Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH:34]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([C:30]([F:29])([F:39])[F:40])[CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 537.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[O:36]C)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12.B(Br)(Br)Br>C(Cl)Cl.CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:38])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][CH:19]=3)[S:17][C:10]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cncn4C)sc23)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4O)cc3F)c2s1
Reaction time: 1 h
Yield: 27.6 %

Procedure:
To a solution of compound 28c (example 10, scheme 8) (115 mg, 0.21 mmol) in DCM (10 mL) at −40° C. was added BBr3 (1.0M, 0.86 mL, 0.86 mmol). The reaction mixture was allowed to stir for 1 hr then diluted with MeOH (2 mL) and water (1 mL) and concentrated. The residue was purified by preparative HPLC (Thermo C-18 column, gradient MeOH/water from 95:5 to 60:40) to afford title compound 115 (30 mg, 27% yield) as a white solid. 1H NMR (DMSO-d6). δ (ppm): 10.57 (s, 1H), 9.88 (s, 1H), 9.59 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.92 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 7.86 (dd, J=12.7 Hz, J=2.1 Hz, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.42 (dd, J=9.0 Hz, J=1.7 Hz, 1H), 7.40 (s, 1H), 6.93-6.84 (m, 2H), 6.75 (t, J=8.0 Hz, 1H), 6.63 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.61 (s, 2H). MS (m/z): 518.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][C:19](OCC)=[O:20])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH2:18][CH2:19][OH:20])=[CH:5]2
Reactant: CCOC(=O)Cc1cc2cc(C)ccc2nc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccccc3)c(CCO)cc2c1

Procedure:
0.50 g (1.64 mmol) of 16, dissolved in 5 ml of THF, was slowly added dropwise to a suspension of 0.12 g (3.27 mmol) of lithium aluminium hydride (LiAlH4, powder) in 10 ml of THF with stirring and ice-cooling. The mixture was stirred for 3 h at RT, excess LiAlH4 was destroyed by addition of saturated ammonium chloride solution, and the mixture was extracted 2× with ethyl acetate. The combined organic phases were dried, the solvent was removed, and the residue was purified by column chromatography (ethyl acetate/cyclohexane), giving a colourless solid (compound 17).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13]([O:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[S:27][N:26]=[CH:25][C:24]=2[C:28]=1Br)=[O:19])([CH3:16])([CH3:15])[CH3:14].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.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[C:13]([O:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[S:27][N:26]=[CH:25][C:24]=2[C:28]=1[NH:12][C:3]1[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=1[F:1])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)c1ccc2sncc2c1Br
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc2sncc2c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 90 °C
Yield: 78.1 %

