Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:18]1([P:24](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:18]1([P:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([O:10][C:7]2[CH:8]=[CH:9][C:4]([S:1]([C:11]3[CH:16]=[CH:15][C:14]([O:17][P:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:25])=[CH:13][CH:12]=3)(=[O:3])=[O:2])=[CH:5][CH:6]=2)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=P(Oc1ccc(S(=O)(=O)c2ccc(OP(=O)(c3ccccc3)c3ccccc3)cc2)cc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
An oven-dried 100 mL 3-necked flask equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, was charged with 4,4'-sulfonyldiphenol (3.9 g, 15.6 mmol), 4-dimethylaminopyridine (0.39 g, 3.2 mmol), and anhydrous pyridine (35 mL), and the stirred solution was treated slowly with diphenylphosphinyl chloride (6.5 mL, 34.1 mmol) via syringe. The resulting mixture was heated at reflux for 7 hours, then was allowed to stand at room temperature for 16 hours. The reaction was monitored periodically by HPLC. After completion of the reaction, the mixture was partitioned between water (100 mL) and CH2Cl2 -Et2O (1:3; 400 mL), and the organic phase was washed successively with 50 mL portions of 5 percent NaOH, water, 5 percent HCl, water and brine, then it was dried (MgSO4), filtered and concentrated leaving a white solid residue. Recrystallization from ethyl acetate-THF (9:1) afforded 9.5 g (94 percent yield) of the title compound as a white fluffy solid, m.p. 210-211° C. which had a PDSC (O2) onset/extrap (° C.) of 376/397.
Reaction SMILES: [S:1]1[C:5]2[C:6](O)=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:12](=[O:15])([O-])[O-].[K+].[K+].I[CH3:19].N>CC(C)=O.CO>[CH3:19][O:10][C:8]1[CH:7]=[C:6]([O:15][CH3:12])[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:9]=1
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(O)c2sccc2c1
Agent: N
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cc(OC)c2sccc2c1
Temperature: 25 °C

Procedure:
To a solution of 1-benzothiophene-5,7-diol (1.16 g, 6.98 mmol) in acetone (20 ml) under argon were added potassium carbonate (2.89 g, 20.9 mmol) and iodomethane (912 μl, 14.6 mmol). The resulting mixture was stirred under reflux for 18 h. After cooling to rt, the mixture was treated with a 7 M solution of ammonia in methanol (10 ml) for 30 min and then adsorbed on silica gel. Purification by column chromatography over silica gel (cyclohexane/ethyl acetate 40:1) afforded 0.52 g (32% of th.) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 1-bromo-4-fluorobenzene. HRMS (ESI+): m/z=343.1258 [M+H]
Reaction SMILES: ClC1C=[C:6]([C:8]([C:10]2[CH:15]=[C:14](Br)[CH:13]=[C:12](Br)[CH:11]=2)=O)C=CN=1.[CH3:18][O:19][C:20](=[O:38])[NH:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)=[O:29])[CH:25]=[C:24](Br)[CH:23]=1.COC(=O)[NH2:42]>[Pd]>[CH3:18][O:19][C:20](=[O:38])[NH:21][C:22]1[CH:23]=[C:24]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:10]=2[CH:8]=[CH:6][NH:42]3)[CH:25]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)=[O:29])[CH:27]=1
Reactant: O=C(c1cc(Br)cc(Br)c1)c1ccnc(Cl)c1
Reactant: COC(=O)Nc1cc(Br)cc(C(=O)c2ccnc(Cl)c2)c1
Reactant: COC(N)=O
Agent: [Pd]
Product: COC(=O)Nc1cc(C(=O)c2ccnc(Cl)c2)cc(-c2cccc3[nH]ccc23)c1

