Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]2[CH:11]=[N:10]1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]2[CH:11]=[N:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1ccc(-n2ncc3c(I)ccnc32)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1Cl
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing 1-(2-chloro-4-fluorophenyl)-4-iodo-1H-pyrazolo[3,4-b]pyridine (68.5 mg, 0.183 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (81.7 mg, 0.322 mmol), potassium acetate (85.1 mg, 0.867 mmol), and anhydrous DMSO (1 mL). The reaction mixture was purged with argon, then treated with PdCl2(dppf).CH2Cl2 (11.5 mg, 0.016 mmol). The reaction mixture was again purged with argon, securely capped, and heated to 85° C. for 1 h to give the desired intermediate. LC/MS (Condition B): ret. T=3.0 min, (M+H)+ 292.01.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>[Fe].CCO>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=1
Reactant: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1cc(N)cc(Cl)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a stirred solution of 3-chloro-1-methyl-5-nitropyridin-2(1H)-one (Step 5.1) (10.38 g, 55.0 mmol), EtOH (200 mL) and NH4Cl (79 mL, 550 mmol) was added iron (9.22 g, 165 mmol). The reaction mixture was stirred for 1 hr at 85° C., filtered through a pad of celite, and concentrated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 2-10%) to afford the title product (6.77 g, 42.7 mmol, 78% yield) as a black solid. tR: 0.29 min (LC-MS 1); ESI-MS: 159 [M+H]+ (LC-MS 1); Rf=0.28 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][O:22][C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([O:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][OH:28])=[CH:29][CH:30]=3)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1ccc(OCCOc2cnc(-c3ccccc3)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
(4-(2-[(5,6-Diphenyl-2-pyrazinyl)oxy]ethoxy)benzaldehyde (2.90 g) was dissolved in ethanol (30 mL), and sodium borohydride (615 mg) was added to the resultant solution under ice cooling. The mixture was stirred at room temperature for one hour. Subsequently, water was added to the reaction mixture, and the thus-formed organic matter was separated through extraction by use of methylene chloride, followed by washing sequentially by water and saturated saline. The washed product was dried over sodium sulfate anhydrate, and the residual solvent was removed through distillation under reduced pressure. The thus-yielded residue was crystallized from n-hexane, to thereby yield 2.69 g of the title compound as colorless crystals (yield 92.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@@H:20]4[O:32][CH3:33])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:20]=[C:19]([CH3:24])[N:18]=[CH:16][N:15]=5)[CH2:21][C@@H:20]4[O:32][CH3:33])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Agent: Cl
Solvent: ClCCl
Product: CO[C@H]1CN(c2cc(C)ncn2)CC[C@H]1Nc1nc2c(-c3ccc(F)c(F)c3)cccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0 %

Procedure:
To a solution (3S,4R)-tert-butyl 4-(8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-3-methoxypiperidine-1-carboxylate (37 mg, 80.5 mol) in dichloromethane (1 mL) was added HCl (2 M in diethylether, 201 L, 403 mol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then filtered and the white precipitate was washed with dichloromethane and diethylether and dried to afford the title compound (32 mg, 92%) as an off white solid.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1>>[CH:1]([NH:3][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[CH3:12])=[O:2]
Reactant: NC=O
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CC(NC=O)c1ccc(Cl)cc1
Yield: 99.7 %

Procedure:
In the same manner as in Example 1 except that 110.7 g of formamide was used in place of ammonium formate and 126.7 g of 4'-chloroacetophenone was used in place of acetophenone, the reaction and post treatment were carried out to obtain 150 g of crude N-formyl-1-(4-chlorophenyl)ethylamine; the purity: 87.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18]([C:17]2[C:16]([F:15])=[N:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1cccnc1F
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1cccnc1F

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-fluoronicotinic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3-carboxamide. MS (Q1) 328.1 (M)+.
Reaction SMILES: [OH-].[K+].[CH2:3](N)[CH2:4]N.[CH3:7][O:8][C:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH:10]=1>C(O)(C)(C)C>[C:3]([C@@:18]1([OH:28])[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C:11]([CH:10]=[C:9]([O:8][CH3:7])[CH2:26][CH2:25]1)=[CH:12][CH2:13]3)#[CH:4]
Reactant: NCCN
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C#C[C@@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 4 h

