Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)/[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]>CC(O)=O.C1(C)C=CC=CC=1.[Cl-].[Na+].O.[Zn]>[C:1]([CH:3]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)C(C#N)Cc1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A suspension of (E)-tert-butyl 2-cyano-3-(3,4-dichlorophenyl)acrylate (1.05 g, 3.52 mmol) and zinc (3.45 g, 52.8 mmol) in AcOH (20 ml) was allowed to stir at 100° C. After stirred for 1 hour, the reaction mixture was cooled to ambient temperature, and diluted with toluene and brine. The phases were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 2-cyano-3-(3,4-dichlorophenyl)propanoate (819 mg); Retention time=1.41 minutes (condition B); MS (ES+)=317.0 (m+18).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=[O:21])CCCCCCCCCCC>O=C1CC(C)(C)CC(C)=C1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:20]1(=[O:21])[O:22][C:23](=[O:25])[CH:24]=[CH:19]1
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Agent: CN(C)CCO
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: O=C1C=CC(=O)O1
Temperature: 70 °C

Procedure:
A reaction vessel containing 53.5 parts of Polyepoxide A (80 percent solids in isophorone) was heated to 70°C. There were added 3 parts of an amine produced by reacting dimethylethanolamine with dodecylsuccinic anhydride, and then there were added 6 parts of a second amine produced from dimethylethanolamine and maleic anhydride. During the second addition the temperature was raised to 95°C. and stirring was continued for 15 minutes at this temperature. The product when diluted with water and electrodeposited, as in the above examples, provided an adherent solvent-resistant coating.
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15])[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH2:29])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17].C(=O)(O)[O-].[Na+]>CCOCC.O>[C:16]([O:19][CH2:20][C:21]1[CH2:28][S:27][CH:26]2[N:23]([C:24](=[O:30])[CH:25]2[NH:29][C:6](=[O:7])[CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=[O:15])[C:22]=1[C:31]([OH:33])=[O:32])(=[O:18])[CH3:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=Cc1cccn1C(C(=O)Cl)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(n3cccc3C=O)S(=O)(=O)O)C2SC1

Procedure:
A solution of 2-sulfo-2-(2-formyl-1-pyrryl)acetyl chloride (0.01 m) in ether is added to 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.01 m) and sodium bicarbonate (0.03 m) in water. After 30 minutes the phases are separated, the pH adjusted to about 6.5 and the aqueous extracted with ethyl acetate. The ethyl acetate is separated from the aqueous phase, dried over magnesium sulfate and flash evaporated to give the title compound.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:18]=[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=O.[CH2:44]([NH2:47])[CH2:45][CH3:46].CO>ClCCCl>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:36])=[O:37])=[CH:18][C:17]=1[CH2:15][NH:47][CH2:44][CH2:45][CH3:46])([O-:25])=[O:24]
Reactant: CCCN
Reactant: O=Cc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
NaBH(OAc)3 (0.0031 mol) was added to a mixture of N-[2-(3′-formyl-4′-nitro-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.0021 mol) and propylamine (0.0023 mol) in DCE (2 mL), and the reaction mixture was stirred overnight under N2. The excess of NaBH(OAc)3 was decomposed with CH3OH, and the solvent was evaporated. The residue was purified by Biotage column chromatography (eluent: 95:5 CH2Cl2:CH3OH). The purest product fractions were collected and then the solvent was evaporated and co-evaporated with toluene to yield the title compound as a residue.
Reaction SMILES: [CH3:1][C:2]1(CO)[C:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1.[S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)([O:3][CH3:2])(=[O:25])=[O:24]
Reactant: CC1(CO)OCCC2=C1Cc1ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC1OCCC2=C1Cc1ccccc12
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
1-Methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-methanol (9.0 g), described in Example 462, is dissolved in dry pyridine (20 ml.). p-Toluenesulfonyl chloride (7.4 g) is added portionwise to the vigorously stirred and cooled solution. The mixture is stirred further at 0° C for 1 hr., ice and water is then added and the aqueous mixture is extracted with ether. The combined ether extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate water and dried (Na2SO4). Concentration of the extracts affords 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-methyl tosylate.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[CH2:11][CH:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:9]([C:17]([O:19][CH3:20])=[O:18])[CH2:8]1)=O>C(O)(=O)C.[Zn]>[NH3:7].[C:17]([CH:9]1[CH:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:11][NH:7][CH2:8]1)([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1CN(C(=O)OCC(Cl)(Cl)Cl)CC1c1ccsc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC1c1ccsc1
Product: N
Temperature: 40 °C
Reaction time: 4 h
Yield: 199.1 %