Procedure:
(2-Chloro-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone was converted to [3-bromo-5-(2-chloro-pyridine-4-carbonyl)-phenyl]-carbamic acid methyl ester under the palladium catalyzed conditions described for Example 86, using carbamic acid methyl ester in place of methanesulfonamide. The Suzuki reaction and removal of the triisopropylsilyl protecting group were carried out as described in Example 35. 1H NMR (400 MHz, CDCl3): δ 8.56 (d, J=4.9 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.77 (t, J=1.5 Hz, 1H), 7.69 (s, 1H), 7.55 (dd, J=5.0, 1.3 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.30-7.25 (m, 2H), 7.18 (dd, J=7.2, 0.8 Hz, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][C:21]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=2)[CH:31]=O)=[C:24]([CH3:36])[O:23][N:22]=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:31][C:30]2[CH:33]=[C:26]([C:25]3[C:21]([CH3:20])=[N:22][O:23][C:24]=3[CH3:36])[CH:27]=[CH:28][C:29]=2[O:34][CH3:35])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2c(C)noc2C)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3c(C)noc3C)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 5-(3,5-dimethylisoxazol-4-yl)-2-methoxybenzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C[N+]1([O-])CC[O:20]CC1>CC#N.CCOC(C)=O>[CH:2]([C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:20]
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Reactant: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(C=O)c1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
To a mixture of (A2) (1.0 eq.) and 4 Å mol. sieves in MeCN (0.2M) at RT was added NMMO (2.0 eq.) and the reaction mixture was stirred for 1.5 hr under N2 atmosphere. Then, the mixture was diluted with EtOAc, filtered and the filtrate was washed with H2O, 1N HCl, brine and dried (Na2SO4). Evaporation of the solvent gave (A3) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3, 300K) δ 9.96 (1H, s), 8.26 (1H, d, J=7.9 Hz), 8.18 (1H, d, J=7.9 Hz), 7.77 (1H, t, J=7.9 Hz), 3.93 (3H, s). MS (ES) C9H7NO5 requires: 209. found: 208 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.68 mmol) is dissolved in DMF (7 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction mixture is heated to 100° C. in the microwave for 30 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane ethyl acetate) as yellow oil in a yield of 62%; HPLC (method C): 1.93 min; LC-MS (method A): 1.80 min, 291.15 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][C@@H:29]([CH3:45])[CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][C@@H:29]([NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[CH3:45])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cnn(C)c2)on1
Reaction time: 24 h
Yield: 13.8 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (51 mg, 0.2 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 12 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.00 (s, 3H), 4.23-4.31 (m, 1H), 4.42-4.48 (m, 1H), 4.55-4.66 (m, 1H), 6.63 (d, 1H), 6.66 (s, 1H), 7.50 (d, 1H), 7.69 (d, 1H), 7.79-7.94 (m, 4H), 8.07 (m, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([I:21])=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([I:21])[C:14]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate N) (13.12 g, 32.7 mmol) was suspended in acetone (240 mL) and the mixture was cooled to 0° C. Added aqueous 5 N HCl (200 mL) dropwise, keeping the temperature less than 4° C. during the addition. After the addition was complete the mixture was allowed to come to ambient temperature and stirred for 18 hours. The remaining solid was removed by filtration, and the filtrate was neutralized with saturated aqueous sodium bicarbonate. The precipitate was collected by filtration and washed with water and dried in vacuo to give 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanone (8.20 g, 32.8 mmol): 1H NMR (DMSO-d6, 400 MHz) 8.23 (s, 1H), 5.18 (m, 1H), 2.64-2.73 (m, 2H), 2.26-2.37 (m, 4H), 2.17-2.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:5]=[C:4]([Cl:33])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([O:38]CC)=[O:37].[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:33][C:4]1[CH:5]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([OH:38])=[O:37]
Reactant: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)OCC)c(Cl)c3)n2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)O)c(Cl)c3)n2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
Ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (14, 6.70 g) obtained in the fifth step was dissolved in THF (20 ml,) and ethanol (20 mL), a 4 mol/L sodium hydroxide aqueous solution (13.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with hydrochloric acid, and extracted with ethyl acetate. The extraction residue was recrystallized with methanol to obtain (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)-phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-1B, 5.8 g, yield 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:47]C(=O)OC(C)(C)C)[C:11](=[O:46])[NH:12][C@H:13]2[CH2:38][O:37][C:36](=[O:39])[C@H:35]3[N:31]([CH2:32][C@H:33]([CH3:40])[CH2:34]3)[C:30](=[O:41])[C@H:29]([CH3:42])[NH:28][C:27](=[O:43])[C@H:26]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:44])[C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]2=[O:45])[CH:5]=[C:6]([F:8])[CH:7]=1.ClCCl.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>O>[F:58][C:59]([F:64])([F:63])[C:60]([O-:62])=[O:61].[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C@H:10]([NH3+:47])[C:11](=[O:46])[NH:12][C@H:13]2[CH2:38][O:37][C:36](=[O:39])[C@H:35]3[N:31]([CH2:32][C@H:33]([CH3:40])[CH2:34]3)[C:30](=[O:41])[C@H:29]([CH3:42])[NH:28][C:27](=[O:43])[C@H:26]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[C:20](=[O:44])[C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]2=[O:45])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)[C@@H]([NH3+])Cc3cc(F)cc(F)c3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Product: O=C([O-])C(F)(F)F
Reaction time: 0.75 h