Procedure:
A solution of 2-fluoro-4-trimethylsilanyl-phenylamine (340 mg, 1.43 mmol), 4-bromo-benzo[d]isothiazole-5-carboxylic acid tert-butyl ester (449 mg, 1.43 mmol), Pd2 dba3 (65 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium phosphate tribasic (455 mg, 2.14 mmol) in toluene (5 mL) was degassed and then the reaction mixture heated at 90° C. for 18 hours. The cooled reaction mixture was diluted with ethyl acetate, filtered through Celite®, and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 2.5 to 5% diethyl ether in pentane) to give the title compound as a dark oil (465 mg, 78%). LCMS (Method B): RT=5.76 min, [M+H]+=417.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C([Sn]([N:53]=[N+:54]=[N-:55])(CCCCCCCC)CCCCCCCC)CCCCCCC>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:55][N:54]=[N:53][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCC[Sn](CCCCCCCC)(CCCCCCCC)N=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
A mixture of 2.11 g of 2-butyl-4-chloro-5-formyl-1-(2'-cyanobiphenyl-4-yl)methylimidazole, 8.38 g of trioctyltin azide (tri-n-octyltin azide) and 10 ml of toluene was stirred at 120° C. for 18 hours. After cooling, the reaction mixture was concentrated. To the residue was added 10 ml of ethanol as well as an aqueous solution of sodium nitrite (1.3 g/5 ml) and the mixture was adjusted to pH 3.3 with concentrated hydrochloric acid. The mixture was diluted with 20 ml of water and extracted with two 20 ml portions of ethyl acetate. The ethyl acetate solution was concentrated and the residue was purified by chromatography on 30 g of silica gel (CH2Cl2 -MeOH). The active fraction was concentrated to provide 1.82 g of 2-butyl-4-chloro-5-formyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole. Yield 73%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:44]([O:48][C:49](=[O:88])[CH:50]([CH2:73][C:74]1[CH:75]=[N:76][C:77]([NH:80][C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])=[CH:78][CH:79]=1)[CH:51]([S:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=1)[CH2:52][CH2:53][C:54]1[CH:55]=[C:56]([CH:60]=[CH:61][CH:62]=1)[C:57]([OH:59])=O)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C>[C:84]([O:83][C:81]([NH:80][C:77]1[N:76]=[CH:75][C:74]([CH2:73][CH:50]([CH:51]([S:63][CH2:64][C:65]2[CH:66]=[CH:67][C:68]([O:71][CH3:72])=[CH:69][CH:70]=2)[CH2:52][CH2:53][C:54]2[CH:62]=[CH:61][CH:60]=[C:56]([C:57]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:59])[CH:55]=2)[C:49]([O:48][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:88])=[CH:79][CH:78]=1)=[O:82])([CH3:85])([CH3:86])[CH3:87]
Reactant: COc1ccc(CSC(CCc2cccc(C(=O)O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Reactant: CNCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CSC(CCc2cccc(C(=O)N(C)CCc3ccccc3)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 81.4 %

Procedure:
N-methylphenethylamine (20 μL, 0.14 mmoL), HATU (55 mg, 0.15 mmoL) and iPr2EtN (46 μL, 0.26 mmoL) was added to a solution of 3-{5-tert-butoxy-4-({6-[(tert-butoxycarbonyl) amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-oxopentyl}benzoic acid (84 mg, 0.132 mmol) in DMF (2 mL) under argon at 0° C. The reaction mixture was stirred for 2 h and was then quenched with ice. Diethylether and water was added and the aqueous phase was extracted diethyl ether. The combined organic phase was dried and concentrated. Flash chromatography (heptan/EtOAc, 3:1) gave tert-butyl 2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-(3-{[methyl(2-phenylethyl)amino]carbonyl}phenyl)pentanoate (81 mg, 81.4%).
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(F)ccc1Cl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(F)ccc1Cl

Procedure:
Prepared according to the method of Example 41 from 1-adamantanemethylamine (0.1 ml) and 2-chloro-5-fluorobenzoic acid (0.098 g) to give the title compound as a white solid (0.165 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:10]=1[N+:31]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1.CO.O.[Fe]>[NH2:31][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[C:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (21) (6.7 g, 12.4 mmol) in THF/MeOH/H2O (100 mL/50 mL/30 mL) was added Fe powder (3.47 g, 62 mmol) and NH4Cl (6.63 g, 124 mmol). The reaction mixture was heated at 50° C. for 5 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (30 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (22) (6 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: Cl.[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[C:21]([O:30][CH3:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CCOC1C=CC(CCC(=O)[C:58]([F:61])([F:60])[F:59])=CC=1)C)CCCCCCCCCCC>>[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:29])[C:58]([F:61])([F:60])[F:59])=[C:21]([O:30][CH3:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)c(OC)c1
Agent: Cl
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)c(OC)c1
Yield: 58 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, hydrochloride (274 mg, 0.598 mmol) was reacted by the general procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N-methylamino)- ethoxy]phenyl]-1,1,1-trifluoro-2-butanone and afforded the title compound (165 mg, 58%) as a pale yellow oil (b.p. 138-140° C./0.015 mmHg).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]2[O:12][C:11]([CH3:18])([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:19]=1)(=[O:3])[CH3:2].O.[C:25]1(C)C=CC(S(O)(=O)=O)=C[CH:26]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:25]([O:16][C:15](=[O:17])[CH2:14][CH2:13][C:11]1([CH3:18])[CH2:10][CH2:9][C:8]2[CH:19]=[C:4]([C:1](=[O:3])[CH3:2])[C:5]([OH:23])=[C:6]([CH2:20][CH2:21][CH3:22])[C:7]=2[O:12]1)[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(C)(CCC(=O)OCC)CC2
Yield: 385.4 %