Procedure:
To a solution of 1.1 g (2.9 mmol) of 1-(2,2,2,-trichloroethoxycarbonyl)-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine in 30 mL of acetic acid at 40° C. was slowly added 0.5 g (7.6 mmol) of Zn powder and the reaction mixture was stirred a further 4 h at 40° C. The reaction mixture was filtered to remove the solid and the filter was washed with MeOH. The organic fraction was concentrated and the residue was purified by chomatography. (silica, CH2Cl9: MeOH: NH3 (2M in MeOH),100:4:2) to give 0.61 g of the title compound. 1H NMR (CDCl3) δ2.92 (m, 1H). 3.02 (m, 1H), 3.29 (m, 2H), 3.48-3.62 (m, 2H), 3.72 (s, 3H), 6.99 (d, 1H, J=5 HZ), 7.05 (s, 1H), 7.31 (m, 1H);
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:16]([Mg]Cl)[CH3:17].[CH2:20]1COC[CH2:21]1>>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]([OH:13])([CH2:16][CH3:17])[CH2:20][CH3:21])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CC[Mg]Cl
Reactant: C1CCOC1
Product: CCC(O)(CC)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (0.754 g, 3.52 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (20 mL) cooled to −78° C. under argon was added a ethylmagnesium chloride (9 mL, 18 mmol, 2 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ether/hexanes) to afford the product.
Reaction SMILES: BrCC(C1N=C(NC(=O)C2C(F)=CC=CC=2F)SC=1C1C=CC=C(C(F)(F)F)C=1)=[O:4].[C:31]([O:36][CH2:37][CH3:38])(=S)[C:32]([NH2:34])=O.[F:39][C:40]1[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:41]=1[C:42]([NH:44][C:45]1[S:46][C:47]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)=[C:48]([C:50]2N=C(C)[S:53][CH:54]=2)[N:49]=1)=[O:43]>>[F:39][C:40]1[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:41]=1[C:42]([NH:44][C:45]1[S:46][C:47]([C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)=[C:48]([C:50]2[N:34]=[C:32]([C:31]([O:36][CH2:37][CH3:38])=[O:4])[S:53][CH:54]=2)[N:49]=1)=[O:43]
Reactant: O=C(CBr)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=S)C(N)=O
Reactant: Cc1nc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cs1
Product: CCOC(=O)c1nc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cs1

Procedure:
Compound 88 was prepared from Compound 85 and ethyl thiooxamate similarly as described for the preparation of Compound 86.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].CN1CCOCC1.[C:22]([N:30]1[C@@H:34]([CH3:35])[C:33](=O)[O:32]C1=O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N[C@H](C(O)=O)C)(=O)C1C=CC=CC=1.Cl>O1CCCC1>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:33](=[O:32])[C@H:34]([CH3:35])[NH:30][C:22](=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65 %

Procedure:
L-Phenylalanine methyl ester hydrochloride (518 mg, 2.4 mmol) was suspended in tetrahydrofuran (12 mL), and at 0° C., N-methylmorpholine (242 mg, 2.4 mmol) was added, followed by stirring for 20 minutes. (S)-3-Benzoyl-4-methyl-2,5-oxazolidinedione (N-benzoyl-L-alanine-NCA (438 mg, 2 mmol) was added as crystals at 0° C. After the resulting mixture was stirred for 15 minutes, the mixture was allowed to rise in temperature to room temperature, at which the mixture was stirred for 15 minutes. The reaction mixture was poured into 1 N hydrochloric acid (25 mL), followed by extraction with ethyl acetate (25 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (25 mL) and a saturated aqueous solution of sodium chloride (25 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting white solid was washed with hexane-ethyl acetate to afford the title compound (462 mg, 65%) as white crystals.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].Cl.[Cl:27][CH2:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>COCCOC>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([CH2:20][CH2:21][S:22]([NH:31][CH2:30][CH2:29][CH2:28][Cl:27])(=[O:24])=[O:23])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCCl
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl
Yield: 97.5 %

