Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[CH2:14]1[CH:18]2[CH2:19][NH:20][CH2:21][CH:17]2[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[CH3:12][N:6]1[C:5](=[O:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:20]3[CH2:19][CH:18]4[CH2:14][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:17]4[CH2:21]3)[CH:3]=2)[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Cn1cnc2ccc(Br)cc2c1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cc2c1=O
Temperature: 90 °C
Yield: 38 %

Procedure:
A mixture of 6-bromo-3-methylquinazolin-4(3H)-one (Intermediate 19A) (0.46 g, 1.92 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H) carboxylate (0.49 g, 2.31 mmol), potassium phosphate, tribasic (1.33 g, 5.77 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1-biphenyl (26.9 mg, 0.06 mmol) and tris(dibenzyllideneacetone)dipalladium (0) (17.6 mg, 0.02 mmol) in dioxane (10 mL) was heated at 90° C. for 20 h. The mixture was diluted with water and the product extracted into dichloromethane. The organic layer was evaporated to dryness, re-dissolved in methanol and purified using a 5 g SCX column. The mixture was then further purified on silica (25 g SNAP column on SP4). Eluting with dichloromethane to 60/40 dichloromethane/(2M NH3 in methanol) to afford tert-butyl 5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (270 mg, 0.73 mmol).
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:1].[Cl:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[C:20]([Cl:21])[CH:19]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(O)c2cc(Cl)sc2C1
Product: CN1CCC(Oc2ccc(Cl)c(Cl)c2)c2cc(Cl)sc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2-chloro-7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 24) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:19].C(N(CC)CC)C.Cl>C(O)CCC.C(O)C>[ClH:12].[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=3)[N:5]=2)[CH2:26][CH2:25]1)[CH3:19]
Reactant: CCOCCOC1CCNCC1
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCCCO
Product: CCOCCOC1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)CC1

Procedure:
4-Amino-2,6-dichloro-7,8-dimethoxyquinazoline (4.9 g.), 4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) in n-butanol (400 ml.) are heated at reflux overnight under an atmosphere of nitrogen. The mixture is then cooled, evaporated in vacuo, and the residue basified (aqueous Na2CO3) and extracted 3 times with chloroform. The combined chloroform extracts are evaporated and the residue chromatographed on neutral alumina to give the crude product which is converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol to afford the title compound. C. By the above procedures the following compounds are similarly provided from the appropriate starting materials in each case.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)([CH3:14])[CH3:13].C(OC(N1CCC2C=CC(N)=CC=2CC1)=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Agent: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)Oc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isopropoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isopropoxyphenylboronic acid in a manner analogous to Example 2c (0.24 g, 40%). MS=288 (MH)+. 302b) 7-[8-(2-Isopropoxy-phenyl]-[1,2,4]triazolo[1,5a]pyridine-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-isopropxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine and 7-amino-1,2,4,5-tetrahydro-3-benzazepin-3-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.35 g, 82%). MP=112-114° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.73 (d, 1H), 7.60 (m, 2H), 7.48 (s, 1H), 7.38 (m, 2H), 7.17 (m, 1H), 7.05 (m, 3H), 4.57 (m, 1H), 3.44 (m, 4H), 2.80 (m, 4H), 1.41 (s, 9H), 1.15 (m, 6H). MS=514 (MH)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:29]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=4[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 315) (52 mg), imidazole (27 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, 31%).
