Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32]([C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)=[O:33])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: Cn1ccnc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ccnc1C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), 1-methyl-1H-imidazole-2-carbonyl chloride (0.026 g, 0.283 mmol), dry THF (5 mL), DIPEA (2 mL). The obtained crude was purified by column chromatography using 2% ammonia in 20% MeOH:DCM as mobile phase to afford 0.020 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 3.50 (s, 3H), 4.41 (d, J=18.0 Hz, 1H), 6.99 (s, 1H), 7.43 (br, 2H), 7.67 (d, 1H), 7.78 (s, 1H), 8.28 (d, J=4.5 Hz, 2H), 8.30 (s, 1H), 9.08 (t, 1H); MS (m/z): 477.10 (M+H)+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[ClH:36].O1CCOCC1>CO>[Cl:36][CH2:4][CH2:3][CH2:2][NH:1][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=2)[N:9]=[C:8]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Reactant: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2cn(CCNCCCCl)c(C3CCN(c4ncnc(N)c4C(C)C)CC3)n2)ccc1F
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a solution of 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (70.0 mg; 0.15 mmol; 1.0 eq.) in methanol (0.5 ml), was added 4.0M HCl in dioxane (0.37 ml; 1.47 mmol; 10.0 eq.). The reaction mixture was stirred at 40° C. for 72 hr. After removal of the solvents, the crude was purified by prep HPLC to afford the title compound. LC-MS (M+H=515, obsd=515).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=1)=[O:4].[CH3:13][CH:14](C)[CH2:15]N(C=CC)CC(C)C.[OH:25][CH2:26][C:27]([CH3:31])([CH2:29][OH:30])[CH3:28].S(=O)(=O)(O)O>O.CN(C)C=O>[CH3:28][C:27]1([CH3:31])[CH2:29][O:30][CH:13]([CH:14]([CH3:15])[CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH3:12])[CH:6]=2)=[O:4])[O:25][CH2:26]1
Reactant: CC=CN(CC(C)C)CC(C)C
Reactant: CC(C)(CO)CO
Reactant: Cc1ccc(C(=O)CBr)cc1C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)CC(C)C2OCC(C)(C)CO2)cc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
2-Bromo-1-(3,4-dimethylphenyl)ethan-1-one (220 g) and N,N-bis(2-methylpropyl)-1-propenylamine (249 g) were added to 990 ml of dimethylformamide under an atmosphere of nitrogen and the mixture was stirred at around 50° C. for 2 hours. After cooling the reaction mixture to 10° C., 990 ml of water, 170 g of neopentyl glycol and 173 g of concentrated sulfuric acid were added successively to the reaction mixture and the mixture was stirred at around 60° C. for 2 hours. After cooling the reaction mixture to the room temperature, crystals precipitated. These crystals were isolated by filtration to give 262 g (yield 83%) of the title compound as white crystals.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C@@H:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:15]>C(O)C>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][C@H:14]([CH3:15])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: C[C@@H](N)C(C)(C)C
Solvent: CCO
Product: CCOc1c(N[C@H](C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (10 g, 59 mmol) and (R)-2-amino-3,3-dimethylbutane (353 mL of a 0.2M solution in absolute ethanol, 71 mmol) was stirred at room temperature for 24 hours. Another portion of (R)-2-amino-3,3-dimethylbutane (150 mL of a 0.2M solution in absolute ethanol, 30 mmol) was added, and the resulting solution was stirred at room temperature for 24 hours. The slurry was filtered, and the filtrate concentrated under reduced pressure. The resulting solid was triturated with hexane:ethyl acetate (150:5 mL), and washed with hexane to give 9.78 g (74%) of a white solid: 1H NMR: (DMSO-d6): δ 8.72 and 8.50 (two d, 1H, rotamers), 4.65 (m, 2H), 3.90 and 3.42 (two m, H, rotamers), 1.37 and 1.35 (two overlapping t, 2H, rotamers), 1.10 (two overlapping d, 3H, rotamers), 0.85 and 0.84 (two s, 9H, rotamers) ppm. IR(KBr): 3150, 2950, 1800, 1700 cm-1 ; MS (m/z): 225 (M+); Anal. Calcd. for C12H19NO3 : C, 63.98; H, 8.50; N, 6.22. Found: C, 64.33; H, 8.54; N, 6.52.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2-c2ccc(F)cc2)CC1
Temperature: 10 °C
Yield: 44 %

Procedure:
