Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[K+].C(O[C:14]([S-:16])=[S:15])C.O.C(O)(=O)C>CN1CCCC1=O>[Cl:9][C:5]1[CH:6]=[C:7]2[S:15][C:14]([SH:16])=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Sc1nc2ncc(Cl)cc2s1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of 133 g (0.64 mol) of 2-amino-3-bromo-5-chloropyridine from Example 1.1 in 1.02 l of N-methylpyrrolidone was admixed with 205 g (1.28 mol) O-ethylxanthic acid potassium salt. The reaction mixture was refluxed for 6 h and then allowed to cool to ambient temperature. 2.7 l of demineralized water were added then acetic acid to adjust the reaction mixture to pH 4.5. The resulting precipitate was filtered, washed with demineralized water (2×600 ml). The solid was triturated in succession with demineralized water (2×4.2 l) and ethanol, (1.5 l), filtered, washed with ethanol (2×300 ml) followed by hexane (2×400 ml) and dried in vacuo at 45° C. to give 127 g (yield: 98%) of 6-chloro-2-mercaptothiazolo[4,5-b]pyridine used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]1([C:29]2[CH:33]=[C:32]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]3)[O:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O1CCCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:42]([CH2:41][CH:38]1[CH2:37][CH2:36][N:35]([CH2:34][C:32]3[O:31][N:30]=[C:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:33]=3)[CH2:40][CH2:39]1)[C:6]([OH:7])([C:13]([O:15][CH3:16])=[O:14])[CH:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(O)C(c2ccccc2)c2cc(Br)ccc2C(=O)N1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 60 °C

Procedure:
Methyl 6-bromo-1-oxo-4-phenyl-1H-isochromene-3-carboxylate (0.319 g, prepared according to the reported preparation in US 2005/0148624) and the compound prepared in Example 9 (0.458 g) were suspended in methanol (10 mL) and diisopropylethylamine (0.772 mL) was added. Tetrahydrofuran (5 mL) was added and the reaction mixture was heated at 60° C. overnight. The reaction mixture was then cooled to room temperature and concentrated. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound (0.560 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[K].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34](=[O:37])(=[O:36])[NH2:35])=[CH:29][CH:28]=1>CS(C)=O.CO>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:35][S:34](=[O:36])(=[O:37])[NH:33][C:30]2[CH:29]=[CH:28][C:27]([CH3:26])=[CH:32][CH:31]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: Cc1ccc(NS(N)(=O)=O)cc1
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(NS(=O)(=O)Nc2ncnc(Cl)c2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.1 %

Procedure:
To 4,6-dichloro-5-p-tolyl-pyrimidine (Referential Example 7) (2.0 g) dissolved in DMSO (35 ml) was added di-isopropyl-ethyl-amine (1.46 ml) followed by addition of 4-methyl-phenyl sulfamic acid amide potassium salt (2.78 g) [prepared from the product described in Referential Example 19 and potassium tert.-butylate in methanol followed by evaporation of the solvent]. The mixture was stirred for 48 h at rt then poured onto water (500 ml) and diethylether (250 ml) was added and the solution was stirred for 30 min. The layers were separated and the water layer was acidified with acetic acid (2.0 ml) and cooled to 0° C. for 1 h. The precipitated product was filtered off and washed with water and diethylether and dried to give 4-methyl-phenyl sulfamic acid-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-amide (2.02 g). tR=5.00 min (LC); [M+H]+=389.11 (ES+);
Reaction SMILES: [Br:1]CC1C=C[C:6]([C:7]([O:9][CH3:10])=[O:8])=CC=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Br-:1].[CH3:10][O:9][C:7]([CH:6]([P+:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:8]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccccc1
Product: COC(=O)C(c1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 2 h