Reaction SMILES: [H-].[Na+].COP([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)OC.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.O>C1COCC1>[N:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[C:9](\[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]#[N:24])/[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:27][CH:26]=1
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc(C#N)c1
Reactant: O=Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(/C(=C\c2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Sodium hydride (2.28 g, 94.98 mmol) was added to a solution of [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic acid dimethyl ester (20.58 g, 63.3 mmol) in dry THF and the mixture was stirred at room temperature for 15′. Pyridine-4-carbaldehyde (6.78 g, 63.3 mmol) was then added and the reaction mixture was stirred at 50° C. for 3 h under nitrogen atmosphere. In order to affect completion a further addition of pyridine-4-carbaldehyde (0.68 g, 6.33 mmol) was required. Distilled water (40 ml) was slowly poured into the reaction mixture and the solvent (THF) was removed under reduced pressure. The water layer was extracted with EtOAc (3×100 ml), DCM (1×100 ml) and the organic layers were dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product 3-[(E)-2-Pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrile as a brown oil (19.0 g, 62.10 mmol, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCN(C)C1=O>[CH3:1][O:2][C:3](=[O:8])[CH:4]([C:5](=[O:7])[CH3:6])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)/C=C(\C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CCCc1ccccc1)C(C)=O
Temperature: 80 °C

Procedure:
85 g (616 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate suspended in 1,3-dimethyltetrahydro-2(1H)-pyrimidone and 3.50 g (21.1 mmol) of potassium iodide are treated dropwise with 129 g (646 mmol) of 1-bromo-3-phenylpropane and the mixture is stirred under reflux at 80° C. for 1 h. The cooled mixture is then added to ice water and extracted with diethyl ether. The ether phase is washed with sodium thiosulphate solution, dried, concentrated and chromatographed. The eluent used is cyclohexane containing an increasing proportion of ethyl acetate.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[C:4](=[O:14])[O:3]1.[CH2:15]([NH2:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1.Cl>C(Cl)Cl.CC(O)=O>[CH2:15]([N:18]1[C:4](=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([OH:13])=[O:12])[CH:6]=2)[C:2]1=[O:3])[CH:16]=[CH2:17]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: C=CCN
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
To a 25 mL pear-shaped flask was added solid 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041 mmol) and allylamine (234 μL, 3.12 mmol, 3 eq) via syringe. Toluene (2 mL) and AcOH (1 mL) were added via syringes and the flask was refluxed for 12 h. The flask was allowed to cool and then subjected to a DCM (75 mL) and HCl (1N, 50 mL) work up. The aqueous layer was extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The residue thus obtained was azeotropically dried with toluene (2×, 5 mL) and heptane (2×5 mL). The resulting reside was placed on a high vacuum for 3 to give 2-allyl-1,3-dioxoisoindoline-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1O.COC1C=CC(C(Cl)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>N1C=CC=CC=1.ClCCl>[F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:8]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.244 gms. (20 mMoles) of 5-fluorouridine is dissolved in 20 mL anhydrous pyridine and then dried under vacuum. This procedure is repeated at least one more time in order to make 5-fluorouridine devoid of moisture. The dried 5-fluorouridine is then dissolved in 20 mL of pyridine. 8.131 gms (24 mMoles, 1.2 eq.) of 4,4'-dimethoxy trityl chloride is added as solid in 4 fractions over a period of 2 hours. The reaction mixture is then stirred at room temperature overnight and is then diluted with 25 mL of dichloromethane and washed with saturated sodium bicarbonate solution. The aqueous layer is then washed with 20 mL dichloromethane. The organic layers are mixed and washed with saturated bicarbonate solution two more times. The organic layer is then dried over anhydrous sodium sulphate. The solvent is removed under vacuum to yield a yellow foam which is purified on a silica gel column using 90:10 chloroform:methanol as eluent. The 4, 4'-dimethoxytrityl derivative of 5-fluorodeoxyuridine is prepared in an analogous manner.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=1)=[O:12].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:20][O:21][C:32](=[O:33])[O:22]2)[CH:14]=1)=[O:12])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Product: O=C1OCC(c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Temperature: 80 °C
Reaction time: 12 h
Yield: 9 %

Procedure:
A 300 mg portion of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and 200 mg of 1,1′-carbonyldiimidazole were dissolved in 7 ml of Tol and stirred at 80° C. for 12 hours. After concentration of the reaction liquid, the thus formed residue was purified by a silica gel column chromatography to obtain 30 mg (9%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(2-oxo-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione as a yellow solid from a chloroform-methanol (10:1) eluate. ES+: 445
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH2:14]>C(Cl)Cl>[CH3:14][C:13]1([CH2:15][CH:16]([CH3:23])[CH2:17][CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[O:6][CH2:12]1
Reactant: C=C(C)CC(C)CC(C)CCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCC(C)CC(C)CC1(C)CO1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (7.31 g, 60% purity, 25.42 mmol) was added to a stirred solution of 2,4,6-trimethyl-1-nonene (5) (3.56 g, 21.19 mmol) in 70 ml of dry methylene chloride in a 250 ml flask in an ice bath. The chilled reaction mixture was stirred for one hour, and then stirred vigorously overnight at room temperature. The reaction mixture was cooled to 10° C. before filtering out a white slurry, which was washed with cooled methylene chloride. The combined filtrates were washed three times with cooled aqueous carbonate, water, and brine and dried over sodium sulfate. Evaporation of the solvent yielded a crude oil which was distilled at 65°-70° C. and 1.5 mm Hg to yield pure 2,4,6-trimethyl-1,2-epoxynonane (6).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)C.N1C2C=CC=CC=2N=CC(C(OC)=O)=C1>O1CCCC1.CC(C)=O>[CH3:15][C:9]1[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[C:17]([F:16])([F:26])[F:27])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)C=C(C)Nc1ccccc1N
Agent: COC(=O)C1=CNc2ccccc2N=C1
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)Nc2ccccc2NC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-[(2-aminophenyl)amino]-2-butenoic acid, methyl ester (2.50 g., 12.0 mmole) in anhydrous tetrahydrofuran (12 ml.) is treated with 2-(trifluoromethyl)benzaldehyde (1.74 g., 10.0 mmole) and acetic acid (0.2 ml.). The resulting reaction mixture is stirred at room temperature under argon for 24 hours. The solvent is removed and the resulting yellow solid is triturated with isopropyl ether to give 3.27 g. of an off-white product. Recrystallization from dichloromethane-isopropyl ether gives 2.39 g. of 2,5-dihydro-4-methyl-2-2-(trifluoromethyl)phenyl]-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester; m.p. 190°-192°. TLC (silica gel; acetone:hexanes, 35:65) Rf =0.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([NH:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36](Cl)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].O.[CH2:49]([O:51][C:52](=O)[CH3:53])C>CC#N>[CH3:1][O:2][C:3](=[O:41])[C@H:4]([NH:27][S:28]([C:31]1[CH:40]=[CH:39][C:34]2[N:35]=[C:36]([S:28][C:31]3[CH:40]=[CH:53][C:52]([O:51][CH3:49])=[CH:33][CH:32]=3)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Cl)sc2c1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Sc3ccc(OC)cc3)sc2c1

Procedure:
(2R)-2-[(2-Chlorobenzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl)propionic acid methylester (0.24 g, 0.39 mmol) prepared in a similar manner as in Example 59 was dissolved in MeCN (3 mL). K2CO3 (0.081 g, 1.5 equi.) were added to the solution in a solid form and then, 4-methoxybenzthiol (0.053 mL, 1.1 equi.) was added and refluxed for 3 hours. After starting material was exhausted, water/ethylacetate (5 mL/10 mL) was added and the product was extracted with an organic solvent. The organic phase was washed with NaCl solution, dried over anhydrous MgSO4, distilled under reduced pressure and then, purified on silica gel chromatography using ethylacetate/n-hexane (1/2) to prepare the titled compound, (2R)-2-[(2-(4-methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl)propionic acid methylester (0.2 g, 70%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C@:16]1([CH2:20][C:21]#[CH:22])[C:11](=[CH:12][C:13](=O)[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH3:24][C@@]12[C@@H](O)CC[C@H]1[C@@H]1CCC3[C@@](C)([C@H]1CC2)CCC(=O)C=3>>[CH2:24]=[C:13]1[CH2:14][CH2:15][C@@:16]2([CH2:20][C:21]#[CH:22])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:17]2[CH2:18][CH2:19][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[OH:1])=[CH:12]1
Reactant: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Product: C#CC[C@]12CCC(=C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
To obtain the compounds of the present invention in which R4 is =CH2, 17β-hydroxy-10-(2-propynyl)estr-4-en-3-one is used as the starting material. This testosterone derivative is subjected to a Wittig reaction to give 3-methylene-10-(2-propynyl)estr-4-en-17β-ol. The 17-hydroxy group is then oxidized to the corresponding ketone and a hydroxyacetyl side chain is introduced at the 17-position using methyl methoxyacetate and the general procedure described earlier.
