Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49]C5CCCCO5)=[CH:41][N:40]=4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[N:23]1>O>[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][C:39]4[N:40]=[CH:41][C:42]([O:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:43][CH:44]=4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[N:23]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCO)cn4)cc23)n1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Pyridinium p-toluenesulfonate (243 mg, 0.97 mmol) was added to an ethanol solution (2 ml) of N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, 0.48 mmol) obtained in the above reaction, and stirred under reflux for 2 hours. The reaction solution was cooled to room temperature, saline water was added, and extracted with chloroform/methanol (9:1), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:5) to obtain 3-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-1-ol (131 mg, yield: 69%) as a pale yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([C:23]1[O:27][N:26]=[C:25]([NH2:28])[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:27][N:26]=[C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1noc(Cc2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3noc(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 5-benzyl-[1,2,4]oxadiazol-3-ylamine (Zeitschrift für Chemie 14, 94 (1974)). The title compound was obtained as a light yellow solid (Yield=41%). MS ISP (m/e): 357.1 (100) [(M+H)+].
Reaction SMILES: C([Mg]Br)C.C1COCC1.[CH2:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:11]#[CH:12].[CH2:20]([O:22][CH:23](OCC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]([O:24][CH2:25][CH3:26])[C:12]#[C:11][CH2:10][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: C#CCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(C#CCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A 1M solution of ethylmagnesium bromide in THF (200 ml, 0.2 mol) was treated with 29 ml (0.2 mol) of a solution of 3,4,5,6-tetrahydro-2-(2-propynyloxy)-2H-pyran in toluene, while maintaining ambient temperature through use of a cool water bath. The resulting solution was stirred for 4 h and treated with 47 ml (0.28 mol) of a solution of triethylorthoformate in toluene, while maintaining ambient temperature with a cool water bath. The resulting solution was heated to 85° C. for 8 h, allowing the removal of THF by distillation. After being allowed to cool, the resulting solution was poured into 500 ml of ice-water containing 29 g of NH4OAc, extracted with two portions of ether, added over K2CO3, and concentrated in vacuo. The residue was distilled at ca. 0.5 mm Hg pressure (b.p. 103°-108° C.) to provide 39.5 g (79%) of the desired compound. 1H NMR (CDCl3) δ 1.24 (t, J=7 Hz, 6H), 1.5-1.9 (m, 6H), 3.5-3.65 (m, 3H), 3.7-3.9 (m, 3H), 4.32 (AA', 2H), 4.81 (m, 1H), 5.31 (m, 1H). Mass spectrum: (M+NH4)+ =260.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[Br:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH:12]([N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:13]([O:18][Si:2]([CH3:5])([CH3:4])[CH3:1])[C:14]([CH3:16])([CH3:17])[CH3:15])=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)C(O)C(Oc1ccc(Br)cc1)n1cncn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(O[Si](C)(C)C)C(Oc1ccc(Br)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
At 0° C., a solution of 8.5 g of trimethylchlorosilane in 20 ml of THF is dripped into a solution of 3.4 g of 1-p-bromophenoxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol and 1.5 g of triethylamine in 40 ml of tetrahydrofuran. The mixture is stirred overnight at room temperature and evaporated, and the residue is taken up in CHCl3, washed several times with water and dried over Na2SO4. After evaporation, the crude product is chromatographed (SiO2, CHCl3). There is obtained 2 g of 1-p-bromophenoxy-3,3-dimethyl-2-trimethylsiloxy-1-(1,2,4-triazol-1-yl)-butane as a colorless resin.
