Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8]O)=[CH:6][N:5]=[CH:4]1)[CH3:2].C1C(=O)N([Cl:17])C(=O)C1.P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C:29]1[N:34]=[C:33]([SH:35])[N:32]=[C:31]([OH:36])[CH:30]=1>O1CCOCC1>[Cl:17][C:6]1[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH2:8][S:35][C:33]1[N:32]=[C:31]([OH:36])[CH:30]=[C:29]([CH3:28])[N:34]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1cncc1CO
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCn1cnc(Cl)c1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To the solution of (1-ethyl-1H-imidazol-5-yl)methanol (1.26 g, 10 mmol) in dioxane (50 mL) in a 250 mL round bottom flask, was added NCS (1.38 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. Dioxane was removed under vacuum, and the crude solid was dissolved in chloroform (40 mL), followed by addition of PBr3 (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was then evaporated. The crude 5-(bromomethyl)-4-chloro-1-ethyl-1H-imidazole was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The mixture was stirred at room temperature for 2 hours. DMF was removed under vacuum, and the residue was purified by column chromatography to provide 2-{[(4-chloro-1-ethyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (100 mg, 3% overall yield); 1H NMR (400 MHz, CD3OD): δ 1.41 (t, 3H), 2.29 (s, 3H), 4.12 (q, 1H), 4.60 (s, 2H), 4.59 (m, 1H), 6.01 (br, 1H), 7.66 (s, 1H); M+285.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[C:11](SC)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([NH:4][C:5]1[N:14]=[CH:13][C:12]2[C:11]([NH:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CSc1ncnc2cc(NC(C)=O)ncc12
Product: CC(=O)Nc1cc2ncnc(NCc3ccccc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A mixture of 7-acetylamino-4-methylthiopyrido[4,3-d]pyrimidine (0.40 g, 1.71 mmol) and benzylamine (1.0 mL, 9.15 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product is chromatographed on silica gel (EtOAc) to give 7-acetylamino-4-benzylaminopyrido[4,3-d]pyrimidine (0.31 g, 62%) as a white solid. 1H NMR (DMSO) δ 10.79 (1H, s), 9.42 (1H, s), 9.23 (1H, t, J=5.8 Hz), 8.49 (1H, s), 8.18 (1H, s), 7.39 (1H, dt, Jd=6.9 Hz, Jt=1.7 Hz), 7.34 (1H, tt, J=7.3, 1.7 Hz), 7.25 (1H, tt, J=7.1, 1.7 Hz), 4.80 (2H, d, J=5.8 Hz), 2.15 (3H, s).
Reaction SMILES: CO[C:3](=[O:17])[CH:4]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:5]([O:7]C)=O.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25].C(N(CCCC)CCCC)CCC>CO>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:4]1[C:3]([OH:17])=[N:18][C:19]2[N:23]([N:22]=[CH:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[C:5]=1[OH:7]
Reactant: COC(=O)C(C(=O)OC)c1c(F)cccc1Cl
Reactant: COC(=O)c1cn[nH]c1N
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1cnn2c(O)c(-c3c(F)cccc3Cl)c(O)nc12
Yield: 139.1 %

Procedure:
At room temperature, 15 g (57.5 mmol) of dimethyl(2-chloro-6-fluorophenyl)malonate were mixed with 9.4 g (57.5 mmol) of methyl 5-amino-1H-pyrazole-4-carboxylate and 15 ml (63.3 mmol) of tri-n-butylamine. The mixture was then stirred at 185° C. for 8 hours, during which time methanol was distilled off. After cooling, excess tri-n-butylamine was carefully decanted off. Concentration under reduced pressure gave 27 g of methyl 6-(2-chloro-6-fluorophenyl)-5,7-dihydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (logPs=0.55; content according to HPLC: 83%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])(=[O:12])=[O:11].[CH3:18][C:19]1[C:20]([CH:26]=O)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:26][C:20]1[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=1)(=[O:12])=[O:11]
Reactant: NCCCCS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A solution of 4-(1H-benzoimidazole-2-sulfonyl)-butylamine (350 mg, 1.4 mmol) and 3,5-dimethylpyridine-2-carbaldehyde (187 mg, 1.4 mmol) in dry MeOH (10 mL) was stirred for 3 h. At this time, solid NaBH4 (116 mg, 4.2 mmol) was added in one portion. Stirring was continued for 1 h, then saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL) was added. The biphasic mixture was extracted with CH2Cl2 (3×20 mL), then the combined organic fractions were dried (MgSO4), and concentrated. Purification of the crude material by flash chromatography (silica gel, CH2Cl2/MeOH/NH4OH; 20:2:1) afforded 70 mg of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine (14% yield). 1H NMR (CDCl3) δ 184-1.86 (m, 4H), 2.26 (s, 3H), 2.29 (s, 3H), 2.95-3.00 (m, 2H), 3.34-3.56 (m, 2H), 4.12 (s, 2H), 7.34-7.37 (m, 2H), 7.44 (s, 1H), 7.67-7.71 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14](N)([NH2:17])(=[O:16])=[O:15].O>O1CCOCC1>[NH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Yield: 65.5 %

