Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[C:19]2[O:18][CH2:17][O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:8][C:6]3[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[C:19]=2[O:18][CH2:17]1
Reactant: Brc1cccc2c1OCO2
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1cccc2c1OCO2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromo-benzo[1,3]dioxole (2.0 g, 10 mmol), Pd2(dba)3 (0.80 g, 0.87 mmol), Xantphos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol) was suspended in dioxane (40 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (1.0 g, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.13 (s, 3H), 5.99 (s, 2H), 6.80-6.90 (m, 3H), 8.01 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 264 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21].[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(-c2ccc(C(=O)O)cc2C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Methyl 4-bromo-3-methylbenzoate (Intermediate 17, step 1) (4 g; 17.46 mmol; 1 eq.), 2,5-dimethoxyphenylboronic acid (3.50 g; 19.21 mmol; 1.10 eq.), potassium carbonate (12.07 g; 87.31 mmol; 5 eq.), tetrakis(triphenylphosphine)palladium(0) (2.02 g; 1.75 mmol; 0.10 eq.) were taken in Toluene (20 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was degassed with N2 and then refluxed for 24 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with toluene (200 mL). The filtrate was concentrated to afford a brown oil which was taken up in EtOAc (300 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (100 mL), water (100 mL) and brine (1000 mL), dried over MgSO4 and concentrated affording methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate as a brown oil (5.1 g) used without further purification (HPLC (Method A) Rt 4.73 min (Purity: 59.7%)). A solution of methyl 2′,5′-dimethoxy-2-methylbiphenyl-4-carboxylate (4.50 g; 15.72 mmol; 1 eq.) in EtOH (135 mL) at RT was treated with sodium hydroxide (9.43 mL; 5 M; 47.15 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a beige solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2. Then it was concentrated until precipitation (volume divided by 2). The suspension was filtered affording the title compound as a beige solid (3.43 g, 80%). 1H NMR (DMSO-d6, 300 MHz) δ 12.91 (br s, 1H), 7.85-7.78 (m, 2H), 7.27-7.24 (d, J=7.17 Hz, 1H), 7.08-6.96 (m, 2H), 6.72-6.71 (d, J=3.01 Hz, 1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.14 (s, 3H). LC/MS (Method A): 270.9 (M−H)−. HPLC (Method A) Rt 3.84 min (Purity: 97.8%).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:11])[CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9])[CH2:2][CH3:3].[Na].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1.O>C1(C)C=CC=CC=1>[CH3:9][C@H:8]([O:10][C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:6][C@@H:5]([O:4][CH2:1][CH2:2][CH3:3])[CH3:11]
Reactant: CCCO[C@@H](C)CC[C@H](C)O
Reactant: CCCCCCCCOc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(O[C@@H](C)CC[C@H](C)OCCC)nn2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
320 mg (2.0 mM) of the (2S,5S)-5-propoxy-2-hexanol obtained in Reference Example 1 was dissolved in 15 ml of anhydrous toluene. Thereto was added metallic sodium with stirring at room temperature. To the mixture was added 478 g (1.5 mM) of 3-chloro-6-(4-octyloxyphenyl)pyridazine. The resulting mixture was refluxed for 3 hours. The reaction mixture was cooled and mixed with water and toluene. The toluene layer was separated and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluting solvent: n-hexane-ethyl acetate (4:1)] to obtain 190 mg of the title compound.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[O:12].C([Li])CCC.[CH3:18][C:19]1([CH3:28])[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21](=[O:27])[CH2:20]1>O1CCCC1.C(O)C.O>[OH:27][C:21]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][CH:11]=[O:12])[CH2:22][C:23]([CH3:26])([CH3:25])[CH2:24][C:19]([CH3:28])([CH3:18])[CH2:20]1
Reactant: O=CNc1ccccc1Br
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(C)(C)CC(O)(c2ccccc2NC=O)C1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of sodium hydride (content 60%, 360 mg, 9.00 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of N-(2-bromophenyl)formamide (1.50 g, 7.50 mmol) in tetrahydrofuran (5 mL) while stirring at room temperature under a nitrogen atmosphere, followed by stirring at the same temperature for 30 minutes. The reaction mixture was cooled to −78° C., n-butyllithium (2.67 M solution in hexane, 3.37 mL, 9.00 mmol) was added dropwise thereto, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was further added dropwise a solution of 3,3,5,5-tetramethylcyclohexanone (771 mg, 5.00 mmol) in tetrahydrofuran (1 mL) at the same temperature, followed by stirring at the same temperature for 1 hour and at room temperature for 1 hour. To the reaction mixture were added water (10 mL), thereafter extraction with ethyl acetate was carried out. The organic layer was washed with water and a 5% aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtrated, and concentrated. To the obtained crude crystals was added ethanol (7.7 mL), followed by heating and stirring at 60° C., and after the crystals were dissolved, the mixture was allowed to cool down to room temperature. Upon confirming the precipitation of crystals, water (6 mL) was added to the mixture, followed by stirring for 2 hours. The crystals were collected by filtration and dried to give 947 mg of the title compound as yellow crystals.
