Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]([NH:10]C(=O)OCC1C=CC=CC=1)([CH3:9])[CH3:8].O=[C:27]([CH3:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[NH2:25][C:24]1[C:3]2[C:2](=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][C:7]([NH2:10])([CH3:8])[CH3:9])[N:1]=[C:27]([CH3:34])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N

Procedure:
Prepared as in Example Ba from benzyl 1-(3-amino-2-cyanophenoxy)-2-methylpropan-2-ylcarbamate (Example Dc) and ethyl 3-oxobutanoate as a yellow-brown solid (91%). 1H NMR (400 MHz, DMSO-d6) δ 1.15 (s, 6H), 1.31 (t, J=4 Hz, 3H), 2.54 (s, 3H), 3.87 (s, 2H), 4.31 (q, J=4 Hz, 2H), 6.85 (d, J=4 Hz, 1H), 7.21 (d, J=4 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH+).
Reaction SMILES: C[C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].[CH:15]1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[O:5][C:6]([CH3:7])=[CH:2][N:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1nc(-c2ccc(O)cc2)oc1C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2ncc(C)o2)cc1
Yield: 35.5 %

Procedure:
2-(4-Methoxyphenyl)-5-methyloxazole was prepared in 35.5% yield by decarboxylation of the compound of part (c) with copper powder in Dowtherm at reflux temperature. The isolated product was distilled, b.p. 136°-140° C. (0.1 mm).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[NH2:33][N:34]([CH2:42][CH3:43])C(=O)OC(C)(C)C>C(O)C>[ClH:32].[CH2:42]([N:34]1[C:6]2[C:7]3[CH:8]=[C:9]([F:27])[CH:10]=[CH:11][C:12]=3[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[C:5]=2[CH:4]=[N:33]1)[CH3:43]
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CCN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCn1ncc2c1-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1 mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3.6 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (3.7 mL of 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent was further removed under reduced pressure providing 1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (880 mg, 82%). ESI-MS m/z talc. 287.1, found 288.1 (M+1)+. Retention time 0.79 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22](Cl)[CH:21]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[C:15]([N:19]1[C:24](=[O:25])[C:23]([CH3:26])=[C:22]([S:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:14][CH:13]=2)[CH:21]=[N:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: CC(C)(C)c1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(SCc2ccc(C(C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Yield: 46.6 %

Procedure:
To 30 ml of dry tetrahydrofuran was added 0.5 g of 55% sodium hydride. The resulting mixture was kept at room temperature and added dropwise with a solution of 1.8 g of p-t-butylbenzyl mercaptan dissolved in 10 ml of tetrahydrofuran. After ten minutes passed, the resulting mixture was added dropwise with a solution of 2.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone dissolved in 10 ml of tetrahydrofuran. After completion of dropwise addition, the resulting mixture was reacted for 2 hours under heat-reflux. After the reaction mixture was concentrated under reduced pressure, it was poured into 50 ml of water and extracted twice with 50 ml of diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 3.5 g of crude product. The crude product was recrystallized from 5 ml of hexane to obtain 1.6 g of 2-t-butyl-5-(p-t-butylbenzylthio)-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>O1CCOCC1.O.O>[CH2:17]([NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5])=[O:21])[CH3:18]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution of 2-amino-6-methylbenzoic acid (500 mg, 3.3 mmol) and sodium bicarbonate (277 mg, 3.3 mmol) in 9 mL of dioxane/water (2:1) was added ethyl isocyanate (281 mg, 3.96 mmol). The reaction was slowly warmed to room temperature while stirring overnight. The reaction mixture was diluted with water and extracted with EtOAc. The acueous fraction was acidified with 2N HCl and extracted with EtOAc. The organic fraction was dried (MgSO4), filtered, and evaporated under reduced pressure affording 272 mg of 2-[[(ethylamino)carbonyl]amino]-6-methylbenzoic acid used directly in the next reaction: 1H-NMR (300 MHz, d6-DMSO) δ 1.02 (t, J=7 Hz, 3H), 2.32 (s, 3H), 3.03 (m, 2H), 6.67 (d, J=8 Hz, 1H), 6.87 (br. t, 1H, exchangeable), 6.99 (t, J=8 Hz, 1H), 7.79 (d. J=8 Hz, 1H), 9.46 (br. s, 1H, exchangeable).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH2:3]1.[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH:3]1[CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)C1Sc2ccccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Product: COC(=O)C1Sc2ccccc2OC(CCCN2CCN(c3ccccc3)CC2)C1=O

