer) as a solvated foam (1.567 g.) λmax. (EtOH) 267.5 nm (E11 240), τ values (CDCl3) include 3.00 (singlet, --CHPh2), 3.75 (singlet; CHCl2) and 7.35 (singlet; CH3).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][OH:9])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[C:10](ON1C(=O)CCC1=O)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].O.[OH-].[Na+]>CC#N.CC(N(C)C)=O.O.CC(N(C)C)=O.[Cl-].[Na+].O>[OH:9][CH2:8][C:2]1([CH3:1])[NH:3][CH2:4][CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7]1
Reactant: CC1(CO)CNCCN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: O
Product: CC1(CO)CN(C(=O)OCc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To crude (2-methylpiperazin-2-yl)methanol (10 C) (0.042 mol) dissolved in CH3CN/DMA/H2O (20 mL, 20 mL, 20 mL) cooled to 0° C. was added CBZ-OSu (9.5 g, 0.038 mol) in DMA (15 mL). The reaction was stirred at 0° C. for 30 min then warmed to RT. To the mixture was added H2O (500 mL), sat'd brine (50 mL) and 1M NaOH (50 mL), then the residue was extracted four times with EtOAc (100 mL). The combined EtOAc layers were washed twice with brine then dried over MgSO4 and the solvent removed in vacuo to give racemic benzyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (9.7 g). HPLC RT: 1.302 min (4 min Chromolith column TFA).
Reaction SMILES: [I-].C(O[C:5]([C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[C:10](C[N+](C)(C)C)=[CH:9][CH:8]=1)=[O:6])C.[F:21][C:22]([F:33])([F:32])[S:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])(=[O:25])=[O:24].[CH2:34](N(CC)CC)C>C(#N)C>[F:33][C:22]([F:32])([F:21])[S:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[C:5](=[O:6])[C:7]2[N:12]3[C:13](=[CH:14][N:15]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:34]1)(=[O:24])=[O:25]
Reactant: CCOC(=O)c1ccc(C[N+](C)(C)C)c2nccn12
Reactant: NCCCCNS(=O)(=O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: [I-]
Solvent: CC#N
Product: O=C1c2cccc3ncc(n23)CN1CCCCNS(=O)(=O)C(F)(F)F

Procedure:
A solution of 778 mg (2.0 mmol) of 5-ethoxycarbonylimidazo[1,2-a]pyridin-8-ylmethyl trimethylammonium iodide, 616 mg (2.4 mmol) of 4-trifluoromethanesulfonamido-1-butylamine and 1.12 ml (8.0 mmol) of triethylamine in 40 ml of acetonitrile was heated for 14 hours under reflux. The solvent was distilled off. To the residue was added chloroform, and washed with water. The aqueous layer was further extracted with chloroform. The chloroform layers were combined, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was crystallized from chloroform. The crystalline product was collected by filtration, washed with chloroform and dried to afford 141 mg (18.8%, colorless crystals) of the desired compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=O)=O.ClC1N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:10]=[C:9]2[N:28]([CH2:36][C:37]3[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=3)[N:29]=[C:30]([CH2:31][CH:32]([OH:35])[CH2:33]O)[C:8]=12.ClC1N=[C:52]([N:54]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:51]=C2N(CC3C(C)=C(OC)C(C)=CN=3)N=C(CCC=O)C=12.N1C(C)=CC(C)=CC=1C.Cl>ClCCl>[OH:35][CH:32]1[C:33]2[CH2:1][S:2][N:51]=[C:52]([N:54]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])[C:9]3=[N:10][N:28]([CH2:36][C:37]4[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=4)[N:29]=[C:30]([C:8]=23)[CH2:31]1
Reactant: COc1c(C)cnc(Cn2nc(CC(O)CO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: COc1c(C)cnc(Cn2nc(CCC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 50 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
A solution of methanesulfonyl chloride (73 μL) in dehydrated dichloromethane was added dropwise to a mixture composed of di-tert-butyl {4-chloro-3-(2,3-dihydroxypropyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of Step 7) of Example 1 (510 mg), 2,4,6-collidine (1.15 mL) and dehydrated dichloromethane (17 mL) under cooling in an ice bath, and then the mixture was stirred for 15 hours. 0.5 N hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with water, and then dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (10 mL). Sodium bisulfide monohydrate (76 mg) was added under cooling in an ice bath, followed by stirring for 20 minutes. Potassium carbonate (142 mg) was added to the reaction mixture and the ice bath was removed. The mixture was stirred for one hour, and then heated to 50° C. and further heated with stirring for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (453 mg, 92%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH2:12](I)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:12][CH2:13][CH3:14])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCn1c(=O)oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 100 mL round-bottomed flask was charged with 5-bromo-2-benzoxazolinone (0.750 g, 3.50 mmol), n-propyl iodide (0.684 mL, 7.01 mmol), potassium carbonate (1.211 g, 8.76 mmol) and Dioxane (5 mL). The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with water. Colorless precipitate was collected through filtration and 5-Bromo-3-propyl-3H-benzooxazol-2-one was obtained, ESI-MS: m/z 258.2 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])[CH:13]=[CH2:14]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
