Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=[C:21]([Br:23])[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:23][C:21]1[CH:22]=[C:17]([NH:1][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH:13]=[CH2:14])[CH:5]=[CH:4][CH:3]=2)[C:18](=[O:25])[N:19]([CH3:24])[CH:20]=1
Reactant: C=CC(=O)NCCNc1cccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=CC(=O)NCCNc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.8 %

Procedure:
A mixture of 105d (2.06 g, 10 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (2.65 g, 10 mmol), Pd2(dba)3 (91.6 mg, 0.1 mmol) Xant-phos (116 mg, 0.2 mmol), Cs2CO3(9.78 g, 30 mmol) in dioxane (100 mL) was degassed and stirred at 100° C. for 16 h under nitrogen. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (EA/PE=5/1) to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-ylamino)ethyl)acrylamide 105e (2.54 g, 65%) as yellow solid. MS-ESI: [M+H]+ 394.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]4)[C:4]=2[CH:3]=1)=[CH:14][C:13]([NH2:23])=[CH:12][CH:11]=3.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@:16]2([C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([F:8])[C:5]=3[O:9][C:10]3[C:15]2=[CH:14][C:13]([NH:23][C:31](=[O:32])[C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)=[CH:12][CH:11]=3)[N:17]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(Cl)nc1F
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(Cl)nc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
A mixture of (S)-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.048 g, 0.143 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.025 g, 0.158 mmol) was purged with N2 followed by the addition of THF (2 mL) and MeOH (0.5 mL). 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.046 g, 0.158 mmol) was added in one portion and the resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated NaHCO3, diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-4% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0258 g, 0.054 mmol, 37.9% yield). MS m/z=474.0 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][O:5][N:6]=[C:7]([C:11]1[N:15]=[C:14]([NH2:16])[S:13][N:12]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[K+].Cl>CN(C)C(=O)C.O.C(OCC)(=O)C>[CH3:17][S:18]([O:9][C:8](=[O:10])[C:7](=[N:6][O:5][CH2:4][C:1]([OH:3])=[O:2])[C:11]1[N:15]=[C:14]([NH2:16])[S:13][N:12]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)O)ns1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)OC(=O)C(=NOCC(=O)O)c1nsc(N)n1
Yield: 47.2 %

Procedure:
To a solution of 2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (45.0 g) in N,N-dimethylacetamide (432 ml) was added methanesulfonyl chloride (29.8 g) under stirring and cooling in an ice bath. The mixture was stirred for 25 minutes at 4° to 6° C. and finely powdered potassium hydrogen carbonate (48.4 g) was added thereto. The reaction mixture was stirred for 2.5 hours at 4° to 6° C. and then poured into a cold mixture of ethyl acetate (1.2 l), 1N hydrochloric acid (484 ml) and water (500 ml) below 10° C. under stirring. The organic layer was separated out and the aqueous phase was extracted with ethyl acetate (300 ml). The combined extracts were washed with cold water (800 ml) and a saturated aqueous solution of sodium chloride (800 ml), dried over magnesium sulfate and evaporated. The residue was triturated in methylene chloride (200 ml) to give 2 -carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic methanesulfonic anhydride (syn isomer) (28.0 g), mp. 143° to 146° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH:23][C:24]3[C:25]4[CH:32]=[CH:31][N:30](S(C5C=CC(C)=CC=5)(=O)=O)[C:26]=4[N:27]=[CH:28][N:29]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH:23][C:24]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)Cc5ccccc54)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1Cc2ccccc2C(Nc2ncnc3[nH]ccc23)C1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(4-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (0.15 g, 0.24 mmol) in MeOH (4 mL) and water (1 mL) was added K2CO3 (0.133 g, 0.96 mmol) and heated to 60° C. for 2 h. The reaction mixture was concentrated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in DCM) to give (25 mg, 23%) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 11.75 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 7.68-7.62 (m, 1H), 7.42-7.18 (4H, m), 6.71-6.56 (m, 3H), 5.19 (s, 1H), 5.06 (s, 1H), 4.23 (d, J=12 Hz, 1H) 4.12-3.94 (bs, 1H), 3.82-3.65 (m, 1H), 2.75 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:29][CH3:30])=[C:18]([NH:22]C(=O)OCC=C)[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:29][CH3:30])=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 123.2 %

Procedure:
To the solution of 2-propen-1-yl [3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)phenyl]carbamate (12.1 g, 22.5 mmol) in DCM (200 mL), acetic acid (3.8 mL, 66.6 mmol), Pd(PPh3)2Cl2 (0.45 g, 0.56 mmol) were added. Then tri-n-butyl tin hydride (8.5 mL, 33 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (200 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (500 mL) to afford the title compound of Step G (10 g, 60.8% yield), which was used directly in the next step.
Reaction SMILES: O=S(Cl)[Cl:3].[O:5]1[C:9]2([CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:3][CH2:15][CH:12]1[CH2:13][CH2:14][C:9]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:10][CH2:11]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCC1CCC2(CC1)OCCO2
Yield: 88.1 %

