Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>CCOCC.C(O)C.CN(C)C=O>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])[CH2:9][C@H:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1
Reactant: CC(C)=CCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)=CCN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Temperature: 79 °C

Procedure:
A mixture of 4.34 g trans-4-(4-fluorophenoxy)-3-phenylpiperidine, 4.8 g of anhydrous potassium carbonate, 2.62 g of 1-bromo-3-methyl-2-butene and 64 ml of dry dimethylformamide is heated and vigorously stirred overnight at 79° C. under nitrogen. The mixture is cooled to room temperature and partitioned between water (300 ml) and ether (500 ml). The phases are separated and the ether phase is washed with water (3×300 ml), followed by 300 ml of saturated sodium chloride solution. After drying over anhydrous sodium sulfate the ether extracts are filtered and concentrated in vacuo to a brown oil which crystallized upon standing. The crystalline solid is dissolved in 50 ml of boiling hexane and filtered to remove a dark brown gummy residue. Evaporation of the solvent in vacuo afforded an oil which crystallized under high vacuum to afford a dark orange solid. The solid is dissolved in ether (50 ml) and treated dropwise with a solution of 1.53 g of fumaric acid in a mixture of 100 ml of ether and 25 ml of absolute ethanol. The crude salt is filtered, washed with ether, dried and recrystallized from 325 ml of isopropanol to give product as colorless, fluffy platelets, mp 215°-217° C. dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][O:10]C2=O)[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:3]=1.[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH:8][C:6]2[CH:5]=[C:4]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:3]=[C:2]([NH:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[N:7]=2)[CH2:11][OH:10])=[CH:18][CH:17]=1
Reactant: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Nc3cnccn3)nc(NC(CO)c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
80 mg of 3-[6-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-4-(4-fluorophenyl)oxazolidin-2-one, 20 mg of 2-aminopyrazine, 20 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 22 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2.5 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 1 hour under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 34 mg of the objective compound as white powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.S1C=CN=C1C1C=CC(C=O)=CC=1>>[S:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][OH:11])=[CH:12][CH:13]=2)[N:3]=[CH:2]1
Reactant: O=Cc1ccc(-c2cscn2)cc1
Agent: O=Cc1ccc(-c2nccs2)cc1
Product: OCc1ccc(-c2cscn2)cc1
Yield: 7.4 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 4-(a) except for using 4-(thiazol-4-yl)benzaldehyde (1.28 g, 6:76 mmol) obtained in Reference Example 15-(a) in place of 4-(thiazol-2-yl)benzaldehyde to afford the title compound (1.07 g) as a white solid. (Yield: 83%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10]Cl.[C-:12]#[N:13].[K+].COC(C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: [C-]#N
Reactant: Cc1cc(CCl)c(Cl)cc1Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: Cc1cc(CC#N)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a solution of 1,5-dichloro-2-chloromethyl-4-methylbenzene (CAS #101349-87-5, 5.22 g) in dimethyl sulfoxide (20 ml) was added potassium cyanide (1.36 g) and the reaction solution was stirred at room temperature for 6 hours. Potassium cyanide (0.68 g) was added to the reaction solution and the solution was further stirred at room temperature overnight. To the reaction solution were added ice-cold water and tert-butyl methyl ether and the organic layer was separated. The water layer was re-extracted by the tert-butyl methyl ether. The combined organic layer was sequentially washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Walcogel™ C-200; elution solvent:heptane:ethyl acetate 49:1→19:1) to obtain the title compound (1.88 g). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 2.38 (s, 3H), 3.78 (s, 2H), 7.38 (s, 1H), 7.43 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:16])=O.[Na]>ClCCCl>[CH:14]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)Nc1ccc(OC(F)(F)F)cc1

