Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH:23]=O.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([CH:1]=[CH:23][C:16]3[N:15]([CH3:14])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=3)=[N:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: Cc1nnc(-c2ccc(Cl)cc2)s1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccc(Cl)cc2)s1
Yield: 79.3 %

Procedure:
21 g of 2-methyl-5-(4-chlorophenyl)-1,3,4-thiadiazole and 22.8 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde are heated with 0.5 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml acetic anhydride for 5 hours at reflux temperature. After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 27.5 g of product of obtained, corresponding to 77% of the theory. The compound melts at 268° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Si]([C:17]#[N:18])(C)(C)C.[CH3:19][C:20]([CH3:22])=O>>[C:17]([C:20]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)([CH3:22])[CH3:19])#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)=O
Reactant: CNC(=O)c1ccc(N)cc1F
Product: CNC(=O)c1ccc(NC(C)(C)C#N)cc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
N-methyl-2-fluoro-4-aminobenzamide 4a (1.68 g, 10 mmol) was added a TMS-CN (4.93 g 50 mmol) solution in acetone (30 mL). The reaction mixture was stirred at 80° C. for 12 h, then concentrated in vacuo. The residue was diluted with water (50 mL). The suspension was extracted with ethyl acetate (3×30 mL). Combined organic layers were washed with brine (3×50 mL), dried (MgSO4) and concentrated in vacuo to dryness. The resulting residue was triturated with a mixed solvent of hexanes and ethylether (20 mL-20 mL). The solid was collected by filtration, affording the title compound 6b (1.8 g, 79% yield). MS (ES-API Negative): 234 (M−H)−.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][N:31]([C:33]([C:35]1[CH:39]=[C:38]([Cl:40])[S:37][C:36]=1[Cl:41])=[O:34])[CH3:32])(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:41][C:36]1[S:37][C:38]([Cl:40])=[CH:39][C:35]=1[C:33]([N:31]([CH2:30][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:42])=[O:5])[CH3:32])=[O:34]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(CN(C)C(=O)c2cc(Cl)sc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of 3-{2-{[(2,5-dichloro-thiophene-3-carbonyl)-methyl-amino]-methyl}-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid tert butyl ester (50 mg, 0.079 mmol) in CH2Cl2 (2 mL) was treated with anisole (1.0 mL) then TFA (0.6 mL). The solution was stirred at ambient temperature 2 h, and more TFA (1.0 mL) was added. After 15 min, the reaction was concentrated and co-evaporated with CCl4 (3×). The residue was triturated with hexanes to yield a foam (43 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.48 (t, 0.6H, J=7.8 Hz), 2.58 (t, 1.4H, J=7.8 Hz), 2.72 (t, 0.6H, J=7.8 Hz), 2.84 (s, 2H), 2.90 (t, 1.4H, J=7.8 Hz), 2.93 (s, 1H), 2.98 (brs, 2H), 4.17 (t, 2H, J=6.4 Hz), 4.47 (s, 0.6H), 4.71 (s, 1.4H), 6.61 (brs, 0.3H), 6.71-6.76 (m, 2H), 6.79 (s, 0.7H), 7.04 (d, 0.3H, J=8.3 Hz), 7.08 (d, 0.7H, J=8.3 Hz), 7.41-7.43 (m, 3H), 7.94 (brs, 2H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24](=[CH:25][C:14]=1[CH2:13]3)[C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=[CH:20]2)=[O:11].C(O)=O.C(N(CC)CC)C.C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH2:2][C@@:3]1([OH:29])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:24]([C:23]([NH2:26])=[CH:22][CH:21]=[CH:20]2)=[CH:25][C:14]=1[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c([N+](=O)[O-])cccc3nc2-1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(N)cccc3nc2-1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
9-nitro camptothecin (3.4 g) was dissolved in distilled DMF (100 ml). Palladium acetate (0.08 g), formic acid (0.95 ml), and triethylamine (3.5 ml) were added. The solution was heated to 80° C., and the heating was continued for 1 hour. DMF (200 ml) and charcoal were added to the reaction mixture, and the stirring was continued for 0.5 hours at 80° C. The mixture was filtered hot through a celite filter aid, and the filtrate was concentrated to small volume. The precipitated orange solid was collected by filtration to yield 2.5 g of 9-amino camptothecin.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:23].[CH3:22][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-bromo-2,4-dimethylbenzene (1.85 g) were added 1-BOC-1,4]diazepane (2 g), palladium (II) acetate (0.115 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g), sodium tert-butoxide (1.34 g) and toluene (35 mL), and the mixture was refluxed for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g). To 4-(2,4-dimethylphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (2.16 g) were added 4N hydrogen chloride/ethyl acetate (6.9 mL) and chloroform (17 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated to give the title compound (1.74 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81-mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (522 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([O:14][Si](CCCC)(CCCC)CCCC)=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)c1ncccc1O
