Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[N:7]=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O1CCCC1>[C:20]1([O:26][C:27](=[O:28])[NH:2][C:3]2[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[O:11])[N:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1noc(C)c1C(=O)N(C)Cc1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
N-((2-aminothiazol-4-yl)methyl)-N,3,5-trimethylisoxazole-4-carboxamide hydrochloride (6.16 g, 20.34 mmol) was dissolved in pyridine (35 mL) and DMAP (150 mg, 5 mol %) was added. The solution was cooled to 0° C. and a solution of phenylchloroformate (2.55 mL, 3.18 g, 20.34 mmol) in tetrahydrofuran (35 mL) was added dropwise. The mixture was stirred overnight at room temperature and the volatiles were evaporated in vacuo. The residue was taken up in water/EtOAc. The organic phase was dried over MgSO4 and the volatiles were evaporated under reduced pressure. The material was crystallized from EtOAc/i-Pr2O to afford (4-{[methyl(3,5-dimethylisoxazole-4-carbonyl)-amino]-methyl}-thiazol-2-yl) carbamic acid phenyl ester (1.80 g) as a tan-colored solid (purity ˜85%). 1H NMR (CDCl3): δ 9.85 (bs, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.20 (m, 2H), 6.80 (b, 1H), 4.75 (bs, 1H), 4.45 (bs, 1H), 3.00 (bs, 3H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:48][C:49]1[O:53][C:52]([CH:54]=O)=[CH:51][CH:50]=1>C1(C)C=CC=CC=1>[CH3:22][N:7]1[C:6]2=[C:5]3[N:4]([C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:11]2[C:10](=[O:19])[N:9]([CH3:20])[C:8]1=[O:21])[CH2:3][CH2:2][S:1][CH:54]3[C:52]1[O:53][C:49]([CH3:48])=[CH:50][CH:51]=1
Reactant: Cc1ccc(C=O)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCS)cc2n(C)c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2SCCn3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 100 °C

Procedure:
To 6-(2-mercapto-ethyl)-1,3-dimethyl-5-phenyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (Intermediate A) (207 mg, 0.656 mmol) and bismuth triflate (43.1 mg, 0.066 mmol) in toluene (5 ml) was added 5-methylfuran-2-carbaldehyde (commercial) (0.065 ml, 0.656 mmol) the mixture heated to 100° C. for 1 hour. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (20 mL) and water (20 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2×20 ml) the combined organic phases were dried over magnesium sulfate and the solvent removed under vacuum. Purification by chromatography on silica, eluting with 0-50% EtOAc/hexane gave the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:27])[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)C(OCC)=O>CS(C)=O.[Cl-].[Na+].O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:27])[CH2:13][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1
Reactant: CCOC(=O)C(C(=O)c1c(OC)ccc(OC)c1F)c1cccc(OC)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(CC(=O)c2c(OC)ccc(OC)c2F)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 57.1 %

Procedure:
A mixture of ethyl 3-(2-fluoro-3,6-dimethoxyphenyl)-2-(3-methoxyphenyl)-3-oxopropanoate (7.8 g, 20.7 mmol) in DMSO (75 mL) and brine (7.5 mL) was stirred at 150° C. for 5 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (1:10 EtOAc/petroleum ether) to give the title compound (3.6 g). 1H NMR (CDCl3): δ 7.24-7.15 (m, 1H), 6.90 (t, 1H), 6.84-6.75 (m, 3H), 6.56 (dd, 1H), 4.08 (s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:4](OC)=[O:5].[OH-].[NH4+:18]>O>[NH2:2][CH:3]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:4]([NH2:18])=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)C(N)Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)C(N)Cc1cc(F)cc(F)c1
Yield: 51 %

