Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[NH2:9][CH2:10][C@H:11]([CH3:39])[O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[C:26]([Cl:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>>[Cl:38][C:26]1[CH:25]=[C:24]([NH:23][C:15]2[C:14]3[C:19](=[CH:20][CH:21]=[CH:22][C:13]=3[O:12][C@@H:11]([CH3:39])[CH2:10][NH:9][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:18]=[CH:17][N:16]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CS(=O)(=O)CC(=O)O
Product: C[C@@H](CNC(=O)CS(C)(=O)=O)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 72 %

Procedure:
The procedure described in Example 1 was repeated using methanesulfonylacetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 72% yield; NMR spectrum (DMSO-d6) 1.42 (d, 3H), 3.02 (s, 3H), 3.49 (m, 1H), 3.76 (m, 1H), 4.06 (s, 2H), 4.89 (m, 1H), 5.28 (s, 2H), 7.22 (m, 2H), 7.34 (m, 2H), 7.56 (d, 2H), 7.72 (t, 1H), 7.86 (dt, 1H), 8.15 (d, 1H), 8.48 (s, 1H), 8.58 (d, 1H), 8.71 (t, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 556.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:39][CH:40]([F:42])[F:41])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1OC1CCN(CC(F)F)CC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 65 °C
Yield: 95.6 %

Procedure:
To a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (450 mg, 0.88 mmol) in THF (8 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (282 mg, 1.32 mmol) in THF (1 mL), followed by DIPEA (250 μL). The resultant reaction mixture was heated at 65° C. for 7 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (485 mg, 96%). 1H NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 2H), 7.78 (t, J=7.5 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 6.13 (tt, J=55.8, 4.3 Hz, 1H), 4.85-4.85 (m, 1H), 3.17-3.12 (m, 2H), 2.75 (td, J=15.7, 4.3 Hz, 2H), 2.37 (t, J=10.9 Hz, 2H), 2.08-2.07 (m, 2H), 1.96-1.95 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([OH:15])=O)=[CH:11][N:12]=2)[CH:9]=1)(=[O:3])[NH2:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.C[NH:28][C:29]1[CH:34]=[C:33]([C:35]2[N:39]=[C:38]([CH:40]3[CH2:43][C:42]([F:45])([F:44])[CH2:41]3)[O:37][N:36]=2)[CH:32]=[CH:31][C:30]=1[CH3:46]>ClCCl.N1C=CC=CC=1>[F:45][C:42]1([F:44])[CH2:41][CH:40]([C:38]2[O:37][N:36]=[C:35]([C:33]3[CH:32]=[CH:31][C:30]([CH3:46])=[C:29]([NH:28][C:13]([C:10]4[N:8]5[CH:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=[CH:6][C:7]5=[N:12][CH:11]=4)=[O:15])[CH:34]=3)[N:39]=2)[CH2:43]1
Reactant: CNc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1C
Reactant: NC(=O)c1ccc2ncc(C(=O)O)n2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(C(N)=O)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-carbamoylimidazo[1,2-a]pyridine-3-carboxylic acid (110) (50 mg, 0.172 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (16 uL, 0.189 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated. A stirring mixture of the acid chloride and methyl 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (23 mg, 0.0861 mmol) in anhydrous pyridine (2 mL) was stirred at room temperature for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give N3-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3,6-dicarboxamide (F62). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.99-9.98 (m, 1H), 8.68 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.98 (dd, J=1.6, 9.2 Hz, 1H), 7.88-7.83 (m, 2H), 7.66 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 3.91-3.84 (m, 1H), 3.22-3.06 (m, 4H), 2.38 (s, 3H). MS m/z 452.14 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CN(C=O)C.Cl.[F:29][C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32]>O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:32][CH2:31][C:30]([F:29])([CH3:34])[CH3:33])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(F)CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(F)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (2.76 g, 27.3 mmol) was added to a mixture of 2,4-dichloro-3-nitroquinoline (André et al, U.S. Pat. No. 4,988,815, Example 2, 4.44 g, 18.2 mmol) and DMF (50 mL), and then 2-fluoro-2-methylpropan-1-amine hydrochloride (2.5 g, 20 mmol) was added. The reaction was stirred at room temperature overnight and then poured into water (500 mL). The resulting mixture was stirred for 15 minutes. A solid was present and was isolated by filtration to provide 4.8 g of 2-chloro-N-(2-fluoro-2-methylpropyl)-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[Cl:47][CH2:48][CH2:49][CH2:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[Cl:47][CH2:48][CH2:49][CH2:50][S:51]([NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)(=[O:53])=[O:52]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)CCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 12 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2Cl2 (2 mL) was added 3-chloropropane-1-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at 12° C. for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.O>O1CCOCC1.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][CH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1)=[O:4]
Reactant: NCCc1cc[nH]n1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccccc1C(=O)NCCc1cc[nH]n1
Temperature: 25 °C

