Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].C(N(CC)C(C)C)(C)C>CCO>[OH:17][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC(O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(O)c1ccc(NCC(O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A flask, containing 4-fluoro-3-nitrobenzoic acid (8.00 g, 43.2 mmol) and 2-amino-1-phenylethanol (8.89 g, 64.8 mmol) dissolved in EtOH (80 mL), was purged with N2. Anh. N,N-diisopropylethylamine (19 mL, 108 mmol) was added and the reaction mixture was heated at reflux for 24 h. Later the reaction was cooled to rt and concentrated under reduced pressure. The solid residue was dissolved in EtOAc, washed (1 M aq HCl (3×), H2O (2×), brine), dried (Na2SO4) and evaporated to dryness to afford the title compound as a bright yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.67 (t, J=5.2 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.92 (ddd, J=0.4 Hz, 2.0 Hz, 9.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (t, 7.2 Hz, 2H), 7.28 (tt, J=1.2 Hz, 6.8 Hz, 1H), 7.18 (d, J=9.2 Hz, 1H), 5.89 (d, J=4.4 Hz, 1H), 4.91 (q, J=3.6 Hz, 1H), 3.72-3.63 (m, 1H), 3.53-3.45 (m, 1H). MS (ES+): m/z 285.1 (100) [MH+−18]; HPLC: tR=2.80 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I.[Na+].[Cl-]>C1COCC1.CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][OH:17])[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CN(CCOCCO)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H) 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8ethoxymethylene-6,8-dihydro-I-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (brt, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: O.O.[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([OH:25])=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([O:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ON1C(=O)CCC1=O>[CH2:3]([O:10][C:11]([NH:13][C@H:14]([C:23]([N:26]1[CH2:27][CH2:28][CH:29]([O:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:31]1)=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)CC1
Yield: 85.2 %

Procedure:
10.2 g (30 mmol) of N-(benzyloxycarbonyl)-L-tyrosine dihydrate, 6.48 g (30 mmol) of t-butyl (4-piperidinyloxy)acetate and 0.17 g (1.5 mmol) of N-hydroxysuccinimide were dissolved in 200 ml of ethyl acetate while stirring under argon. 6.5 g (31.5 mmol) of dicyclohexylcarbodiimide dissolved in 33 ml of ethyl acetate were added dropwise to the yellowish solution within 19 minutes. A suspension formed slowly and this was stirred at 22° for 22 hours. The precipitated dicyclohexylurea was filtered off and the filtrate was extracted with 1N hydrochloric acid, water and sodium chloride solution. The organic phase was dried over sodium sulphate and, after removing the drying agent, evaporated. 13.1 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-tyrosyl]-4-piperidinyl]oxy]acetate were obtained as a white, hard foam, the microanalysis of which corresponded to that of authentic material.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11][C:10]=2[CH:21]=1)#[N:2].[NH:29]([C:31]1[N:36]=[N:35][C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=1)[NH2:30]>CC(O)C>[N:35]1[C:34]2[C:37]3[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=3[CH2:39][CH2:40][CH2:41][C:33]=2[CH:32]=[C:31]([N:29]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[CH2:15][CH2:14][C@@H:13]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH2:12][CH2:11][C:10]=4[CH:21]=3)=[N:30]2)[N:36]=1
Reactant: NNc1cc2c(nn1)-c1ccccc1CCC2
Reactant: N#CN=C(Nc1ccc2c(c1)CCC(N1CCCC1)CC2)Oc1ccccc1
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc3c(c2)CC[C@H](N2CCCC2)CC3)nn1-c1cc2c(nn1)-c1ccccc1CCC2
Temperature: 90 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Phenyl (S)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate and phenyl (R)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate were treated with 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine in a similar manner as described above in Synthetic Example 2 to yield 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(S)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine. For example, a suspension of a single enantiomer of phenyl N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamimidate (0.06 g, 0.16 mmol) and 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (0.036 g, 0.16 mmol) in 1 mL of IPA was stirred at 90° C. for 18 h. After cooling to ambient temperature, the solvent was evaporated and the residue was purified by HPLC to provide enantiomerically pure 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(7-(R)-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine as a yellow solid (0.04 g, 50%). 1H NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 7.94 (s, 1H), 7.85 (br s, 2H), 7.72 (m, 1H), 7.46 (m, 3H), 7.37 (m, 2H), 7.06 (m, 1H), 3.46 (m, 4H), 3.12 (m, 2H), 2.72 (m, 4H), 2.61 (m, 3H), 2.25 (m, 5H), 2.09-1.82 (m, 5H) ppm; MS (ES) 507 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17]N(C)C)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C(O)(C)C>[CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:17][N:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36 g (129 mmol) of methyl 2-benzyloxycarbonylamino-3-dimethylaminoacrylate and 24.12 g (142 mmol) of diphenylamine were dissolved in 630 ml of isopropanol at 40° C. Subsequently, the solution was admixed with 17.4 ml of concentrated hydrochloric acid within 5 min and stirred at 40° C. for a further 30 min. The reaction solution was concentrated to 300 ml and admixed slowly with 300 ml of water. The crystallized product was filtered off with suction and dried at 40° C. under reduced pressure.
Reaction SMILES: [C:1](=[C:3]1N=C2C=CC=CC2=N1)=O.[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:17])=[O:16])([CH3:14])[CH3:13].C([Mg]Br)C.CO>C(OCC)C>[CH:12]([S:15]([N:18]1[C:22]2[CH:23]=[C:24]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([OH:34])[CH2:1][CH3:3])[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH2:35])(=[O:16])=[O:17])([CH3:14])[CH3:13]
Reactant: O=C=C1N=c2ccccc2=N1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: CO
Product: CCC(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1