Allyl 3-hydroxyphenylacetate (5.72 g, 32.9 mmol), potassium carbonate (6.82 g, 49.35 mmol), and ethyl 2-bromoisobutyrate (7.35 mL, 49.35 mmol) were dissolved in dimethylformamide (10 mL), and the mixture was stirred for 60 hours at 80° C. The reaction mixture was added to water, and the resultant mixture was extracted with diethyl ether, followed by washing sequentially with water and saturated brine, drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (6.40 g, 20.90 mmol, 63.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:8]([CH:10]=1)[NH2:9])[CH3:2].CC(C)([O-])C.[K+].[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28]Br.O>CN(C)C=O>[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:10][C:8]=2[NH2:9])=[CH:13][CH:14]=1
Reactant: CCOc1ccc(Oc2ccc(O)cc2)c(N)c1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc(OCc3cc(F)ccc3F)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 5-ethoxy-2-(4-hydroxyphenoxy)aniline (3.68 g, 15 mmol) in N,N-dimethylformamide (50 ml) were added potassium tert-butoxide (2.02 g, 18 mmol) and 2,5-difluorobenzyl bromide (3.11 g, 15 mmol), followed by stirring at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and after drying, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate-hexane (1:4)] to give the title compound (4.29 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15]>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
A solution of 4-chloro-3-nitrobenzoic acid (30 g, 1.0 eq) in 200 mL CH3NH2 (aq) was stirred at 100° C. for 14 h, cooled, and concentrated in vacuo. The residue was poured into 200 mL 2N HCl (aq) at ° C. The suspension was filtered and washed with water to give the product as yellow solid (quant). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.0 Hz, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.95 (dd, J=9.2 Hz, 2.0 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 2.98 (s, 3H).
Reaction SMILES: C(=O)([O-])N.[NH4+].[C:6]1(=[O:19])[O:16]CC[O:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:7]1=[CH:8][CH:9]=2>O>[C:6]([OH:19])(=[O:16])[C:7]1[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1OCCOC(=O)c2ccc1cc2
Agent: NC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 200 °C

Procedure:
In a heated autoclave, provided with a mixer and filled partially with water, disintegrated poly/ethyleneterephtalate/ wastes in a form of scraps of film and bottles in the amount of 1000 g were placed together with a solution of 407 g of ammonium carbamate (NH4CONH2) in 10 liters of water. Then a content of the reactor was heated up to 200° C. and the temperature was kept till the digestion of poly/ethylene terephtalate/. The autoclave was relieved and the excess of carbon dioxide and water were removed. The water solution of products formed in the autoclave was filtered hot through a filter with active carbon. The chilled filtrate was acidified with sulphuric acid and the precipite of terephtalic acid was separated from a filtrate in a centrifuge. The resulted product was washed with distilled water, giving 862 g of terephtalic acid. From a solution, resulted after precipitation and separation ethylene glycol in amount of 321 g was separated, using distillation process, and the residue was ammonium sulphate.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].O>CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3][CH:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -50 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.2 g, 16 mmol, 1.0 equiv) in Et2O (20 mL) at −50° C. were added BF3.Et2O (2.3 g, 16 mmol, 1.0 equiv) in dropwise. After completion of addition of BF3.Et2O, ethyl 2-diazoacetate (2 g, 17.6 mmol, 1.1 equiv) was added dropwise. The reaction was then stirred at −50° C. for an hour and kept at room temperature overnight. Then the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (3×100 mL), combined of the organic layers and dried over Na2SO4. The solvent was removed under reduced pressure to give the desired product (4 g), which was purified by silica gel chromatography. MS (ESI): 286 (MH+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C@@H:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[CH:11]=[CH:12][CH:13]=1)[OH:7].Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C@@H:6]([OH:7])[C:5]([OH:41])=[O:4])[CH:9]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.010 mL) was added to a solution of (R)-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-3-yl)hydroxy-acetic acid methyl ester (Example 156-(3); 2.6 mg, 0.0048 mmol) in methanol (0.10 mL) at room temperature, and the mixture was stirred at room temperature for four hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (2.5 mg, 100%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(O)=O>[CH:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1)=[O:5]
