Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)(=[O:30])=[O:31])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]
Reactant: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product from Example 78E (44 mg, 0.061 mmol) was treated with trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation under vacuum and the residual oil dried under hi-vacuum. Purification by silica gel chromatography using 5% methanol/methylene chloride as eluent provided the title compound as a trifluoroacetic acid salt (25 mg, 48%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.62 Hz, 6 H), 3.13-3.38 (m, 1 H), 6.63 (d, J=8.46 Hz, 2 H), 6.87 (d, J=7.72 Hz, 1 H), 7.01-7.09 (d, J=8.82 Hz, 2 H), 7.12 (d, J=8.46 Hz, 2 H), 7.44 (d, J=8.82 Hz, 2 H), 7.61 (dd, J=7.72, 1.47 Hz, 1 H), 7.71 (s, 1 H), 7.81 (dd, J=6.62, 1.47 Hz, 1 H), 8.66-8.80 (m, 1 H), 8.90 (d, J=6.99 Hz, 1 H), 10.55 (s, 1 H); MS (ESI+) m/z 621/623 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:4]=[CH:5][N:6]2[C:12](=[S:13])[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=12.[N:18]#[C:19]Br>O1CCCC1>[S:13]([C:12]1[N:6]2[CH:5]=[CH:4][N:3]=[C:7]2[S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[N:11]=1)[C:19]#[N:18]
Reactant: N#CBr
Reactant: S=C1Nc2ccccc2Sc2nccn21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CSC1=Nc2ccccc2Sc2nccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: To the suspension of 1.44 g of 50% sodium hydride in mineral oil and 150 ml of dry tetrahydrofuran, 6.45 g of imidazo[2,1-b][1,3,5]benzothiadiazepin-5(6H)-thione are added in portions, and the mixture is stirred at room temperature under nitrogen for one hour. The resulting white suspension is cooled to 0° and the solution of 3.5 g of cyanogen bromide in 10 ml of tetrahydrofuran are added dropwise. The mixture is stirred at room temperature for 0.5 hour and evaporated. The residue is triturated with methylene chloride, the mixture washed with water, dried, concentrated to a small volume, washed with diethyl ether and filtered, to yield the 5-thiocyanatoimidazo[2,1-b][1,3,5]benzothiadiazepine melting at 111°-113°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[CH:9]=2)[NH:4][CH:3]=1.C(OCC)(=O)C>C1COCC1.[Li+].[OH-]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: COC(=O)c1ccc2[nH]cc(Cl)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]cc(Cl)c2c1
Yield: 79.9 %

Procedure:
A solution of Example 62A (361 mg, 1.62 mmol) in THF (7 mL) and 1M LiOH (3.3 mL) was heated at 50° C. for 5 hours, treated with ethyl acetate and extracted with 10% NaHCO3 (3×). The extract was treated with 6M HCl and extracted with ethyl acetate (2×40 mL). The organic layer was dried (MgSO4), filtered, and concentrated to provide 253.2 mg of the desired compound.
Reaction SMILES: N([C:8]1[C:9](=[O:21])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13]([CH3:19])=[C:12]([CH3:20])[CH:11]=2)C1C=CC=CC=1.S(=O)(=O)(O)[OH:23]>O>[CH3:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH3:20])[C:9](=[O:21])[C:8]([OH:23])=[CH:17][C:16]2=[O:18]
Reactant: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(O)=CC2=O

