Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:11])[S:4]([NH:7][CH2:8][CH2:9][NH2:10])(=[O:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[ClH:1].[CH:12](=[N:10][CH2:9][CH2:8][NH:7][S:4]([N:3]([CH3:11])[CH3:2])(=[O:6])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)S(=O)(=O)NCCN
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Yield: 41.1 %

Procedure:
A mixture of 4.0 g (0.02 mole) of 2-[N-[(dimethylamino)sulfonyl]amino]ethylamine hydrochloride and 2.0 g (0.02 mole) of benzaldehyde was stirred and treated immediately with 2.0 g (0.02 mole) of triethylamine, followed by the addition of 200 ml of dry benzene. The solution was heated to reflux employing a Dean-Stark apparatus. After 2 hr at reflux, the benzene solution was cooled and washed twice with 100 ml portions of water. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to an oil, which was dissolved in ether and treated with HCl gas to precipitate a yellowish solid. The product was collected by filtration, washed with ether and air dried to provide 2.4 g (50%) of product. The NMR spectrum was consistent with the assigned structure and the solid was used without additional purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]([O:32][CH2:33][CH3:34])=[CH2:31])CCC.N#N>CN(C=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>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([C:30]([O:32][CH2:33][CH3:34])=[CH2:31])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:21]([F:22])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Temperature: 95 °C

Procedure:
A solution of 6-chloro-3-[1-(4,6-difluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (80 mg, 0.23 mmol) and tributyl(1-ethoxyvinyl)stannane (0.234 mL, 0.69 mmol) in 15 mL of DMF was purged with N2 for 30 min and then Pd(PPh3)4 (80 mg, 0.069 mmol) was added and the solution was heated at 95° C. overnight. After the reaction was complete, it was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution then brine, dried over Na2SO4. Solvent was evaporated and the crude (80 mg, 90%) was used in the next step without further purification. LCMS (method C): [MH]+=384.0, tR=4.67 min
Reaction SMILES: [H][H].[Cl:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pt]>[Cl:3][C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1Cl
Yield: 99.9 %

Procedure:
Hydrogen gas was passed through a solution of methyl 2-chloro-3-nitrobenzoate (10.0 g, 46.4 mM) and 1.0 g of 3% sulfided platinum on carbon in 150 mL ethyl acetate for 48 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 8.6 g (100%) of methyl 2-chloro-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ 7.25 (dd, 1H, J=1 and 8 Hz), 7.2 (t, 1H, J=8 Hz), 6.95 (dd, 1H, J=1 and 8 Hz), and 3.9 (s, 3H). IR (CHCl3, cm−1) 3450, 3380, 2980, 2900, 1729, 1615, 1456, 1434, 1322, 1290, and 1268. MS (ES) m/e 186, 188.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:2]=12.C([Li])CCC.[C:17]1([CH3:25])[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=1.[ClH:26]>O1CCCC1.CCCCCC.CCOCC.O>[ClH:26].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:25])=[CH:18][CH:19]=3)[OH:24])[C:2]=12
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cnc2c(c1)CCCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2CCCCc3cccnc32)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6,7,8,9-Tetrahydro-5H-cyclohepta[b] pyridine (7.4g 0.05m) in tetrahydrofuran (100ml) was cooled to -10° C. and treated with a 1.57M solution of n-butyl lithium in n-hexane (32ml), then stirred at -10° C. for a further 0.5h. 4-Tolualdehyde (10g, 0.083m) in tetrahydrofuran (10ml) was added rapidly and the mixture allowed to warm to room temperature, then water and ether were added. The combined ether extracts were treated with 2N hydrochloric acid and the separated aqueous acid extract was basified with solid sodium carbonate and then extracted with chloroform. The combined chloroform solutions were washed with water, dried (MgSO4) and evaporated to give an oil. This was purified by chromatography using silica columns eluted with DIPE or chloroform. The purification was monitored by t.l.c. using DIPE and chloroform on silica plates or samples were silylated with 1-(trimethylsilyl)-imidazole and injected on a g.l.c. (injection temp. 200° C.) with a 25 meter BPI column, running a temperature programme from 120 ° to 300° C. at 10° C./min., then isothermal and carrier gas helium at 10psi. The products were isolated and these were converted into the hydrochloride salts by dissolving in ether and treating with ethereal HCl to give R*, S* 1-(6,7,8,9-tetrahydro-5H-cyclohepta-[b] pyrid-9-yl)-1-(4-methylphenyl) methanol hydrochloride (retention time 16.72 min, 1.4g, 9%) m.p. 205°-7° C. (Found: C, 71.4;H, 7.5; N, 4.6; C18H21NO.HCl requires C, 71.2;H, 7.3; N, 4.6%). R*, R* 1-(6,7,8,9-tetrahydro-5H-cyclohepta[b] pyrid-9yl)-1-(4-methylphenyl) methanol, hydrochloride, three