Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[OH-].[Na+].[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:7][CH2:6]1>O>[O:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=[O:13])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCOCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
20 ml of methanol, 10 ml of water and 1 g of sodium hydroxide were added to 0.9 g of ethyl 4-tetrahydropyranylacetate and agitated at 80° C. for 1 hour. The solvent was removed by distillation, to which water was added. After washing with ethyl acetate, a hydrochloric acid aqueous solution was added to the resultant aqueous phase to an extract of pH of 3, followed by extraction with chloroform under salting-out conditions and drying with anhydrous magnesium sulfate. This was removed by filtration and the solvent was distilled off, thereby obtaining 0.87 g of a crude intended compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH2:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:2]2[CH:11]=[CH:10][C:9]3[C:8]([C:12]([NH:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:26]1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CC#N
Product: N[C@H]1CCCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 130 °C
Yield: 40.4 %

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43(a)) (250 mg), (3S)-3-piperidinamine dihydrochloride (260 mg) and tetrabutylammonium bromide (20 mg) in acetonitrile (2 mL) was heated at 130° C. in a microwave for 90 minutes after which it was cooled to room temperature and concentrated. The residue was purified by chromatography (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 96:3:1 as eluant) and subsequent recrystallisation (acetonitrile) gave the title compound as a solid (120 mg).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[I:7].[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[C:6]=1[I:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Ic1nc[nH]c1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(I)c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
4,5-Diiodoimidazole (prepared according to D. S. Carver, S. D. Lindell, and E. A. Saville-Stones, Tetrahedron, 1997, 53, 42, 14481-14496) (10.1 g, 31.6 mmol) was added portionwise to a room temperature suspension of sodium hydride (1.38 g, 31.6 mmol, 55% in mineral oil) in dry DMF (45 ml). The reaction mixture was stirred at room temperature for 90 min, then cooled to 0° C. and treated slowly with a solution of 2-(trimethylsilyl)-ethoxymethylchloride (6.81 ml, 34.7 mmol) in DMF (10 ml). After 2 h stirring at 0° C., the reaction mixture was poured onto a mixture of H2O (200 ml) and AcOEt (50 ml). The mixture was filtered and the mother liquor was extracted 3 times with AcOEt. The combined extracts were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution with hexane/AcOEt=9:1) to provide the title compound (9.44 g, 66.4%) as a pale yellow oil. MS: m/e=450.0 (M+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:12][NH:13][C:14]([NH:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1)=[S:15]
Reactant: CN=C=S
Reactant: NCCSCc1ccsn1
Agent: Cl
Solvent: CCO
Product: CNC(=S)NCCSCc1ccsn1

Procedure:
i. A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.). dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After stirring for 2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene/ethyl acetate as eluant gave N-methyl-N'-[2-(3isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:44])[NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[CH2:15][NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:61](Cl)(=[O:63])[CH3:62].C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:44])[NH:23][C@H:24]([C:40]([O:42][CH3:43])=[O:41])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:45]4[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:49][CH:50]=4)[CH2:15][N:16]3[C:61](=[O:63])[CH3:62])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester (85 mg) in DCM (5 mL) at 0° C. was treated with acetyl chloride, and triethylamine. The mixture was allowed to slowly warm to room temperature. After 3 hours, ethyl acetate was added and the organic layer was washed with 1N HCl. The organic layer was washed saturated sodium bicarbonate solution and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give the crude amide. The residue was purified by flash chromatography (using hexanes/ethyl acetate, from 70:30 to 55:45, as an eluent) to give the product (76 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](Br)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.S1(CCCC1)(=O)=O.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: Brc1ccc2c(c1)Sc1ccccc1CC2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Brc1ccc2c(c1)Sc1ccccc1CC2

Procedure:
10.55 G. 3,11-dibromo-10,11-dihydrodibenzo[b,f]thiepin is suspended in 150 cc. sulfolane and gradually, in portions, 3.5 g. sodium borohydride is added. When the foaming has subsided, water is added and the mixture extracted four times with ether, the combined extracts are washed several times with water, dried and evaporated to dryness, and the residual oil chromatographed on silica gel. On elution with 10% benzene in hexane, 3.31 g. of pure material as a white solid is obtained, m.p. 69°-71° C.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cccc2c1-c1ccccc1C2