Procedure:
A solution of 2-anilino-6,7-dimethyl-1,4-naphthoquinone (3.1; 0.014 mole) in concentrated sulphuric acid (70ml) was diluted with an equal volume of water and refluxed for 1 minute. After pouring into cold water the precipitated hydroxy derivative was filtered off and extracted into petrol ether (b.p. 100°-102° C). After treatment of the extract with charcoal the title compound separated as a yellow solid, 1.29g (55%), m.p. 175°-177° C (d). (Found; C, 71.29; H, 5.07; C12H10O3 requires; C, 71.28; H, 4.98%)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:32])C>O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:32])[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1Sc1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1S(=O)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3-benzylamino-4-phenylthio-5-sulfamylbenzyl alcohol (8.0 g; prepared as described in Example 24), hydrogen peroxide (10 ml, 30% in water) and acetic acid (80 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is diluted with water (40 ml) and cooled to precipitate crude 3-benzylamino-4-phenylsulfinyl-5-sulfamylbenzyl alcohol. After recrystallization from a mixture of ethanol and 2-methoxyethanol it is obtained with a melting point of 213°-214° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([N+:14]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O1CCCC1>CO.[Pd]>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH2:13])[C:9]([NH2:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)c(N)c(F)c1N
Yield: 108.4 %

Procedure:
A mixture of methyl 2,4-diamino-3-fluoro-5-nitrobenzoate (5) (40.0 g, 173.7 mmol) and 5% Pd/C (3.0 g, Type 487; 0.4 mol % Pd relative to starting material), in methanol (300.0 mL) and tetrahydrofuran (300.0 mL) was stirred at 2000 RPM, under hydrogen (˜3.5 bar), at 50° C. in a 1.5 L hydrogenation vessel. After 6 hours the vessel was purged with nitrogen and HPLC analysis indicated that no starting material remained. The mixture was then filtered under nitrogen pressure and the filter washed through with THF (160 mL), to give a clear yellow solution. The solvent was removed by rotary evaporation, to provide methyl 2,4,5-triamino-3-fluorobenzoate (9) 37.5 g (93.3% w/w by NMR) as a solid, yield ˜100%. 1H NMR (400 MHz, d6 DMSO) δ 3.69 (3H, s, NMe), 4.20 (2H, br s, NH2), 5.24 (2H, br s, NH2), 5.70 (2H, br s, NH2), 6.83 (1H, d, J 1, Ar—H). 13C NMR (100 MHz, d6 DMSO) δ 51 (CH3), 98 (C, d, J 5), 110 (CH, d, J 2), 125 (C, d, J 6), 131 (C, d, J 12), 133 (C, d, J 12), 139 (CF, d, J 225), 166 (C═O). νmax/cm-1 3480, 3461, 3373, 3356, 3280, 3163, 1679, 1655, 1314. MS APCI (+) m/z 200 (M+1) detected.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:38]4[CH2:39][CH2:40][C@H:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 451 [M+H]
Reaction SMILES: [C:1]([C:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[CH:10]OCC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>CC(N(C)C)=O>[C:1]([C:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[CH:10][NH:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(S(=O)(=O)C(=CNc2ccc(Br)cn2)C(=O)c2ccccc2)cc1
Yield: 34 %

Procedure:
A solution of 1-benzoyl-2-ethoxy-1-(4-methylphenylsulphonyl)ethene (0.85 g) and 2-amino-5-bromopyridine (0.45 g) in dimethylacetamide (30 ml) was heated at reflux for 2 hours. It was then cooled and poured onto ice (60 g). The resulting off-white precipitate was filtered off, washed with water, dried, and recrystallised from ethyl acetate, to give 1-benzoyl-2-(5-bromopyrid-2-ylamino)-1-(4-methylphenylsulphonyl)ethene (0.4 g), m.p. 205° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([OH:46])[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[C:56](Cl)(=[O:58])[CH3:57]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:47])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:46][C:56](=[O:58])[CH3:57])[CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:48])[CH3:10]
Reactant: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)OCC)c1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(OC(C)=O)c1)(C(=O)OCC)c1ccccc1
Yield: 77.6 %