Reaction SMILES: Cl[C:2]1([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3(Cl)[N:22]=[C:21](Cl)[N:20]=[CH:19][NH:18]3)[CH:11]=2)[N:7]=[C:6](Cl)[N:5]=[CH:4][NH:3]1.[C:25]1([CH3:32])[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.C(OCC)(=O)C>[CH3:32][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][C:30]=1[C:4]1[N:5]=[C:6]([C:30]2[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[N:7]=[C:2]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[N:22]=[C:21]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:20]=[C:19]([C:30]4[CH:29]=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[CH3:32])[N:18]=3)[CH:11]=2)[N:3]=1
Reactant: Cc1cccc(C)c1
Reactant: ClC1=NC(Cl)(Oc2cccc(OC3(Cl)N=C(Cl)N=CN3)c2)NC=N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(Oc3cccc(Oc4nc(-c5ccc(C)cc5C)nc(-c5ccc(C)cc5C)n4)c3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask fitted with a magnetic stirrer, a condenser and a nitrogen atmosphere are added 2.33 g (5.74 mmol) of the product of Example 11 and 25 mL of m-xylene. The mixture is stirred with warming and, when it becomes homogeneous at about 40° C., 1.84 g (0.0138 mol) of aluminum chloride are added all at once. The mixture is brought to reflux and stirred at this temperature for three hours. After cooling to room temperature, a 100 mL portion of 2N hydrochloric acid is added. The mixture is heated with stirring for 15 minutes and allowed to cool. Portions of ethyl acetate and heptane are added and the solids formed are collected by vacuum filtration. The solids are washed with ethyl acetate and water, then dried to afford 2.58 g of the title compound as an off-white solid.
Reaction SMILES: [ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:20].C=O.[C:34]([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+].Cl>CO.C(O)C.C(OCC)(=O)C>[ClH:1].[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=1)=[O:20]
Reactant: O=C(CCCCCNCC1COc2ccccc2O1)Nc1ccc(C(F)(F)F)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCCCCC(=O)Nc1ccc(C(F)(F)F)cc1)CC1COc2ccccc2O1

Procedure:
6-[(2,3-Dihydro-1,4-benzodioxin-2-yl)methylamino]-N-[4-(trifluoromethyl)phenyl]hexanamide monohydrochloride (201 mg), 37% aqueous formaldehyde (0.18 mL) and sodium cyanoborohydride (38 mg) were stirred in methanol (4.8 mL) for 96 hours at 20°-25° C. under nitrogen atmosphere. Saturated sodium bicarbonate (20 mL) was added to the reaction and extracted with dichloromethane (2×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo. The resulting oil was chromatographed eluting with ethyl acetate and 10:90 ethanol:ethyl acetate to give a white solid (Rf of 0.52 in 10:90 ethanol:ethyl acetate) which was dissolved in ethanol and treated with 1.0M aqueous HCl (1 ml). The solution was concentrated in vacuo to give an oil which was dissolved in 70:30 ethyl acetate:hexane and concentrated. A hygroscopic white solid (151 mg) remained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=1.[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:33]=[C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=4)[N:32]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(O)cc3)ncc1CC2
Temperature: 120 °C