Procedure:
A partial solution of 196.2 mg (1 mmol) of 4-hydroxy-fluoren-9-one in 2 mL EtOAc and 3 mL EtOH with 40 mg 10% Pd/C was stirred under a balloon of hydrogen for 27.5 hours. The catalyst was removed by filtration through celite, washed well with EtOAc, and the filtrate evaporated. The residue was purified by plate layer chromatography with CH2Cl2-EtOAc(50:1) to give 102.7 mg of the title substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]#[N:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH3:15]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([NH2:15])([CH2:12][C:13]#[N:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=CC#N)CC1
Reactant: N
Solvent: CO
Product: CCOC(=O)N1CCC(N)(CC#N)CC1

Procedure:
A solution of 51.38 g (264.53 mol) of 4-cyanomethylene-piperidine-1-carboxylic acid ethyl ester in 301 ml of an aqueous ammonia solution (29%) and 50 ml of methanol was heated at 110° C. in a sealed tube for 48 h. The reaction mixture was concentrated, and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 96/4 to afford 40 g of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]Cl)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:17]3[C:16](=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1cc(Cl)ccc1SCl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=c1c2cc(Cl)ccc2sc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 70 %

Procedure:
One half of the solution of 5-chloro-2-chlorosulfenylbenzoyl chloride (135 ml of 0.05 mole of Example 4) was charged into 200 ml three neck flask equipped similarly as the reaction flask in Example 4. About 11.2 g of chlorobenzene was added and at the temperature of this mixture maintained in the range of 20°-30° C while 6.75 g of powdered aluminum chloride (0.05 mole) was charged in small portions in approximately 30 minutes. After the charging the batch was stirred for an additional 1 hour, while the temperature was maintained in the range of 25°-30° C. The crystalline aluminum chloride complex, which separated from the solution, was filtered and the cake was washed with hexane. The cake was then treated with 1.3 mole NaOH dissolved in 300 ml of water. The isolated product, 10 g of light yellow crystalline powder (m.p. 230C) was crude 2,7-dichloro-thioxanthen-9-one (70% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][C:8]2=[O:32])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc([N+](=O)[O-])cc1)(CC(C)C)O2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc(N)cc1)(CC(C)C)O2

Procedure:
1.4 g of 6-acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 7) was dissolved in 35 ml of methanol, and, in the presence of 1 g of 10% w/w palladium-on-carbon, it was reduced for 3 hours under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the solvent was then distilled off under reduced pressure to give the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:10]=1[CH:11]=[N:12][NH2:13])=[O:5])C>C(O)(=O)C.C1(C)C=CC=CC=1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:8]1[N:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[N:12][NH:13][C:4](=[O:5])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1C=NN
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=c1[nH]ncc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-hydrazonomethyl-1H-imidazole-4-carboxylic acid ethyl ester (I-2f, 54 mg, 0.134 mmol) and glacial acetic acid (1 drop) in toluene (3 ml) was heated under reflux for 18 hours, at which time a white solid precipitated out of solution. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified via 1 mm chromatotron plates using 100% EtOAc as solvent to give the desired product (I-2g) as a white solid (22 mg): +APCI MS (M+1) 357.1; 1H NMR (CD2Cl2) δ 7.18–7.48 (8H, m), 8.01 (1H, s), 10.60 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][NH2:25])[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:24][NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: CN(C)CCC(CN)c1ccc(Cl)cc1
Product: Cc1ccccc1C(=O)NCC(CCN(C)C)c1ccc(Cl)cc1

Procedure:
From 2-methylbenzoic acid and 3-(4-chloro-phenyl)-N1,N1-dimethyl-butane-1,4-diamine. LCMS (MH+): m/z=345.1, tR (minutes, Method A)=0.8
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH3:23][C:24]1[S:25][C:26]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:27]([CH3:29])[N:28]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:33][S:30]([C:26]2[S:25][C:24]([CH3:23])=[N:28][C:27]=2[CH3:29])(=[O:31])=[O:32])=[O:21])=[CH:19][CH:18]=1
Reactant: Cc1nc(C)c(S(N)(=O)=O)s1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)c1sc(C)nc1C

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 2,4-dimethyl-thiazole-5-sulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 2.71 (s, 6), 3.63 (s, 3), 4.76 (s, 2), 6.47 (s, 1), 7.01 (m, 2), 7.26 (m, 2). 13C NMR (125 MHz, CDCl3) δ: 16.51, 19.25, 48.29, 63.20, 92.66, 115.70, 115.87, 127.43, 130.23, 130.30, 130.97, 158.92, 159.24, 159.58, 161.69, 163.66, 170.81, 172.19.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Br:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([Br:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:18]([NH:17][C:10]1[C:11]([Br:16])=[CH:12][C:13]([Br:15])=[CH:14][C:9]=1[Br:8])=[O:19]
Reactant: O=C=Nc1c(Br)cc(Br)cc1Br
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1c(Br)cc(Br)cc1Br
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base (4.0 g.; 0.05 mole -- assuming 100% conversion) by adding 5 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 16.79 g. (0.0472 mole) of 2,4,6-tribromophenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene, is added with stirrng. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo to give a solid residue of 1-(1-methyl-2-pyrrolidylidene)-3-(2,4,6-tribromophenyl)urea. Recrystallizations from acetone yields the pure product, m.p. = 165°-167.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 61 %