Procedure:
A solution of 9.33 g of p-trifluoromethoxyaniline, 4.1 mL of acetone, and 14.53 g of sodium triacetoxyborohydryde in 50 mL of 1,2-dichloroethane were stirred overnight at RT. The reaction mixture is then poured onto ice-water and product extracted with 100 mL of dichloromethane. The organic layer is washed with water, sat NaHCO3, dried with Na2SO4 and solvent evaporated to afford 12 g of Isopropyl-(4-trifluoromethoxy-phenyl)-amine: 1H NMR (300 MHz, CDCl3) δ7.06 (d, 2H, J=8.5), 6.56 (d, 2H, J=8.5), 3.63(m, 1H), 1.25 (d, 6H, J=6.8).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH:9]([C:11](OC)=[O:12])[CH2:8][CH:7]([C:15](OC)=[O:16])[CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>C1COCC1>[OH:16][CH2:15][CH:7]1[CH2:8][CH:9]([CH2:11][OH:12])[CH2:10][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:6]1
Reactant: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CC(CO)CC2(C1)OCCO2
Temperature: 0 °C
Yield: 135.4 %

Procedure:
o a solution of dimethyl 1,4-dioxaspiro[4.5]decane-7,9-dicarboxylate (6.0 g, 23 mmol) in dry THF at 0° C. was added lithium aluminum hydride (4.67 g, 68.7 mmol) under argon. The reaction was then refluxed overnight. The reaction was cooled to 0° C., and diethyl ether (100 ml) was added followed by drop-wise addition of 5 N NaOH until the gray lithium aluminum hydride was converted to a white solid. The reaction mixture was then filtered through a Celite pad, which was then washed with diethyl ether (100 ml). The combined filtrates were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give the alcohol as a viscous colorless liquid (6.3 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[I:11]>C(O)C>[Cl:1][C:2]1[C:3]([I:11])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1I
Solvent: CCO
Product: Nc1cccc(Cl)c1I
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-chloro-2-iodo-3-nitrobenzene (143-2; 1.4 g, 0.00490 mol) in ethanol (20 mL) was added stannous chloride dihydrate (5.5 g, 0.0245 mol) portion wise at 0° C. Reaction mixture was allowed to stir at 70° C. for 30 min. The reaction mixture was concentrated and diluted with ice cold water (150 mL) and PH was made slightly basic by addition of saturated aqueous sodium carbonate solution before being extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.048-7.008 (t, 8 Hz, 1H), 6.713-6.693 (dd, J=8, 8.8 Hz, 1H), 6.655-6.632 (dd, J=8.4, 9.2 Hz, 1H), 5.5 (bs, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:18][CH2:19][CH:20]=[CH2:21])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>CO.[Pd]>[CH2:19]([O:18][C:15]([CH3:16])([CH3:17])[CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:20][CH3:21]
Reactant: C=CCOC(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CCCOC(C)(C)CC1CCNCC1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
A mixture of 0.09 g (0.3 mmol) of 1-t-butoxycarbonyl-4-(2-allyloxy-2-methyl-1-propyl)piperidine and 0.0058 g of Pd/C (10%) in 2 mL of CH3OH was stirred under H2 (1 atm) for 24 h. The reaction mixture was filtered through a thin pad of Celite and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ether, 6:1) to give 0.06 g of the title compound.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[C:30]([O:31][CH:32]([CH3:34])[CH3:33])=[C:29]([O:35][CH3:36])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:31][CH:32]([CH3:34])[CH3:33])[C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1cc(C(=O)c2c([Si](C)(C)C(C)(C)C)oc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2coc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7-isopropoxy-benzofuran (0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title compound as a light yellow paste (23 mg) that was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H, C2H), 7.78 (d, 1H, J=8.60 Hz), 7.15 (s, 2H, benzoyl Hs), 7.04 (d, 1H, J=8.61 Hz), 4.73 (m, 1H), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 1.37 (d, 6H, J=6.14 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[CH3:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH:27]1([N:26]([CH3:25])[C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CNC1CCCC1
Solvent: CN1CCCC1=O
Product: CN(c1cnc2c(n1)c(C(=O)C(C)(C)C)cn2COCC[Si](C)(C)C)C1CCCC1
Temperature: 200 °C
Reaction time: 72 h
Yield: 56.6 %