Procedure:
A solution of 692 mg of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid and 100 mg of p-toluenesulfonic acid monohydrate in 10 ml of absolute ethanol was stirred and refluxed for 17 hours. The resulting solution was cooled and treated with a small amount of saturated sodium bicarbonate then concentrated in vacuo to remove the ethanol. The residue was treated with ether and the ether solution was processed in the usual manner given 752 mg of a yellow oil. This material was chromatographed on 50 g of silica gel. Elution with 4:1 toluene-ethyl acetate provided 706 mg (92.9%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a yellow oil.
Reaction SMILES: N.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]4[NH:17][C:18](=[O:20])[CH2:19][C:14]4=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(O)C.[CH3:24][C:25]([CH3:27])=O>O>[C:25](=[C:19]1[C:14]2[C:15](=[CH:16][C:10]3[NH:9][C:8]([C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=2)[NH:17][C:18]1=[O:20])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc3nc(-c4ccncc4)[nH]c3cc2N1
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)=C1C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reaction time: 4 h

Procedure:
Ammonia is passed up to saturation into a suspension of 0.4 g. (1.6 mmol) 2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 20 ml. ethanol and 10 ml. acetone and the reaction mixture then stirred for 2 hours at 60° C. Subsequently, a further 10 ml. acetone are added thereto and stirring continued for 4 hours at 60° C., whereafter the reaction mixture is evaporated, the residue is taken up in ethanol, acidified and suction filtered from the precipitate. The residue obtained is dissolved in water and rendered neutral and the crystals obtained are filtered off with suction and recrystallised from isopropanol/ethyl acetate. Yield: 40 mg. (9% of theory); m.p.>300° C.
Reaction SMILES: [CH:1]12[CH2:8][CH:7]=[CH:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1.C1(C)C(C)=CC=CC=1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:9](=[O:11])[CH:4]3[CH2:3][CH:2]([CH:1]4[CH2:8][CH:7]=[CH:6][CH:5]43)[C:12]2=[O:14])[CH2:28][CH2:29]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C(O)C1CC(C(=O)O)C2CC=CC12
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CC=CC21
Reaction time: 24 h

Procedure:
Bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic acid (12.6 g., 67 mmol.) was converted to 4.24 g. of anhydride by treatment with excess acetic anhydride as in Example 1. In this instance, however, the anhydride was purified by extraction of the dark residual gum with hexane, filtration, and evaporation in vacuo. The anhydride was combined with 6.0 g. (24 mmols) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 250 ml. of xylene and refluxed under N2 for 24 hours with water separation via a Dean-Stark trap. The supernatant liquid was removed at this point and replaced with an additional 150 ml. of xylene. Reflux under N2 was continued for 24 hours. The combined xylene solutions were then evaporated and the residue column chromatographed on 250 g. of silica gel with a gradient elution beginning with CHCl3 and ending with 10% CH3OH/CHCl3. The product-containing fractions were combined and evaporated and the residue crystallized from isopropanol with the addition of 4N HCl in isopropanol to give 3.25 g. of white solid title compound as the dihydrochloride salt, m.p. 232°-234° C.
Reaction SMILES: O([C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12]2)S(C(F)(F)F)(=O)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.C1(C)C=CC=CC=1>[N+:18]([C:10]1[C:9]([NH:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][CH2:14]2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCC2
Reactant: N#Cc1cccc(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCC3)c1
Yield: 30.1 %

