Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl.[C:6]([Cl:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]>O.C(Cl)(Cl)Cl>[ClH:11].[C:6]([NH:3][CH2:2][CH2:1][NH2:4])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: NCCN
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NCCN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of ethylenediamine (15 mmol, 10.1 cm3) in water (150 cm3) at 0° C. was adjusted to pH 8.5 with 3N HCl. To this, was added a solution of methacryloyl chloride (16.5 mmol, 16.1 cm3) in chloroform (100 cm3), dropwise, over 2 h. After the addition was complete, the reaction mixture was stirred at 0° C. for a further 2 h. The organic and aqueous layers were then separated, and the aqueous layer extracted with chloroform (3×50 cm3). The aqueous layer was then collected and conc. in vacuo (freeze-dryer) to give a white solid. The residue was subjected to repeated fractional recrystallization from room temperature methanol, and the filtrate concentrated to give N-methacryloyl-ethylenediamine monohydrochloride as a clear, yellow oil (14.32 g, 58%). N-methacryloyl-ethylenediamine monohydrochloride (16 mmol, 20.0 g) was stirred in 2M NaOH (60 cm3) for 10 min. This solution was subsequently diluted to a volume of 160 cm3 with water, and stirred at 0° C. To this mixture was added a solution of acryloyl chloride (17.6 mmol, 14.3 cm3) in chloroform (300 cm3), dropwise, over 3 h. After the addition was complete, the reaction mixture was then stirred at 0° C. for a further 2 h. The organic and aqueous layers were separated, and the aqueous portion extracted with chloroform (3×100 cm3). The organic extracts were combined and concentrated to give the crude product as a white solid. Recrystallization from acetonitrile then gave N-acryloyl, N′-methacryloyl-ethylenediamine as colorless needles (10.70 g, 37%), m.p. 140-142/C. δH (400 MHz; CDCl3) 6.84 (1H, br s), NH; 6.74 (1H, br m), NH; 6.27 (1H, dd, J 16.9, 1.5 Hz), HC═CHaHb; 6.13 (1H, dd, J 17.0, 10.2), HC═CHaHb; 5.74 (1H, s), (H3C)C═CHcHd; 5.65 (1H, dd, J 10.3, 1.6 Hz), HC═CHaHb; 5.34 (1H, br m), (H3C)C═CHcHd; 3.49 (4H, m), 2×CH2; 1.95 (3H, s), CH3. δC (75.4 MHZ; CDCl3) 169.4, NHOC(H3C)C═CH2; 167.0, NHOCHC═CH2; 139.2, (H3C)C═CH2; 130.7, HC═CH2; 126.2, HC═CH2; 120.1, (H3C)C═CH2; 40.4, CH2CH2; 39.5, CH2CH2; 18.4, CH3. Found: M+. 182.1059.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[C@@:10]2([CH3:16])[C:13]([CH3:15])([CH3:14])[C@@H:7]1[CH2:8][CH2:9]2)=[O:5])C.[F:17][C:18]([F:23])([F:22])[CH2:19][NH:20][NH2:21].Cl.O1CCOCC1>O>[CH3:16][C@@:10]12[C:13]([CH3:14])([CH3:15])[C@@H:7]([C:6]3[C:4](=[O:5])[N:20]([CH2:19][C:18]([F:23])([F:22])[F:17])[NH:21][C:11]=31)[CH2:8][CH2:9]2
Reactant: CCOC(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(CC(F)(F)F)c(=O)c12
Temperature: 100 °C
Yield: 17 %