Procedure:
485 mg (0.64 mmol) of the compound from example 28A are introduced into dichloromethane (7 ml) at 0° C. 7 ml of a solution of 9 parts by volume of trifluoroacetic acid and 1 part of water are added and the reaction mixture is stirred for 45 min. The solvent is removed in vacuo and the residue is in each case taken up using dichloromethane and subsequently using toluene and concentrated to dryness. 588 mg of crude product are obtained, which is employed in the subsequent step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=[C:3]1[C:12]([OH:14])=O.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1n[nH]c2ccccc2c1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1n[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.2 %

Procedure:
4-Oxo-1,4-dihydro-3-cinnolinecarboxylic acid (0.10 g, 0.53 mmol) is dissolved in 5 mL DMF. To this is added 4-chlorobenzylamine (0.07 ML, 0.58 mmol) and the reaction mixture is stirred at room temperature for 5 min. EDC (0.11 g, 0.57 mmol) and HOBt (0.08 g, 0.56 mmol) are added and the reaction is stirred at room temperature over 2 days. The mixture is poured into 30 mL H2O. A brown precipitate formed which is filtered. The crude product is triturated with hot EtOAc, filtered and dried to yield 0.012 g (7%) of the desired product. Physical characteristics are as follows: m.p. 269-271° C.; 1H NMR (300 MHz, DMSO) δ 14.2, 10.0, 8.17, 7.87, 7.74, 7.56, 7.38, 4.53; MS (fab) m/z 314 (M+H)+, 316, 315, 299, 298, 297, 127, 125, 123, 58.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.O>[F:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)ncc(OC)c2c1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(F)ncc(OC)c2c1
Temperature: 145 °C
Yield: 20.1 %

Procedure:
To a solution of 1-chloro-4,6-dimethoxyisoquinoline (1.5 g, 6.71 mmol) in DMSO (15 ml) was added cesium fluoride (4 g, 26.8 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (280 mg, 20.15%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.99-7.97 (d, J=8 Hz, 1H), 7.44-7.39 (m, 2H), 7.27-7.11 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 19F NMR: δ ppm −79.32 (1F); MS: MS m/z 208.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][C:12](=[O:14])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NNc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2=NN(c3ccccn3)C(=O)CC2)cc1
Temperature: 25 °C