Procedure:
A dry toluene (50 mL) suspension of 4-nitroindan-5-yl triflate (3.11 g, 10.0 mmol), 3-aminobenzonitrile (1.77 g, 15.0 mmol), potassium carbonate (1.38 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.57 g, 0.50 mmol), and triphenylphosphine (0.26 g, 1.00 mmol) was refluxed for 66 hours. After cooling on standing, insoluble was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/5) to give the titled compound as orange crystal (0.84 g, yield 30%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]([F:21])([F:20])[S:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>C1COCC1>[OH:5][CH2:4][CH2:3][C:2]([NH:1][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:9]([F:20])([F:8])[F:21])=[CH:12][CH:13]=1)=[O:19])([CH3:7])[CH3:6]
Reactant: O=C=Nc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)(N)CCO
Solvent: C1CCOC1
Product: CC(C)(CCO)NC(=O)Nc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of 3-amino-3-methyl-butan-1-ol (941 mg, 9.12 mmol) in 10 mL THF was added 4-(trifluoromethylthio)phenylisocyanate (2.0 g, 9.12 mmol). The reaction was stirred at ambient temperature for 16 h. The solution was concentrated and subjected to a hot filtration with CH2Cl2 to give solid 1-(4-hydroxy-2-methylbutan-2-yl)-3-{4-[(trifluoromethyl)sulfanyl]phenyl}urea (95%). LCMS [M+H]+=323.1.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28].C(Cl)(=O)C(Cl)=O.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].C(N(C(C)C)C(C)C)C.CN(C1C=CC=CN=1)C>CN(C)C=O.C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:23])[C:17]=3[CH:27]=2)[C:3]1=[O:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)NS(C)(=O)=O)c3c2)c1=O
Yield: 13.5 %

Procedure:
N,N-Dimethylformamide (8 drops) is added to a mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (2.00 g, 0.00484 mol) and methylene chloride. The mixture is cooled on an ice bath and oxalyl chloride (2.0 M in methylene chloride, 6.05 ml, 0.0121 mol) is added. The resultant mixture is stirred one hour on an ice bath and concentrated in vacuo. The residue is taken up in tetrahydrofuran. Methylsulfonamide (0.690 g, 0.00726 mol) is added, followed by ethyldiisopropylamine (0.940 g, 0.00727 mol) and dimethylaminopyridine (0.100 g). The resultant mixture is stirred at room temperature and filtered. The filtrate is concentrated in vacuo and the residue is filtered through silica gel with hexanes:ethyl acetate. The filtrate is concentrated in vacuo to a tan solid. The solid is suspended in methylene chloride, stirred, and refiltered to give the title compound as a white solid (0.320 g, 13.5%, mp 264-265° C.).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:28][CH2:29]C1C=C(C2N=C(N3CCOCC3)C3=CC(C(O)=O)=CN3N=2)C=CC=1>>[OH:28][CH2:29][C:7]1[CH:6]=[C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[CH:22][N:10]3[N:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1
Product: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3cccc(CO)c3)nn2c1

Procedure:
Compound 18 was prepared by the method which was identical with that for preparing compound 12a, wherein compound 17 (92 mg, 0.26 mmol) was used as the starting material. White solid (80 mg, 80.8%). m.p. 170-171° C. 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 8.20-8.17 (m, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.46-7.43 (m, 2H), 7.04 (d, J=1.5 Hz, 1H), 4.77 (s, 2H), 4.11 (t, J=4.7 Hz, 4H), 3.87 (t, J=4.7 Hz, 4H), 3.20 (br, s, 6H). LC-MS: 382 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[O:31])[C:3]1=[O:20]
Reactant: COc1ccccc1N=C=O
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 258°-260° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:38]=[CH:37][C:24]([O:25][C@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[OH-].[Na+:40].C(O)C>C(O)C>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([O-:29])=[O:28])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1.[Na+:40]
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1

Procedure:
To a solution of (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (135 mg, 0.27 mmol) in ethanol (5 ml) was added 1N sodium hydroxide-ethanol (245 ml, 0.25 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 25 mg, (18%)