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 2-(4-fluorobenzoyl)-3-(tributylsilyloxy)pyridine (3.75 g, 11.3 mmol) in tetrahydrofuran (17 ml) was cooled to 0° C. and tetrabutylammonium fluoride (17ml, 1.0 M in tetrahydrofuran) was added. After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was separated, washed with sodium bicarbonate and brine, and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified on a silica gel column using ethyl acetate-hexane (2:8) as the eluant to give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33]([O:35][CH2:36][CH2:37]O)[CH3:34].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl>O1CCCC1>[CH2:33]([O:35][CH2:36][CH2:37][N:5]1[C:6]([C:11]([NH2:13])=[O:12])=[C:7]([N+:8]([O-:10])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]1)[CH3:34]
Reactant: CCOCCO
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCn1nc(CC)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A 1 L flask was charged with 3-ethyl-4-nitropyrazole-5-carboxamide (prepared as described in EP 1176142 at page 18) (15.0 g, 81 mmol), triphenylphosphine (25.6 g, 97.8 mmol), and tetrahydrofuran (120 mL). The resulting mixture was cooled by placing the flask in a 0° C. bath and 2-ethoxyethanol (9.5 ml, 98 mmol) was added to the flask. A solution of di-tert-butyl azodicarboxylate (22.5 g, 97.8 mmol) in tetrahydrofuran (90 mL) was then added to the flask over a period of 2.5 hours. The mixture was stirred with cooling for an additional hour and then warmed to room temperature and stirred for one additional hour. The mixture was again cooled to 0° C., treated with 6M hydrochloric acid (40 ml), and heated to 40° C. for one hour. The mixture was partially concentrated and extracted between ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with water, washed with brine, dried over magnesium sulfate, filtered and then concentrated. The resulting viscous oil was treated with 2-propanol and this mixture was then concentrated. The resulting material was treated with 2-propanol and heated. Upon cooling, the resulting crystals were filtered, rinsed with cold 2-propanol, and dried to afford 16.5 g of the title compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1)=[C:2]=[S:3].[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.O(C(C)C)C(C)C>C(O)C>[ClH:15].[N:22]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:3][C:2]=1[NH:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CCOC(=O)N1CCC(N=C=S)CC1
Reactant: Nc1cccnc1Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cccnc3s2)CC1
Product: Cl
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 51 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate, 30 parts of 2-chloro-3-pyridinamine and 240 parts of ethanol was stirred and refluxed for 24 hours. The reaction mixture was cooled to room temperature. Upon the addition of 70 parts of 2,2'-oxybispropane, the product was allowed to crystallize. It was filtered off and dried, yielding 40 parts (50%) of ethyl 4-(thiazolo[5,4-b]pyridin-2-ylamino)-1-piperidinecarboxylate monohydrochloride (65).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C1=CCCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1C=CCCCC1
Temperature: 65 °C

Procedure:
To 5-amino-3-cyano-4-iodo-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (2.23 g, 5 mmol, WO97/07102) and cycloheptene (3 ml) in dry DMF (25 ml), under a nitrogen atmosphere, was added bis(triphenylphosphine)palladium dichloride (100 mg, 0.13 mmol), cuprous iodide (100 mg) and triethylamine (2 ml). The mixture was heated at 65° C. for 18 h. A further 3 ml of cycloheptene was added and the mixture heated at 70° C. for 82 h. The cooled mixture was poured into water (500 ml) and extracted with DCM (2×100 ml). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to leave a brown oil. This was purified by silica chromatography (eluting with hexane/diethyl ether 1/1 v/v). The resulting cream solid was further purified by silica chromatography (eluting with hexane, hexane/diethyl ether 19/1, hexane/diethyl ether 9/1 and finally hexane/diethyl ether 3/1) to yield 564 mg of the title compound as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[F:10].[F:11][CH:12]([F:15])[CH2:13][NH2:14].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:14][CH2:13][CH:12]([F:15])[F:11])=[CH:4][C:3]=1[F:10]
Reactant: NCC(F)F
