Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1
Reactant: Cc1nc2ccc(O)cc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4nc(C)[nH]c4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 189, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline, (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylbenzimidazole (200 mg, 0.62 mmol) and after work-up and purification on a 10 g silica ISOLUTE column using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5), gave 6-methoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (68 mg, 25%).
Reaction SMILES: [NH:1]([C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:24])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].O[N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl>[NH:1]([C:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:24])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:11])[O:12][N:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47])=[O:5])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
To a solution of palmitoyl-L-Ala-D-Glu(OH)OBzl (1)(1.84 g) in a mixture of tetrahydrofuran (20 ml) and chloroform (30 ml) were added N-hydroxysuccinimide (425 mg) and dicyclohexylcarbodiimide (728 mg). The reaction mixture was kept for 18 hours at room temperature and the precipitate was filtered off and washed with chloroform. The filtrate was concentrated in vacuo and the diisopropylether was added to the residue. The product was collected and dried to afford palmitoyl-L-Ala-D-Glu(OSu)OBzl (2)(1.70 g).
Reaction SMILES: [OH:1][CH:2]([C:19]1[O:20][C:21]([C:24]2[N:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[CH:22][N:23]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][C:2]([C:19]2[O:20][C:21]([C:24]3[N:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)=[CH:22][N:23]=2)=[O:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
Methyl 6-(2-(1-hydroxy-3-(4-(phenoxymethyl)phenyl)propyl)oxazol-5-yl)pyridine-3-carboxylate (77 mg, 0.17 mmol) was dissolved in anhydrous CH2Cl2 (6 mL) and Dess-Martin periodinane (110 mg, 0.260 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2.5 h. The addition of saturated aqueous NaHCO3 quenched the reaction and the organic layer was washed with saturated aqueous Na2S2O3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 0-15% EtOAc/benzene) to provide methyl 6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate as a white solid (60 mg, 78%): 1H NMR (CDCl3, 600 MHz) δ 9.22 (dd, 1H, J=2.0, 0.7 Hz), 8.39 (dd, 1H, J=8.2, 2.1 Hz), 7.96 (s, 1H), 7.90 (d, 1H, J=8.2 Hz), 7.36 (d, 2H, J=8.0 Hz), 7.29-7.25 (m, 4H), 6.96-6.93 (m, 3H), 5.01 (s, 2H), 3.97 (s, 3H), 3.46 (t, 2H, J=7.6 Hz), 3.11 (t, 2H, J=7.6 Hz); 187.2, 165.0, 158.7, 157.6, 152.5, 151.2, 149.3, 140.0, 138.3, 135.1, 129.4, 128.7, 128.7, 127.8, 125.8, 120.8, 119.6, 114.8, 69.6, 52.6, 40.6, 29.3; HR ESI-TOF m/z 443.1600 (M+H+, C26H22N2O5, requires 443.1601).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][N:21]=1)#[N:19].CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:26][C:25]2[C:20]([C:18]#[N:19])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1cccnc1C#N)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine in CH3CN with 2-cyano-3-bromomethyl-pyridine, KI and DIPEA gave 3-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridine-2-carbonitrile as a dark red oil. 1H NMR (CDCl3) δ 2.04 (s, 6H), 3.86 (s, 4H), 3.99 (s, 2H), 7.07 (m, 2H), 7.38 (m, 3H), 7.84 (d, 1H, J=9.0 Hz), 8.37 (m, 2H), 8.53 (m, 1H).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37]>CN(C=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH2:26][NH:27][C:36](=[O:37])[O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(=O)Cl
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)OCC(C)C)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (37 mg, 0.10 mmol) in DMF (2.0 mL) is added 4-methylmorpholine (44 μL, 0.40 mmol) followed by isobutyl chloroformate (21 mg, 0.15 mmol). After stirring at room temperature for 12 hours, the mixture is evaporated in vacuo and the resulting oil purified on reverse phase HPLC to obtain a white solid, 26 mg, 54%, LC/MS ESI m/z (M+H)+=470.4.
Reaction SMILES: COC1C=CC(C[S:8][C:9]2[NH:13][C:12]([CH:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[CH3:15])=[CH:11][N:10]=2)=CC=1>FC(F)(F)C(O)=O>[N:21]1[C:22]2[C:17](=[C:16]([CH:14]([C:12]3[NH:13][C:9](=[S:8])[NH:10][CH:11]=3)[CH3:15])[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(CSc2ncc(C(C)c3cccc4ncccc34)[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(c1c[nH]c(=S)[nH]1)c1cccc2ncccc12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
5-{1-[2-(4-Methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E6) (3 g, 8.0 mmol) and trifluoroacetic acid (100 mL) in a resealable tube was heated to 115° C. for 1 h 20 m. The mixture was cooled to rt and TFA removed under vacuum. The residual acid was quenched with NH3-MeOH. The residue was evaporated and resolvated with 3:1 chloroform:isopropanol (500 mL). The organic solution was washed with water (3×40 mL) and brine (1×30 mL). The solution was dried over MgSO4, filtered, and evaporated to leave a solid. This material was purified on a short column of silica gel by gradient elution with 3 to 9% NH3-MeOH: CH2Cl2 to give 4-(1-quinolin-5-yl-ethyl)-1,3-dihydro-imidazole-2-thione (Compound 7) 1.44 g (71%).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CC2)C1=O
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except [5-cyclohexyl-1-(2-cyclopropyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 119, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.90 (1H, br s), 8.44 (1H, s), 7.49 (3H, m), 7.29 (2H, m), 7.19 (1H, t), 7.08 (2H, t), 4.81 (1H, d), 4.56 (1H, d), 4.22 (2H, m), 3.65 (2H, s), 2.79 (1H, m), 2.01-1.68 (7H, m), 1.26 (4H, m), 1.09 (2H, m), 0.93 (2H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 55.42; H, 6.74; N, 8.42%; C29H32N4O5S.C7H17NO5.1.8H2O.0.4C4H8O2 requires: C, 55.65; H, 6.93; N, 8.63%.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([OH:28])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.C([NH:46]C1C=CC(C#CC(Cl)=O)=CC=1)CCCCCCCCCCCCCCC>>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]([NH2:46])=[O:28])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C#CC(=O)O)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C#CC(N)=O)cc1