Yield: 3 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (200 mg, 7.6 mmol), N-(4-hydroxy-phenyl)-guanidine nitrate (163 mg, 7.6 mmol), NaOH, (30 mg, 7.6 mmol), and 2-methoxyethanol (2 mL) was heated at 120° C. for 24 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a yellow solid (70 mg, 30%): mp 268-269° C. Anal. RP-HPLC: tR 12.4 min (10-70% MeCN, purity 95%). 1H-NMR (DMSO-d6): δ 9.28 (s, 1H, OH/NH), 9.07 (s, 1H, OH/NH), 8.30 (s, 1H, Py-H), 7.58 (d, 2H, J 8.9, Ph-H), 6.75 (d, 2H, J 8.9, Ph-H), 3.02 (m, 4H, CH2—CH2), 2.80 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.94, 159.64, 159.13, 156.26, 155.73, 152.35, 132.70, 120.94, 115.44, 115.19, 25.13, 23.45, 19.79. MS (ESI+): m/z 311.06 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>O>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Solvent: O
Product: Cc1ccccc1-c1ccc(C(C)CNS(C)(=O)=O)cc1

Procedure:
The title compound was prepared from the product of Example 1 as described in Example 100 with the exception that 2-methylbenzeneboronic acid was used instead of 2-formylbenzeneboronic and 10 mL of water was added to the reaction mixture.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[C:14](OC)[CH:13]=[C:12]([O:18]C)[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C.[Cu](I)I>[CH2:22]([C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:18])[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1)[CH3:23]
Reactant: COc1cc(OC)c2c(c1)Oc1ccc(Br)cc1CC2=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: I[Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1ccc2c(c1)CC(=O)c1c(O)cccc1O2
Temperature: 80 °C
Yield: 2664.1 %

Procedure:
2-Bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one 500 mg (F. W. 349.18, 1.43 mmol) prepared in the first stage of Production Example 79, triphenylphosphine 75 mg (F. W. 262.29, 0.062 mmol), trisbenzyldene acetone dipalladium chloroform complex 74 mg (F. W. 1035.08, 0.015 mmol), diisopropylethylamine 575 μl (F. W. 98.22, d=0.742, 2.86 mmol), ethynyl trimethylsillane 350 μl (F. W. 98.22, d=0.742, 2.86 mmol) and copper iodide 27.5 mg (F. W. 190.44, 0.143 mmol) were dissolved in N-methyl-2-pyrrolidone (5 ml) and, after substituting with argon atmosphere, they were stirred with heating at 80° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography to give the title compound 420 mg (F. W. 367.419, 66%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)n3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-chloro-2-pyridinol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 226.4-227.4° C. 1H NMR (acetone-d6 /300 MHz) 7.99 (m, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.30 (d, 1H, J=7.7 Hz), 7.16 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -79.3 (d, J=7.2 Hz). FABLRMS m/z 404 (M-H). ESHRMS m/z 405.9853 (M+H, Calc'd 405.9861). Anal. Calc'd for C16H8Cl2F3NO4 : C, 47.32; H, 1.99; N, 3.45; Cl, 17.46. Found: C, 47.26; H, 1.93; N, 3.35; Cl, 17.19.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:37][CH:36]=2)(O)[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>C(OC(=O)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])=[CH:39][CH:40]=2)=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:18][OH:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCOc1ccc(C(O)(c2ccc(OCc3ccccc3)cc2)C(CCO)c2ccc(OCc3ccccc3)cc2)cc1
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)CCOc1ccc(C(=C(CCO)c2ccc(OCc3ccccc3)cc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture containing 5.8 g of 1,2-bis(4-benzyloxyphenyl)-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butan-1,4-diol and 20 ml of acetic anhydride is heated at 90° C. for 1 hour. 3.7 g of acetyl chloride is added and the mixture is heated at 80° C. for 0.5 h. The solvent is evaporated. 0.75 g of sodium hydroxide in 200 ml of 80% methanol is added and the mixture is refluxed for 3 hours. The mixture is allowed to cool to room temperature. The crystallized product is collected by filtration. The yield is 4.7 g (83%).