Procedure:
A mixture of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (Intermediate 4; 5.00 g, 22.3 mmol) and 2,2,2-trifluoroethylhydrazine (70% in water; Aldrich; 25.00 g, 153 mmol) was heated in a sealed tube at 100° C. for 19 h. The reaction mixture was allowed to cool, and HCl in dioxane (4 M; 40 mL, 160 mmol) was added cautiously. The reaction mixture was heated again at 100° C. for 45 min, cooled to room temperature, and added to water (200 mL). The mixture was extracted with dichloromethane (3×150 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, evaporated, purified by flash chromatography (20-50% ethyl acetate) to give (4S,7R)-7,8,8-trimethyl-2-(2,2,2-trifluoro-ethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.04 g, 17%) as a light orange solid.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20]Br.O>C1COCC1>[Br:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH2:20][CH2:2][C:1]#[N:3]
Reactant: COc1cc(Br)c(CBr)cc1OC
Reactant: CC#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Br)c(CCC#N)cc1OC
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 mL of acetonitrile (5.8 mmoles, 1.8 eq.) in 15 mL of THF there are added, at −60° C., 1.77 mL of n-butyllithium (2M in cyclohexane, 3.5 mmoles, 1.1 eq.). The solution is stirred for 15 minutes at −60° C. and then 1 g of 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene (3.2 mmoles) dissolved in 5 mL of THF is added. The reaction mixture is stirred for 1 hour and then hydrolysed using 10 mL of water and extracted twice with ethyl acetate. The organic phases are combined and evaporated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (eluant: methylcyclohexane/ethyl acetate (70/30)). After evaporating off the solvent under reduced pressure, 505 mg of an orange oil which crystallises in the form of a beige solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][NH:10][C:3]=12.[Cl:11][CH2:12][CH2:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)O>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][N:10]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][Cl:11])[C:3]=12
Reactant: Clc1ccnc2cc[nH]c12
Reactant: O[C@H](CCCl)c1ccccc1
Product: ClCC[C@@H](c1ccccc1)n1ccc2nccc(Cl)c21

Procedure:
7-Chloro-1-(3-chloro-1-(S)-phenyl-propyl)-1H-pyrrolo[3,2-b]pyridine was prepared from 7-chloro-1H-pyrrolo[3,2-b]pyridine and 3-chloro-1-(R)-phenyl-propan-1-ol following the procedure of steps 1 and 2 of Example 11 (20% yield, 40 mg).
Reaction SMILES: ClCCl.[OH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:27])[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(OCC)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:27])[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C(NC1CCCCC1O)c1ncccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1CCCCC1=O)c1ncccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To 20 ml dichloromethane solution of 3.4 g 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxole-3(1H)-one, was added 20 ml dichloromethane solution of 1.3 g N-(2-hydroxycyclohexyl)-3-benzyloxypicolinic amide at room temperature. After stirring the solution for 2 hours, the solution reacted was poured into 80 ml diehtyl ether, and 2N-aqueous solution of sodium hydroxide and ice were added to the resulting solution. The organic layer obtained was washed with aqueous solution of sodium hydrogencarbonate, water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, affording oily substance, N-(2-oxocyclohexyl)-3-benzyloxypicolinic amide in an amount of 1.18 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH2:4].Cl.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Cl)[CH:7]=1>>[CH3:3][NH:4][CH2:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1
Reactant: CN
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To 25 ml of a 20% aqueous solution of NaOH stirred under cooling with ice-water, a 40% aqueous solution of methylamine (13.6 g, 0.175 mole) was added dropwise over 5 minutes, followed by further dropwise addition of an aqueous solution (10 ml) of 8.2 g (0.05 mole) of 3-pyridylmethyl chloride hydrochloride over 10 minutes. The mixture was further stirred at room temperature for 2 hours and, then, extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove the solvent. The residue was subjected to vacuum distillation to give 2.6 g of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]([Br:11])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:11][C:10]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cc2c(cc1Br)OCO2
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: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Yield: 71.1 %

Procedure:
Under nitrogen, 1.1 g of Pd(PPh3)4 was added to a stirred solution of 10.4 g (37.2 mmol) of 5,6-dibromo-1,3-benzodioxole and 2.6 g (18.6 mmol) of 4-fluorophenylboronic acid in 100 mL of toluene, 60 mL of ethanol, and 40 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried over Na2SO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane as the eluent gave 3.9 g (71%) of 5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole as a colorless solid: mp 86.0-87.5° C.; NMR (CDCl3) δ 6.02 (s, 2H), 6.77 (s, 1H), 7.04-7.13 (m, 3H), 7.28-7.35 (m, 2H)
Reaction SMILES: C(OC(NCC1C=C(NC(=O)COC2C=CC([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=CC=2)C=CC=1)=O)C1C=CC=CC=1.[CH2:60]([O:67][C:68]([NH:70][CH2:71][C:72]1[CH:73]=[C:74]([NH:83][C:84](=[O:98])[CH2:85][O:86][C:87]2[C:92]([CH3:93])=[CH:91][C:90](B(O)O)=[CH:89][C:88]=2[CH3:97])[CH:75]=[CH:76][C:77]=1[S:78]([CH2:81][CH3:82])(=[O:80])=[O:79])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>>[CH2:60]([O:67][C:68]([NH:70][CH2:71][C:72]1[CH:73]=[C:74]([NH:83][C:84](=[O:98])[CH2:85][O:86][C:87]2[C:92]([CH3:93])=[CH:91][C:90]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[N:39][CH:38]=[CH:37]4)[C:30]([OH:32])=[O:31])=[CH:89][C:88]=2[CH3:97])[CH:75]=[CH:76][C:77]=1[S:78]([CH2:81][CH3:82])(=[O:80])=[O:79])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Reactant: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(B(O)O)cc2C)cc1CNC(=O)OCc1ccccc1
Product: CCS(=O)(=O)c1ccc(NC(=O)COc2c(C)cc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1CNC(=O)OCc1ccccc1
Yield: 82 %