Reactant: Fc1cc(CCl)cnc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cc(CNCC(F)F)cnc1Cl
Reaction time: 16 h
Yield: 57 %

Procedure:
At 45° C., 520 mg (2.89 mmol) of 6-chloro-3-chloromethyl-5-fluoropyridine (Va-4), 1.05 ml (14.44 mmol) of 2,2-difluoroethylamine and 400 μl (2.89 mmol) of triethylamine in 50 ml of acetonitrile are stirred for about 48 hours. During the reaction, after about 16 hours and 32 hours, a further 0.42 ml (5.78 mmol) of 2,2-difluoroethylamine are added in each case. The reaction mixture is concentrated under reduced pressure and then taken up in 1 N aqueous hydrochloric acid and washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Drying of the combined organic phases over sodium sulphate and concentration under reduced pressure gives 370 mg (57% of theory) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]-2,2-difluoroethylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:25]=3[O:24][CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1.C(=O)(O)[O-].[K+].CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[C:29]([C:2]4[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=4)[CH:30]=[CH:31][C:25]=3[O:24][CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(B(O)O)cc3C2)CC1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c([N+](=O)[O-])c4)cc3C2)CC1
Temperature: 99 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a mixture of 5-bromo-3-nitropyridin-2-amine (0.69 g, 3.2 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (1.0 g, 3.2 mmol) (example 2, step 4), potassium bicarbonate (1.3 g, 2.3 mmol) and DIPEA (1.1 mL, 6.3 mmol) in DMA (12 mL) and water (3 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.12 g, 0.16 mmol). The reaction mixture was stirred at 99° C. for 12 hours and then partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting brown residue was suspended in methanol (20 mL), filtered and washed with ethyl ether (2×30 mL) to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-3-nitropyridin-2-amine (1.0 g, 77% yield) as a yellow solid. MS (EI) for C21H25N5O4: 412 (MH+)
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:12][CH2:13][CH2:14][OH:15].[CH2:16](N(CC)CC)C>ClCCl>[CH3:16][C:5]1[CH:6]=[CH:1][C:2]([S:7]([O:15][CH2:14][CH2:13][F:12])(=[O:8])=[O:9])=[CH:3][CH:4]=1
Reactant: OCCF
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Yield: 76.4 %

Procedure:
Add toluenesulfonyl chloride (1.8 g, 9.4 mmol) to the mixture of 2-fluoroethanol (500 mg, 7.8 mmol) and triethylamine (1.6 g, 15.6 mmol) in dichloromethane (30 mL) at 0-5° C. Stir the reaction at ambient temperature for 5 hrs. Remove the volatiles under reduced pressure to yield the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=2:1) to afford a white solid as the title compound (1.3 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[N:4][C:3]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]([O:25][CH3:26])[O:23][CH3:24].C(OCC)(=O)C>CN(C)C=O>[CH3:24][O:23][CH:22]([O:25][CH3:26])[CH2:21][N:9]1[C:10]2[C:5](=[N:4][C:3]([CH3:13])=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: Cc1nc2ccc(=O)[nH]c2cc1F
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(Cn1c(=O)ccc2nc(C)c(F)cc21)OC
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 0.74 g of 7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one in 5 mL of N,N-dimethylformamide, 2.0 g of cesium carbonate and 0.84 g of 2-bromo-1,1-dimethoxyethane were added, the temperature was increased to 90 to 100° C., and the mixture was stirred for 2 hours 30 minutes. The reaction mixture was cooled to room temperature, thereto was added ethyl acetate, the insoluble substance was filtered off, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.69 g of 1-(2,2-dimethoxyethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]3[O:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[O:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>CO>[ClH:4].[ClH:4].[O:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[O:27][CH2:26][C@@H:25]1[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:15]2[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]2)=[CH:24][CH:23]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Solvent: CO
Product: Cl
Product: c1ccc2c(c1)OC[C@H](c1ccc(CN3CCNCC3)cc1)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanol (30 mL) is added dropwise to acetyl chloride (1.4 mL) at 0° C. The solution is added to 4-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (408 mg, 0.99 mmol) (prepared according to the General Method E). The resulting mixture is stirred at room temperature for 16 h and concentrated. The residue is suspended in a mixture of heptane and EtOAc, and the precipitate is collected and dried under vacuum to give 1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperazine dihydrochloride.