Reaction SMILES: Cl.[C:2]1([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][O:27]C4CCCCO4)=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:2]1([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Nc1ncnc2cc(OCCOC3CCCCO3)c([N+](=O)[O-])cc12)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Nc1ncnc2cc(OCCO)c([N+](=O)[O-])cc12)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
120 ml of methanol and 2 ml of concentrated hydrochloric acid were given to 8.05 g of 4-[(R)-(1-Phenylethyl)amino]-7-[2-(tetrahydropyran-2-yloxy)ethoxy]-6-nitroquinazoline. After stirring for 1.5 hours at 50° C. the reaction mixture was neutralized with concentrated aqueous sodium carbonate solution and evaporated. The solid residue was dissolved in ethyl acetate and the obtained solution was washed with water, with concentrated aqueous sodium chloride solution, dried over magnesium sulfate solution and evaporated. The obtained yellow residue was stirred with 20 ml of tert-butyl methyl ether, suction filtered and dried in an exsiccator. Yield: 4.53 g (91% of theory); melting point: 192° C.-194° C.; mass spectrum (ESI−): m/z=353 [M−H]−.
Reaction SMILES: [Br-].[CH2:2]([C:6]([CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+]>C(Cl)Cl>[CH2:2]([C:6]([CH:8]=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
111.6 g of isobutylcarbonylmethyltriphenylphosphonium bromide in 1500 ml of methylene chloride is mixed with 1500 ml of 2N NaOH and stirred for 30 minutes at room temperature. The organic phase is separated, washed with water and dried on sodium sulfate. After filtration and evaporation of the solvent, the residue is recrystallized in tert-butyl methyl ether. 72.2 g of title compound 1, with a melting point of 120°-121° C., is obtained. By variations of the ketone component in reaction step a), other phosphoranes of the formula can be produced analogously. ##STR9## II. (5E,7E,22E)-(1S,3R)-1,3-bis-(tert-butyl-dimethyl silyloxy-9,10-seco-24a-homo-5,7,10(19)-22-cholestatetraene-24-one 2
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[C:1]12([NH:11][C:12]3[CH:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[N:15]=[C:14]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1nc(NC23CC4CC(CC(C4)C2)C3)cc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CNCCN1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(N2CCNCC2)nc1NC12CC3CC(CC(C3)C1)C2
Yield: 94.4 %

Procedure:
4,6-bis(1-adamantylamino)-2-chloropyrimidine is reacted with piperazine according to the method of Example 4 to obtain the title compound in a yield of 94.4%, m.p.:210°-220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[NH2:12]
Reactant: [H][H]
Reactant: Cc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C(F)(F)F)c1N

Procedure:
A suspension of 50 g (0.24 mol) 1-methyl-2-nitro-3-trifluoromethyl-benzene and 4.4 g 10% Pd/C in 300 mL MeOH was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off, washed with MeOH and the filtrate was evaporated down. The crude product was further reacted without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]3[S:23][C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27](O)=[O:28])=[N:21][N:17]3[C:18](=[O:20])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38](=[O:41])[CH2:39][NH2:40])([CH3:36])([CH3:35])[CH3:34].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.O.CCOC(C)=O>[C:33]([O:37][C:38](=[O:41])[CH2:39][NH:40][C:27]([C:26]1[CH:25]=[C:24]([C:22]2[S:23][C:16]3=[N:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[CH:19][C:18](=[O:20])[N:17]3[N:21]=2)[CH:32]=[CH:31][CH:30]=1)=[O:28])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(C(=O)O)c4)sc3n2)CC1
Reactant: CC(C)(C)OC(=O)CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)c1cccc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.3 %

Procedure:
3-(7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)benzoic acid (45 mg, 0.098 mmol, 1.0 equiv), is prepared using the procedure similarly described in Example 7, is dissolved in 1 mL in dimethylformamide. To the solution is added glycine tert-butyl ester (0.016 ml, 0.118 mmol, 1.2 equiv), PyBOP (77 mg, 0.148 mmol, 1.5 equiv), then N,N-diisopropylamine (0.052 ml, 0.295 mmol, 3.0 equiv). The mixture stirred at room temperature for 18 h. Upon completion, the mixture is taken up in water and EtOAc. The layers are separated and the aqueous layer is back-extracted with EtOAc. The combined organic extracts are then washed with water twice, then brine, dried (MgSO4) and concentrated in vacuo to give a yellow oil which is purified by chromatography (silica gel, 2-5% MeOH/dichloromethane) to give tert-butyl 4-(2-(3-(2-tert-butoxy-2-oxoethylcarbamoyl)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (41 mg, 73.0% yield) as a yellow oil. The residue is then taken on to the next reaction, which follows the same deprotection procedure as above to give 2-(3-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)benzamido)acetic acid (16 mg, 53.7% yield) as a white solid.