Reactant: CCOC(=O)c1csc(CNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
To 1.50 g of the above-obtained ethyl 2-(tert-butoxycarbonylamino)methylthiazole-4-carboxylate was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue to adjust the pH of the mixture to approximately 8. To this was added 30 ml of dichloromethane. To the mixture was added with vigorous stirring a mixture which had been prepared by reacting 1 ml of formic acid with 1 ml of acetic anhydride at 50° C. for 30 minutes, and the resulting mixture were stirred for an additional one hour. The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 1.15 g of crude ethyl 2-(formylamino)methylthiazole-4-carboxylate. This compound was dissolved in 30 ml of dichloromethane. To the solution was added 1.2 ml of phosphorus oxychloride at -20 C., and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. To this was added 12 ml of phosphorus oxychloride, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was cooled to room temperature, and then concentrated to dryness under reduced pressure. The residue was dissolved in 30 ml of water, and the solution was washed with 20 ml of dichloromethane. To this was added sodium hydrogencarbonate to adjust the pH of the solution to 8, and the mixture was extracted with dichloromethane (30 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.885 g (yield 85%) of the title compound as light brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:21]=4[S:20](=[O:31])(=[O:30])[N:19]=3)=[C:14]([OH:32])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:33][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[ClH:36]>CO.[Pd]>[ClH:36].[NH2:29][CH2:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:15]3[C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:35][CH:34]=4)[C@@H:8]4[C@H:13]([C:14]=3[OH:32])[C@@H:12]3[CH2:33][C@H:9]4[CH2:10][CH2:11]3)=[N:19][S:20](=[O:31])(=[O:30])[C:21]=2[CH:27]=1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(1R,2S,7R,8S)-3-[3-(4-Fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.38 g, 0.77 mmol) was dissolved in methanol (required gentle heating via heat gun). Concentrated aqueous hydrochloric acid solution (5 mL) was added followed by 10% palladium on carbon (−150 mg). The mixture was degassed and backfilled with hydrogen gas via balloon. The mixture stirred at 25° C. for 3 h. The mixture was passed through a plug of Celite, eluting with additional methanol (200 mL). The filtrate was concentrated in vacuo to afford the desired product, (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one hydrochloride (˜0.77 mmol), as a pale yellow solid. The solid was used directly in the next step without further purification or characterization. LC-MS (ESI) calculated for C25H25FN4O4S 496.16. found 497.3 [M+H+].
Reaction SMILES: [CH:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=[O:45])[C@H:24]([CH2:43]O)[NH:25]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH:1]1([C:7]2([O:20][CH2:43][C@@H:24]([C:23]([OH:45])=[O:22])[NH2:25])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1(C2CCCCC2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: N[C@@H](COC1(C2CCCCC2)c2ccccc2-c2ccccc21)C(=O)O

Procedure:
from 9-cyclohexyl-9H-fluoren-9-ol (Example 1r) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc2c1CCCC2
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc4c3CCCC4)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 176.7 mg (1.2 mmol) of 1-amino-5,6,7,8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride in 12 mL of 2-ethoxyethanol was refluxed for 2 hr. The work up gave 195.1 mg (54.3%) of the product as a yellow solid, m.p. 248° C. (dec.), mass (electrospray, m/e): M+H 360.1. HRCIMS: calcd 359.163 for C22H16N3O2Cl(M+), obsd 359.1632.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].[BH4-].[Na+]>O1CCCC1.C(O)C.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
500 mg of 11β-fluoro-3-hydroxy-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 5 ml of tetrahydrofuran, 2.75 ml of ethanol and 1.1 ml of water, and 100 mg of sodium borohydride is added at a bath temperature of 0° C., and it is stirred for 0.5 hour at room temperature. Then, it is added to water, extracted 3 times with ethyl acetate, washed neutral with saturated common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 441.3 mg of 11β-fluoro-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as crystals with a melting point of 174-176° C. [α]D22=14.9° (c=0.5% in pyridine).