Procedure:
The 1-hydroxy-1-(C1 -C7 alkyl)benzyl derivatives, the carbinols, can also be prepared by reacting the corresponding carbonyl derivative with the appropriate Grignard reagent followed by hydrolysis. The carbonyl benzimidazole, 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, is reacted with ethylmagnesium bromide in anhydrous ethyl ether and then hydrolyzed to form the carbinol, 1-isopropylsulfonyl-2-amino-6-(1-phenyl-1-hydroxy-1-propyl)benzimidazole. The Grignard reagent, ethylmagnesium bromide, is made from ethylbromide and metallic magnesium in anhydrous ethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][O:29]C2CCCCO2)[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCOC1CCCCO1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC(CCCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of 0.453 g of t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(tetrahydropyranyloxy)propyl]-octanoate in 7 ml tetrahydrofuran is added 5 ml of 1N hydrochloric acid and the solution is allowed to stir for 18 h. The reaction mixture is diluted with water and extracted with ethyl acetate to give a yellow oil which is chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to yield t-butyl 8-(p-chlorophenylsulfonamido)-4-(3-hydroxypropyl)-octanoate; NMR (CDCl3): delta 3.65 (m,2H), 3.0 (q,2H), 2.2 (t,2H).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14]3[C:18]=2[N:17]=[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=32)C=CC=CC=1.[CH3:43][O:44][C:45]([C:47]1[O:48][C:49]([C:52](=O)[CH3:53])=[CH:50][CH:51]=1)=[O:46]>>[CH3:43][O:44][C:45]([C:47]1[O:48][C:49](/[C:52](/[CH3:53])=[CH:9]/[C:10]2[CH:11]=[CH:12][CH:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14]3[C:18]=2[N:17]=[C:16]2[CH2:19][CH2:20][CH2:21][CH2:22][C:15]=32)=[CH:50][CH:51]=1)=[O:46]
Reactant: COC(=O)c1ccc(C(C)=O)o1
Reactant: CCCCCCCCC1C=CC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)=C2N=C3CCCCC3=C21
Agent: [Br-]
Product: CCCCCCCCC1C=CC(/C=C(\C)c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Yield: 51 %

Procedure:
Using the conditions described in Example 37, the Wittig condensation reaction of 2.8 g of the phosphonium salt from Example 26 with 0.76 g of 5-acetyl-2-furancarboxylic acid methyl ester from Example 45 produced 1.0 g (52.5%) of (E)-5-[1-methyl-2-(1,2,3,4- tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)ethenyl]-2-furan carboxylic acid methyl ester as a yellow oil after chromatographic purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:20](=[O:23])([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:19][N:8]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:23][C:20]2[CH:14]=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CN(c1cccc(C(F)(F)F)c1)c1cc(Cl)ncn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc(C(F)(F)F)c1)c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Temperature: 60 °C
Yield: 77.4 %

Procedure:
4-Chloro-6-(N-methyl-3-trifluoromethylanilino)-pyrimidine (0.30 g, 0.001 mol.) and sodium carbonate (0.28 g, 0.003 mol.) in DMF are stirred for 10 minutes. m-Trifluoro-methylphenol (0.16 g, 0.001 mol) is added and the mixture is heated to 60° C. for 12 hours. The mixture is then cooled and poured into water. The product is extracted into ethyl acetate, washed with 10% sodium hydroxide, 10% hydrochloric acid, and 5% potassium carbonate, dried over Na2SO4, filtered, and is concentrated under reduced pressure. 6-(N-methyl-3-trifluoromethylanilino)-4-(3-trifluoromethyl-phenoxy)pyrimidine (0.16 g) obtained by chromatography as a white solid. M.p. 118-119° C.
Reaction SMILES: [Na].[CH2:2]([SH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[C@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)(=O)=O>C(O)C>[CH2:2]([S:9][C@@H:15]1[CH2:20][CH2:19][C@H:18]2[C@H:21]3[C@H:31]([C:32](=[O:34])[CH2:33][C@:16]12[CH3:17])[C@:29]1([CH3:30])[C:24](=[CH:25][C:26](=[O:35])[CH:27]=[CH:28]1)[CH2:23][CH2:22]3)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccccc1