Procedure:
Potassium hydroxide (7.75 g), calcium carbide (21.0 g), t-butanol (19 ml) and ethylene diamine (187 ml) are combined in a 500 ml Parr pressure bottle which is sealed with a foil covered rubber stopper which is wired to the bottle. The heterogenous mixture is stirred at 40° for about 16 hr (though about 4 hr is sufficient). The mixture is cooled to 20°-25° and 3-methoxyandrosta-3,5-dien-17-one (IAa, 11.80 g) is added as a solid. The reaction mixture is then stirred at 20°-25° for 5 hr. The mixture is transferred to a flask with a mechanical stirrer. The mixture is washed with methylene chloride (300 ml), cooled to 0°, quenched under a nitrogen atmosphere by the slow addition of acetic acid (57.2 ml). Water (300 ml) is added at a sufficiently slow rate to keep foaming under control. The mixture is filtered and the solids washed with methylene chloride. The filtrate phases are separated, the aqueous phase is back-extracted (twice) with methylene chloride. The organic phases are combined, washed with water (three times), dried over sodium sulfate and concentrated to an oil. The oil in ethyl acetate (75 ml) is heated to reflux and is allowed to crystallize at 20°-25° overnight to give the title compound, NMR (CDCl3) 0.90, 1.0, 2.47, 3.59, 5.15 and 5.23 δ.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([NH:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=2[N+:16]([O-])=O)[C:4]([C:19]#[N:20])=[N:3]1>C(O)C.Cl>[ClH:14].[NH2:20][C:19]1[C:4]2[C:5](=[N:6][N:2]([CH3:1])[N:3]=2)[NH:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:9]=2[N:16]=1
Reactant: Cn1nc(C#N)c(Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])n1
Agent: Cl
Solvent: CCO
Product: Cn1nc2c(n1)C(N)=Nc1cc(Cl)c(Cl)cc1N2

Procedure:
To a slurry of 2-methyl-4[4,5-dichloro-2-nitroanilino]-1,2,3-triazole-5-carbonitrile(1.1 g) in ethanol (10 ml) was added anhydrous stannous chloride (2.0 g) in concentrated hydrochloric acid (10 ml) and the solution heated at reflux for one hour, cooled and the resulting solid filtered and dried at 70° C. under reduced pressure to give an orange crystalline solid, recrystallised from ethanol, melting point>255° C.
Reaction SMILES: Cl.NN=CC1C=CC([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12]2)=O)=CC=1.[CH:30]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=C>C(#N)C>[N:35]1[CH:36]=[CH:37][C:32]([CH2:30][CH2:9][N:11]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][CH:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]3)[CH2:13][CH2:12]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)CC1CCC2(CC1)CCN(C(=O)c1ccc(C=NN)cc1)CC2
Reactant: C=Cc1ccncc1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CC1CCC2(CC1)CCN(CCc1ccncc1)CC2

Procedure:
A solution of 0.48 g (2.0 mmol) of the intermediate from Example 1. Step C and 0.21 g (2.0 mmol) 4-vinylpyridine in 6 ml acetonitrile were heated at 80° C. over night. The solvent was removed under reduced pressure, and the remaining solid title compound was purified by stirring several times with tert.-butylmethylether, filtered with suction, and dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][N:19]3[CH:27]=[CH:28][CH:29]=[C:18]3[CH2:17]2)=[O:15])[CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>O1CCCC1.C(OCC)(=O)C>[Cl:36][C:37]([Cl:42])([Cl:41])[C:38]([C:27]1[N:19]2[C:18]([CH2:17][N:16]([C:14]([C:10]3[CH:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH:13]=[CH:12][CH:11]=3)=[O:15])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20]2)=[CH:29][CH:28]=1)=[O:39]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1cccc(C(=O)N2Cc3cccn3Cc3ccccc32)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
To a mixture of 10-[(2′-methyl-1,1′-biphenyl-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (1.7 g, 4.5 mmol) and sodium carbonate (0.95 g, 9.0 mmol) in dry tetrahydrofuran (40 mL) was added dropwise trichloroacetyl chloride (0.75 mL, 6.7 mmol) and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction mixture was then diluted with ethyl acetate (150 mL), washed with 1 M hydrochloric acid (150 mL), water (150 mL) and brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a dark foam. Purification by flash chromatography using a solvent gradient of 60% to 80% dichloromethane in hexane afforded a white solid that was recrystallized from hot ethyl acetate to give the title compound (1.2 g, 50%) as a white needles.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16](Cl)[C:15]=1[N+:25]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[NH2:25][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reaction time: 48 h
Yield: 66 %