Procedure:
A solution of 1-benzylpiperazine (5 g, 28.4 mmol) and sulphamide (2.77 g) in 1,4-dioxane (25 ml) was heated under reflux for 24 hours. The solution was cooled and poured into water (100 ml). The solid was filtered off, washed with toluene (100 ml) and dried under reduced pressure to give the title compound (4.75 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C[Li].Cl.[C:15](=O)([O-])O.[Na+]>O1CCCC1.ClCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH3:15]
Reactant: O=C([O-])O
Reactant: Cc1cccc(C(=O)O)c1Cl
Agent: Cl
Agent: [Li]C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-methylbenzoic acid (1.71 g, 10.0 mmol) in anhydrous tetrahydrofuran (10 ml), at 0° C. and under nitrogen, was added methyllithium (1.6M in diethyl ether, 13.1 ml, 21.0 mmol), via syringe. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to room temperature over 1 h. To the reaction mixture was added cold hydrochloric acid (1M, 100 ml) and dichloromethane (110 ml). The mixture was adjusted to pH 7 by addition of saturated aqueous sodium hydrogen carbonate solution and the two layers were separated. The aqueous layer was extracted with further dichloromethane and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.19 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:23](=[O:25])[CH3:24])[CH2:27][CH2:28]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CC(=O)N1CCNCC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Product: CC(=O)N1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)CC1

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Intermediate J, 50 mg, 0.160 mmol) and 1-acetylpiperazine (41.0 mg, 0.320 mmol) (tR 3.17 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.85 (d, 1H); 8.33 (d, 1H); 7.94 (d, 1H); 7.84 (d, 1H); 7.74 (d, 1H); 7.46 (m, 1H); 7.44 (s, 1H); 7.14 (d, 1H); 4.40 (s, 2H); 3.48 (s, 6H); 3.42 (m, 2H); 2.00 (s, 3H)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](O)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[OH:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of borane dimethyl sulphide complex (2.85 ml, 30 mmol) in THF (50 ml) was added dropwise at 0° C. to a solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (2.43 g, 10 mmol) in THF (100 ml). The reaction mixture was stirred at 0° C. for 15 minutes and at room temperature for 3 hours, methanol was cautiously added and the mixture was concentrated. The crude product was repeatedly treated with methanol and concentrated again, and finally dried under a high vacuum. Used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:21]([NH:23][CH:24]2[CH2:26][CH2:25]2)=[O:22])=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18](O)=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CN(C=O)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:43][O:44][C:45](=[O:54])[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C(N(CC)CC)C>O>[CH:24]1([NH:23][C:21](=[O:22])/[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([NH:53][CH2:52][C:49]3[CH:50]=[CH:51][C:46]([C:45]([O:44][CH3:43])=[O:54])=[CH:47][CH:48]=3)=[O:19])=[CH:12][CH:11]=2)[CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)C=Cc1ccc(/C=C(/C(=O)NC2CC2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)C=Cc2ccc(/C=C(/C(=O)NC3CC3)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
To a suspension of (1E)-3-(4-(2-(4-fluorophenyl)-3-(cyclopropylamino)-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (prepared according to the procedure described in Example 59, step-II, 0.35 g, 1 mmol) in DMF (15 mL) EDCI (0.83 g, 2 mmol), HOBt (0.13 g, 1 mmol) and methyl-4-aminomethylbenzoate hydrochloride salt (0.18 g, 0.9 mmol), were added, followed by triethylamine (0.4 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, after which the mixture was added to cold water (50 mL). The aqueous layer was extracted with ethyl acetate (1×150 mL) and washed with water (2×50 mL), 10% dilute HCl (50 mL) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound (0.225 g, 53.5% yield).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:35][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)([CH3:6])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cncnc4)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cncnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-methyl-2-(4-{2-[5-methyl-2-(4-pyrimidin-5yl-phenyl)-oxazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to yield the desired product. 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 9.20 (s, 2H), 8.16 (d, 2H), 7.65 (d, 2H), 6.86 (d, 2H), 6.76 (d, 2H), 4.20 (t, 2H), 3.00 (t, 2H), 2.39 (s, 3H), 1.48 (s, 6H); MS (EI) 460.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](=[NH:21])OCC)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[C:23]1([C@H:29]([CH3:34])[C:30]([NH:32][NH2:33])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C.O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]2[NH:21][C:30]([C@H:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:34])=[N:32][N:33]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: C[C@H](C(=O)NN)c1ccccc1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C/c2nnc([C@@H](C)c3ccccc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 19 h
Yield: 33.3 %