Procedure:
According to the procedure for the preparation of 66D, 79C (150 mg, 0.271 mmol) afforded 205 mg (82%) of 79D as an orange solid. MS (ESI) m/z 926.5 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)=[O:2].[Cl-].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][NH3+:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6](=[N:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH:4]=1)=[O:2]
Reactant: O=Cc1cccc(-c2ccccn2)n1
Reactant: [NH3+]OCCCCc1ccccc1
Agent: [Cl-]
Product: O=CC1=CCC(=NOCCCCc2ccccc2)C(c2ccccn2)=N1

Procedure:
If 6-formyl-2,2'-bipyridine is used instead of 4-formyl-2-(2-pyridyl)-pyrimidine and O-phenylbutylhydroxylammonium chloride instead of hydroxylammonium chloride, 6-formyl-O-4-phenylbutyloximino-2,2'-bipyridine (compound 105c) is obtained in a corresponding manner.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:13]3[CH2:14][CH2:15][CH2:16][O:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CNOC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: C1CON(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-one (358.5 mg, 2.3 mmol), and isoxazolidine (168 mg, 2.3 mmol), and sodium triacetoxyborohydride (1.46 g, 6.9 mmol) were taken in acetonitrile and stirred for 18 h at room temperature. The mixture concentrated under vacuum and the residue basified with NaHCO3, saturated with solid NaCl and extracted with EtOAc/iPrOH (4:1) four times. Organic layer separated, dried over Na2SO4 and evaporated. Residue purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:30]CC.O>O1CCCC1>[CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:10][CH2:11][CH2:12][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 mmoles), sodium borohydride (0.47 g., 12.5 mmoles), and tetrahydrofuran (25 ml.) is added dropwise a solution of boron fluoride etherate (2.1 ml., 16.7 mmoles) in tetrahydrofuran (5 ml.) at ice-bath temperatures under a nitrogen atmosphere. The resulting mixture is further stirred at room temperature overnight (ca. 15 hours). The reaction flask is chilled in an ice bath and water (2 ml.) is very cautiously added to destroy the excess hydride, followed by the additions of sodium hydroxide (5N, 4ml.) and hydrogen peroxide (30%, 8 ml.). The final mixture is stirred at room temperature for one half hour, diluted with cold water and then extracted with chloroform three times. The combined extracts are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo leaving the title compound as a viscous oil (3.00 g., 10 mmoles, 100%). ir (neat) 2.97, 3.30, 3.41, 6.22, 6.68, 6.90, 8.03, 8.30, 9.16, 9.44, 12.10, 13.20, 13.60, 14.40μ; pmr (CCl4)δ1.4-1.9 (4H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:16]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[N+:17]=[N-:18]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 20 h
Yield: 100.9 %