Procedure:
CF3(CF2)5(CH2)2SO2Cl (10 g), 3-chloropropyl amine hydrochloride (4.1 g), and 1,2-dimethoxyethane (20 g) solvent were added to the round bottom flask equipped with mechanical stirring under nitrogen. Solution of triethylamine (4.5 g) in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 min at 20-30° C. at 250 rpm. Stirred for 12 h after the addition is completed. The reaction was monitored by GC to ensure the complete conversion 1. The final reaction mixture with pH of about 5 was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane (7 g) and combined filtrate was evaporated in vacuum to obtain 11.0 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl. The product was additionally dissolved in hot toluene (8 g) and washed with 15.5 mL of 1 wt % HCl aqueous solution to remove traces of NH2(CH2)3Cl.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[CH2:15]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(Cc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (2 mL) and acetic acid (2 drops) was added to (S)-tert-butyl piperidin-3-ylcarbamate (100 mg, 0.5 mmol) and benzaldehyde (1 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (422 mg, 2 mmol) was added in one portion. The reaction was stirred overnight. Saturated sodium bicarbarbonate (5 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×10 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([F:36])[CH:27]=2)[C:19](=[O:37])[C:18]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=2)=[CH:41][CH:40]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[C:28]([F:36])[CH:27]=2)[C:19](=[O:37])[C:18]=1[CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]2[NH:3][C:4](=[O:7])[O:5][N:52]=2)=[CH:43][CH:44]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)c(F)c2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC(C)C)c(F)c2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({7-butyl-4-[3-fluoro-4-(1-methylethoxy)phenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.37 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].[Cl-].[Cl-].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:13][N:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nnn1-c1ccc(Br)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of 1-bromo-4-isocyanatobenzene (5.00 g, 25.4 mmol) in THF (30 mL) was added sodium azide (5.00 g, 76.9 mmol) followed by the addition of a solution of aluminum trichloride (4.00 g, 30.3 mmol) in THF (18 mL) slowly. The reaction mixture was heated to reflux overnight. After cooling to rt, the reaction was quenched with H2O (50 mL). The organic solvent was removed under reduced pressure. The solids were collected by filtration to obtain compound 14a as a white solid (4.50 g, 71% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C2H5BrN4O: 241.0 (M+H). Found 241.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:20]1.C(=O)(O)[O-].[Na+].CN(C)C=O>O1CCCC1>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:30][CH2:29]2)=[CH:20]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.3 g), 4-(3-indolyl)piperidine (4.5 g) and sodium bicarbonate (1.9 g) in a mixture cf dimethylformamide (100 cc) and tetrahydrofuran (100 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling methyl ethyl ketone (60 cc), 2-{3-[4-(3-indolyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 162° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:31])C(=O)C1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:31])=[CH:9][N:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2ccc3c(Cl)ncnc32)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
A mixture of (R)-tert-butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1.7 g, 5.05 mmol) and NIS (1.25 g, 5.55 mmol) in DMF (20 mL) was stirred for 12 h at room temperature. Water was added to the mixture, which was extracted with EA, the combined organic layers were dried and purified by column to give (R)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (2.0 g, 86% in yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 6-chloro-2-(bromoacetamido)benzoic acid from Example 42 (7 g, 0.024 mol), aniline (5.6 g, 6 mL, 250 mol %) and DMF (40 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled to rt, poured onto ice and the resulting crystalline product was solubilized by adding 5% KOH (70 mL, pH=9). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL), and the aqueous layer was acidified to pH=3 with 5% HBr and extracted with EtOAc (4×100 mL). Combined EtOAc washings were dried and concentrated. Recrystallization of the resulting solid from EtOAc/Hex, afforded 6 g (82%) of the title compound as white crystals, 176°-178.2° C.; 1H NMR (DMSO-d6) δ 9.93 (s, 1H , COOH), 7.97 (d, 1H, J=8), 7.42 (t, 1H, J=8), 7.30 (d, 1H, J=7.6), 7.12 (t, 2H, J=7.2), 6.65 (t, 3H, J=7.2), 3.82 (s, 2H); 13C NMR (DMSO-d6) 170.19, 166.30, 148.15, 136.56, 131.12, 130.53, 128.98, 125.51, 121.39, 117.23, 112.71, 48.13; MS (EI, m/z) 304 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:32])[CH2:20][C:21]([N:23]3[C@H:27]([CH:28]([CH3:30])[CH3:29])[CH2:26][O:25][C:24]3=[O:31])=[O:22])=[C:8]2[CH3:33])=[CH:4][CH:3]=1.[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI>C1COCC1>[Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C@H:19]([CH3:32])[C@@H:20]([CH3:36])[C:21]([N:23]3[C@H:27]([CH:28]([CH3:29])[CH3:30])[CH2:26][O:25][C:24]3=[O:31])=[O:22])=[C:8]2[CH3:33])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(C[C@H](C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Temperature: -40 °C

Procedure:
To the imide of Example 7, Step 7, isomer A (200 mg, 0.369 mmol) dissolved in THF (2.0 mL) at -78° C. was added a solution of KHMDS (0.5 mL) in toluene (1.10 mL, 0,660 mmol). The temperature was then increased slowly to -40° C. To the mixture recooled at -78° C. was added MeI (100 mL). The temperature was allowed to wam slowly to -40° and the reaction was quenched by the addition of 25% aqueous solution of NH4OAc. The mixture was extracted with EtOAc, dried over Na2SO4, evaporated in vacuo and purified by flash chromatography (20% EtOAc in hexane) to afford the title product (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15](Cl)=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[NH2:21].N1C=CC=C[CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:18][C:19]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=1[N:21]([CH3:28])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(F)ccc1OC2
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)c1cc2c(s1)-c1cc(F)ccc1OC2)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 31 %

Procedure:
To a reaction vial charged with 8-fluoro-4H-thieno[3,2-c]chromene-2-carbonyl chloride (0.120 g, 0.447 mmol) and 2,4-difluoroaniline (0.0959 g, 0.670 mmol) was added a catalytic amount of DMAP. Pyridine in methylene chloride (1.2 M, 1.49 mL) was added. The reaction was stirred at room temperature with LC/MS monitor. The reaction was complete in a couple hours. After aqueous work up, the reaction was concentrated in vacuo, taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 163bp. Yield=31% of theoretical. MS: (ESI+)=376.4