Procedure:
By the same procedure as described in Example 1, methyl 3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as obtained in Reference Example 24 is allowed to undergo condensation with 3-(4-phenylpiperazin-1-yl)propyl chloride, and methyl 3-oxo-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate is isolated as the hydrochloride salt. Recrystallization from methanol produces white crystals, m.p. of 176°-178° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:16][C:17](=[O:18])[C:12]3=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]2)=[C:4]([Cl:31])[CH:3]=1.C([Mg]Cl)(C)C.CN([CH:40]=[O:41])C>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:40]=[O:41])[CH:3]=[C:4]([Cl:31])[C:5]=1[N:9]1[C:13]2=[N:14][C:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]1
Reactant: CN(C)C=O
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Br)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(C=O)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO4), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469(M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[Se:27][C:26]=1[C:34]([NH2:36])=[O:35].CN(C=O)C.[OH-].[Na+]>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[O:22][CH3:23])[N:5]=[CH:4][N:3]=[C:2]3[NH:24][C:25]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])[Se:27][C:26]=2[C:34]([NH2:36])=[O:35])[CH2:17][CH2:18]1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound a pale yellow color solid, mp 208-212° C. IR (KBr) vmax 3438, 3158, 2949, 1618, 1570, 1385, 1228, 1127, 1027, 859 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.01 (1H, s, exchangeable with D2O), 8.86 (1H, s), 8.72 (1H, s), 7.38 (1H, s), 7.23 (1H, s), 5.37 (2H, br s), 4.32 (2H, t, J=6.4 Hz), 4.01 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.65 (2H, t, J=7.2 Hz), 2.51-2.52 (4H, m), 2.14 (2H, pentet, J=7.0 Hz), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.9, 168.7, 155.2, 154.5, 153.4, 149.3, 148.2, 147.6, 121.8, 109.8, 109.2, 107.7, 101.4, 67.5, 67.0, 56.2, 55.5, 53.7, 37.2, 32.6, 26.2; LC-MS (negative ion mode): m/z 544, 546 (M−H)−.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([N:20]1[C@@H:25]2[C@H:26]([C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:27][C@@:21]1([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@H:22]([O:33][CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1)[CH2:23][CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:55]([O:59][C:60]([NH:62][CH2:63][CH2:64]O)=[O:61])([CH3:58])([CH3:57])[CH3:56].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:13]([N:20]1[C@@H:25]2[C@H:26]([C:28]3[N:32]=[N:31][N:30]([CH2:64][CH2:63][NH:62][C:60]([O:59][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:61])[N:29]=3)[CH2:27][C@@:21]1([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@H:22]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:23][CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Diethylazodicarboxylate, 0.15 g, 0.86 mmol was added to a solution of (1R*,2 R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxyl 1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 138; 0.5 g, 0.85 mmol), [N-(t-butoxy-carbonyl)ethanolamine] (0.15 g, 0.93 mmol) and triphenylphosphine (0.23 g, 0.88 mmol) in dichloromethane (20 ml). The mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 30% ethyl acetate/iso-hexanes to yield the title compound (543 mg, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@@H:5]([CH3:7])O)[CH3:2].[OH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH:11]1[NH2:20]>>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH:20][CH:11]1[CH2:12][CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]1[OH:9])[CH3:2]
Reactant: NC1CCc2ccccc2C1O
Reactant: CCOC(=O)[C@@H](C)O
Product: CCOC(=O)[C@H](C)NC1CCc2ccccc2C1O

Procedure:
Following General Procedure AM using Ethyl-D-lactate (Fluka) and N-[(1RS,2RS)-1,2,3,4-tetrahydro-1-hydroxy-2-naphthyl]-amine (Liebigs Ann. Chem. 1992, pp273, incorporated herein by reference), the title compound was prepared. C15H21NO3 (MW=263.335); mass spectroscopy (MH+) 264.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:15]([C:12]1[N:13]=[N:14][C:9]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:10][CH:11]=1)=[O:17])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nn1
Yield: 91 %

Procedure:
As described for example 48b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (98 mg, 0.31 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (101 mg, 91%) which was obtained as an off white solid. MS: m/e=354.2 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4])[CH3:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:15][CH:14]=2)=[CH:19][C:18]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCS(=O)(=O)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CCS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
50 mg of 4-(ethylsulfonylmethyl)benzoic acid was coupled with 67 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. This product was recrystallized from methanol to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide. MS (Q1) 415 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10]>>[NH2:1][C:2]1[C:3]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Nc1cccnc1Cl
Product: Nc1cccnc1Nc1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 3.1 %