Procedure:
A mixture of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (2.80 g, 11.9 mmol) and sodium azide (3.86 g, 59.3 mmol) in 50 mL of dry DMF was stirred for 20 h at 100° C. under nitrogen. The final mixture was cooled to room temperature dilute with brine and extracted with three portions of ether. The organic portions were combined, dried over Na2SO4 and concentrated to give 8-azido-1,4-dioxa-spiro[4.5]decane (2.2 g, 100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]([N:10]1[C:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=2[CH2:12][S:11]1(=[O:21])=[O:20])=[O:9])[CH3:6]>>[N+:1]([C:17]1[C:16]([F:19])=[CH:15][C:14]2[N:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[S:11](=[O:21])(=[O:20])[CH2:12][C:13]=2[CH:18]=1)([O-:4])=[O:2]
Reactant: CCOC(=O)N1c2cc(F)ccc2CS1(=O)=O
Reactant: O=[N+]([O-])O
Product: CCOC(=O)N1c2cc(F)c([N+](=O)[O-])cc2CS1(=O)=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To stirred nitric acid (99%; 25 ml) was added 1-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (2.78 g) in portions at 0° C. The mixture was stirred for 2 hours while allowing it to warm to 10° C. The reaction mixture was poured into ice-water mixture then, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution. The extract was dried over magnesium sulfate and concentrated in vacuo. The resulting crude product was washed with methanol, to give 5-nitro-l-ethoxycarbonyl-1,3-dihydro-6-fluoro-2,1-benzisothiazole 2,2-dioxide (3.11 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromochlorobenzene (1.76 mL, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.06 g (91%) of the product 4-(3-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.CCN(C(C)C)C(C)C>C(#N)C>[Br:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(N2CCN(Cc3ccccc3Br)CC2)cc1

Procedure:
A mixture of EXAMPLE 1A (23.43 g), 2-bromobenzyl bromide (26.24 g), and DIEA (20.94 mL) in acetonitrile (200 mL) at 25° C. was stirred for 2 hours and filtered.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Br:12]Br>C(OCC)C>[Br:12][CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: BrBr
Solvent: CCOCC
Product: CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
4-Chloropropiophenone (33.6 g.) was dissolved in anhydrous diethyl ether (50 ml.), stirred and cooled in an ice bath while bromine (32 g.) was added dropwise over 30 minutes. The solid which formed was filtered off, washed with water and air-dried to give 2-bromo-4'-chloropropiophenone, m.p. 77°-79°.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[CH2:17](I)[CH3:18]>>[CH2:17]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]1=2)[CH3:18]
Reactant: CCI
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Product: CCn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (931 mg) was treated with sodium hydride (60% dispersion in oil; 400 mg) and was then stirred with ethyl iodide (10% v/v solution in DMF; 4 ml) to give the title compound (758 mg), m.p. 203°-204.5°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li][CH2:10]CCC.CI>O1CCCC1>[CH3:10][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccsc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1sccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.32 g (41.5 mmol) of 3-thiophenecarboxylic acid in 100 ml of anhydrous tetrahydrofuran (chilled to -78° C.) was added 57.1 ml (91.4 mmol) of 1.6M n-BuLi in hexanes. The cloudy suspension was stirred at -78° C. under a blanket of argon for 40 minutes, and was then transfered via canulla onto a solution of 59.05 g (25.9 ml, 416 mmol) of methyl iodide dissolved in 20 ml of anhydrous tetrahydrofuran (chilled to -78° C.). The resulting clear, colorless solution was allowed to warm to room temperature and stirred for 20 hours. A white solid was formed. The reaction mixture was concentrated in vacuo, partitioned between 75 ml of sat. NH4Cl solution and 150 ml of ethyl ether, and the layers separated. The aqueous phase was washed with 100 ml of ethyl ether and layered with 100 ml of ethyl ether and acidified with 1N sulfuric acid solution until all of the yellow emulsion dissapated. All organic phases were combined, washed with brine solution, dried over MgSO4, filtered and concentrated in vacuo to yield an off-white solid. Purification by flash chromatography (silica gel, 75% ethyl acetate in hexane) yielded the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH3:56][C@H:57]1[CH2:62][CH2:61][CH2:60][C@@H:59]([CH3:63])[NH:58]1>CN(C)C=O>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:4]1[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:58]3[C@H:59]([CH3:63])[CH2:60][CH2:61][CH2:62][C@@H:57]3[CH3:56])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:26]
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(C(=O)O)CC1)c1cccc(Cl)c1
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CCC[C@H](C)N1C(=O)C1CCN(c2ncc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.7 %

Procedure:
To a solution of 0.040 g (0.11 mmol) of 5′-chloro-3′-(3-chloro-benzoylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid in N,N-dimethylformamide (2 mL) is added 0.048 g (0.15 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate followed by 0.042 mL (0.304 mmol) of triethylamine. The mixture is stirred at room temperature for 1 h then 0.034 g (0.304 mmol) of cis-2,6-dimethylpiperidine is added and the mixture is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.002 g (4%) of the title compound (273) as a white solid. [M+H]+=489.2.