Procedure:
2.61 g (11.4 mol) of methyl 4-(bromomethyl)benzoate (IV) synthesized in the 4th step and 3.0 g (11.45 mmol) of triphenylphosphine were dissolved in 100 ml of benzene, and the temperature was raised to the reflux temperature under stirring, at which temperature, the reaction was carried out for 2 hours.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.O.NN>C(#N)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: NN
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(CCCN)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{4-(4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl)acetamide (53.2 mg) in acetonitrile (0.5 ml) was added hydrazine monohydrate (46.1 μl), and the mixture was stirred at 50° C. for 30 min. The volatiles were evaporated. To the mixture was added chloroform (1 ml), and an insoluble material was removed by filtration. The filtrate was purified by preparative thin-layer chromatography over NH silica gel with chloroform/methanol (10:1) as an eluent to give N-{4-[4-(3-aminopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:8][C:6]1[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(CO)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
(3-Methoxy-isoxazol-5-yl)-methanol (822 mg, 6.4 mmol) was dissolved in dichloromethane (10 ml) and triphenyl phosphine (1.84 g, 7.0 mmol) and carbon tetrabromide (2 g, 6.11 mmol) were added at 0° C. The mixture was stirred for 2 hours at 0° C. and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a colourless oil (1.22 g, 99% yield) which was used in the next step without further purification.
Reaction SMILES: [Na+].[I-:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@H:16]([CH3:38])[C@:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([O:24][C:25]([O:27][CH2:28]Cl)=[O:26])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:4]>CC(C)=O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@H:16]([CH3:38])[C@:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([O:24][C:25]([O:27][CH2:28][I:2])=[O:26])[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)#[N:4]
Reactant: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCCl)c1ccc(F)cc1F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@@H](c1nc(-c2ccc(C#N)cc2)cs1)[C@@](Cn1cncn1)(OC(=O)OCI)c1ccc(F)cc1F
Temperature: 50 °C
Yield: 93.1 %

Procedure:
NaI (19.4 mmol) was added to an acetone solution of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[chloromethoxy]carbonyloxy]butane (6.5 mmol). The reaction was heated to 50° C. for 5 hours. After cooling to room temperature, the crude reaction was filtered, concentrated, and then dissolved in EtOAc. The organic layer was washed sequentially with aqueous solutions of NaHCO3 and Na2S2O3. The organic layer was then washed with H2O, dried over MgSO4, and was concentrated to obtain 3.76 g of the subtitled compound as a yellow solid. 1H NMR (DMSO) δ8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 6.08 (s, 2H), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=622).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:37]3[S:41][CH:40]=[N:39][CH:38]=3)[CH:34]=[C:33]([CH3:42])[CH:32]=2)[N:25]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH3:43][C:44]1([CH3:51])[O:49][CH2:48][C:47](=[O:50])[CH2:46][O:45]1>O1CCCC1>[Si:13]([O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]2[CH:36]=[C:35]([C:37]3[S:41][C:40]([C:47]4([OH:50])[CH2:48][O:49][C:44]([CH3:51])([CH3:43])[O:45][CH2:46]4)=[N:39][CH:38]=3)[CH:34]=[C:33]([CH3:42])[CH:32]=2)[N:25]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cncs2)c1
Reactant: CC1(C)OCC(=O)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(Nc2nccc(OCCO[Si](C)(C)C(C)(C)C)n2)cc(-c2cnc(C3(O)COC(C)(C)OC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To diisopropyl amine (185 μL, 1.29 mmol) in tetrahydrofuran (2.2 mL) at 0° C. was added n-butyllithium (2.2 M in hexanes, 589 μL, 1.29 mmol). The mixture was stirred for 15 minutes, then cooled to −78° C. 4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (191 mg, 0.43 mmol), dissolved in tetrahydrofuran (1 mL), was added dropwise over 5 minutes. The mixture was stirred for 30 minutes at −78° C., then 2,2-dimethyl-1,3-dioxan-5-one (57 μL, 0.47 mmol) was added dropwise. The reaction was stirred for 2 h, and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate (3×), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography on silica gel (Biotage 25 G, eluting with 0:100 to 100:0 ethyl acetate:hexanes) gave 5-[5-(3-{[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-2,2-dimethyl-1,3-dioxan-5-ol (185 mg, 0.32 mmol, 75% yield) as a pale yellow solid. MS ESI: [M+H]+ m/z 573.3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)c2ncccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2ncccc12