Procedure:
A slurry containing 17.7 g (O.109 mol) of isatoic anhydride in 80 ml of dioxane was slowly added to a cold (0° C.) solution of 12.1 g (O.109 mol) of 3-(2-aminoethyl)pyrazole in 150 ml of dioxane, under nitrogen. The reaction solution was gradually warmed to room temperature and allowed to react overnight. When the reaction was complete, as indicated by thin layer chromatography, water was added and the solution was reduced to dryness under reduced pressure. The resultant residue was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with water and reduced to dryness to provide an oil. This oil was purified by crystallization from dichloromethane, followed by recrystallization from an ethyl acetate/diethyl ether solution, to provide 12.8 g of the desired subtitled intermediate (m.p. 97°-99° C.).
Reaction SMILES: C[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[C:3]=1[CH2:22][CH2:23][CH3:24].C1C=C[NH+]=CC=1.[Br:31][Br-]Br>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[Br:31][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])[C:3]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(C)c2ccc(C(N)=O)cc2n1Cc1ccccc1Br
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Br)c2ccc(C(N)=O)cc2n1Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a stirred solution of methyl 1-(2-bromobenzyl)-2-propylindole-6-carboxamide (52 mg) in a mixture of dichloromethane (3 ml) and pyridine (1 ml) was added pyridinium bromide perbromide (50 mg), and the mixture was stirred at 0° C. for 1.5 hours. The resulting mixture was diluted with ethyl acetate and washed with diluted hydrochloric acid, aqueous sodium bicarbonate and brine, then dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of hexane and diisopropyl ether to give 3-bromo-1-(2-bromobenzyl)-2-propylindole-6-carboxamide (33 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O.N1C2C=CC=CC=2N=N1.[BH4-].[Na+]>O.CO>[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCCC1=O
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2[nH]nnc2c1
Solvent: CO
Solvent: O
Product: CC1CCCCC1Nc1ccccc1
Yield: 37 %

Procedure:
In a 100-mL flask, the following mixture is heated at reflux for 30 h: 9.3 g aniline, 11.2 g 2-methylcyclohexanone and 12 g benzotriazole. Then, 200 mL of methanol and 5 g of NaBH4 in portions are added to the mixture, which is then heated at reflux for 30 min. The solution is allowed to cool, and 100 mL of water are added to the mixture, which is extracted with 2×100 mL diisopropyl ether. The organic phase is recovered, dried over magnesium sulfate and reduced to dryness. In this manner, 7 g of the desired amine are produced.
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.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.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>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[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
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1cccs1
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: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2cccs2)C1
Yield: 79.8 %

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 2-thiopheneboronic acid (117 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 (160 mg, 79.6%) as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:43][CH2:44][CH2:45][CH3:46])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][C:15]=2[CH3:40])=[C:8]([O:41][CH3:42])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:43]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:15]([CH3:40])=[CH:16][C:17]([CH2:21][OH:22])=[C:18]([CH3:20])[CH:19]=2)=[C:8]([O:41][CH3:42])[CH:7]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO)cc2C)c(OC)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 2.7 g (4.26 mmol) of dibutyl[4-[2-[4-(tert-butyldiphenylsiloxymethyl)-2,5-dimethylphenyl]vinyl]-3-methoxyphenyl]amine, and 13.0 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 3 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.57 g of a yellow liquid (yield: 93.5%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:22]1[CH2:28][CH2:27][CH2:26][C@@H:23]1[CH:24]=O)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCCl.ClCCl.O>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:24][C@H:23]2[CH2:26][CH2:27][CH2:28][NH:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(Oc2cccc(NC[C@H]3CCCN3)c2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3-phenoxyaniline (0.3 g, 1.62 mmol) in 1,2-dichloroethane (4 ml) were added N-(tert-butoxycarbonyl)-D-prolinal (0.322 g, 1.62 mmol) and sodium triacetoxyborohydride (0.480 g, 2.26 mmol). The resulting suspension was stirred overnight at 50° C. The mixture was then cooled to room temperature, water (8 ml) was added and extracted with ethyl acetate (3×20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=70:30) to yield a light yellow oil that was dissolved in dichloromethane (4 ml). Trifluoroacetic acid (1 ml) was added and the mixture was stirred for 3 h at room temperature. Aqueous sodium hydroxide solution (4N) was added until basic pH and the mixture was extracted with ethyl acetate (2 times 30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate) to yield a colourless oil, (0.256 g, 59%); MS (ISP): 269.1 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:13])[N:3]=1
Reactant: O=[N+]([O-])c1cccc2nc(O)c(O)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cccc2nc(O)c(O)nc12

