Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1.C([Li])CCC.[Cl-:27].[Cl-].[CH:29]1([Ti+2:34][CH:35]2[CH:39]=[CH:38][CH:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30]1.O>C1COCC1>[Cl:27][Ti:34]([CH:29]1[CH:30]=[CH:31][CH:32]=[CH:33]1)([CH:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1)[C:3]1[C:4]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:5][C:6]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[N:7][C:2]=1[Cl:1]
Reactant: C1=CC([Ti+2]C2C=CC=C2)C=C1
Reactant: Clc1cc(OC2CCCCC2)nc(OC2CCCCC2)n1
Reactant: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(OC2CCCCC2)nc(OC2CCCCC2)c1[Ti](Cl)(C1C=CC=C1)C1C=CC=C1
Temperature: -40 °C

Procedure:
6.15 g (19.8 mmol) of 6-chloro-2,4-bis(cyclohexyloxy)pyrimidine are dissolved in 40 ml of THF under argon as protective gas, the solution is cooled to -40° C., and 12.4 ml of n-butyllithium (1.6M/hexane) are added dropwise. 2.25 g (9 mmol) of solid biscyclopentadienyltitanium dichloride are added to the resultant solution at -40° C. The reaction mixture is allowed to warm slowly from -40° C. to 25° C., is then poured into 40 ml of water and is filtered through ®Hyflo. The aqueous phase is separated off, and the organic phase is dried using magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is separated by flash chromatography (SiO2), giving 1.0 g of the compound from Example 63 and 0.9 g of the title compound, having a melting range of 145°-155 ° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:19][S:18][C:5]1[CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:8]=[C:3]([C:1]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:2]=2)[N:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1cc(CCC(=O)OC(C)(C)C)cc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cc(CCC(=O)OC(C)(C)C)cc(-c2nc(=O)c3ccccc3s2)n1
Yield: 56.9 %

Procedure:
tert-Butyl 3-[2-cyano-6-(methylthio)-4-pyridyl]propanoate (0.70 g, 2.50 mmol) and methyl thiosalicylate (0.84 g, 5.00 mmol) were dissolved in toluene (50 ml), and triethylamine (1.40 ml, 10.0 mmol) was added thereto. The reaction mixture was refluxed for 18 hrs, and the solvent was evaporated. The residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.59 g, 57%) as pale yellow crystals.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:37]I>C(#N)C.O.C(OCC)(=O)C>[F:14][CH:2]([F:1])[O:3][C:4]1[C:8]([I:37])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([CH3:13])[N:5]=1
Reactant: II
Reactant: COC(=O)c1cc(OC(F)F)nn1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(I)c(OC(F)F)nn1C
Temperature: 25 °C

Procedure:
A solution of 500 mg (2.42 mmol) of methyl 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate in 20 ml of acetonitrile is admixed with 665 mg (1.21 mmol) of ammonium cerium(IV) nitrate and 369 mg (1.45 mmol) of iodine and heated under reflux for three hours and afterstirred at room temperature overnight. The reaction mixture is diluted with water and ethyl acetate, and the organic phase is washed with saturated sodium thiosulphate solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. This gives 750 mg of methyl 3-(difluoromethoxy)-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:13])[N:30]([CH2:31][CH2:32][O:33][CH3:34])[CH2:29][CH2:28][O:27][CH3:26])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1C(=O)Nc1ccncc1
Reactant: COCCNCCOC
Product: COCCN(CCOC)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with bis-(2-methoxy-ethyl)-amine gives “A89”; method 1: HPLC/MS: 1.30 min, [M+H]=450;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 45.9 %

