Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:17])[F:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([CH:15]([F:16])[F:17])[N:21]([CH2:19][CH3:20])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(C(F)F)occ1OCc1ccccc1
Reactant: CCN
Solvent: CO
Product: CCn1cc(OCc2ccccc2)c(=O)cc1C(F)F
Reaction time: 0.17 h
Yield: 52 %

Procedure:
5-Benzyloxy-2-difluoromethyl-pyran-4-one (2.0 g, 7.93 mmol) was suspended in 15 mL of methanol. A 2.0M solution of ethylamine in methanol (8.0 mL) was added at room temperature, and the reaction slowly turned into a clear yellow/green solution over 10 min. After 4 h, the reaction mixture was concentrated in vacuo to an oil. The oil was diluted with 10 mL of ethyl acetate and stirred until a solid precipitated out. The solid was collected by suction filtration, thoroughly washed with ether, and dried to afford the title product (1.14 g, 52% yield). HPLC purity (peak area percent) is 97.5% at λ=280 nm using HPLC Method 1 as described above.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].[C:24](O)(=[O:26])[CH3:25]>>[C:24]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:26])[CH3:25]
Reactant: CC(=O)O
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21

Procedure:
Following General Procedure C-P using acetic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 352 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)C#N.N.Cl>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[CH2:15][C:18]1[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=1
Reactant: COc1cc2nccc(C(C#N)c3ccc(Br)cc3)c2cc1OC
Agent: Cl
Agent: N
Agent: O=S(=O)(O)O
Product: COc1cc2nccc(Cc3ccc(Br)cc3)c2cc1OC
Yield: 32.7 %

Procedure:
2-(6,7-Dimethoxy-4-quinolyl)-2-(4-bromophenyl)acetonitrile (850 mg) obtained in Example 161 was dissolved in 60% aqueous sulfuric acid (5 ml), and the solution was refluxed with heat for 1 hour and then poured into a container with ice and aqueous ammonia. The solution was neutralized with hydrochloric acid and extracted with methylene chloride. After drying with anhydrous sodium sulfate and removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 260 mg of the title compound (yield: 33%).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][C:14]=1[NH:30][C:31](=[O:47])[CH2:32][CH:33]1[C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:40][C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:12])([CH3:11])[CH3:10].[C:48]1(=[O:54])[O:53][C:51](=[O:52])[CH2:50][CH2:49]1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(OCC)C>[C:48]([O:29][CH:21]([CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])=[C:14]([NH:30][C:31](=[O:47])[CH2:32][CH:33]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:39]=3[O:40][C:41]3[C:46]2=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:15]=1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)(=[O:54])[CH2:49][CH2:50][C:51]([OH:53])=[O:52]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)CCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 125 °C
Reaction time: 9 h
Yield: 83.3 %

Procedure:
5 ml of a xylene solution containing 74 mg (0.14 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 15 mg (0.15 mmol) of succinic anhydride, 18 mg (0.15 mmol) of 4-(N,N-dimethylamino)pyridine and 112 mg (1.41 mmol) of pyridine were stirred for 9 hours at 125° C. At the end of this time, the reaction mixture was allowed to return to room temperature. The reaction solution was then diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 20 g of silica gel. Elution using a gradient elution method, with mixtures of methylene chloride and methanol in ratios ranging from 100:5 to 10:1 by volume as the eluent, afforded 73 mg (yield 84%) of the title compound as a foam-like substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4](Cl)[CH:3]=1.[CH:13](OCC)(OCC)OCC>>[Cl:11][C:6]1[C:7]2[C:8](=[O:9])[NH:10][CH:13]=[N:1][C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)c1c(N)cc(Cl)nc1Cl
Product: O=c1[nH]cnc2ccnc(Cl)c12
Temperature: 25 °C