Procedure:
To 13.8 gm. of sodium metal dissolved in 1040 ml. of ethanol is added 47 ml. of benzyl mercaptan, followed by 21 gm. of 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione. Heat to reflux for 72 hours, then cool and filter off insoluble material. Concentrate the filtrate in vacuo to about 150 ml. and precipitate into 1500 ml. of water containing 150 ml. of a 5% aqueous solution of sodium hypochlorite. Extract three times with 500 ml. portions of chloroform which is then washed twice with water. Dry the chloroform extracts over Na2SO4, then vacuum concentrate to dryness. Dissolve the residue in a minimum amount of chloroform/ethyl acetate (1:1) and pass through 300 gm. of silica gel. Take 1 l. fractions utilizing ethyl acetate/chloroform/hexane (1:10:10). Combine desired fractions as determined by thin layer chromatography and evaporate to dryness. Crystallize the resultant residue from ethyl acetate/hexane to obtain the title compound; m.p. 134°-136° C.; λmaxMeOH 237 nm (ε=17,100); [α]D26 +152.5° (DMF).
Reaction SMILES: [OH:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[H-].[Na+].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].O>C1COCC1>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([O:1][C:2]1([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]1[C:15]([F:18])([F:17])[F:16])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1)=[O:24]
Reactant: OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)OC1(Cc2cncnc2)C=CC=CC1C(F)(F)F
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 0.5 g of 5-(1-hydroxy-2'-trifluoromethylbenzyl)-pyrimidine (produced according to Example 7) in 15 ml THF at room temperature, 0.2 g of NaH (80%) were added. Gas evolution was observed. After 30 minutes, 0.4 g of trimethylacetyl chloride were added to the reaction mixture and gas evolution was again observed. After 3 hours of stirring, the reaction mixture was worked up with water and the organic materials extracted with diethyl ether. The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. Elution on a silica gel column with a 1:1 mixture of diethyl ether and hexane yielded 0.56 g of 5-(1-trimethylacetoxy-2'-trifluoromethylbenzyl)-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([CH:20]=O)[CH:16]=1.Cl>CCO.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:20]/[C:17]2[CH:16]=[C:15]([CH3:14])[O:19][N:18]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=O)no1
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(/C=C/C(=O)c2ccc(O)c(C)c2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of commercially available 4′-hydroxy-3′-methylacetophenone (700 mg, 4.66 mmol) and NaOH (365 mg, 9.1 mmol) in 10 mL of absolute EtOH was added commercially available 5-methylisoxazole-3-carbaldehyde (518 mg, 4.66 mmol). The reaction mixture was stirred at room temperature for 18 hr. 5 mL of water was added and the reaction mixture was acidified with concentrated HCl to pH 5-6. The precipitate was filtered, washed with water and dried to give (E)-1-(4-hydroxy-3-methylphenyl)-3-(5-methylisoxazol-3-yl)prop-2-en-1-one. MS (EI) for C14H13NO3: 244 (MH+).
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].Br[C:18]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1cccc(OC)c1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2c(OC)cccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 2-bromo-3-methoxyanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 320.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([N:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:22][CH:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:26]1[CH2:27][CH2:28][C:23]2([N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:20](=[O:36])[CH:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:22]2)[CH2:24][CH2:25]1)=[S:11]
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: Fc1ccc(N=C=S)c(F)c1
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC2(CCN(C(=S)Nc3ccc(F)cc3F)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Difluorophenyl isothiocyanate (256 mg, 1.50 mmol was added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (503 mg, 1.50 mmol) in toluene (14.3 ml) with stirring under a blanket of nitrogen at RT and the reaction mixture was stirred at 50° C. for 8 h. After removal of the solvent, the desired product 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-thiocarboxylic acid (2,4-difluorophenyl)amide was obtained by means of preparative HPLC.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:47]([O:49]CC=C)=[O:48])[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2].N1CCOCC1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:4][C@H:5]([C:47]([OH:49])=[O:48])[CH2:6][C:7]1[CH:44]=[CH:43][C:10]([N:11]([C:34](=[O:42])[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:12]2[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=2[C:14]([O:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[C:9]([CH2:45][CH3:46])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)C(Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)c(CC)c1)NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 103.4 %

Procedure:
A mixture benzhydryl 2-{4-[2-(acetylamino)-3-(allyloxy)-3-oxopropyl][tert-butoxy(oxo)acetyl]-2-ethylanilino}benzoate (3.4 g, 4.8 mmol), Pd(Ph3P)4 (166 mg, 0.144 mmol) and morpholine (0.5 ml, 5.8 mmol) in dichloromethane (25 mL) was stirred under N2 atmosphere for 2 hours, partitioned between ethyl acetate and water (75 mL, 1:1). The organic phase was washed with 1N HCl (1×25 mL), brine (1×25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to provide the titled compound (3.3 g). MS (ESI(+)) m/e 665 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.51-7.98(m, 2H), 7.73-6.86 (m, 16H), 4.53-4.33 (m, 1H), 3.12-2.76 (m, 2H), 2.58-2.42 (m, 2H), 1.82-1.77 (m, 3H), 1.22-0.78 (m, 3H), 1.06, 1.04, 1.00 (s, s, s, 9H).