Procedure:
A solution of 4-hexadecylaminophenylpropiolic acid is converted to 4-hexadecylaminophenylpropiolic acid chloride hydrochloride as described in Example 18. After evaporation of the solvent, the unpurified acid chloride is slurried in methylene chloride and treated with anhydrous ammonia as in Example 31. Workup as described therein provides the title compound. Likewise, 4-(hexadecylamino)cinnamamide is prepared from 4-(hexadecylamino)cinnamic acid.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31]>C(O)C>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]([NH:30][OH:31])=[NH:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C#N)c2)n3C(C)(C)C)c1
Reactant: NO
Solvent: CCO
Product: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C(=N)NO)c2)n3C(C)(C)C)c1
Yield: 100 %

Procedure:
3-[1-tert-Butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-benzonitrile (0.480 g, 1.255 mmol) is dissolved in ethanol (5 mL). Hydroxylamine (1.0 mL, 50% in water) is added. The reaction mixture is heated under reflux for 6 hours. The solvent is removed in vacuum to give 3-[1-tert-butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (0.531 g, 100%) as a yellow solid.
Reaction SMILES: [F-:1].[K+].[N+]([C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-])=O.C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: [F-]
Reactant: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)O
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A mixture of spray-dried KF (410 mg, 7.06 mmol), intermediate 11 (200 mg, 0.706 mmol) and catalytic amount of 18-crown-6 in dry DMSO (5 mL) was stirred at 170-180° C. for 30 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (117 mg, 65%), mp 136-138° C. 1H NMR (400 MHz, DMSO-d6): 812.74 (1H, br s), 8.96 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=9.6 Hz), 8.16 (1H, d, J=8.4 Hz), 7.82 (1H, t, J=7.6 Hz), 4.42 (1H, pentet, J=7.0 Hz), 1.38 (3H, d, J=7.2 Hz); LC-MS (negative ion mode): m/z 255 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH2:20][OH:21])[C:3]=1[OH:22]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:20]=[O:21])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(CO)c(O)c(F)cc21
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1c(O)c(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
A solution of 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (200 mg, 687 μmol; Intermediate 95) in MeOH (2.14 mL) was treated with 2M NaOH (860 μL) and formaldehyde (2 mL of a 37 wt. % solution in H2O, 26.8 mmol) and heated in an Emrys optimizer (MW) at 120° C. for 5 min. The solvent was removed in vacuo, the residue taken up with H2O and 1M HCl (pH 1), extracted with EtOAc (3×), washed with sat. NaHCO3, brine, dried (Na2SO4) and the solvent removed in vacuo to yield a brownish syrup (265 mg), which was directly used in the oxidation step. A solution of crude 6-fluoro-4-(hydroxymethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (858 μmol) in CH2Cl2/MeOH (4.5+0.1 mL) was treated with MnO2 (1.12 g, 12.9 mmol) and stirred at rt for 30 min. The reaction mixture was filtrated over a plug of SiO2 and it was washed with CH2Cl2 (40 mL) to give the title compound as yellow solid (72 mg). This material was directly used in the next steps.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(O)[CH3:21])=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:21])=[C:16]([F:30])[CH:15]=1
Reactant: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.52 g (5.64 mmol) of the compound from Example 183A in analogy to the synthesis of the compound from Example 278. 0.95 g (39% of theory) of the target compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC)[N:6]3[N:14]=[C:15]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1>C(N)(C)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[N:8][CH:9]([CH3:10])[CH3:4])[N:6]3[N:14]=[C:15]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cl)cc2c2nc(-c3ccco3)nn12
Solvent: CC(C)N
Product: CC(C)N=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccco3)nn12