Procedure:
16.25 g (86 mmol) of 8-hydroxy-5-quinolinecarboxylic acid were dissolved in 70 ml of methanol, 3 ml of concentrated sulfuric acid were added and the mixture was heated under reflux for 25 hours. The solvent was then removed and the residue was taken up in ice-water, adjusted to a pH of 8 using sodium carbonate solution and filtered hot. The residue was extracted with methyl-tert-butyl ether for 7 hours on a jacketed Soxhlet extractor, and the solvent was subsequently removed from the extract. This gave 6.8 g of a brown powder;
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:26]4=[C:27]5[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]4)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]5=[CH:17][C:16]=3[F:33])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:35]=[CH:34][C:7]([CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:26]4=[C:27]5[N:22]([CH:23]([CH3:28])[CH2:24][CH2:25]4)[CH:21]=[C:20]([C:29]([OH:31])=[O:30])[C:19](=[O:32])[C:18]5=[CH:17][C:16]=3[F:33])[CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC1CCc2c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1CCc2c(N3CCN(Cc4ccc(N)cc4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 37.1 %

Procedure:
The Compound [II] (0.71 g), mixed with 10% palladium on charcoal (0.2 g) and acetic acid (25 ml), was hydrogenated with the calculated volume of hydrogen under normal pressure at room temperature. After the calculated volume of hydrogen was taken up, palladium on charcoal was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in a small amount of water, and neutralized with 10% sodium hydroxide solution. The resulting precipitate was collected, dried, and purified by column chromatography on silicagel using a mixture of chloroform and ethanol (10:1) as the developing solvent. The purified product was recrystallized from ethanol to give 0.25 g (yield: 37.1%) of 8-[4-(4-aminobenzyl)-1-piperazinyl]-9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (Compound [I]) as pale yellow needles, m.p. 215.5°-217.5° C. (decompd.).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:27]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:25][CH2:26]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.5 parts of 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 1-{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 218° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:8]2=[N:7][C:6]=1[CH3:17].[H][H]>[C].[Pd].C(O)(=O)C>[Cl:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][CH2:14][CH:15]([OH:16])[C:8]2=[N:7][C:6]=1[CH3:17]
Reactant: [H][H]
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCCl
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (formula-5) (40 grams), acetic acid (200 ml) and palladium carbon (40 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0-3.5 Kg/cm2 was applied to the above mixture at 35° C. for 6 hrs. The reaction was quenched with water and filtered the resultant mixture through a hyflow bed. The pH of the filtrate was adjusted to 6 using aqueous sodium hydroxide solution The reaction mixture was cooled to 0° C. and stirred for 1 hr. The solid formed was filtered, washed with water and dried to yield the title compound.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[O-:16])([CH3:13])([CH3:12])[CH3:11].[Na+]>O1CCOCC1>[C:21]([C:17]1[CH:18]=[C:19]([C:2]2[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=2)[CH:20]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[OH:16])([CH3:24])([CH3:23])[CH3:22]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(-c2nc(Cl)nc(Cl)n2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To 18.35 g of cyanuric chloride dissolved in dioxane at 5°C was added 22.83 g of sodium 2,6-di-t-butylphenoxide over a period of 10 to 15 minutes. The reaction was maintained below 10°C for 1 hour after which it was warmed to room temperature and filtered to remove precipitated salt. The filtrate was concentrated to dryness under reduced pressure. The product was recrystallized from petroleum ether and had a melting point of 178°-179°C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:5]=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH:16][C:10](=[O:11])[CH:9]=[CH:8][C:6]1[CH:7]=[N:2][CH:3]=[N:4][CH:5]=1
Reactant: O=C(Cl)C=Cc1cncnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)C=Cc1cncnc1
Reaction time: 0.5 h