Procedure:
A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate (30 mg) and TEA (35 ul) in ethanol (0.5 ml) was added to a solution of (S)-2-phenylpropionic acid hydrazide monohydrochloride (37 mg) and TEA (35 uL) in ethanol (0.5 mL), and the reaction solution was stirred at 75° C. for 19 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-ethanol system) to obtain 13.5 mg of the title compound with positive optical rotation. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][C:14]([OH:16])=[O:15].CCOCC.Cl>C([O-])([O-])=O.[Na+].[Na+]>[C:14]([CH2:13][NH:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:16])=[O:15]
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C(O)CNc1ccc(Br)cc1C(=O)O
Temperature: 80 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
To a solution of 2-amino-5-bromobenzoic acid (2 g, 9 mmol) in 15 ml of 2 N Na2CO3, a solution of chloroacetic acid (0.69 g, 7.3 mmol) in 7.5 ml of 2 N Na2CO3 was slowly added dropwise. Then, after stirred for 20 hours at 80° C., the reaction mixture was cooled down to room temperature. 50 ml of ether and 8 ml of 2 N hydrochloric acid were added to the mixture. The organic phase was separated, and dried with MgSO4. After evaporation, a light brown solid was obtained. The solid was purified by silica gel column chromatography (ethyl acetate/methanol, v/v, 1/1) to obtain a white solid (2-(N-carboxymethylamino)-5-bromobenzoic acid) (1.55 g, yield: 60%; mp: 178-180° C.).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH2:4]1.[N+:27]([O-])([O-:29])=[O:28].[K+].N>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:27]([O-:29])=[O:28])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1ccc1ccc(S(C)(=O)=O)cc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CS(=O)(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
Powdered 205 (350 mg, 0.88 mmol) was added to stirred conc. H2SO4 (4 mL) at 0° C. and the mixture was warmed to room temperature for 20 min. The resulting solution of amine was cooled to −5° C. and treated dropwise with a solution of KNO3 (98 mg, 0.97 mmol) in conc. H2SO4 (1 mL). The mixture was stirred at 0° C. for a further 5 min, then poured into ice/water and neutralized with dilute aqueous NH3. The resulting solid was filtered off, dissolved in CH2Cl2, and the solution was filtered through a column of silica gel and evaporated to dryness. Recrystallization from CH2Cl2/i-Pr2O followed by EtOAc gave 1-(chloromethyl)-8-(methylsulfonyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole (206) (207 mg, 69%) as a red solid: mp 193-194° C.; 1H NMR [(CD3)2SO] δ 8.34 (d, J=1.5 Hz, 1H), 8.31 (d, J=9.1 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J=9.1, 1.9 Hz, 1H), 6.62 (br s, 1H), 4.37-4.28 (m, 1H), 3.93 (dd, J=11.1, 4.1 Hz, 1H), 3.87 (td, J=9.8, 2.3 Hz, 1H), 3.80-3.70 (1, 2H), 3.33 (s, 3H). Anal. (C14H13ClN2O4S) C, Ht N. The structure of 206 was confirmed by x-ray crystallography see FIG. 1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:28][C:29](=O)[NH:30][C:31]1[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1>>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][N:19]4[CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:28])[N:32]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: N[C@H]1CC[C@@H](Oc2ccc3cnn(CCO)c3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4cnn(CCO)c4c3)c3ccccc32)cc1