Procedure:
A solution of methyl 2-amino-3-(3,5-difluorophenyl)propanoate hydrochloride (3.67 g, 14.6 mmol) in aqueous ammonium hydroxide (5.5 mL) and water (22 mL) was stirred at ambient temperature for 18 hours and extracted with dichloromethane (4×50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness to give 2-amino-3-(3,5-difluorophenyl)propanamide as a colorless solid (1.50 g, 51%): 1H NMR (300 MHz, CD3OD) δ 6.92-6.75 (m, 3H), 3.56 (dd, J=7.3, 6.3 Hz, 1H), 3.00 (dd, J=13.4, 6.3 Hz, 1H), 2.83 (dd, J=13.4, 7.4 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][C@H:42]1[C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:51]([OH:53])=O)[CH:49]=2)[CH2:44][CH2:43]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[CH3:54][NH:55][CH:56]1[CH2:61][CH2:60][N:59]([C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:58][CH2:57]1>C1COCC1.ClCCl>[CH3:54][N:55]([CH:56]1[CH2:57][CH2:58][N:59]([C:62]2[CH:63]=[CH:64][N:65]=[CH:66][CH:67]=2)[CH2:60][CH2:61]1)[C:51]([C:48]1[CH:49]=[C:50]2[C:45]([CH2:44][CH2:43][C@H:42]2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:46][CH:47]=1)=[O:53]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(C(=O)O)cc21
Reactant: CNC1CCN(c2ccncc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)(C)C)CC2)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
HATU (0.795 g, 2.09 mmol, 1 eq) and DIPEA (350 μA 2.04 mmol, 2.5 eq) were added to an ice-cooled solution of (R)-3-(tert-butoxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylic acid (368 mg, 2.09 mmol, 1 eq) in THF (5 ml), and stirring was carried out for 30 min. N-Methyl-1-(pyridin-4-yl)piperidin-4-amine (AMN-06) (400 mg, 2.09 mmol, 1 eq) was dissolved in THF (5 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 0.5% MeOH in dichloromethane), the desired product was obtained in the form of a yellowish solid. Yield: 64% (600 mg, 1.33 mmol).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([CH:11]([CH:18]([CH3:20])[CH3:19])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)Cl.ClCCCl>[CH3:19][CH:18]([CH:11]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1)[CH3:20]
Reactant: CC(C)C(CCCC(=O)O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)C1CCCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
Thionyl chloride (5.6 ml, 77 mmol) was added to a solution of 5-phenyl-5-(2-propyl)pentanoic acid (8.35 g, 37.9 mmol) in chloroform (50 ml), followed by heating under reflux for 3.5 hours. Then, thionyl chloride (3.0 ml, 41 mmol) was added thereto and the resulting mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 1,2-dichloroethane (20 ml). The resulting solution was added dropwise to a suspension of aluminum chloride (10.1 g, 75.8 mmol) in 1,2-dichloroethane (100 ml) which had been cooled to 0° C., and the resulting mixture was stirred at 0° C. for 10 minutes. The reaction mixture was poured into a cold 1N hydrochloric acid and extracted twice with ethyl acetate, and the extract solution was washed twice with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to obtain 6.83 g of 9-(2-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: CO.Cl.[CH3:4]N(C)CCCN=C=NCC.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([O:33][CH3:4])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 56 h
Yield: 79.4 %

Procedure:
4-Dimethylaminopyridine (61 mg), methanol (45 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (192 mg) were added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287 mg) [see Preparation 38] in dichloromethane (6 ml). The reaction mixture was stirred at room temperature for 56 hours after which time it was diluted with dichloromethane and washed with 1N aqueous hydrochloric acid solution followed by saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 50:50, by volume, hexane:ethyl acetate, to afford methyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylate (239 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1F)#[N:17]>CS(C)=O>[C:16]([C:18]1[CH:19]=[C:20]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:33][N:32]=[CH:31][N:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][C:23]=1[S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:17]
Reactant: COc1cccc(S)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(Sc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3OC)c3ncns3)cc2C#N)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
3-Methoxythiophenol (0.0801 g, 0.571 mmol) and potassium carbonate (0.158 g, 1.14 mmol) were stirred in dimethylsulphoxide. 3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.248 g, 0.571 mmol) was added to the reaction mixture and the mixture stirred at 50° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. A 1M aqueous solution of sodium hydroxide was added to the mixture. The organic layer was separated and dried over MgSO4, filtered and concentrated in vacuo to afford a white solid. The solid was triturated in ethyl acetate and filtered to afford the title compound (0.204 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][NH:14][C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33]Cl.[I-].[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33][N:14]1[C:15](=[O:16])[C:11]2[C:10]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[C:3]([O:2][CH3:1])[C:12]=2[CH2:13]1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (17 mg, 0.049 mmol) was dissolved in dimethylformamide (0.3 ml) and cooled to 0° C. After adding sodium hydride (2.5 mg, 0.064 mmol), the reaction was stirred for 5 minutes at 0° C. 3,5-Dichlorobenzylchloride (11.5 mg, 0.059 mmol) and a catalytic amount of sodium iodide were then added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. It was then cooled to 0° C., acidified with acetic acid (0.030 ml), and concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (99/1-ethyl acetate/acetic acid) to afford 7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 307 (7 mg, 40%). 1H NMR (CDCl3) δ 9.0 (dd, 1H), 8.40 (dd, 1H), 7.60 (d, 2H), 7.55 (m, 1H), 7.20 (m, 3H), 6.80 (d, 2H), 5.60 (s, 2H), 4.75(s, 2H), 4.40 (s, 2H), 3.95 (s, 3H), 3.75 (s, 3H). MS: 509.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)CCC>C1(C)C=CC=CC=1.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>[F:23][C:22]1[C:17]([C:13]2[N:12]([CH2:11][C:6]3[C:7]([CH2:8][CH2:9][CH3:10])=[C:2]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:3]=[CH:4][N:5]=3)[CH:16]=[CH:15][N:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1-c1ccncc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (268 mg, 0.81 mmol), 4-tributylstannanyl-pyridine (1.21 mmol), Pd(PPh3)4 (0.08 mmol, 93 mg) in toluene (10 mL) is degassed. The mixture is then heated at 100° C. overnight. Saturated KF aqueous solution (8 mL) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is extracted with EtOAc (10 mL). The combined extracts are washed with brine (15 mL), dried (Na2SO4), and evaporated. Preparative TLC (5% methanol in DCM) purification of the residue provides the title product. 1H NMR (CDCl3) 8.95 (s, 1H), 8.65 (d, 1H), 8.26 (d, 1H), 7.77-7.84 (m, 2H), 7.49 (t, 1H), 7.34 (t, 1H), 7.30 (s, 1H), 7.19-7.22 (m, 1H), 7.14 (s, 1H), 5.92 (s, 2H), 2.87-2.91 (m, 2H), 1.46-1.52 (m, 2H), 0.81 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH2:28])[CH:18]=[N:19][C:20]=1[N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C.O1CCOCC1>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:28][C:17]2[CH:18]=[N:19][C:20]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[C:15]([CH3:14])[CH:16]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: Cc1cc(N)cnc1N1CCN(C)CC1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2cnc(N3CCN(C)CC3)c(C)c2)nc1Cl
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (500 mg), 5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-amine (470 mg), diisopropylethylamine (800 μL), and dioxane (10 mL) was stirred in a microwave reaction device at 150° C. for 30 minutes. After leaving to be cooled, water was added thereto, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 5-chloro-6-ethyl-3-{[5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide (210 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH2:17][O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:29])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:29])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl

Procedure:
A solution of 3-isobutyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (11.81 g, 29.9 mmol) in phosphoryl chloride (100 ml) was heated at reflux for 2.5 hours, then the excess phosphoryl chloride evaporated. Water was added and the product extracted into a mixture of dichloromethane and isopropyl alcohol. Drying and evaporation of the organic layer gave crude 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (12.0 g), contaminated with isopropyl alcohol. This was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6].[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O>[N:25]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[CH:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(O)C(=O)OCc1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])C(O)C(=O)OCc1ccccc1

Procedure:
Following the general procedure for the preparation of azides of Description 16, phenylmethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-hydroxybutanoate (32b) (0.10 g, 0.26 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 43 mg (0.66 mmol) of sodium azide (NaN3). After work-up, the crude title compound (32c) was used in the next step without further purification. MS (ESI) m/z 407.96 (M+Na)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18](S(C2C=CC=CC=2)(=O)=O)[C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[OH-].[K+].O>O1CCCC1.O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccco1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cnc2[nH]c(-c3ccco3)cc2c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of the compound obtained in the step of Example 1 (3) (675 mg) in a mixture of tetrahydrofuran/dioxane (5:1, 120 ml), a 1N aqueous potassium hydroxide solution (5 ml) was added and the mixture was stirred at 60° C. for 15 hours. The reaction solution was then poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 431 mg (98%) of the desired product as a brown powder.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[C:26]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccc(C(F)(F)F)c2)C1
Yield: 88.2 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-trifluoromethylphenylboronic acid (173 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (210 mg, 88.2%) as an oil.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[C:19](O)[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1.O=P(Cl)(Cl)Cl.N1CCCCC1.[CH3:35][O:36][C:37](=[O:48])[CH2:38][C:39]1[S:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1>CN(C=O)C.C1(C)C=CC=CC=1>[S:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[C:38]1[C:37](=[O:48])[O:36][C:35]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[C:17]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][OH:7])[CH2:16][CH2:15]1)[CH:18]=2
Reactant: Oc1cccc(N2CCN(CCCOC3CCCCO3)CC2)c1
Reactant: COC(=O)Cc1nc2ccccc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=c1oc2cc(N3CCN(CCCO)CC3)ccc2cc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.6 %

Procedure:
320 mg (1 mmol) 3-{4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-piperazin-1-yl}-phenol is dissolved in 10 mL DMF and treated below 10° C. with 0.1 mL POCl3. The reaction mixture is stirred at room temperature for 6 hours, then evaporated and the crude product taken up in 10 mL acetonitrile and treated with 0.6 mL (6 eq.) piperidine. 207 mg benzothiazol-2-yl-acetic acid methyl ester in 10 mL toluene are added and the reaction mixture stirred for 30 minutes at 90° C. before being evaporated. The residue is taken up in 20 mL anhydrous THF, stirred for two hours in the presence of 1 mL of a 6N aqueous HCl solution and evaporated. The residue is taken up in dichloromethane and washed with aqueous sodium bicarbonate and saline. The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH/aq. NH3 90:9.9:0.1) to yield 70 mg (17%) desired product as a yellow-orange powder.