Procedure:
To a suspension of the product of step 3 (2.05 g) in anhydrous dichloromethane (30 ml), a solution of 2-methyl-5-nitroaniline (3.04 g) and triethylamine (8 ml, excess allowed) in dichloromethane (15 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room to temperature for 3 h. Completion of reaction was indicated by TLC. Potassium carbonate solution (10%) was added to the mixture. Then the mixture was extracted with EtOAc (20 ml*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to recover the solvent. The residue was purified on silica gel column (EtOAc/petroleum ether 4:1). The eluent was collected, concentrated under reduced pressure to give a yellow powdered solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:10][CH:9]=2)[C:5](/[N:31]=C/N(C)C)=[N:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CS(C)=O.CC#N.C([O-])([O-])=O.[K+].[K+]>[NH2:31][C:5]1[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]3[C:18](=[O:30])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:20]([CH3:23])[C:21]=3[CH3:22])=[O:16])=[CH:12][CH:13]=2)=[N:7][C:2]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:3][N:4]=1
Reactant: C1CCNCC1
Reactant: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3/N=C/N(C)C)cc2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1c(C(=O)Nc2ccc(-c3nc(N4CCCCC4)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Yield: 586.9 %

Procedure:
The compound prepared in Example 36 (80 mg) and piperidine (0.300 mg) were mixed in DMSO (0.400 mL) and heated to 120° C. for 18 hours. The reaction mixture was then diluted with MeCN (10 mL) and aqueous 1M K2CO3 (7 mL) and heated to 155° C. for 17 minutes in the microwave. The organic products were extracted with EtOAc/CH2Cl2 (9:1) and washed with brine. The material was purified by HPLC (H2O/MeCN with 0.1% TFA). The solvent was removed and the residue was dissolved in CH2Cl2 and the residual TFA was removed by PL-HCO3 MP SPE ion exchange column to give the title compound (10 mg) having the following physical data.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@:15]23[CH2:30][C@H:22]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=[O:35].[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C@:15]23[CH2:30][C@H:22]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][C:28]=42)[C:21]2[C:16]3=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:35])[CH2:10][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Reaction time: 18 h
Yield: 100 %

Procedure:
To a stirred solution of t-butyl-N-(1-[(9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)carbamate produced in Example 1b (1.24 g, 2.74 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (2.11 mL, 27.37 mmol). After stirring the resulting mixture for 18 h, the reaction was concentrated to give a pale pink syrup. The syrup was dissolved in methylene chloride (100 mL), cooled to 0 C. (ice bath) and treated with 3N sodium hydroxide and extracted with methylene chloride (3×50 mL). The combined extracts was washed with 3N sodium hydroxide (2×75 mL) and brine (75 mL), dried (sodium sulfate), filtered, and concentrated to give the title compound as a white foamy glass (967 mg, 100%); mp 93°-5° C.; MS(CI); 353 (M+H); NMR (300 MHz,DMSO-d6): 1.23(br m, 2H), 1.67-1.85(br m, 2H), 2.71-3.02(br m, 5H), 3.27-3.39(br m, part. submerged, 2H), 3.66(br s, 1H), 4.42(s, 1H), 4.47(s, 1H), 7.00(m, 3H), 7.30-7.66(br m, 4H).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([S:20][CH2:21][CH2:22][C:23](Cl)=[O:24])(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([S:20][CH2:21][CH2:22][C:23]([N:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CCOC(=O)C1NN=C(c2ccccc2)S1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1SC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
A solution of the product of step (a) (2.36g) in toluene (100ml) was treated with polyvinylpyridine (2.0g) and 3-acetylthiopropanoyl chloride (1.7g) and the mixture stirred at room temperature for 4 hours. The mixture was filtered and the filtrate stirred with a saturated solution of sodium bicarbonate (100ml) for 1 hour. The organic phase was separated, washed with water, dried and evaporated to a gum. The residue was purified by flash chromatography to give the sub-title product (2.62g) as an oil.