Procedure:
2-(2-{3-Hydroxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester (0.200 g) obtained in Example 1-a) was dissolved in toluene (4 mL), and to this solution was added triethylamine (0.040 g). After dropwise addition of a solution of acetyl chloride (0.026 g) in toluene (1 mL), the resultant mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with toluene (5 mL) and washed with saturated aqueous sodium bicarbonate (5 mL), 1N hydrochloric acid (5 mL) and water (5 mL). The toluene layer was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=2:3) to give the title compound (0.165 g) as a colorless crystal. The physicochemical properties of the product are shown in Table 3 below.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min)=1.274, method [7], MS (ESI) 433.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.35 (s, 1H), 8.23 (d, J=4.5 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 7.45 (dd, J=9.2, 4.5 Hz, 1H), 7.12 (s, 1H), 4.91 (s, 2H) 3.34-3.33 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:29][N:30]([CH3:32])[CH3:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
5.75 g (17.2 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(4-chlorophenyl) acetamide, 9.00 g (51.6 mmol) of t-butoxybis(dimethylamino)methane and 90 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 6.68 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]([CH3:28])[NH:25][CH2:24][CH2:23]2)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[C:18]([S:15]([CH3:14])(=[O:16])=[O:17])[CH:19]=[CH:20][CH:21]=4)[CH:26]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(S(C)(=O)=O)c21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2c(cccc2S(C)(=O)=O)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1SCl)([O-:11])=[O:10]>C(#N)C.[Ag]>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:7]1[CH:6]=[C:5]([S:8][S:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=3[N+:9]([O-:11])=[O:10])[CH:6]=2)[CH:4]=[CH:3][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S)cc1
Agent: [Ag]
Solvent: CC#N
Product: Cc1ccc(SSc2ccc(C)c(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2)cc1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 31.8 %

Procedure:
In a nitrogen atmosphere, 3.70 g (16.0 mmol) of the silver salt of p-thiocresol and 3.75 g (16.0 mmol) of 2,4-dinitrophenylsulfenyl chloride were stirred for 3 hours in 150 ml of acetonitrile serving as a solvent, while cooling with ice water. The reaction mixture was filtered and the residue obtained after the concentration of the filtrate under reduced pressure was subjected to chromatography on a silica gel column (eluting solvent: hexane/ethyl acetate=5/1), whereby 1.64 g (5.08 mmol, yield: 31.8%) of 2,4-dinitrophenyl p-tolyldisulfide were obtained as yellow crystals.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[C@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16]([OH:18])=[O:17])(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>CO.CN(C=O)C>[N:13]([C@H:10]1[C:11](=[O:12])[NH:8][C@@H:9]1[C:16]([OH:18])=[O:17])=[N+:14]=[N-:15]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@H](N=[N+]=[N-])[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
In 39 ml of methanol was dissolved 1.78 g of compound (23) and 9.85 ml of 1N hydrochloric acid was added to the solution. The mixture was stirred for 1.75 hours at room temperature. The reaction mixture was cooled to 0° C. and 9.85 ml of 1N sodium hydroxide was added thereto. The mixture was concentrated to dryness under reduced pressure to obtain an oil. The oil was dissolved in 10 ml of DMF and 3A molecular sieve was added thereto. After the mixture was allowed to stand overnight, the solvent was removed by distillation under reduced pressure to obtain (2S,3R)-3-azido-4-oxo-2-azetidinecarboxylic acid (24). This compound was used in the following Example 7 as it was.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: CCC1OC(=O)c2ccncc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccncc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (936 mg, 6.20 mmol.) in THF (6 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (12.4 mL of a 1 M solution in THF, 12.4 mmol) dropwise. The resulting solution is stirred at room temperature for 10 min. A solution of 3-ethyl-3H-furo[3,4-c]pyridin-1-one (674 mg, 4.13 mmol) in THF (7 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (160 mL). The resulting mixture is heated to 90° C. for 2 h and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (720 mg, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21]O)[CH:11]=3)=[CH:9][C:2]=12.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH3:47]>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][CH2:21][NH2:47])[CH:11]=3)=[CH:9][C:2]=12
Reactant: N
Reactant: OCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: NCCCn1cc(-c2cc3nccnc3[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-[3-(5H-pyrrolo[2,3-b]pyrazin-6-yl)-indol-1-yl]-propan-1-ol [12 g, Example 2(a)] and carbon tetrabromide (19.1 g) in dichloromethane (300 mL) at ambient temperature was treated with a solution of triphenylphosphine (12.9 g) in dichloromethane (100 mL) over 5 minutes. After stirring at ambient temperature for 3 hour the reaction mixture was filtered and the solid was washed with sparing amounts of dichloromethane. The filtrate and washings were evaporated to yield a brown gum, which was mixed with liquid ammonia (ca 80 mL) in a sealed pressure vessel and allowed to stir at ambient temperature for 18 hours. The vessel was then cooled to −78° C. and then cautiously vented. The ammonia was allowed to evaporate and the residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane, methanol and concentrated ammonia (900:100:7, v/v/v) to give the title compound as a yellow solid (3 g), m.p. 170° C. 1H NMR [(CD3)2SO]: δ 8.28 (1H, d, J=2.7 Hz); 8.18 (1H, s); 8.10, 7.64 (each 1H, d, J=7.7 Hz); 8.09 (1H, d, J=2.7 Hz); 7.29, 7.23 (each 1H, td, J=7.1 and 1.0 Hz); 6.97 (1H, s); 4.32 (2H, t, J=7.0 Hz); 2.57 (2H, t, J=6.5 Hz); 1.89 (2H, quintet, J=6.4 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)(=O)C.O>[CH2:3]1[C:2]2[NH:17][C:11]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[CH2:6][CH2:5][CH:4]1[C:8]([OH:10])=[O:9]
Reactant: NNc1ccccc1
Reactant: O=C1CCCC(C(=O)O)C1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1CCc2c([nH]c3ccccc23)C1
Yield: 75.4 %