Procedure:
A solution of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.051 g, 0.123 mmol) and methylcyclopentylamine (0.050 mL, 0.44 mmol) in 1 mL of N-methyl pyrrolidinone in a sealed tube was stirred at 200° C. for 20 h. Additional methylcyclopentylamine (0.100 mL, 0.88 mmol) was added, and the solution stirred at 200° C. for 3 d. After cooling, the dark orange solution was partitioned between 10 mL of ethyl acetate and 10 mL of a 10% citric acid solution. The organic layer was sequentially washed with three 10 mL portions of water and 10 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to an orange oil. Column chromatography (0-20% EtOAc/hexanes) afforded 0.030 g (58%) of impure 1-[2-(cyclopentyl-methyl-amino)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, which was used without further purification.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH2:37][CH2:38][CH3:39])=[N:30][C:29]([OH:40])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:40][C:29]1[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-((3-(chloromethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide hydrochloride SLA 41090 (128 mg, 0.372 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (103 mg, 0.417 mmol) followed by a 2 N aq. LiOH solution (0.21 mL, 0.42 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 19.4 mg of N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 55 as a yellow solid (20 mg, 9% yield).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=2[N+:25]([O-:27])=[O:26])=[CH:11][CH:10]=1>CC(O)=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([I:8])=[C:19]([F:24])[C:18]=2[N+:25]([O-:27])=[O:26])=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1NCc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(NCc2ccc(-c3ccccc3)cc2)cc(F)c(I)c1F
Temperature: 70 °C

Procedure:
NIS (7.9 g, 35.1 mmol) was added to a solution of N-(biphenyl-4-ylmethyl)-3,5-difluoro-2-nitroaniline (10.86 g, 31.9 mmol) in AcOH (150 mL). After heating at 70° C. for 2 h, the reaction mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was washed with brine, dried (Na2SO3) and concentrated. Recrystallization from DCM/hexanes afforded the desired product as a red solid.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=[C:2]2[C:7]=1[CH:8]=[N:23][NH:24]2
Reactant: O=Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccc(I)cc1F
Reactant: NN
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reaction time: 18 h
Yield: 98 %

Procedure:
To a stirred solution of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-3-nitro-benzaldehyde (864 mg, 2.14 mmol) in DME (15 ml) was slowly added hydrazine hydrate (10 mL) at room temperature and the reaction mixture stirred for 18 hours. The organic solvent was removed in vacuo and the mixture diluted with water (50 mL). The resulting solid was collected by filtration, washed with water and dried under vacuum to yield the title compound (839 mg, 98%). LCMS (Method B): RT=3.61 min, [M+H]+=399.
Reaction SMILES: [N:1]1[NH:2][C:3](=O)[CH:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6]2.O(Cl)[Cl:17].[P+3]>>[Cl:17][C:3]1[N:2]=[N:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1cc2c(nn1)-c1ccccc1CC2