Procedure:
As in Example 37, 9-chloro-2-(2-furyl)-5-methylthio[1,2,4]triazolo[1,5-c]quinazoline (1.06 g) is reacted in a stainless steel pressure vessel with isopropylamine (50 ml) at 150° (external temperature) for 6 hours to afford 9-chloro-2-(2-furyl)-5-isopropylimino-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazoline, which is purified by ethanol recrystallization, mp. 140°-141°.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1CCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1CCCO1
Temperature: 25 °C

Procedure:
To an ice cooled stirring solution of 2-(tetrahydrofuran-2-yl)ethanol (1.9 g) and triethylamine (4.4 ml) in dry dichloromethane (30 ml) was added dropwise over 5 min methanesulphonyl chloride (1.59 ml). The mixture was allowed to warm slowly to ambient temperature over 16 h then washed with saturated sodium hydrogen carbonate. The aqueous layer was further extracted with dichloromethane and the combined extracts washed with brine, dried by passing through a phase separation cartridge and stripped to give the title compound as a light brown oil, yield 3.1 g.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=2)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>Cl>[SH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([SH:42])=[CH:40][CH:41]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCCCN(CCCCN(Cc1ccc(S)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCCN(Cc1ccc(S)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: Sc1ccc(CNCCCCNCCCCCCCNCCCCNCc2ccc(S)cc2)cc1

Procedure:
Dissolve 1,19-bis[(4-mercaptophenyl)methyl]-1,6,14,19-tetra(t-butyloxycarbonyl)-1,6,14,19-tetraazanonadecane (9.60 g, 10 mmol) in saturated methanolic hydrochloric acid (100 mL). Stir for several hours and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:16]([O-])=O)=[N:13][O:14][CH3:15])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1.[CH3:27]N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12](=[N:13][O:14][CH3:15])[NH:16][CH3:27])[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:6]=2[CH:26]=1
Reactant: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]
Reactant: CN
Solvent: CCO
Product: CNC(=NOC)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1

Procedure:
Reaction of 0.5 g of 7-chloro-5-(2-fluorophenyl)-N-methoxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine with methylamine in ethanol (20% v/v) gave the same workup and purification procedure colorless product, crystallized from ether/hexane; mp 140°-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[O:10]1[CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11]1>>[OH:10][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCC1CO1
Product: CCCC(O)COc1cccc(C=O)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde with 1,2-epoxypentane gave 3-(2-hydroxypentyloxy)benzaldehyde as a clear oil. Yield (0.6 g, 24%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.49 (m, 2H), 7.40 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.87-3.93 (m, 1H), 2.28 (d, J=3.6 Hz, 1H), 1.42-1.62 (m, 4H), 0.98 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[N:10][N:9]=2)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]2[N:30]=[CH:31][S:32][C:28]=2[CH:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[S:32]1[C:28]2[CH:27]=[C:26]([NH:25][C:2]3[N:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([C:13]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[O:14])=[N:10][N:9]=4)=[C:4]([NH:21][CH:22]([CH3:24])[CH3:23])[CH:3]=3)[CH:34]=[CH:33][C:29]=2[N:30]=[CH:31]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(=O)N2CCOCC2)o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(=O)N2CCOCC2)o1
Temperature: 115 °C

Procedure:
To solution of (5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone in dioxane (5 mL): H2O (1 mL), 6-amino benzothiazole (1.2 equiv.), xanthphos (0.5 equiv.) and Na2CO3 (3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.5 equiv.) was added and degassed again for 10 min. It was then heated at 115° C., overnight. The reaction mass was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel (230-400 mesh) and MeOH: CHCl3 as eluent. It was further purified by prep HPLC to afford the title compound. 1H NMR: 400 MHz, CD3OD: δ 1.31-1.38 (m, 6H), 3.81-3.86 (m, 7H), 4.19-4.22 (m, 2H), 6.19 (s, 1H), 7.57 (dd, J=2.00, 8.60 Hz, 1H), 7.66-7.68 (m, 1H), 7.99 (d, J=8.80 Hz, 1H), 8.48 (d, J=2.00 Hz, 1H), 8.63 (s, 1H), 9.10 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.604 min; LCMS (ES-API), m/z 463.8 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.224 min; Purity: 98.3%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=[O:29])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([C:23](=[O:27])[CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@H:17]([OH:28])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:5])C.C(=O)(O)[O-].[K+].O>CO>[OH:28][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[C:23](=[O:27])[CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C:7](=[O:29])[CH2:6][C:4]([O:3][CH3:1])=[O:5])[CH2:16]1
Reactant: CCOC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 19.1 %

Procedure:
A solution of 21-ethoxycarbonyl-3α-hydroxy-5α-pregnane-11,20-dione 850 mg) in dry methyl alcohol (40 ml) was treated with potassium bicarbonate (1.02 g) and the mixture was refluxed, under nitrogen, for 1 hr., then poured into water. The product was extracted with ethyl acetate, and the extract washed with water, dried, and evaporated. The residue (506 mg) was purified by preparative t.l.c. and crystallisation from methyl acetate/petrol gave title compound (157 mg) m.p. 150°-152°, [α]D + 111.2°, λmax. 248.5 nm (ε 4,185).