Procedure:
3.0 g (12.04 mmol) of the product prepared in step 8.1 in 40 mL of ethyl acetate are placed in a hydrogenation autoclave, and 0.15 g of 10% palladium-on-charcoal are added, under an inert atmosphere. The mixture is stirred at a hydrogen pressure of 5 bar at room temperature. After filtering through Celite and evaporating under reduced pressure, 1.6 g of the expected product are obtained in the form of a beige-coloured solid, which is used as obtained in the following step. Yield=61%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([O:12][CH2:21][CH3:22])=[O:11])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC#C[C@@H](CC(=O)O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1

Procedure:
To a 0° C. solution of (3S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (2.7 g, 13.2 mmol) in ethanol (135 mL) is added sulfuric acid (2.7 mL) and the mixture is heated at reflux for 4 hours, concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yellow oil (2.1 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 4.9 (bs, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.04 (m, 1H), 2.60-2.75 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=6.8 Hz, 3H).
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=[O:49])[CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:49][C:37]([CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
Tf2O (7.2 mL, 0.0423 mol) was added slowly, drop-wise to a −78° C. solution of tert-butyl 3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl(methyl)carbamate (6.7 g, 14.1 mmol) and pyridine (9.1 mL, 0.113 mol) in dry DCM (110 mL). The reaction mixture was allowed to warm to 0° C. then was stirred at 0° C. for 3 hrs. Aqueous NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the water layer was washed with DCM (3×). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by reverse-phase biotage (water/acetonitrile gradient) to afford tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl(methyl)carbamate (3.3 g, 51%) as a light yellow solid. ESI-MS (EI+, m/z): 458.0 [M+H]+; 1H NMR (500 MHz, CDCl3): δ 7.45-7.36 (m, 5H), 5.09 (d, J=11.5 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.71 (t, J=4.5 Hz, 1H), 3.67-3.59 (m, 2H), 3.37 (s, 1H), 3.31 (t, J=6.5 Hz, 2H), 2.94-2.86 (m, 2H), 2.82 (s, 3H), 2.32-2.28 (m, 2H), 2.15-2.12 (m, 1H), 2.00-1.95 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[ClH:1].[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:8][CH:7]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCN1CCC(OC(c2ccc(C)cc2)c2ccc(C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C(OC2CCN(CCC(=O)O)CC2)c2ccc(C)cc2)cc1
Yield: 99.1 %

Procedure:
A mixture of 3.55 g of ethyl 4-[bis(4-methylphenyl)methoxy]-1-piperidinepropionate hydrochloride, 12.4 ml of 2N sodium hydroxide aqueous solution and 20 ml of methanol was refluxed for 1 hour and then concentrated. Water was added to the residue and made acidic with hydrochloric acid. The resulting precipitate was collected by filtration to give 3.29 g of colorless crystals. The crystals were recrystallized from water to give 2.63 g of colorless needles, mp 159°~162° C.
Reaction SMILES: [Br-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[C@H:23]([CH2:24][CH2:25][C:26](=[O:30])[CH:27]=2)[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][C@@H:21]2[F:31])([CH3:19])[C:17](=[O:32])[CH2:16][CH2:15]1)(=[O:5])[CH3:4].C(=O)([O-])O.[Na+]>C(#N)C.[Cu](Br)Br>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][CH:21]2[F:31])([CH3:19])[C:17](=[O:32])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: Br[Cu]Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CC#N
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2C(F)C[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
18.6 g of copper(II) bromide and 3.6 g of lithium bromide are added at 80° C. to 16.5 g of 7α-(5-acetoxy-pentyl)-11β-fluorooestr-4-ene-3,17-dione in 190 ml of acetonitrile. After 15 min, the reaction mixture is stirred into ice-water containing sodium hydrogen-carbonate. The precipitated product is filtered off with suction, dissolved in ethyl acetate, and the solution is washed with water, dried and concentrated in vacuo. After chromatographing the crude product on silica gel using a hexane-ethyl acetate gradient, 8.5 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-hydroxyoestra-1,3,5(10)-trien-17-one are obtained as a foam.