quarter hydrate (retention time 16.63 min, 1.7g, 11%) m.p. 216°-7° C. (Found C, 68.6; H, 7.3; N, 4.35, C18H21NO.HCl. 0.75H2O requires C, 68.1; H, 7.5; N, 4.4%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[C:28](=[O:29])[C:27]([CH3:31])([CH3:30])[N:26]([CH2:32][C:33]5[C:42]6[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=6)[N:36]=[CH:35][CH:34]=5)[C:25]4=[O:43])[CH:22]=3)[C:17]([CH3:45])([CH3:44])[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:44][C:17]1([CH3:45])[C:18]2[C:23](=[CH:22][C:21]([N:24]3[C:28](=[O:29])[C:27]([CH3:30])([CH3:31])[N:26]([CH2:32][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)[C:25]3=[O:43])=[CH:20][CH:19]=2)[N:15]([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc(N4C(=O)N(Cc5ccnc6ccccc56)C(C)(C)C4=O)cc32)CC1
Agent: Cl
Solvent: CO
Product: CC1(C)CN(CC2CCNCC2)c2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21

Procedure:
A solution of 25 mg 4-[6-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-3,3-dimethyl-2,3-dihydro-indol-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester in 2 ml of a 8 N solution of hydrochloric acid in methanol was stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the combined fractions containing the product yielded a white solid, that was partitioned between 2 ml of a satured aqueous solution of sodium hydrogen carbonate and 2 ml ethyl acetate. The organic layer was dried over sodium sulfate. After filtration the solvent was removed under reduced pressure. The residue was dissolved in a mixture of 1 ml acetonitrile and 2 ml water. After addition of 0.01 ml of a 1 N solution of hydrochloric acid the resulting solution was lyophilized to yield a white foam. The product was obtained as its hydrochloric salt.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:35][C:32]([F:34])([F:33])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:19]=[N:18][N:17]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:16]=2)[CH2:10][C@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CC(=O)OC(C)(C)C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (500 mg) and tert-butyl bromoacetate (225 mg) in N,N-dimethylformamide (7.5 ml) was added potassium carbonate (390 mg), and the mixture was stirred at 60° C. for 7 hours. Water was added to the mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (1:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[[1-(tert-butoxycarbonylmethyl)-1H-pyrazol-4-yl]methyl]-2-(3,4-dimethylbenzyl)piperazine as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@@H:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8][C:7]=2[CH:20]=1)=[O:2].CC(C)([O-])C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.O>CN(C=O)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:10]2[CH2:9][CH2:8][C:7]3[CH:20]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[CH:14][CH:15]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(OCc3cccc(F)c3)cc1)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3,4-dihydro-6-formyl-2-(4-hydroxybenzyl)-2H-benzopyran (1.8 g, 6.7 mmol) in DMF (10 ml) at 0° C. was added potassium tertbutoxide (0.83 g, 7.4 mmol). After 30 minutes m-fluorobenzyl bromide (0.91 ml, 7.4 mmol) was added and the resulting slurry was warmed to room temperature and stirred for 2 hours. Water was added and the precipitate was collected, washed with water and air dried (2.5 g).
Reaction SMILES: [CH:1]1([CH:4]2[NH:9][C:8]3=[CH:10][S:11][CH:12]=[C:7]3[C:6](O)=[N:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:6]1[C:7]2[C:8](=[CH:10][S:11][CH:12]=2)[NH:9][CH:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OC1=NC(C2CC2)Nc2cscc21
Product: ClC1=NC(C2CC2)Nc2cscc21

Procedure:
2-Cyclopropyl-4-hydroxydihydrothieno[3,4-d]pyrimidine (2.4 g, 0.0123M) was refluxed in phosphorus oxychloride (40 ml) for 11/2 hours. The mixture was cooled, concentrated under vacuum, the residue dissolved in chloroform, poured over ice, and basified with ammonia. The layers were separated and the organic solution dried (MgSO4) and concentrated. The residue, chromatographed on silica eluting with ethyl acetate/hexane, (1/6) gave 2.2 g of product, m.p. 86.5°-88.5° C. the structure of which was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(C1C(N)SC2=CC=CC=12)=O)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1=C2C=CC=C2SC1N
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (5.0 g) was dissolved in methanol (150 ml). Thionyl chloride (9.5 ml) was added to the solution at 0° C., and the mixture was heated under reflux with stirring for 15 hr. After the completion of the reaction, distilled water was added thereto at 0° C., and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with distilled water and saturated brine, was dried over sodium sulfate, and was then concentrated to give 5-chloro-2-nitro-benzoic acid methyl ester as a useful intermediate (12.9 g, yield 92%).