Procedure:
A suspension mixture of 4-amino-2,6-dichloronicotinamide (1.12 g, 6.53 mmol) and triethyl orthoformate (20 mL, 17.8 g, 120.3 mmol) was heated at 150° C. for 6 hours in a Teflon screwed pressure vessel. After it was cooled to room temperature, evaporation of triethyl orthoformate afforded crude product that was crystallized from a mixed solvent of toluene and methanol to afford product the title compound. 1H NMR (DMSO-d6) 7.55 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 8.55 (d, J=5.6 Hz, 1H), 12.72 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 116.4, 121.0, 149.9, 150.9, 151.4, 157.6, 158.0; ESI-MS m/z 181.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4](N)[CH:3]=1.N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[C:4]([OH:13])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)c2sccc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1cc(Cl)c2sccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A dispersion of 7-chloro-benzo[b]thiophen-5-ylamine (2.3 g, 0.012 mol) in dil. sulphuric acid (14 ml conc. H2SO4 in 400 ml water) was heated to obtain the clear solution and it was cooled to 0° C. A cold solution of NaNO2 (0.9 g in 5 mL of water, 0.013 mol) was added dropwise and the mixture was stirred at same temperature for 1 h and then warmed to 10° C. over 30 min. Excess nitrite was then quenched with urea. The reaction mixture was then added to dil. sulphuric acid (8 mL conc. Sulphuric acid in 115 mL water) maintained at 90° C. and the mixture was further refluxed for 1 h. The reaction mixture was filtered hot and the filtrate was stirred overnight at room temperature. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water, brine, dried and concentrated. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate/9:1) to give 0.4 g of 7-chloro-benzo[b]thiophene-5-ol.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][C:16]#[N:17].Cl[C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]#[C:28][CH3:29])[N:22]=[CH:21][N:20]=1.[Cl-].[NH4+]>O1CCCC1>[C:16]([CH:15]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]#[C:28][CH3:29])[N:22]=[CH:21][N:20]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[F:7])#[N:17]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: N#CCc1cccc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(C#N)c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.7 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.41 g of potassium t-butoxide, to which 0.56 g of (2,3-difluorophenyl)acetonitrile and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine were added, followed by stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(α-cyano-2,3-difluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (72)).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.S(=O)(=O)(O)[OH:15].[OH-].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([NH2:13])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: N#Cc1ccc(N)c2cccnc12
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc(N)c2cccnc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A reaction mixture of 5-amino-quinoline-8-carbonitrile (1000.00 mg; 4.29 mmol; 1.00 eq.) in sulfuric acid (5.00 ml; 93.80 mmol; 21.86 eq.) was stirred at 100° C. for 1 h. The reaction mixture was then cooled, poured into ice and neutralized with 2N sodium hydroxide to PH=9. The precipitate was filtered, washed with water and dried to afford 5-aminoquinoline-8-carboxamide (800 mg, yield 74.3%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC2CCCCO2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.13 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.90 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 38%).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH2:1]([NH:8][C:9]([NH:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NCc1ccccc1
Product: O=C(NCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use benzylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (45.6% yield). 1H NMR (500 MHz, CDCl3) δ 12.0, 8.28, 7.80, 7.67, 7.62, 7.32, 7.23, 7.02-7.14, 4.54, 3.85-3.91, 3.69-3.76, 3.28-3.40, 2.94-3.10.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([N+:36]([O-])=O)[CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:39]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[NH2:36][C:25]1[CH:24]=[C:23]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]([NH2:39])[CH:10]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:17])([F:18])[F:16])[CH:28]=[CH:27][C:26]=1[NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1cc(C(c2ccc(Nc3ccccc3)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(c2ccc(Nc3ccccc3)c(N)c2)(C(F)(F)F)C(F)(F)F)ccc1Nc1ccccc1
Yield: 49 %

Procedure:
34.6 g (0.06 mol) of 2,2-bis-(4-anilino-3-nitrophenyl)-hexafluoropropane in 220 ml of ethanol are reduced with hydrogen under the catalytic action of 2 g of Pd-on-C (5% by weight in active charcoal) in a 500 ml chromium nickel steel autoclave. The crude product (30.7 g - pure according to H-NMR) is filtered off and recrystallized twice to give 15.1 g of analytically pure 2,2-bis-(3-amino-4-anilinophenyl) -hexafluoropropane (49% yield). The melting point is 177-178° C., and differs from the melting point given in the literature (120° C.).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:21])[NH:7][C:6]1=[O:22])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>CN(C=O)C>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][N:10]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:8](=[O:21])[N:7]([CH2:30][CH3:31])[C:6]1=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-butyl-7-(phenylmethyl)-3,7-dihydro-1H-purine-2,6-dione (0.429 g, 1.24 mmol) and potassium carbonate (0.256 g, 1.85 mmol) were suspended in DMF (8 mL), iodoethane (0.113 mL, 1.42 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the title compound; 1H NMR (400 MHz; CDCl3) δ: 0.96 (3H, t), 1.25 (3H, t), 1.36-1.45 (2H, m), 1.72-1.76 (2H, m), 4.05-4.13 (4H, m), 5.50 (2H, s), 7.32-7.40 (5H, m), 7.52 (1H, s); m/z 327 [MH+].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@H:3]1[CH3:7].CS(C)=O.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:3]1[CH3:7]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
To a suspension of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one (10.45 g) in dry THF (418 mL) was added dropwise Red-Al (104.9 g: 363 mmol: 70% toluene solution) under ice-cooling and a nitrogen stream. The mixture was stirred at room temperature for 20 min, and further refluxed for 3 hr. The reaction mixture was ice-cooled again, and sodium carbonate decahydrate (41.6 g) was added under a nitrogen stream. The mixture was stirred at room temperature overnight, insoluble materials were filtered through celite and washed with THF. The filtrate and washing were combined and concentrated under reduced pressure to give (2S,3S)-3-hydroxy-2-methylpyrrolidine. Without further purification, this compound was diluted with DMSO to give 0.9 mol/L-DMSO solution. A solution (170 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine in 0.9 mol/L-DMSO was diluted with water (200 mL), sodium hydrogen carbonate (24.6 g) and benzyl chloroformate (15 mL) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a pale-yellow oil (yield: 20.64 g, 84%).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=4)[N:6]=3)[CH2:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CCN2CCN(c3nc(Cl)ns3)CC2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(CCN2CCN(c3nc(-c4ccc(C#N)cc4)ns3)CC2)cc1
Temperature: 110 °C