Procedure:
38.69 mg (97.98 mmol) of 4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloro-3-nitroquinoline was dissolved in 900 ml of methanol. 10 g of 10% palladium-carbon was added thereto and the mixture was stirred for 2 days under hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. A sodium hydrogencarbonate aqueous solution was added to the residue and the solution was extracted twice with chloroform. The organic phase was washed with brine and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1 (v/v)) to obtain 21.37 mg (64.67 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino] quinoline shown below as a green brown amorphous substance. ##STR50## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm): 1.44 (9H, s), 1.64 (4H, m), 3.16 (2H, m), 3.26 (2H, t, J=6.8 Hz), 3.8 (2H, br) 4.6 (1H, br), 7.45 (2H, m), 7.82 (1H, m), 7.97 (1H, m), 8.47 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]([CH:22]=[CH2:23])=[N:11]2)[CH:6]=[CH:5][CH:4]=1>CO.[OH-].[OH-].[Pd+2]>[CH2:22]([C:12]1[C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][C:18]=2[N:10]([CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[N:11]=1)[CH3:23]
Reactant: C=Cc1nn(Cc2cccc(OC)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1nn(Cc2cccc(OC)n2)c2cccc(N)c12
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To 1-((6-methoxypyridin-2-yl)methyl)-4-nitro-3-vinyl-1H-indazole (1.89 g, 6.09 mmol) in MeOH (60 mL) was added Pd(OH)2/C (20 wt %, 400 mg). The reaction mixture was purged with N2 and charge with H2 (45 psi). The reaction mixture was recharged H2 to 45 psi after 45 minute. The reaction was stopped after 5 hours. The reaction mixture was filtered through Celite®, washed with MeOH (200 mL) and concentrated to provide the desired product (1.36 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[N:11]([C:12]2[CH:13]=[C:14]([CH2:22][C:23]([NH2:25])=[O:24])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.[C:30](Cl)([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(OCC)(=O)C>[NH2:25][C:23](=[O:24])[CH2:22][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([N:11]2[C:7]([NH:6][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[CH:8][C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:10]2)[CH:13]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cc(CC(N)=O)c3ccccc3c2)n1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of saturated sodium bicarbonate (20 mL), ethyl acetate (20 mL) and 2-(3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)naphthalen-1-yl)acetamide (300 mg, 0.931 mmol) was added Troc-Cl (296 mg, 1.40 mmol). The mixture was stirred vigorously overnight. The mixture was diluted with ethyl acetate (30 mL) and the organic phase was separated, washed with 5% citric acid (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give a solid which was triturated with ethyl acetate and filtered to provide 2,2,2-trichloroethyl 1-(4-(2-amino-2-oxoethyl)naphthalen-2-yl)-3-tert-butyl-1H-pyrazol-5-ylcarbamate (241 mg, 52% yield). MS (ESI) m/z: 499.0 (M+H+).
Reaction SMILES: [OH:1][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[NH2:9][C:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.O>[OH:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[C:23]([NH:9][C:10]1[C:18]2[C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:25])[CH3:24]
Reactant: Nc1cccc2sc3ccccc3c12
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the aminodibenzothiophene triflate (200 mg, 0.58 mmol) in pyridine (4.0 ml), was added acetic anhydride (0.29 ml, 2.88 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours, diluted with water (20 ml), and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed successively with water (2×20 ml), saturated aqueous sodium bicarbonate solution (1×20 ml) and brine (1×20 ml), dried (Na2SO4) and evaporated in vacuo. The residual solid was triturated with petrol to give the title compound (xii).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11](=[O:13])[CH:12]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(=O)c2c([nH]1)CCCC2
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CCBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2c(n1)CCCC2
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (1.95 g), and potassium carbonate (2.28 g) in NMP (75 ml) was heated at 60° C. for 20 minutes with stirring. Compound E (5.2 g) was added and the reaction mixture was heated at 80° C. for 90 minutes. The mixture was allowed to cool to ambient temperature and water (150 ml) was added. The resultant precipitate was collected by filtration, dried at 60° C., then recrystallised from toluene to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5,6,7,8-tetrahydroquinoline, as a solid in 60% yield; m.p. 205°-207° C.; NMR (CDCl3):1.30(3H,t), 1.90(4H,m), 2.60-3.00(6H,m), 5.04(2H,m), 6.52(2H,d), 6.60(1H,s), 6.80(2H,d), 7.11(2H,d), 7.40(1H,d), 7.67(2 H,d), 7.92(3H,m).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([S:11][CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CN(C=O)C>[CH3:12][S:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([N:13]3[CH:17]=[CH:16][CH:15]=[N:14]3)[N:10]2[N:9]=1
Reactant: c1cn[nH]c1
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-n3cccn3)n2n1
Temperature: 110 °C