Reaction SMILES: Cl[CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH2:6][CH2:5][O:4]1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:24]([O-:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([O-:29])=[O:28]>O>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[CH3:16][O:15][C:8]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[C:12]2[C:7]=1[CH2:6][CH2:5][O:4][CH:3]2[CH2:2][N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: COc1ccc(OC)c2c1CCOC2CCl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CN1CCNCC1
Solvent: O
Product: COc1ccc(OC)c2c1CCOC2CN1CCN(C)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
In a sealed tube, 3.0 g of 1-chloromethyl-5,8-dimethoxyisochroman and 6.0 g of N-methylpiperazine were heated at 150°-160° C for 16 hours. After cooling, the reaction mixture was diluted with 200 ml of water and the oily precipitate was extracted with chloroform. The extract was rinsed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, elution being carried out with a solvent mixture of acetone, benzene and methanol (2:2:1). The oil thus obtained was converted to the fumarate and recrystallized from a solvent mixture of methanol and ether. By this procedure was obtained 1.3 g of 5,8-dimethoxy-1-(4-methylpiperazinyl)methylisochroman fumarate as pale-yellow needles, melting point: 188°-191° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Mg+2].[O-]CC.Br[CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:23][CH:24]([CH3:26])[CH2:25][CH:9]([C:2](=[O:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)CBr
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Mg+2]
Product: CCOC(=O)CC(=O)C(CC(C)C)C(=O)OCC
Yield: 61.9 %

Procedure:
Diethyl 3-oxopentanedioate (45.5 ml, 0.25 mol) was added to a suspension of magnesium ethoxide (prepared from magnesium turnings (9 g, 0.375 mol) and iodine (0.1 g) in dry ethanol (275 ml)), and the mixture was heated under reflux for 90 min. 1-Bromo-2-methylpropane (54 ml, 0.5 mol) was added, and the reaction was heated under reflux for 16 h. Further 1-bromo-2-methylpropane (27 ml, 0.25 mol) was added to the boiling mixture, and after 3 h the solvent was evaporated in vacuo. The residue was partitioned between 2 N hydrochloric acid and ether. After extracting the aqueous phase with ether, the combined organics were washed successively with water, 5% sodium bicarbonate, water and brine, then were dried (Na2SO4) and evaporated in vacuo. The residue was distilled to give the title compound as a colourless oil (40 g, 62%), bp 118°-120° C. (1 mmHg). δ (CDCl3): 0.9 (6H, d, J=6Hz), 1.25 (6H, t, J=7Hz), 1.4-1.9 (3H, m), 3.5 (2H, s), 3.7 (1H, d, J=9Hz) and 4.2 (4H, q, J=7Hz).
Reaction SMILES: [C:1]1([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:20])C(=O)C1>CN(C)C=O>[Br:20][C:4]1[CH:5]=[CH:6][C:1]([NH:7][C@@H:8]([CH3:12])[CH2:9][C:10]#[N:11])=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](CC#N)Nc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H](CC#N)Nc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
(3S)-3-(Phenylamino)butanenitrile (for a preparation see Intermediate 105) (11.3526 g, 70.9 mmol) was taken up in N,N-dimethylformamide (DMF) (200 mL) under nitrogen and cooled in an ice-bath. NBS (12.61 g, 70.9 mmol) was added and the reaction stirred. After 20 min, the reaction was partitioned between EtOAc (1000 mL) and water (500 mL). The organic layer was washed with 2M NaOH×2, water and brine (500 mL each) and then dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.3 g).