Procedure:
A microwave tube charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (200 mg; 0.57 mmol), 2,4-dichloroaniline (139 mg; 0.86 mmol), TFA (64 μl; 0.86 mmol) and toluene (1.5 ml) was heated in a microwave at 160° C. for 30 min. The reaction mixture was basified with DIPEA (0.2 ml), volatiles removed in vacuo and the residue purified by prep. LCMS to give 532 as a pale yellow solid (129 mg; 46%). δH (400 MHz, CDCl3) 3.14 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.89-6.92 (m, 2H), 7.25-7.28 (m, 1H), 7.42 (d, J=8.4, 1H), 7.52 (dd, J=8.4 and 2.4, 1H), 7.66 (d, J=2.4, 1H), 7.71 (d, J=2.0, 1H), 8.22 (s, 1H). [M+H]+: 493
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10](CSC2C=CC=CC=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].[C:31](=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:31][S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:23])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1ccccc1S
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87, 0.262 g), 2-methylthiophenol (0.096 ml) and potassium carbonate (0.28 g) in THF (5 ml) was stirred at room temperature for 3 days. The resultant mixture was partitioned between ethyl acetate and NaHCO3 (saturated aqueous solution). The separated organic phase was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give ethyl 3-bromo-2-methoxy-(2-methylphenylthiomethyl)benzoate (0.24 g) as a gum.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1Cl)CCNCC2
Yield: 21.2 %

Procedure:
The title compound (37 mg) was prepared according to Example 189 using 230 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 308 mg of 2,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated for C16H19Cl2N3, 323.10; found, m/z 324.4 [M+H]+, 326.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.37-7.35 (m, 1H), 4.65 (br s, 1H), 4.11-4.05 (m, 1H), 3.43-3.40 (m, 2H), 3.29-3.16 (m, 3H), 2.70-2.63 (m, 2H), 1.39-1.32 (m, 6H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[C:12]([C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C(Cl)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.[Zn]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:11](=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:29][CH:30]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9][OH:8])=[CH:32][CH:33]=1
Reactant: CN(C)CCOc1ccc(C(=C(CCOCc2ccccc2)c2ccc(Cl)cc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(C(=C(CCO)c2ccc(Cl)cc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
(2-{4-[4-Benzyloxy-2-(4-chlorophenyl)-1-phenylbut-1-enyl]phenoxy}ethyl)dimethylamine (1.1 g, 2.1 mmol) is dissolved in toluene, Zn powder (0.4 g, 6.1 mmol) and acetyl chloride (0.6 g, 7.6 mmol) are added and the mixture is stirred at 40° C. for 3 h. Additional Zn (0.5 g) and acetyl chloride (0.6 g) are added and stirring is continued for another 5 h. Ethyl acetate is added and the precipitate is filtered off. The solvents are evaporated and the residue is dissolved in methanol. The acetate ester of the product is hydrolyzed by making the mixture alkaline with 48% aqueous sodium hydroxide and stirring the mixture at room temperature for 2 h. Methanol is evaporated, the residue is dissolved in toluene and washed with water. Toluene is evaporated and the isomers of the product are separated by flash chromatography. The yield of the Z-isomer is 0.25 g and of the E-isomer 0.15 g.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].IC[C:16]#[N:17]>O.C(O)(=O)C.C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=1[S:3][CH2:2][C:16]#[N:17]
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: N#CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N#CCSc1cc(F)ccc1N
Temperature: 10 °C

Procedure:
A suspension of 2-amino-6-fluoro-benzothiazole (5.13 g) was stirred for 6½ h at 165-170 ° C. under nitrogen in a solution of potassium hydroxide (10.3 g) in water (20 ml). The resulting mixture was cooled to 10° C. and adjusted to pH ˜8 by adding acetic acid, keeping the temperature below 25° C. The mixture was cooled to 10° C. and ethanol (30 ml) and iodoacetonitrile (2.20 ml) were added. After stirring for 15 min acetic acid (1.8 ml) was added and approx. half of the solvent was removed in vacuo. The residue was diluted with water (150 ml) and extracted with ethyl acetate (50 ml). The extract was dried over sodium sulfate, filtered and evaporated to give the title compound as a practically pure yellow oil. Yield 4.88 g (88%); 1H-NMR (DMSO-d6), δ (ppm): 7.26-7.14 (m, 1H, Ar—H), 7.09-6.95 (m, 1H, Ar—H), 6.85-6.72 (m, 1H, Ar—H), 5.36 (br, 2H, NH2), 3.99 (s, 2CH2).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[O:38][C:39](=[O:70])[CH:40]([NH2:69])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([CH2:54][N:55](C(OC(C)(C)C)=O)[C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[N:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[NH:55][CH2:54][CH:51]1[CH2:52][CH2:53][N:48]([C:45]2[CH:44]=[CH:43][C:42]([CH2:41][CH:40]([NH:69][C:4](=[O:6])[C:3]3[C:7]([CH3:12])=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=3[CH3:1])[C:39]([OH:70])=[O:38])=[CH:47][CH:46]=2)[CH2:49][CH2:50]1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: COC(=O)C(N)Cc1ccc(N2CCC(CN(C(=O)OC(C)(C)C)c3ccccn3)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(N3CCC(CNc4ccccn4)CC3)cc2)C(=O)O)c(C)c1