Procedure:
5,6-Dihydrobenzo[h]cinnolin-3(2H)-one (4.5 g) was heated at 100° C. with phosphorus (III) Oxychloride (80 mL) for 6.5 h. The solvent was removed under vacuum and the residue was treated with ice water. The resulting solid was filtered off, washed well with water and air dried to give 3-chloro-5,6-dihydrobenzo[h]cinnoline; 1H NMR (DMSO-d6, 300 MHz) 8.32 (m, 1H), 7.36 (s, 1H), 7.32 (m, 2H), 7.19 (d, 1H), 2.91 (s, 4H) ppm; MS (ES) 217/219 (M+H).
Reaction SMILES: NN.[CH3:3][O:4][C:5]1[C:27]([O:28][CH3:29])=[CH:26][C:8]([C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10])=[C:7]([N+:30]([O-])=O)[CH:6]=1.O=[Al]O[Al]=O.C(Cl)(Cl)Cl.CO>CO.[Ni]>[NH2:30][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[C:27]([O:28][CH3:29])=[CH:26][C:8]=1[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[O:10]
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1OC
Agent: [Ni]
Agent: NN
Agent: O=[Al]O[Al]=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(C(=O)N2C[C@H](O)C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of hydrazine (6.59 g, 6.40 mL, 205.5 mmol) in MeOH (110 mL) was added dropwise to a solution of the nitro-compound 24 (18.1 g, 41.1 mmol), over anti-bumping granules and Raney Ni (2.6 g) in MeOH (325 mL) and heated at reflux. After 1 hour at reflux TLC (95% CHCl3/MeOH) revealed some amine formation. The reaction mixture was treated with further Raney Ni (2.6 g) and hydrazine (6.40 mL) in MeOH (50 mL) and was heated at reflux for an additional 30 minutes at which point TLC revealed reaction completion. The reaction mixture was then treated with sufficient Raney Ni to decompose any remaining hydrazine and heated at reflux for a further 1.5 h. Following cooling to room temperature the mixture was filtered through a sinter and the resulting filtrate evaporated in vacuo. The resulting residue was then treated with CH2Cl2 (300 mL), dried (MgSO4), filtered and evaporated in vacuo to provide the amine 25 as a green oil (16.03 g, 95%): [α]22D=−116.32° (c=0.31, CHCl3); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 6.70 (s, 1H), 6.28 (s, 1H), 4.51-4.49 (m, 1H), 4.36-4.34 (m, 1H), 4.06-3.77 (m, 10H), 3.61-3.50 (m, 3H), 2.23-2.21 (m, 1H), 2.01-1.98 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 170.2, 151.5, 141.2, 140.5, 112.2, 112.0, 101.1, 70.4, 62.6, 59.0, 56.9, 56.6, 55.8, 35.7, 25.9 and 25.7, 18.2, −5.4 and −5.5; MS (EI), m/z (relative intensity) 412 (M++2, 3), 411 (M++1, 10), 410 (M+, 32), 354 (6), 353 (23), 263 (3), 212 (5), 181 (11), 180 (100), 179 (3), 165 (3), 164 (6), 152 (10), 137 (4), 136 (4), 125 (5), 120 (3), 100 (3), 94 (6), 75 (9), 73 (7), 57 (3); IR (CHCl3) 3353 (br), 2953, 2930, 2857, 1623, 1594, 1558, 1517, 1464, 1435, 1404, 1260, 1234, 1215, 1175, 1119, 1060, 1005, 915, 836, 777, 755, 666 cm−1; exact mass calcd for C20H34N2O5Si m/e 410.2237, obsd m/e 410.2281.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.[OH-].[K+].[C:24]1([S:30]([CH2:33][CH2:34]Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:24]1([S:30]([CH2:33][CH2:34][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]2=3)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
tert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.111 g, 0.388 mmol) was dissolved in CH2Cl2 (10 mL) and this solution was added to a mixture of 50% aqueous KOH (5 mL) and tetrabutylammonium hydrogen sulfate (0.100 g). The biphasic mixture was stirred vigorously at rt. 2-Chloroethyl phenyl sulfone (0.318 g, 1.55 mmol) was added, then the reaction mixture was stirred for 4 h. The organic phase was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers was concentrated. The crude product was chromatographed (Biotage 40s SiO2 column, eluted with a 10% to 40% EtOAc in hexane gradient) to give tert-butyl 6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.154 g) in 87% as a clear solid. 1H NMR (300 MHz, CDCl3) δ 1.48, 2.87-2.93, 3.38-3.42, 3.63, 3.69, 4.52, 7.04-7.17, 7.42, 7.53-7.59, 7.63-7.70, 7.88.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:25][C:21]1[C:20]([C:26]([F:29])([F:28])[F:27])=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(Cl)c2C(F)(F)F)CC1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4cccc(Cl)c4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 38 %

Procedure:
A mixture of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (0.076 g, 0.156 mmol), zinc cyanide (0.037 g, 0.312 mmol), palladium tetrakis(triphenylphosphine) (0.018 g, 0.0156 mmol), and DMF (2 mL) was heated under microwave irradiation at 130° C. for 30 min. After cooling to ambient temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The extract was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give 3-(4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (0.026 g, 38%): 1H NMR (300 MHz, CDCl3) δ9.70 (s, 1H), 7.97 (dd, J=9.5, 1.0 Hz, 1H), 7.52-7.32 (m, 4H), 5.74-5.69 (m, 1H), 5.00-4.95 (m, 1H), 3.52-3.31 (m, 2H), 2.99 (m, 1H), 2.06-1.75 (m, 4H); MS (ESI+) m/z 434 [M+H]+.