Procedure:
A mixture of 3-amino-2-chloropyridine (2.57 g) and 3-nitroaniline (2.76 g) was heated at 200° C. for 1 hour. The mixture was cooled and partitioned between aqueous sodium bicarbonate solution and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, concentrated and subjected to silica gel column chromatography (chloroform-methanol, 40:1) to afford 3-amino-2-(3-nitrophenylamino)pyridine (141 mg) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: CCCCCCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 65.7 %

Procedure:
4-fluoro-2-nitroaniline (1.56 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) were stirred in toluene (5 ml) at 80°-90 C. for 5 hrs. This solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous MgSO4, and the solvent was distilled off. The resulted crystals were washed with hexane to give 1-(4-fluoro-2-nitrophenyl)-3-heptylurea (1.95 g, 66%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4](C)[C:5]([O:7][CH3:8])=[O:6].N[C@H:11](C)CC(O)=O>>[ClH:1].[NH2:2][C@H:3]([CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C)CN
Reactant: C[C@@H](N)CC(=O)O
Agent: Cl
Product: COC(=O)C[C@@H](C)N

Procedure:
Compound 57-B was prepared in analogy to compound W in Example 20 by using (R)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:8]=2[CH2:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([C:7]2[N:11]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[C:8]=2[CH2:16][CH2:17][CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(C(=O)OC)c[nH]c1-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1-c1ccccc1
Yield: 86.6 %

Procedure:
Using methyl 5-phenyl-4-propyl-1H-pyrrole-3-carboxylate (2.0 g), sodium hydride (60% in oil, 434 mg) and benzenesulfonyl chloride (1.60 g), a procedure as in Reference Example 4 was performed to give the title compound as colorless crystals (yield 2.73 g, 69%).
Reaction SMILES: [ClH:1].Cl.[N+](OC[CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:41])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:40])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O.Cl.[N+:43]([O:46]CCCOC(=O)[C@@H]1CCCN1)([O-:45])=[O:44]>>[ClH:1].[ClH:1].[N+:43]([O:46][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:41])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:40])[C@H:19]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:45])=[O:44]
Reactant: O=C(OCCCO[N+](=O)[O-])[C@@H]1CCCN1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)OCCCCO[N+](=O)[O-]
Agent: Cl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)OCCCO[N+](=O)[O-]

Procedure:
Starting from N2-[(1S)-ethoxycarbonyl-3-phenylpropyl]-N6-BOC-L-lysine (obtained as described in Example 6) and L-proline 3-nitrooxypropyl ester hydrochloride (obtained as described in Example 3) applying the same procedure described in Example 6) the title compound was obtained as a highly hygroscopic white powder (0.85 g, 28%).
Reaction SMILES: [SH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:26](I)([CH3:28])[CH3:27]>>[CH:26]([S:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)([CH3:28])[CH3:27]
Reactant: SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Reactant: CC(C)I
Product: CC(C)SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 1, 4-mercapto-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran was reacted with isopropyl iodide to give 4-isopropylthio-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran in 67% yield, as an oil.
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:2]([O:6][NH:7][S:16]([C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=1)(=[O:18])=[O:17])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CON
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOCC(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Isobutoxyamine hydrochloride (7.96 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (7.24 mmol, 1.5 g), diisopropylethylamine (18.09 mmol, 3.15 mL) and anhydrous THF (15 mL) were combined under nitrogen. The reaction stirred at room temperature for 15 hours. The reaction solution was concentrated to a white solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum to yield an off-white colored solid. Rf: 0.5 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84 (2H,d), 6.99 (2H,d), 6.81 (1H,s), 3.87 (3H,s), 3.74 (2H,d), 1.90 (1H,septet), 0.86 (6H,d).
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH4+].[OH-]>O1CCCC1.CCOCC>[C:18]1([CH:13]2[NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]3[CH2:1][CH2:2][C:3]4=[CH:4][CH:5]=[CH:6][C:7]2=[C:8]34)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(C2Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of 2.1 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 16 ml of dry tetrahydrofuran is cooled under N2 to 0°-5° C., then treated dropwise with 9.4 ml of a 2.8 molar solution of phenyl magnesium bromide in ether at such a rate as to keep the reaction temperature below 10° C. When the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and then poured into 100 ml ice-water containing 10 ml of concentrated HCl. The resultant mixture is made alkaline with NH4OH and extracted with methylenechloride. The organic phase is separated, washed with brine, dried over Na2SO4 and concentrated to give 6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 161°-164° C.