Reaction SMILES: C[O-].[Na+].[C:4](=[O:9])(OC)[O:5]C.[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][C:23]3=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.B.[Na]>ClCCl.O.CO>[C:10]1([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22]([C:4]([OH:5])=[O:9])=[CH:23]3)=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)OC
Reactant: O=C1CCCc2ccc(-c3ccccc3)cc21
Agent: B
Agent: C[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(-c3ccccc3)ccc2CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A mixture of sodium methoxide (18.3 g), dimethyl carbonate (107 ml) and 7-phenyl-1-tetralone (15.1 g) was refluxed for 30 minutes. The reaction mixture was cooled to 0° C. To the mixture was gradually added 3N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give a brown solid. The solid was dissolved in dichloromethane (100 ml), and to the mixture was added sodium boron hydride (1.60 g) at 0° C. To the mixture was added dropwise methanol (10 ml) for 30 minutes, and the reaction mixture was stirred for 4 hours at 0° C. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The ressidue was dissolved in methanol (45 ml). To the mixture was added 2N sodium hydroxide (50 ml), and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, acidified with concentrated hydro-chloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in Diglyme (1,1′-oxybis[2-methoxyethane]) (50 ml), and to the mixture was added concentrated hydrochloric acid (10 ml). The mixture was stirred for 2 hours at 100° C., and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide (200 ml), washed with diethylether, acidified by adding concentrated hydrochloric acid to the aqueous layer and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give 7-phenyl-3,4-dihydronaphthalene-2-carboxylic acid (7.47 g) as brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][C:14]3([C:17]4[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:12])[CH:10]=1)[N:7]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH:6]=[CH:5]2.[OH-].[K+:39]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][C:14]3([C:17]4[CH:26]=[CH:25][C:20]([C:21]([O-:23])=[O:22])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:12])[CH:10]=1)[N:7]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=1)[CH:6]=[CH:5]2.[K+:39]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1ccc(C2(NC(=O)c3cc(F)cc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 4-{1-[({5-fluoro-1-[4-(trifluoromethyl)benzyl]-1H-indol-7-yl}carbonyl)amino]cyclopropyl}benzoate (67 mg, 0.13 mmol) was dissolved in 1 ml THF/MeOH (1:1) and 0.5 ml 2N KOH. Then reaction mixture was stirred at RT for 18 h. The mixture was cooled and the solvents were evaporated under reduced pressure. 2N HCl was added (until pH=3) and the aqueous phase was extracted 3× with DCM. The combined organic layers were washed with water and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in 1 ml methanol and 1 eq of KOH (0.065 ml of 2N KOH) was added, the methanol was then evaporated under reduced pressure. The resulting solid was solubilised in water and the solution was lyophilized. 1H NMR (500 MHz, DMSO-d6): δ 9.15 (s, 1H), 7.70 (d, 2H), 7.55 (m, 4H), 7.15 (m, 1H), 7.05 (d, 2H), 6.90 (d, 2H), 6.65 (d, 1H), 5.65 (s, 2H), 1.70 (s, 2H), 1.05 (s, 2H), 0.80 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13])[NH2:5].N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH3:13]
Reactant: COCCOc1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirred solution of 3-fluoro-4-(2-methoxyethoxy)aniline (2.0 g, 10.8 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (2.5 mL, 32.4 mol, 3.0 eq.) and phenyl chloroformate (1.36 mL, 10.8 mmol, 1.0 eq.) at 0° C. and stirred at RT for 1 h. The solvent was evaporated, the residue diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and evaporated again. The resulting residue was purified by column chromatography using EtOAc/PE (1:4) as eluent to yield phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (2.7 g, 76.8%) as a white solid (TLC system: EtOAc/PE (3:7), Rf: 0.5).