Procedure:
The title compound was prepared starting from Intermediate 11b and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 315 mg, 0.78 mmol) by using an analogous procedure to that described in Example 1 step d. LCMS (Method 5): Rt 4.99 min, m/z 578 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.22 (9 H, s), 1.81-1.92 (2 H, m), 2.02-2.06 (2 H, m), 2.31 (3 H, s), 3.74-3.75 (2 H, m), 4.34 (2 H, t, J 5.75), 4.78 (2 H, m), 5.53 (1 H, t, J 4.8), 6.28 (1 H, s), 6.74 (1 H, dd, J 8.75 and 2.03), 7.08 (1 H, d, J 8.53), 7.27-7.28 (9 H, m), 7.57 (1 H, d, J 8.75), 7.89 (1 H, s), 7.96 (1 H, s).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:12][CH2:13][CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CCCCBr
Reactant: CCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCN1CCN(CCCC#N)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 25 mL flask was placed 1-butyl-piperazine (712 mg, 5.0 mmol), 4-bromobutyronitrile (779 mg, 5.3 mmol) and potassium carbonate (687 mg, 5.0 mmol) suspended in acetonitrile (5 mL). The reaction mixture was stirred at rt for 12 h., followed by addition of H2O (20 mL) and extraction with ethyl acetate (3×25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO4) and evaporated to dryness to produce 0.89 g of crude 16 which was used without further purification in the synthesis of compound 17.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([CH:10]1[C:15](=[O:16])[CH:14]=[C:13]([CH3:17])[O:12][C:11]1=[O:18])=[O:9].[O:19]1CCCC1>>[CH3:17][C:13]1[O:12][C:11](=[O:18])[CH:10]([C:8]([CH3:7])=[O:9])[C:15](=[O:16])[CH:14]=1.[CH:6](=[O:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CC(=O)C(C(=O)C=Cc2ccco2)C(=O)O1
Reactant: C1CCOC1
Product: CC(=O)C1C(=O)C=C(C)OC1=O
Product: O=Cc1ccco1

Procedure:
In 270 ml of tetrahydrofuran was dissolved 32.0 g of 3-(2-furylacryloyl)-6-methyl-2H-pyran-2,4(3H)-dione which had been obtained by condensation between dehydroacetic acid and furfural. To the solution, 1.6 g of 5% palladium on carbon was added as the hydrogenation catalyst. Hydrogenation was carried out at room temperature under a pressure of 5 kg/cm2 for 10 hours. The catalyst was removed by filtration and the solvent was evaporated under a reduced pressure. The light-yellow oily product thus obtained was purified by silica gel chromatography to obtain a 21.0 g (yield: 65%) of 3-(3-(2-tetrahydrofuryl)propionyl)-6-methyltetrahydropyran-2,4-dione in the form of the light-yellow crystal, m.p. 43°-45° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Sn](C)(C)C>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Reactant: C[Sn](C)(C)c1c(F)cccc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3Cl)cc3c1N2CCS3
Yield: 57.4 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2-chloro-6-fluorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (276 mg, 57%) was prepared via coupling tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (1.0 g, 1.043 mmol) with 2-chloro-6-fluorophenyltrimethyl stannane (3.0 g, 3.129 mmol) as illustrated by the general procedure described in Example 447 Step G. 1H NMR (CDCl3, 300 MHz) δ1.44 (s, 9H), 1.83-1.99 (m, 2H), 2.80-3.32 (m, 5H), 3.33-3.50 (m, 2H), 3.55-3.71 (m, 3H), 6.82 (d, 1H, J=8.1 Hz), 7.01 (t, 1H, J=8.1 Hz), 7.12-7.35 (m, 3H) ppm.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([Cl:7])[N:6]=1.C(N(CC)C(C)C)(C)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C.O>[Cl:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[S:3][C:4]=1[C:8]#[N:9]
Reactant: N#Cc1sc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1sc(N2CCOCC2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
2,4-dichloro-5-cyanothiazole (1.26 g, 0.00704 mol) and N,N-diisopropylethylamine (3.68 mL, 0.0211 mol) were dissolved in ethanol at 70° C. Morpholine (0.614 mL, 0.0704 mol) was added to the hot solution and the mixture was stirred for 30 minutes, cooled down to rt, diluted with water (50 mL) and the formed precipitate was collected to give the title compound (1.55 g, 91%). LCMS: (FA) ES+, 230. 1H NMR (300 MHz, d6-DMSO) δ: 3.71-3.67 (m, 4H), 3.52-3.48 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:16])[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 95.6 %

Procedure:
A mixture of 1.54 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 8 ml of glacial acetic acid, 6 ml of water and 1 ml of conc. sulfuric acid was stirred at 120° C. for 1.5 hours. After cooling, the crystals which precipitated were collected by filtration, and washed successively with water and ethanol to give 1.34 g of 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles. m.p. 295°-297° C. (decomp.)