Procedure:
A mixture of 3-ketocyclohexanecarboxlic acid (4.78 g, 33.9 mmol) and phenyihydrazine (3.66 g, 40 mmol) in 35 mL of acetic acid was heated under reflux for one hour, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 5.5 g of the title compound as a crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C(O)CO.O>[CH3:26][C:21]1[CH:20]=[C:19]([O:18][CH3:17])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Reactant: COc1ccc(N)c(C)c1
Solvent: OCCO
Solvent: O
Product: COc1ccc(N2CCc3c2c2cccc(OC)c2[nH]c3=O)c(C)c1
Temperature: 210 °C
Yield: 80.3 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 10 ml of ethylene glycol and 4-methoxy-2-methylaniline (322 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 210° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 270 mg of desired compound as solid in 81% of yield.
Reaction SMILES: [CH:1]12[C:13](=O)[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13.[BH4-].[Na+].[NH3:21]>CO>[CH:1]12[CH:13]([NH2:21])[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1C2c3ccccc3C3C(c4ccccc42)C13
Reaction time: 48 h

Procedure:
An amount of 464 mb (2mMoles) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one is dissolved in 15 ml of a 15% solution of ammonia in methanol, and the solution allowed to stand in a closed flask for 48 hours at 20°. An addition is then made at ca. 20°, with stirring, of 152 mg of sodium borohydride. After 30 minutes, the reaction mixture is briefly refluxed and again cooled. Processing is carried out analogously to Example 1 to obtain 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cycloheptene-11-amine; M.P. 126°-127°.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11].O>CS(C)=O>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:14](=[O:15])[NH:13][CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(C)N=C=O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)NC(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.3 %

Procedure:
13.0g (0.1 mole) of 5-fluorouracil was dissolved in 100ml of dimethyl sulfoxide, then 9.4g (0.11mole) of isopropyl isocyanate was added thereto at room temperature and stirred at the same temperature for 15 hours. The reaction mixture was poured into 800ml of water. The resultant precipitate was filtered off, washed with water and dried to give 14.7g (68.5% yield) of 5-fluoro-1-(iso-propylcarbamoyl)-uracil melting at 275°-285° C (decomposition).