Procedure:
SOCl2 (37.1 mL, 509 mmol, 1.3 equiv) was slowly added to a stirred solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (67.3 g, 391 mmol) and pyridine (94.8 mL, 1175 mmol, 3 equiv.) in CHCl3 (400 mL) Caution: The reaction is exothermic. The resulting yellow mixture was heated at reflux for 1.5 h and concentrated. The residue was partitioned between water (500 ml) and ether (500 ml). The layers were separated and the aqueous layer was re-extracted with ether (200 ml). The combined ether layers were washed with 1N HCl (2×100 ml), water (200 ml) followed by brine (200 ml), then dried (MgSO4), filtered and concentrated to give the title compound as a dark amber oil (65.7 g, 88% yield). 1H NMR (500 MHz, CDCl3) δ: 3.94 (4 H, t, J=2.9 Hz), 3.41 (2 H, d, J=6.4 Hz), 1.83-1.88 (2 H, m), 1.75-1.79 (2 H, m), 1.63-1.73 (1 H, m), 1.55 (2 H, td, J=4.3, 13.2 Hz), 1.29-1.39 (2 H, m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([OH:10])=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:11]([O:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1cccc2sccc12
Solvent: c1ccncc1
Product: O=C(Oc1cccc2sccc12)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzo[b]thiophen-4-ol (4 g), benzoyl chloride (3.3 ml) and pyridine (10 ml) was heated under reflux under nitrogen for 3 hours, then cooled to ambient temperature and poured onto ice-water (130 ml). The product was extracted into ether (3×50 ml), the combined extracts were washed with 5% aqueous sodium hydrogencarbonate solution (50 ml), 2M hydrochloric acid (50 ml) and water (3×50 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give benzo[b]thiophen-4-yl benzoate (6.7 g) as a cream solid which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:16]([BH3-])#N.[Na+].[Cl-].[NH4+]>CO.O.CO.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CN1CCN(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a solution of 1-(3-bromo-phenyl)-piperazine (about 1 g) and acetic acid (about 0.4 mL) in methanol (about 25 mL) is added 37% formaldehyde in water/methanol (about 56.7:37:6.3, water:formaldehyde:methanol; about 5 mL). The mixture is stirred at room temperature for about 18 hours. The suspension is cooled to about 5° C. in an ice/water bath and sodium cyanoborohydride (about 5 g) is added in small portions. The mixture is stirred and warmed to room temperature for about 18 hours. The mixture is slowly poured into saturated aqueous ammonium chloride (about 200 mL) and stirred for about 1 hour. The mixture is extracted with dichloromethane (3× about 75 mL). The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The material is placed under high vacuum for about 18 hours to yield 1-(3-bromo-phenyl)-4-methyl-piperazine as a pale yellow oil (about 1 g). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS=255, 257 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6](B1OC(C)(C)C(C)(C)O1)[CH:5]=2.Cl[C:21]1[C:30]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[CH3:36])=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:21]1[C:30]([N:31]3[CH2:35][CH2:34][CH2:33][C@@H:32]3[CH3:36])=[N:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=3)[N:22]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Reactant: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
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: COCCOC
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (378 mg, 1.47 mmol) in ethylene glycol dimethyl ether (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (150 mg, 0.49 mmol), sodium carbonate (156 mg, 1.47 mmol) and Pd(PPh3)4 (29 mg, 0.03 mmol) with stirring for 2 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as light yellow solid (140 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[N:15][C:14]([CH2:17][OH:18])=[C:13]3[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:12]=23)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]>O=[Mn]=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:11]1[CH:16]=[N:15][C:14]([CH:17]=[O:18])=[C:13]2[O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22][C:12]=12)=[O:10]
Reactant: CC1(C)OCc2c(C(=O)c3ccc(F)c(Cl)c3)cnc(CO)c2O1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OCc2c(C(=O)c3ccc(F)c(Cl)c3)cnc(C=O)c2O1