150 mg of 4-(5-Bromo-3-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (181) were dissolved in a mixture of 9 ml of dioxane and 3 ml of water, 47 mg of 4-fluoro-benzene-boronic acid, 47 mg of Na2CO3 and 40 mg of Pd(PPh3)4 were added and the resulting mixture was heated to 10° C. for 6 h. The solvent was removed in vacuo and the residue subjected to chromatography on a HPLC system. Yield: 44%
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH2:26][CH2:27][OH:28])[CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.CCOCC>[CH3:29][S:30]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][O:8][Si:9]([C:22]([CH3:24])([CH3:23])[CH3:25])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)[Si](OCC(CCO)COCCO)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(CCOS(C)(=O)=O)COCCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a stirred CH2Cl2 (400 mL) solution of diol, 1-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-3-(tert-butyldiphenylsilyloxy)-propane (5.48 g, 13.6 mmol) under N2 atmosphere was added TEA (11.2 mL, 78 mmol), followed by dropwise addition of methane sulfonyl chloride (3 mL, 39.00 mmol) in CH2Cl2 (100 mL) over a period of 30 minutes. After 12 hours, the reaction was diluted with ether (500 mL), washed with water (100 mL×3), brine (100 mL), dried, and concentrated under reduced pressure to a residue. The residue was eluted through a short silica gel column with ethyl acetate/hexane (10% to 50% ethyl acetate gradient) and evaporation of the eluting solvent gave the bismesylate, 1-(2-(methylsulfonyloxy)-ethoxy)-2-((methylsulfonyloxy)ethyl)-3-(tert-butyldiphenylsilyloxy)-propane (7.40 g, 97%). Rf =0.55 (50% ethyl acetate in hexane). NMR. ##STR24##
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[N:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=O)[CH3:8].Cl.[NH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1>C(O)C>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([C:7](=[N:18][O:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH:28]3[S:32][C:31](=[O:33])[NH:30][C:29]3=[O:34])=[CH:35][CH:36]=2)[CH3:8])=[CH:11][N:12]=1
Reactant: CC(=O)c1ccc(O)nc1
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(O)nc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
124 μl of pyridine were added at room temperature to a suspension of 100 mg of 3-acetyl-6-hydroxypyridine and 232 mg of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in step (e) above] in 10 ml of ethanol, and the resulting mixture was stirred and heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled to room temperature and the precipitate was collected by filtration to give 183 mg of the title compound as a crystalline powder, melting at 240-242° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C[Si](C)(C)[N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][N:21]=1>C1CCCCC1.O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:13]2[CH2:14][CH2:15][NH:11][C:12]2=[O:16])=[CH:22][N:21]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: ClCc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=C1NCCC1Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere at a temperature of from −78° C. to −60° C., 180 ml of a 1.5 molar solution of lithium diisopropylamide (IDA) in cyclohexane are added dropwise to 31.4 g of N-trimethylsilylpyrrolid-2-one in 150 ml of tetrahydrofuran (THF) and the reaction mixture is stirred at the same temperature for a further one hour. Then, at from −78° C. to −60° C., 25.5 g of 2-chloro-5-chloromethylpyridine in 40 ml of THF are added, and the mixture is stirred for a further 16 hours at that temperature and then for a further three hours at room temperature. The reaction mixture is poured onto a mixture of ice/water and extracted with ethyl acetate, and the organic phase is separated off The ethyl acetate phase is dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is purified on silica gel using ethyl acetate/hexane (7:1) as eluant. The title compound having a melting point of 117-118° C. (compound 1.3) is obtained