Reaction SMILES: [O:1]([CH2:8][CH2:9][C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]3[CH:24]=[C:23]([CH3:26])[S:22][C:21]=3[NH:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:47]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:47].[ClH:47].[CH3:33][N:15]1[CH2:14][CH2:13][N:12]([C:16]2[C:25]3[CH:24]=[C:23]([CH3:26])[S:22][C:21]=3[NH:20][C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)[CH2:11][C@@H:10]1[CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCOc2ccccc2)C1
Reactant: CC(Cl)Cl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCOc2ccccc2)C1
Product: Cl

Procedure:
Combine (S)-10-[3-(2-phenoxyethyl)piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diazabenzo[f]azulene, formaldehyde (1.1 equiv, 37% aqueous solution), and sodium triacetoxyborohydride (1.5 equiv.) in dichloroethane (10 mL) and stir at room temperature for 2 hours. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane gives the free base of the title compound. Isolate as the dihydrochloride salt by dissolving the free base in ethanol and adding a solution of 5 equivalents of hydrochloric acid in ethanol. Evaporating the solution and drying the salt provides the title compound (0.059 g, 0.129 mmol, 8%) as an orange-solid. Mass spectrum (APCI): m/z=433.2 (M+1 of free base).
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Cl-].C[N+]1C=CN([C:48]([O:50][CH2:51][C:52]2[C:61]([N+:62]([O-:64])=[O:63])=[CH:60][C:57]([O:58][CH3:59])=[C:54]([O:55][CH3:56])[CH:53]=2)=[O:49])C=1>ClCCl.N1C=CC=CC=1>[N+:62]([C:61]1[C:52]([CH2:51][O:50][C:48]([O:38][C@@H:25]2[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26]2)=[O:49])=[CH:53][C:54]([O:55][CH3:56])=[C:57]([O:58][CH3:59])[CH:60]=1)([O-:64])=[O:63]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COc1cc(COC(=O)n2cc[n+](C)c2)c([N+](=O)[O-])cc1OC
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(COC(=O)O[C@H]2C[C@H](n3cc(C)c(=O)[nH]c3=O)O[C@@H]2CO)c([N+](=O)[O-])cc1OC
Temperature: 4 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 1.97 g 5′-O-(4,4′-dimethoxytrityl)thymidine (3.62 mmol) in 18 ml absolute dichloromethane and 2 ml absolute pyridine is added in a nitrogen atomsphere and in the absence of light to an N-methyl-N3-[(6-nitroveratryl)oxycarbonyl]imidazoliumchloride acylation reaction (19) (produced from 7.25 mmol chloroformic acid-6-nitroveratryl ester). The reaction mixture is stirred in the dark at 4° C. overnight. The molecular sieve is separated and the organic phase is extracted twice against saturated NaHCO3 (100 ml). After drying via Na2SO4, 200 ml of a 10% trichloroacetic acid in dichloroethane are added to the organic phase and stirred at room temperature for 5 minutes. The deep-red solution is extracted twice with saturated NaHCO3 (200 ml), the organic phase is dried via Na2SO4 and evaporated. Purification via flash chromatography (66-80% ethyl acetate in toluene) yielded 1.153 g of the title compound (66% yield)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(C)c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 120a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (14 mg, 26%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.62-1.93 (m, 2H) 2.02 (s, 3H) 2.31 (s, 3H) 2.99 (t, J=7.35 Hz, 2H) 5.11 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.97-7.33 (m, 8H) 7.34-7.50 (m, 3H) 7.80 (d, J=8.82 Hz, 1H) 8.36 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.01 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 549 (M+H)+.