Reaction SMILES: C([C:5](=[CH2:9])[C:6]([NH2:8])=[O:7])(C)(C)C.[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[C:10]([NH:8][C:6](=[O:7])[CH:5]=[CH2:9])([CH3:16])([CH3:15])[CH3:11]
Reactant: C=C(C(N)=O)C(C)(C)C
Reactant: Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: C=CC(=O)NC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 50.0 g of t-butylacrylamide and 250 ml of toluene was heated at 80° C. with stirring under a nitrogen atmosphere in a 500 ml three-necked flask. 10 ml of a toluene solution containing 500 mg of azobisisobutyronitrile was added thereto as a polymerization initiator thereby polymerization was initiated. After polymerization for 3 hours, the polymerization solution was cooled and poured into 1 liter of hexane. The solids thus-deposited were collected by filtration, washed with hexane and dried with heating under a reduced pressure to obtain 47.9 g of P-17.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([OH:31])=O)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:35][C:36]1[CH:37]=[C:38]([CH:54]=[CH:55][C:56]=1[CH3:57])[C:39]([NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:43]=1)=[O:40].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([NH:35][C:36]2[CH:37]=[C:38]([CH:54]=[CH:55][C:56]=2[CH3:57])[C:39]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:43]=2)=[O:40])=[O:31])[CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 0 °C
Reaction time: 40 h
Yield: 51.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g) was added to a stirred mixture of 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid (0.307 g), 3-amino-4-methyl-N-(3-morpholinophenyl)benzamide (0.312 g), 1-hydroxybenztriazole (0.202 g) and DMF (5 ml) which had been cooled to 0° C. The resultant reaction mixture was stirred at ambient temperature for 40 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel using a 3:1 mixture of isohexane and ethyl acetate as eluent. There was thus obtained the title compound as a solid (0.31 g); NMR Spectrum: (DMSOd6) 1.38 (s, 9H), 2.12 (m, 2H), 2.27 (s, 3H), 3.08 (t, 4H), 3.37 (m, 3H), 3.57 (m, 1H), 3.74 (t, 4H), 5.05 (m, 1H), 6.67 (d, 1H), 7.17 (m, 2H), 7.3 (d, 1H), 7.42 (m, 3H), 7.52 (s, 1H), 7.57 (d, 1H), 7.78 (d, 1H), 7.93 (s, 1H), 10.0 (s, 1H), 10.01 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].P(Cl)(Cl)(Cl)=O.O.CN(C)[CH:34]=[O:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:34]=[O:35])[C:7]1=[O:21]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=CN1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was added to a solution of phosphorus oxychloride (0.55 ml.) in N,N-dimethylformamide (20 ml.) and the mixture was stirred at 60° C. for 90 minutes. The solution obtained was then poured into water (150 ml.). The solid which formed was collected by filtration, washed with water, air-dried and then recrystallised twice from ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-formyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.6 g.), m.p. 244°-46° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.NC1C([N+:17]([O-:19])=[O:18])=C(C)C=C(C)N=1.OS(O)(=O)=O.[N+]([O-])(O)=O.[NH4+].[OH-]>>[NH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(C)nc(N)c1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1cc(C)nc(N[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
2-Amino-4,6-dimethyl-3-nitropyridine 2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of H2SO4 (conc. d=1.84) which was stirred (mechanical) at 0° C. After complete addition, the mixture was warmed to room temperature until the mixture became homogeneous. The solution was then cooled to -10 C. and a pre-cooled (0° C.) mixture of concentrated HNO3 (11.5 mL, d=1.40) and H2SO4 (8.2 mL, d=1.84) was added at such a rate as not to raise the internal reaction temperatures above -9° C. Ten minutes after the addition was complete this cooled (-10°C.) mixture was poured onto 400 g of crushed ice. The resulting slurry was neutralized by the addition of conc NH4OH (to pH 5.5) while cooling (ice bath). The solid was isolated by filtration, and dried at room temperature to give 13.3 g of 2-nitramino-4,6-dimethylpyridine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:22]2[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]2)=[O:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C(F)(F)F)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (9.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (8.5 mg). Calcd for C17H17F3N2O2: 338.1242, found 338.1238.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH:18]([CH3:20])[CH3:19])[C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:17].C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[Cl:1][CH2:2][C:3]([O:17][C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:8]1[N:7]([CH3:6])[CH:18]([CH3:20])[CH3:19])=[O:4]
Reactant: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C)[C@H]1c2ccccc2C[C@H]1OC(=O)CCl
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
2.00 grams (17.5 mmol) of chloroacetyl chloride was added drop by drop, in 5 minutes, to a solution of 3.00 grams (14.6 mmol) of (1S,2R)-N-methyl,N-i-propyl-1-amino-2-indanol in 40 ml of dichloromethane at room temperature. The temperature increased to 35° C. The reaction was stirred for 15 hours at room temperature. This was followed by the addition of 50 ml of a 5% K2CO3 solution in water and extraction. The basic water layer was once again extracted using 30 ml of dichloromethane. After the collected organic layers had been washed with water, dried using Na2SO4 and evaporated, 3.96 grams (85%) of product was isolated as a yellow oil. 1H NMR (200 MHz, CDCl3): 1.05 (2*d, 6H), 2.09 (s, 3H), 2.96 (dd, J=8.6 and 3.5 Hz +septet, 2H), 3.14 (dd, J=8.6 and 3.5 Hz, 1H), 3.99 (s, 2H), 4.47 (d, J=3,1 Hz, 1H), 5.47 (dt, J=3,1 and 3.5 Hz, 1H) and 7.10-7.25 (m, 4H). 13C NMR (50.31 MHz, CDCl3): 20.59 (q), 33.00 (q), 37.06 (t), 41.10 (t), 53.61 (d), 66.08 (d), 78.47 (d), 124.84 (d), 125.81 (d), 126.62 (d), 127.61 (d), 138.96 (s), 140.46 (s) and 166.85 (s).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[C:6]([I:13])[CH:5]=1.[Li+].[OH-].Cl>C1COCC1>[N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:14])=[O:2])=[CH:5][C:6]=1[I:13])=[N+:11]=[N-:12]