Procedure:
A solution of 202 mg (1.23 mmol) of 2,4,6-trimethylbenzoic acid, 467 mg (1.23 mmol) HATU, 300 mg (0.64 mmol) of (4) and 660 μl (3.85 mmol) DIPEA in 5 ml DMF were stirred at room temperature over night. The reaction mixture was diluted with 100 ml ethyl acetate, washed 3 times with 2 N NaOH/brine (2:1) and once with brine and dried over Na2SO4. The solvent was then removed under reduced pressure.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[C:2]1(=[O:1])[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1NCCCC12CCNCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To the stirred solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (3.0 g, 11.19 mmol) in DCM (60 mL) was added 4N HCl in dioxane (20 mL) and the mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and triturated with diethyl ether (2×5 mL) to yield the title compound as a solid (2.2 g, 96%). Note: The product is moisture sensitive. [1H-NMR (DMSO-d6, 300 MHz): δ 9.25-8.68 (m, 2H), 7.43 (s, 1H), 7.20-6.25 (m, 2H), 3.61-2.90 (m, 5H), 2.12-1.95 (m, 2H), 1.76-1.49 (m, 5H); LCMS RtA=0.326, [M+H]+=169.0].
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]>CC(C)=O.O>[CH2:1]([C@H:4]1[C:21]2[C@H:16]([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C[C@]12O
Solvent: CC(C)=O
Solvent: O
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@H]2CCC(=O)C=C12
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
6β-Propargyl-5α-hydroxyestrane-3,17-dione (11). The 6β-propargyl triol 9 (0.6 mmol) was dissolved in acetone (30 ml) and cooled to 4° C. followed by dropwise addition of Jone's reagent until the solution turned light brown. The reaction mixture was stirred at 4° C. for approximately 5 minutes, was diluted with water, extracted with ethyl acetate, washed (5% NaHCO3, brine, water) and dried, The ethyl acetate was evaporated in vacuo and the product obtained was purified by column chromatography to yield the dione 11 in 90% yield: m.p. 186°-188° C.; 1H-NMR (CDCl3) δ 0.91 (s, 3H, 18-CH3), 2.65 (d, 1H, 6-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.O[C:26]1[C:35]([OH:36])=[CH:34][C:33]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)[O:36][C:35]3[CH:34]=[C:33]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(O)c1O
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc2c1OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2

Procedure:
4,4′-Dimethoxybenzophenone (225 mg, 0.93 mmol, 1.5 eq.), oxalyl chloride (944 mg, 7.44 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-(toluene-4-sulfonyl)-benzoate (200 mg, 0.62 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 20:1→9:1) to yield the title compound as a colorless solid.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=[O:26]>C(O)(C)C>[OH2:26].[ClH:1].[Cl:1][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH2:8][CH2:3][CH2:4][CH3:5])[NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1.[Cl:1][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[CH2:18][CH2:9][CH2:10][CH3:11])[NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1.[ClH:1]
Reactant: CN(C)C=O
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1Cl
Product: O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 500 ml. 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with the remainder of the filtrate from part A, the compound of Example I, C.(20.9 g. 0.0962 mole) and an additional 100 ml. dimethylformamide. The mixture was stirred overnight while heating at 110°C. The solution was chilled and the crystals were collected by filtration and dried at 60°C to yield 23 g. off white crystals, m.p. 260°- 268°C. The filtrate was concentrated to 150 ml. by rotary evapaorator and chilled. Crop II was collected and dried to yield 3.9 g. light yellow crystals, m.p. 238°-251°C. Both crops were dissolved in isopropanol (600 ml.) and filtered while hot. The filtrate was chilled and the crystals were collected and dried at 60°C to yield 13.2 g. light yellow crystals, m.p. 273°-276°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:12]=1[O:13][CH2:14][C:15](N)=[NH:16]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][C:12]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=2[Cl:10])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1cccc(Cl)c1Cl
Solvent: CCO
Product: Nc1nc(COc2cccc(Cl)c2Cl)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 3.6 g (0.030 mole) of 3-amino-2-pyrazinecarbonitrile and 6.6 g (0.030 mole) of 2-(2,3-dichlorophenoxy)acetamidine in 100 ml of absolute ethanol. Refluxing time: 14 hours. Yld: 8.1 g (84%), m.p. 216°-218° C. (ethanol).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][CH:6]=[CH:7][CH2:8]Cl>>[ClH:5].[Cl:5]/[CH:6]=[CH:7]/[CH2:8][NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCN
Reactant: ClC=CCCl
Product: CCCNC/C=C/Cl
Product: Cl
Reaction time: 3 h
Yield: 70 %