Procedure:
In a 1 neck round bottom flask equipped with a Dean-Stark trap and condenser, 4-(4-methoxyphenyl)-4-oxo-butyric acid (5.0 g, 20 mmol), 2-hydrazinopyridine (3.9 g, 36 mmol) and p-toluene sulfonic acid (0.3 g) in 100 mL benzene were heated to reflux for 2 h while water was removed. The reaction was cooled to rt, an equal volume of Et2O was added and the product collected; Mp>300° C. This solid was dissolved in HOAc (50 mL) and heated at 100° C. for 6 h. The reaction was concentrated, dissolved in EtOAc and washed with saturated NaHCO3 solution, water, NaCl solution and dried (MgSO4). The solvent was concentrated to a thick oil; MS m/z 282 (M+H).
Reaction SMILES: [C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])(=[O:5])[C:2]([CH3:4])=O.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18].C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH3:14][O:15][C:16]([CH:17]([NH:18][C@H:2]([C:1]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:4])[CH2:19][CH2:20][S:21][CH3:22])=[O:23]
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(CCSC)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 72 h
Yield: 24.1 %

Procedure:
A solution of pyruvoyl-L-proline (185 mg), L-methionine methyl ester (600 mg), and sodium cyanoborohydride (200 mg) in 20 ml of methanol is adjusted to neutrality with dilute methanolic sodium hydroxide. After standing at room temperature for three days the product is absorbed on strong acid ion-exchange resin and eluted with 2% pyridine in water to yield 80 mg of product. The nmr spectrum shows OCH3 at 3.95δ, S-CH3 at 2.2δ and CH-CH3 at 1.55 and 1.7δ. The mass spectrogram on silylated material shows the expected molecular ion at 404 m/e.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CBr
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Bromoacetylbromide (40 g, 0.2 mole) was added slowly to a mixture of 20 g (0.1 mole) (4-amino-5-methylisoxazol-3-yl)-phenylmethanone of Example Ib in 500 ml dichloromethane with 200 ml of 2N sodium carbonate and 500 ml saturated sodium bicarbonate at 5° C. After stirring for 30 minutes the mixture was diluted with 400 ml dichloromethane and 400 ml water. The organics were washed with water and brine and dried (magnesium sulfate). Concentration gave 32 g of an oil which was chromatographed on high pressure liquid chromatograph (HPLC) using dichloromethane as an eluent to yield 23 g (71%) of a solid, melting point 89°-92° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.Cl[CH2:37][CH2:38][N:39]=[C:40]=[S:41]>C(Cl)Cl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:40]2[S:41][CH2:37][CH2:38][N:39]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: S=C=NCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC2=NCCS2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.5 g), triethylamine (0.3 ml) and 2-chloroethylisothiocyanate (0.16 ml) were dissolved in methylene chloride (5 ml) and the mixture was stirred at room temperature for 2 hours. The mixture was then washed with water (5 ml), dried, filtered and evaporated to give a gum. Chromatography of the gum on silica "Kieselgel 60H" (Trade Mark) eluting initially with toluene then with chloroform with a trace of methanol gave the title compound, which was recrystallized from ether, yield 0.102 g, m.p. 145°-147°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Br-:9].[CH2:10]([N+:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Product: [Br-]
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-4-piperidinone (15 g, 132.6 mmol) in dry acetone (100 mL) was added 1-bromomethylbenzene (24.9 g, 145 mmol) dropwise. It was stirred for 3 h. The title compound (116) separated which was filtered, washed with dry acetone and dried.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]([F:20])([F:19])[CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1.[OH2:21]>CO>[F:20][C:8]([F:7])([F:19])[CH2:9][CH2:10][S:11]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)(=[O:1])=[O:21]
Reactant: FC(F)(F)CCSc1ccc(Br)cc1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=S(=O)(CCC(F)(F)F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Oxone (3.7 g, 6 mmol) was added to a solution of 1-(3,3,3-trifluoropropylthio)-4-bromobenzene (Method 68 1.36, 4.75 mmol) in MeOH (25 ml) and water (5 ml) and the mixture was stirred at ambient temperature for 18 hours. The MeOH evaporated and water (20 ml) added and the mixture extracted with DCM. The extracts were dried (Chemelut column CE1005) and solvent removed by evaporation to give the title compound (1.43 g, 95%) as a white solid. NMR 2.62 (m, 2H), 3.67 (m, 2H), 7.86 (s, 4H); m/z 316 (M+).