Reactant: COC(=O)c1ccc(N=[N+]=[N-])c(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1I
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the azido-ester from Step 2 (1.0 eq) in 6 mL of THF (0.2M) was added LiOH (2 N in H2O; 1.5 eq). The resulting mixture was stirred at 50° C. for 4 h, then acidified to pH 4 using HCl (1N) and extracted with Et2O (3×). The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated to afford the 4-azido-3-iodo-benzoic acid compound as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[CH2:3](O)C.[SH:6][C:7]1[N:8]=[N:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:12]=1.CI>O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:7]([S:6][CH3:3])[N:8]=[N:9][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: CCO
Reactant: COc1ccc(-c2nnc(S)nc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Eight grams (0.20 mole) of sodium hydroxide were dissolved in 600 ml. of ethanol. The resulting solution was cooled to ambient temperature and 67.0 grams (0.20 mole) of 3-mercapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine were added. Methyl iodide, 67 g. (0.47 mole), was added to the reaction mixture and the mixture immediately became a slurry. Three hundred milliliters of ethanol were added to the slurry and stirring was continued for about 3 hours. One hundred milliliters of water were added to the reaction mixture and the solid product was collected by filtration. The yield of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine, m.p. about 152°-155° C., was 67.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(4-isopropylphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (143 mg, 0.35 mmol, see step (b) Example 10) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 110 mg (57%).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O>O1CCCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 82.9 %

Procedure:
A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 8.7 g.), 50% formic acid (42.5 ml.) and tetrahydrofuran (42.5 ml.) was stirred at 60° C. for 40 minutes. After concentrating the resultant solution in vacuo, the residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.7 g.), mp. 102° to 104° C.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:25]2[C@:20]([CH3:28])([C@H:21]3[CH2:27][C@H:22]3[C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:8]([C@H:9]3[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@:12]([OH:30])([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)[CH:7]=1.C(O)(=O)C.[Cl:35]C1C2[C@](C)(CCC(=O)C=2)[C@@H]2[C@H]([C@H]3[C@](C)(CC2)[C@@](O)(C(=O)C)CC3)C=1>>[Cl:35][C:24]1[C:23](=[O:26])[C@@H:22]2[CH2:27][C@@H:21]2[C@@:20]2([CH3:28])[C:25]=1[C:6]([Cl:5])=[CH:7][C@@H:8]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:29])[C@H:9]1[CH2:10][CH2:11][C@:12]2([OH:30])[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: CC(=O)O
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=C(Cl)C(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Preferred compounds of formula (I) are 6-chloro-17-hydroxy-1α,2α-methylene-pregna-4,6-diene-3,20-dione acetate (cyproterone acetate) and 6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione acetate (chlormadinone acetate).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:20]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]C1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][C:17]([N:28]3[CH2:27][CH2:26][N:25]([CH:20]4[CH2:22][CH2:23][CH2:24]4)[CH2:30][CH2:29]3)=[O:19])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CC(=O)c1ccc(N2CCC(CC(=O)O)CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCC(CC(=O)N3CCN(C4CCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(4-acetyl-phenyl)-piperidin-4-yl]-acetic acid (0.11 mmol) in anhydrous DCM (2 mL) is added 1-cyclopentylpiperazine (1.1 eq.), TEA (0.22 mmol), and BOP (0.14 mmol). The resulting mixture is stirred at rt overnight. DCM is evaporated. The residue is dissolved in EtOAc (20 mL), washed with water (5 mL×3) and brine, dried over sodium sulfate, and concentrated. The crude product is purified through PTLC to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (2H, d), 6.85 (2H, d), 3.89 (2H, br), 3.66 (2H, t), 3.49 (2H, t), 2.91 (2H, dt), 2.46˜2.57 (8H, overlapped), 2.26 (2H, d), 2.12 (1H, m), 1.22˜1.95 (12H, m); LC-MS (M+1) 398.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].C1N=CN([C:25](N2C=NC=C2)=[S:26])C=1>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[N:1]=[C:25]=[S:26]
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1F
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(N=C=S)c1)C1(C(F)(F)F)CC1
Temperature: 50 °C

Procedure:
A mixture of N-(3-amino-4-fluorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (3.17 g; 11.5 mmol) and TCDI (3.07 g; 17.2 mmol) in DCM (50 mL) was heated overnight at 50° C. The mixture was concentrated and the residue was purified by column chromatography.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: FC(F)(F)c1ccccc1I
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccccc2C(F)(F)F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-trifluoromethylphenylilithium (˜3 equiv, freshly prepared from 1-iodo-2-trifluoromethylbenzene as in Example 2A), to give (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-trifluoromethyl-phenyl)-methanone. MS (M+H)+: 328.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:35][CH2:36][N:37]([C:2]([O:4][CH3:5])=[O:3])[CH2:38][CH2:39]5)[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl chloroformate (11 μL) is added to a solution of {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (60 mg) and triethylamine (68 μL) in dichloromethane (2 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature for 2 h. Water is added and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on reversed phase (HPLC; acetonitrile/water) to give the title compound. LC (method 4): tR=0.99 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:16][CH:17]=2)=[O:23])[CH2:27][CH2:28]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: NC1CCOCC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 81 %

Procedure:
As described for example 75b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (86 mg, 81%) which was obtained as a white solid. MS: m/e=413.3 [M+H]+.