Reaction SMILES: C([Li])CCC.CCCCCC.[NH2:12][C:13]([O:15][CH2:16][C@@H:17]1[CH2:22][C:21]([C:23]2[N:24]=[C:25]([SH:28])[S:26][CH:27]=2)=[CH:20][CH2:19][N:18]1[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[O:14].O(P(OC1C=CC=CC=1)O[C:44]1[C@H:50]([CH3:51])[C@H:49]2[N:46]([C:47](=[O:59])[C@@H:48]2[C@H:52]([O:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH3:53])[C:45]=1[C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])C1C=CC=CC=1.C(#N)C>C1COCC1.CN(C=O)C>[CH2:32]([O:31][C:29]([N:18]1[CH2:19][CH:20]=[C:21]([C:23]2[N:24]=[C:25]([S:28][C:44]3[C@H:50]([CH3:51])[C@H:49]4[N:46]([C:47](=[O:59])[C@@H:48]4[C@H:52]([O:54][Si:55]([CH3:56])([CH3:57])[CH3:58])[CH3:53])[C:45]=3[C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[S:26][CH:27]=2)[CH2:22][C@H:17]1[CH2:16][O:15][C:13]([NH2:12])=[O:14])=[O:30])[CH:33]=[CH2:34]
Reactant: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1COC(N)=O
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](COC(N)=O)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (1.56M, 68 ml, 0.11 mmol) was added at −70° C. to a solution of allyl(2S)-2-{[(aminocarbonyl)oxy]methyl}-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (37.8 mg, 0.11 mmol) in THF (1 ml)/DMF (0.5 ml). The mixture was warmed to 0° C. and then stirred for 15 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 0.42 g, 0.22 mmol) and the solution was allowed to stand in a refrigerator for 13 hours. To the reaction solution was added ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate) to give crude allyl (4R,5S,6S)-3-{[4-((2S)-1-[(allyloxy)carbonyl]-2-{[(aminocarbony)oxy]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1,3-thiazol-2-yl]sulfanyl}-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (154 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:28])[CH2:18][CH2:17]4)[C@@H:14]([OH:29])[CH2:13][C:12]=2[CH:11]=1.[OH-].[Li+]>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:27]=[CH:26][C:25]2[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:28])[CH2:18][CH2:17]4)[C@@H:14]([OH:29])[CH2:13][C:12]=2[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Reactant: BrCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
12.83 g (75 mmol) of benzylbromide is added to a suspension of 20 g (67.74 mmol) of 3,7β-dihydroxy-estra-1,3,5(10)-trien-17-one, 3.55 g (148.23 mmol) of lithium hydroxide in 700 ml of dry dimethylformamide, and it is stirred under an argon atmosphere for 30 minutes at 100° C. For working-up, the reaction solution is poured into tartaric-acid ice water, the precipitated product is suctioned off and dried in air. The crude product is taken up in dichloromethane, the organic phase is washed with water and dried on sodium sulfate. After the solvent is drawn off in a vacuum, it is chromatographed on silica gel (dichloromethane-ethyl acetate, gradient of up to 3:2), yield 22.81 g (87%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-:31].[K+].[K+].OO.S([O-])(O)=O.[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]([C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH2:27])=[O:31])=[CH:28][CH:29]=4)[NH:14][C:15]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2nc(-c3ccc4c(c3)OCCO4)c(-c3ccccn3)[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ccc(-c2nc(-c3ccc4c(c3)OCCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl]benzonitrile (1 g) was dissolved in methanol (200 ml). Potassium carbonate was added (1 g) and the resulting suspension treated dropwise with an aqueous hydrogen peroxide solution (10 ml of 30% w/v solution) at 0° C. The suspension was stirred at room temperature for 18 hours then cautiously poured into saturated sodium hydrogen sulfite solution (200 ml) at 0° C. The mixture was tested for the presence of oxidant (starch-iodide test strips) before organic solvent removal by rotary evaporation under reduced pressure. The crude product was digested in ethyl acetate (200 ml). The ethyl acetate layer was dried (MgSO4) and evaporated to dryness under reduced pressure. The title compound was isolated by silica gel column chromatography (using a 1:9:190 ammonia:methanol:dichloromethane solution as eluent) as a beige solid (153 mg, 15%). 1H NMR (250 MHz, CDCl3) δ: 4.26 (4H, brs), 6.05 (1H, brs), 6.60 (1H, brs), 6.87 (1 H, brd, J=7. 7 Hz) 7.0-7.25 (3H, 7.53 (2H, d, J=3.7 Hz), 7.76 (2H, d, J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 8.47 (1H, d, J=4.6 Hz); m/z (ESMS): 399 (MH+).