Procedure:
2.00 g of 2,3-dihydroxy-5-nitroquinoxaline was dissolved in 100 g of a 1:1 methanol and dioxane solvent, after which the reaction system was well purged with argon, followed by further addition of 1.00 g of 5% Pd/C (hydrous). Thereafter, the system was purged with hydrogen, followed by reaction at room temperature for 20 hours. After completion of the reaction, the reaction product was dispersed in a solution of 6.00 g of potassium carbonate in 130 ml of water and then dissolved therein. 35% hydrochloric acid was gradually added to the solution obtained after filtration thereby obtaining a precipitate.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][OH:19])[CH2:4][CH2:3][CH2:2]1.O[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]3)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][O:19][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[C:33]([C:37]([O:39][CH3:40])=[O:38])=[CH:32][CH:31]=[CH:30]4)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 100 °C
Yield: 24.6 %

Procedure:
To a solution of [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (150 mg, 0.503 mmol), methyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (140 mg, 0.503 mmol), triphenylphosphine (145 mg, 0.553 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.099 mL, 0.553 mmol) dropwise. The solution was heated in a microwave reactor at 100° C. for 10 minutes. The product was purified by chromatography (silica gel, 0-15% ethyl acetate in hexanes gradient elution) to afford a white solid (0.069 g, 25%). 1H-NMR (DMSO-d6,) 8.77 (d, J=9 Hz, 1H), 8.23-8.20 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.93 (d, J=11 Hz, 1H), 7.70-7.51 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 3.92 (s, 3H), 2.43-2.31 (m, 4H), 2.10-1.92 (m, 2H). APCI-LCMS m/z 558 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:35])=O)(C)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[CH2:48][C:46](=[O:47])[NH:45][CH:44]3[C:38]3[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=3[Cl:36])[C:11]2=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(F)ccc1Cl)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2Cl)C12C(=O)Nc1cc(Cl)ccc12
Yield: 11.2 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.76 mmol) was reacted with 1-(2-chloro-5-fluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (23 mmol) in toluene to give the title compound as a white solid (400 mg).
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[C:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[S:9][N:8]=[CH:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Clc1cccc2c1-c1ccccc1SN=C2
Reactant: C1CNCCN1
Product: C1=NSc2ccccc2-c2c1cccc2N1CCNCC1

Procedure:
EP 0282236-A1 describes that a dibenzothiazepine derivative of the above-mentioned formula (5) can be processed to give 11-[4-(2-(2-hydroxyethoxy) ethyl]-1-piperadinyldibenzothiazepine derivative which is of value as an antipsychotic pharmaceutical. In more detail, dibenzo-[b,f] [1,4]thiazepin-11-one, which is a representative compound of the dibenzothiazepine derivatives of the formula (5), is reacted with phosphorus oxychloride to yield a 11-chloro-dibenzothiazepine derivative; and to the 11-chloro-dibenzothiazepine derivative is added piperazine to yield a 11-piperazinyl-dibenzothiazepine derivative, which is subsequently reacted with 2-chloro-ethoxyethanol under basic conditions to give the desired 11-[4-(2-(2-hydroxyethoxy)ethyl]-1-=piperadinyldibenzothiazepin.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH2:32][O:33]C3CCCCO3)[N:29]=[C:28]([CH3:40])[CH:27]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:40])[N:29]=[C:30]([CH2:32][OH:33])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 1.5 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (140 mg, 35%).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH2:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:46]([NH:48][C@H:49]([C:55]([OH:57])=[O:56])[CH2:50][CH2:51][C:52](=[O:54])[NH2:53])=[O:47])[CH3:45])=[O:42])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.41 Grams of Z-Ile-OSu, the above-obtained H-Leu-Leu-Ala-Gln-OH and 0.36 ml of triethylamine were dissolved in 50 ml of dimethylformamide, then the mixture was stirred at a room temperature for 20 hours. After removal of dimethylformamide by distillation, 1N-citric acid was added to the residue, and crystals being precipitated were collected by filtration and washed with hot methanol to obtain 1.17 g of Z-Ile-Leu-Leu-Ala-Gln-OH.