Procedure:
A 5 ml micro wave vial was charged with 3-chloro-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole (50 mg, 148 μmol) in 3 mL DME. 4-Cyanophenylboronic acid (26.0 mg, 177 μmol), Na2CO3 (18.8 mg, 177 μmol), tetrakis(triphenylphosphine) palladium (0) (3.41 mg, 2.95 μmol) and water (1.5 mL) was added. The vial was capped and the mixture was heated in oil bath at 110° C. over night. 2 mL EtOAc were added and the aqueous part was separated. The organic layer was dried over Na2SO4, filtered off and concentrated in vacuo. The crude product was dissolved in MeCN (3 mL)/DIPEA (100 μL) and purified by preparative HPLC on reversed phase eluting with a gradient formed from MeCN, water and NEt3 to yield, after evaporation of the product containing fractions, 13.6 mg (23%) of the title compound as white solid. MS (m/e): 406.3 (MH+).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15](/[C:16](=[N:28]/[O:29][CH2:30][CH:31]=[CH2:32])/[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[CH2:30]([O:29]/[N:28]=[C:16]1/[C@@H:15]2[C@@H:25]([C@:23]3([CH3:24])[CH:22]([CH2:17]/1)[CH2:21][C:20](=[O:52])[CH2:19][CH2:18]3)[CH2:26][CH2:27][C@@:4]1([CH3:5])[C@H:6]2[CH2:7][CH2:8][C:3]1=[O:2])[CH:31]=[CH2:32]
Reactant: C=CCO/N=C1\CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C=CCO/N=C1\CC2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Yield: 76 %

Procedure:
The title compound II-av was prepared in 76% yield from 3,3:17,17-bis(ethylendioxy)-7-(E)-allyloxyiminoandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 8/2). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 5.98 (1H, m), 5.24 (1H, m), 5.14 (1H, m), 4.48 (2H, m), 2.40-1.10 (20H, m), 1.00 (3H, s), 0.81 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([N:14]=[C:15]=[S:16])=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]([NH2:17])=[S:16])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(N=C=S)c(-c2ccccc2)c1
Reactant: N
Solvent: CCO
Product: Cc1ccc(NC(N)=S)c(-c2ccccc2)c1

Procedure:
Reaction of 5-methyl-2-biphenylylisothiocyanate (7.5 g) in ethanol (20 ml) with 25% aqueous ammonia solution (60 ml) at ambient temperature for 2 hours yielded N-(5-methyl-2-biphenylyl)thiourea as a colourless solid (m.p. 175°-177° C.).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH:17]=[O:18])[C:5]([NH:7][C:8]1[S:9][C:10]([S:13][CH3:14])=[N:11][N:12]=1)=[O:6])[CH2:2][CH3:3].Cl>O>[CH3:14][S:13][C:10]1[S:9][C:8]([N:7]2[CH:17]([OH:18])[CH2:16][CH2:15][N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[O:6])=[N:12][N:11]=1
Reactant: CCCN(CCC=O)C(=O)Nc1nnc(SC)s1
Agent: Cl
Solvent: O
Product: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-propyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)Cl
Reactant: NCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-benzyloxyethylamine (25 g) and potassium carbonate (50 g) in dichloromethane (500 ml) was treated dropwise with methyl chlorooxoacetate (25 g) at 0° C. After stirring for 3 h at room temperature, the mixture was washed with aq. sodium bicarbonate and dried over magnesium sulfate. Removal of solvent in vacuo gave methyl (2-benzyloxyethyl)aminooxoacetate as an oil. Yield: 40 g. The oil was dissolved in tetrahydrofuran, conc. aq. ammonia (500 ml) was added followed by reflux for 1/2 h. After cooling, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate. Removal of the solvent gave 4a as a crystalline material. Yield: 32 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[C:12]([O:28][CH2:29][CH2:30][OH:31])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:63][S:64](Cl)(=[O:66])=[O:65].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:32][C:33]([NH:35][C@@H:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:39]([O:46][C:47]3[CH:48]=[CH:49][C:50]4[N:51]([C:53]([N:56]5[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]5[CH3:62])=[N:54][N:55]=4)[CH:52]=3)[CH2:38][CH2:37]2)=[O:34])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])=[C:12]([CH:11]=2)[O:28][CH2:29][CH2:30][O:31][S:64]([CH3:63])(=[O:66])=[O:65])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCO)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCOS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 55eB (26.0 mg, 0.30 mmol), methanesulfonyl chloride (70.0 μL, 0.90 mmol) and DIPEA (208 μL, 1.20 mmol) in DCM (8 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (275 mg, 97%). LCMS (Method 3): Rt 5.23 min, m/z 943 [MH+].