Procedure:
(4-fluorophenyl)(8-(hydroxymethyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-yl)methanone (total yield from step 1d) was added to 200 mL of CHCl3 and 15 g MnO2. The resulting suspension was refluxed for 4 h to completion. MnO2 was then removed by filtration through Celite and washed 2× with CHCl3. Evaporation of the solvent gave 5 g of crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([NH:29][CH2:30][CH2:31][NH2:32])[N:21]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:11][CH:12]=[C:13]([NH:32][CH2:31][CH2:30][NH:29][C:22]2[N:21]=[C:20]([NH2:19])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(Cl)cc1Cl
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2ccc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To 2-(2,4-dichlorophenyl)-4-fluoro-1-nitrobenzene (20 mgs, 0.06 mmol) in N,N-dimethylformamide was added 2-amino-3-nitro-6-(2-aminoethylamino)pyridine (14 mgs, 0.07 mmol) and N,N-diisopropylethyl amine (16 μl, 0.07 mmol) and heated to 80° C. over-night. The mixture was partitioned between ethyl acetate and water and the organic layer was dried (MgSO4) and concentrated. Purification on silica gel with 5% methanol in dichloromethane as eluent yielded 7 mgs of N˜6˜-{2-[(2′,4′-dichloro-6-nitro-1,1′-biphenyl-3-yl)amino] ethyl}-3-nitropyridine-2,6-diamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3.[C:20]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]3
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCSCC1)O2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC)c2c1OC1(CCSCC1)O2
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A suspension of 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (570 mg, 2.02 mmol), K2CO3 (558 mg, 4.04 mmol) and dimethyl sulphate (0.25 mL, 2.62 mmol) in acetone (14 mL) was stirred at 50° C. overnight. At room temperature water (30 mL) was added. The aqueous phase was extracted with dichloromethane (3×15 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard silica gel column chromatography afforded methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate (407 mg, 68%). 13C NMR (DMSO) δ 163.8, 148.1, 146.9, 134.6, 123.4, 118.3, 107.1, 105.9, 56.1, 51.6, 35.9, 25.4.
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.N1CCCC1.[F:18][C:19]1[CH:44]=[CH:43][C:22]([C:23]([NH:25][C:26]2[S:27][C:28]3[C:34]([N:35]4[CH2:40][CH2:39]O[CH2:37][CH2:36]4)=[CH:33][CH:32]=[C:31]([O:41][CH3:42])[C:29]=3[N:30]=2)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][C:26]2[S:27][C:28]3[C:34]([N:35]4[CH2:36][CH2:37][CH2:39][CH2:40]4)=[CH:33][CH:32]=[C:31]([O:41][CH3:42])[C:29]=3[N:30]=2)=[O:24])=[CH:43][CH:44]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1CCNC1
Product: COc1ccc(N2CCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and pyrrolidine as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light brown solid in about 10% overall yield, MS: m/e=372 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[C:4]([CH3:13])[CH:3]=1.CN(C)CCCN(C)C.CS(Cl)(=O)=O.[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)[CH:9]([CH3:11])[CH3:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1cc(Br)ccc1C(O)C(C)C
Agent: CN(C)CCCN(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(c2ccc(Br)cc2C)C(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a mixture of 1-(4-bromo-2-methylphenyl)-2-methylpropan-1-ol (600 mg), N,N,N′,N′-tetramethyl-1,3-propanediamine (0.492 mL) and toluene (0.823 mL) was added methanesulfonyl chloride (0.229 mL), and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture were added methyl 4-aminobenzoate (560 mg) and N,N-diisopropylethylamine (0.862 mL) at room temperature, and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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 (ethyl acetate/hexane) to give the title compound (457.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].Br.[CH2:26]([N:28]([CH2:32][CH3:33])[CH2:29][CH2:30]Br)[CH3:27].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:27][CH2:26][N:28]([CH2:32][CH3:33])[CH2:29][CH3:30])=[CH:18][CH:17]=1
Reactant: CCN(CC)CCBr
Reactant: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (27 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. 2-(Diethylamino)ethyl bromide hydrobromide (88 mg) was added to the solution, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (30 mg, yield 23%).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][C:21]1[NH:25][N:24]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3](=[O:4])[CH2:2][N:25]3[C:21]([CH3:20])=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24]3)[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Reactant: COc1cc(N2CCC(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(N2CCC(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (580 mg, 1.919 mmol; see Example 1a, Step 2), 5-methyl-3-(trifluoromethyl)-1H-pyrazole (576 mg, 3.84 mmol), potassium carbonate (796 mg, 5.76 mmol) and acetonitrile (20 mL) was stirred at RT for 12 h. After this time, the solvent was removed under reduced pressure and the resultant residue was partitioned between EtOAc (100 mL) and water (50 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator to yield a residue. The residue was purified by flash chromatography using a 40 g silica gel cartridge and gradient elution from 10:1 Hex/EtOAc to 1:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)-2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethanone (650 mg, 1.563 mmol, 81% yield) as clear oil. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.49 (1 H, d, J=2.42 Hz), 6.44 (1 H, dd, J=8.68, 2.53 Hz), 6.35 (1 H, s), 5.01-5.04 (2 H, m), 3.84-3.89 (3 H, m), 3.62-3.69 (2 H, m), 2.77 (2 H, td, J=12.03, 2.75 Hz), 2.58 (1 H, tt, J=11.29, 3.87 Hz), 2.21 (3 H, s), 1.99 (2 H, s), 1.80-1.91 (2 H, m).