Procedure:
To a RB flask under argon were introduced 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (300 mg, 1 mmol), 1H-Pyrazole (88.5 mg, 1.30 mmol), Cesium carbonate (801 mg, 2.46 mmol), Copper(I) iodide (50 mg, 0.3 mmol) and DMF (5 mL). The mixture was degassed for few minutes and heated at 110° C. overnight under argon. Solvent was removed and the mixture was taken in EtOAc and was passed through a pad of celite. Solvent evaporation gave the crude product which was purified by flash chromatography (ISCO, hexane :EtOAc 3:1). 2-Methylsulfanyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine was isolated as a yellow syrup (23, 8%). LCMS (E/I+) 232 (M+H). 2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamine (47.1 mg, 0.162 mmol), 2-Methanesulfinyl-7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.08 mmol), N,N-Diisopropylethylamine (30 uL, 0.2 mmol) and 1-Methoxy-2-propanol (200 uL,) were combined in a microwave vial. The reaction was microwaved at 200° C. for 2.5 hours, taken up in DMSO, purified by Gilson RP-HPLC. The product, [2-Methoxy-4-(4-morpholin-4-yl-piperidin-1-yl)-phenyl]-(7-pyrazol-1-yl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine was isolated as a tan solid (8 mg, 21%). LCMS (E/I+) 475 (M+H). NMR 1H (DMSO-d6)-9.75 (br s, 1H), 8.94 (s, 1H), 8.58 (d, 1H, J=2.09 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.67 (d, 1H, J=8.72 Hz), 6.94 (s, 2H), 6.70 (s, 1H), 6.60 (s, 1H), 6.52 (d, 1H, J=8.74 Hz), 4.04-3.13 (series of m, s along with the water peak, 14H), 2.71 (m, 2H), 2.15 (d, 2H, J=11.30 Hz), 1.72 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:49][C@@H:50]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:51]([O:53][CH3:54])=[O:52].C(N(CC)CC)C>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:49][C@@H:50]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[C:51]([O:53][CH3:54])=[O:52])=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2
Reactant: COC(=O)[C@@H](N)CCN(C)C
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](CCN(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Reaction time: 3 h
Yield: 71 %

Procedure:
5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (17d; prepared according to Example 110) (0.396 g, 1.14 mmol) was stirred with HOBt (0.192 g, 1.26 mmol) and EDCI (0.241 g, 1.26 mmol) in dichloroethane (2 mL) for 10 minutes at room temperature. This mixture was then added to a suspension of (S)-methyl 2-amino-4-(dimethylamino)butanoate dihydrochloride (0.280 g, 1.20 mmol) and triethylamine (1 mL, 6.9 mmol) in dichloromethane (6 mL). The reaction mixture was stirred for 3 hours and then was concentrated under reduced pressure. The residue was diluted with chloroform (50 mL) and washed with 1N HCl (2×25 mL), saturated K2CO3 (2×50 mL), water (25 mL), brine (25 mL), and dried over MgSO4. The filtered solution was concentrated under reduced pressure to provide yellow oil. The oil was chromatographed eluting with 5% MeOH in dichloromethane to afford a viscous colorless oil that solidified upon drying under high vacuum (0.393 g, 71% yield). MS (ESI+) m/z 489 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.91 (d, 1H), 8.36 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.03 (m, 1H), 7.00 (s, 1H), 6.93 (m, 1H), 4.88 (m, 1H), 4.21 (d, 2H), 3.74 (s, 3H), 2.34 (m, 3H), 2.06 (s, 6H), 2.01 (m, 2H), 0.92 (d, 6H).