Procedure:
To 19.7 ml (0.24 mol) of n-propylamine was added 1.82 ml (20 mmol) of 1,3-dichloropropene (E/Z=9/1) under ice cooling. The mixture was stirred for 3 hours at the same temperature, and concentrated under reduced pressure to remove n-propylamine. The residue was treated with 50 ml of ethyl acetate and precipitated n-propylamine hydrochloride was filtered and washed with 10 ml of ethyl acetate. The filtrate and washing were combined, washed with 20 ml of saturated sodium hydrogen carbonate aqueous solution and 20 ml of water and 20 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The yellow residual oil was dissolved in 4 ml of 23% hydrogen chloride methanol solution. The solvent and excess hydrogen chloride were distilled off under reduced pressure. The resulting crystals were suspended in 8 ml of diisopropyl ether, filtered, washed with 1 ml×2 of diisopropyl ether and then dried to obtain 2.38 g (yield: 70%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: [C:1]1(/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3[O:15][CH:16]=[CH:17][C:11]=3[CH2:10]2)=[O:8])=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28].[CH2:29]=O>C(O)(=O)C>[CH3:26][N:27]([CH2:29][C:16]1[O:15][C:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[CH:2][C:1](/[CH:18]=[CH:19]/[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:6][CH:5]=3)=[O:8])[CH2:10][C:11]=2[CH:17]=1)[CH3:28]
Reactant: CNC
Reactant: O=C(c1ccc(/C=C/c2ccccc2)cc1)N1CCc2occc2C1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(/C=C/c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.280 g (0.850 mmol) of (E)-5-(4-stilbenecarbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.115 ml (1.28 mmol) of 50% aqueous dimethylamine and 0.103 ml (1.28 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1 to 25/1). The resulting product was washed with diethyl ether to yield the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>N1C=CC=CC=1.C(OCC)C>[C:27]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1)(=[O:29])[CH3:28]
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 94 g of crude 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione in 620 ml of pyridine is slowly mixed with 310 ml of acetic anhydride and stirred for 2 hours at 25° C. Then, it is slowly mixed with 116 ml of water while being cooled with ice, diluted with 3 l of diethyl ether, and, after washing with sodium bicarbonate solution, the organic phase is dried and concentrated by evaporation. The residue is chromatographed on silica gel, and 84.4 g of 7α-(5-acetoxypentyl)-estr-4-ene-3,17-dione is obtained as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](O)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[BrH:13]>C(O)(=O)C.C(Cl)Cl>[Br:13][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11]
Reactant: CC(O)c1cccc([N+](=O)[O-])c1
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(Br)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
26.15 g (156 mmol) of 1-(3-nitrophenyl)ethanol are dissolved in 130 ml of glacial acetic acid, and 55 ml (313 mmol) of 33% HBr in glacial acetic acid are added dropwise with ice cooling. The reaction mixture is stirred at room temperature for 5 days. The mixture is subsequently diluted with 300 ml of DCM, washed with 3×200 ml of H2O and 200 ml of saturated NaHCO3 solution, dried over sodium sulfate and evaporated to dryness, and the residue is crystallised from petroleum ether.