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1)#[CH:2].[Br:13][C:14]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:17](I)=[CH:16][N:15]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:13][C:14]1[N:15]=[CH:16][C:17]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH2:8][C:9]([F:11])([F:12])[F:10])[CH:7]=3)[N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]=2[CH:19]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(CC(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(-c2cnn(CC(F)(F)F)c2)cc2cnc(Br)cc21
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Ethynyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole (Preparation 148, 326 mg 1.87 mmole) was dissolved in DMF (4.9 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide (Preparation 8, 565 mg 1.50 mmole) was added. To the solution was added triethylamine (0.91 mL, 655 mg 6.5 mmole) and copper(I) iodide (10 mg 0.052 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (37 mg 0.052 mmole) was added and the reaction was again flushed with nitrogen, then heated at 60° C. for 110 minutes. The reaction was cooled and added to water (50 ml). The reaction were extracted with ethyl acetate thrice (3×20 ml). The combined organic extracts were washed with water (3×20 mL) and brine, dried and concentrated in vacuo. The residue was purified using column chromatography eluting with 100% dichloromethane, 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane to afford the title compound (300 mg, 47%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.80 (q, J=8.20 Hz, 2H), 6.76 (d, J=0.95 Hz, 1H), 7.84 (d, J=0.63 Hz, 1H), 7.94 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.67 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3, 470.385 MHz): −71.56.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C#CC2C=C(C=O)SC=2)C=CC=CC=1.C(C1C=C(C=O)SC=1)CC1C=CC=CC=1>>[CH2:8]([C:9]1[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C#Cc2ccccc2)s1
Agent: O=Cc1cc(C#Cc2ccccc2)cs1
Agent: O=Cc1cc(CCc2ccccc2)cs1
Product: O=Cc1ccc(CCc2ccccc2)s1

Procedure:
5-Phenethylthiophene-2-carbaldehyde was synthesized from 5-(phenylethynyl)thiophene-2-carbaldehyde (4.0 g, 18.8 mmol) following the conditions used to hydrogenate 4-(phenylethynyl)thiophene-2-carbaldehyde to 4-phenethylthiophene-2-carbaldehyde (Example 1.1.b). 5-Phenethylthiophene-2-carbaldehyde (3.8 g, 93%) was used in the next step without further purification 1H NMR (400 MHz, CDCl3) δ (ppm): 9.83 (s, 1H), 7.60 (d, 1H), 7.30 (m, 2H), 7.23 (m, 1H), 7.19 (m, 2H), 6.86 (dt, 1H), 3.21 (t, 2H), 3.03 (t, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1C(=O)CCC1>C1COCC1>[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)nc2Br)cc(F)c1NS(C)(=O)=O
Yield: 55.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (41.2 mg, 0.148 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 42 mg), DMTMM (1.0 eq, 41 mg) and NMP (1.2 eq, 20 μl) in THF to give the title compound (42 mg, 55.8%) after purification by column chromatography (Hex/EtOAc=3/2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH3:28][O:27][C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 2.5.2 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (2.21 g, 5.51 mmol) and methanesulfonyl chloride (0.7 mL, 9.0 mmol) to give the title compound: Rf=0.47 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([CH3:15])=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CO.[CH3:18][N:19]1[CH:21](SC)[CH:20]1[N+:24]([O-:26])=[O:25].C(OCC)(=O)C.CO.[OH-].[NH4+]>COCCOC>[CH3:3][N:2]([CH2:4][C:5]1[S:6][C:7]([CH3:15])=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]([NH:19][CH3:18])=[CH:20][N+:24]([O-:26])=[O:25])[N:9]=1)[CH3:1]
Reactant: CSC1C([N+](=O)[O-])N1C
Reactant: Cc1sc(CN(C)C)nc1CSCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: COCCOC
Product: CNC(=C[N+](=O)[O-])NCCSCc1nc(CN(C)C)sc1C
Reaction time: 8 h

Procedure:
Following the procedure of Example 5, a stirred solution of 1.38 g. of 2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethylamine in 10 ml. of methanol was treated with N-methyl-1-methylthio-2-nitroethyleneamine. The reaction mixture was kept at room temperature overnight by which time all solids had dissolved. Thin layer chromatography (silica-10:10:1 ethyl acetate-methanol-ammonium hydroxide) indicated substantially a single product. The reaction mixture was concentrated by evaporation of the me±.hanol and the resulting gummy yellow residue was triturated with several portions of cold ether, thus providing an off-white gum. Repeated trituration with cold 1,2-dimethoxyethane yielded N-2-(2-dimethylaminomethyl-5-methyl-4-thiazolylmethylthio)ethyl-N'-methyl-2-nitro-1,1-ethenediamine formed in the above reaction melting at about 104°-106° C.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[C:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:34][CH:35]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-benzoyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.5 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.9 (t, 3H), 7.65 (t, 3H), 7.5 (t, 2H), 7.2 (d, 1H); ESI-MS m/z 475 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=[N:24]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:23]([C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:14])[NH2:24]
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C(=O)NN)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.00 g), 1H-1,2,3-benzotriazol-1-ol (0.48 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.68 g) at room temperature. The mixture was stirred at 50° C. for 30 min, and hydrazine monohydrate (0.74 g) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.88 g, yield 84%) as colorless crystals. melting point 273-274° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:5][C:6]=1[C:7](O)([CH3:9])[CH3:8].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([SH:31])[CH:26]=1.ClCCCl>C(OCC)(=O)C.[I-].[Zn+]>[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31][C:7]([CH3:9])([C:6]2[O:5][C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])[CH:26]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)(C)O
Reactant: COC(=O)Cc1cccc(S)c1
Agent: [I-]
Agent: [Zn+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(SC(C)(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-2-ol (0.1 g, 0.351 mmol), (3-Mercapto-phenyl)-acetic acid methyl ester (0.070 g, 0.386 mmol), zinc (I) iodide (0.056 g, 0.176 mmol), and 1,2-dichloroethane (2 mL) is stirred at room temperature 24 hr. The reaction mixture is diluted with ethyl acetate (25 mL), and washed with aqueous saturated sodium hydrogen carbonate, water, brine (25 mL each), dried over anhydrous magnesium sulfate, filtered, concentrated, and purified via silica chromatography eluting with 8:2 hexanes:ethyl acetate to afford the product as a colorless film, 0.105 g, 66%. MS M++1 286. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36]O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36][O:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(O)c1-c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.2 %

Procedure:
To a solution of 7-chloro-4-hydroxy-6-nitro-3-thiophen-2-yl-1H-quinolin-2-one (50 mg in 2.5 mL of tetrahydrofuran) at 0° C. was added 44 mg of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and 63 mg of triphenylphosphine followed by 0.04 mL of diethyl azodicarboxylate and the mixture warmed to room temperature. After 24 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 90:10; then 80:20; then 60:40) to give the title compound (44 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14].[CH2:15](Br)[CH:16]=[CH2:17]>CN1C(=O)CCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:15]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14])[CH:16]=[CH2:17]
Reactant: CNc1ccc([N+](=O)[O-])cc1CCO
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1CCO
Temperature: 25 °C

Procedure:
To a solution of N-methyl-2-(2-hydroxyethyl)-4-nitrobenzenamine (4.90 g, 0.025 mol) in NMP (15 ml) is added allyl bromide (4.55 g, 0.037 mol) at room temperature. The mixture is heated to 85°-90° C. for 6 hours and cooled to room temperature. The mixture is diluted with 1 M sodium carbonate solution (250 ml) and extracted with ether twice (250 and 150 ml portions). The extracts are washed with water twice, dried over potassium carbonate and concentrated to a solid. The solid is purified by chromatography on silica gel with hexane-tetrahydrofuran solvent to give N-allyl-N-methyl-2-(2-hydroxyethyl)-4-nitrobenzenamine.