Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[K].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4]([S:24][C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH:3]=1
Reactant: NC(=O)c1cc([N+](=O)[O-])cc(Br)n1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Sc2ccc([N+](=O)[O-])cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
0.25 g (0.001 mol) of 6-bromo-4-nitropyridine-2-carboxamide was dissolved in 5 ml of dimethylformamide, treated with 0.19 g (0.001 mol) of 4-nitrothiophenol potassium salt and stirred at room temperature for 18 hrs. The reaction mixture was partitioned in water and ethyl acetate and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4 and concentrated in a vaccum. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.31 g (86%) of 6-bromo-4-(4-nitrophenylsulphanyl)-pyridine-2-carboxamide as yellowish crystals; m.p.: 192-194° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][O:27]C4CCCCO4)[CH:24]=3)[N:15]=2)[CH:11]=[CH:10][N:9]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][OH:27])[CH:24]=3)[CH:17]=[N:18][CH:19]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Fc1ccccc1-c1cc(-c2cncc(-c3cnn(CCOC4CCCCO4)c3)n2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: OCCn1cc(-c2cncc(-c3ccnc(-c4ccccc4F)c3)n2)cn1

Procedure:
680 mg of the above prepared 2-[2-(2-fluoro-phenyl)-pyridin-4-yl]-6-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyrazine are dissolved in 12 ml dioxane. 1.1 l of HCl in dioxane (4 mol/l) is added. The product precipitates from the solution and is filtered. 147 mg of 2-(4-{6-[2-(2-fluoro-phenyl)-pyridin-4-yl]-pyrazin-2-yl}-pyrazol-1-yl)-ethanol are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=433.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH3:16])[CH:8]=1)(=O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1>[CH3:16][C:9]1[CH:8]=[C:7]([C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:12]=[CH:11][C:10]=1[C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4-acetyl-3-methylphenyl trifluoromethanesulfonate (6.90 g, 24.0 mmol), 4-nitrophenylboronic acid (3.80 g, 24 mmol), 2 N aqueous sodium carbonate (88.0 mL), dioxane (88.0 mL), and toluene (296 mL) was purged with argon for 30 minutes before [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 1.90 g, 2.30 mmol) was added. The reaction mixture was heated at 85° C. and stirred overnight. The layers were separated and the organic layer was washed with water (2×50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. This material was purified by flash chromatography (7 to 20% ethyl acetatethexane) to give 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (6.12 g, 99% yield). GC-MS m/z 255 (M+), ret. time 9.89 min; 1H NMR (CDCl3) δ: 2.61 (s, 3H), 2.62 (s, 3H), 7.49-55 (m, 2H), 7.78 (d, 2H), 7.81 (d, 1H), 8.32 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCN(CC1CCNCC1)C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCC(CN2CCc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.8 %

Procedure:
2,5-dichlorobenzene-1-sulfonyl chloride (108.1 mg, 0.44 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (92.1 mg, 0.40 mmol) and N,N-diisopropylethylamine (206.9.2 mg, 1.60 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (138 mg, 78%).
Reaction SMILES: C(CN)O.C([O:12][C:13]1[CH:14]=[C:15]([C:24](=[O:28])[CH:25](O)O)[C:16]2[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=2[CH:23]=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>>[Br:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:40][CH2:25][CH:24]([C:15]2[C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=[C:13]([OH:12])[CH:14]=2)[OH:28])([CH3:38])[CH3:39])=[CH:34][CH:35]=1
Reactant: CC(C)(N)Cc1ccc(Br)cc1
Reactant: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)C(O)O)N1
Solvent: NCCO
Product: CC(C)(Cc1ccc(Br)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The preparation of the ethanolamine and debenzylation were carried out as described in Example 19 from 300 mg (0.91 mmol) of 6-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 250 mg (1.09 mmol) of 2-(4-bromophenyl)-1,1-dimethylethylamine. Beige solid. Yield: 54 mg (14%); mass spectrometry: [M+H]+=435, 437.
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:7])[CH:6]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>>[C:17]([O:7][C:5]1[N:4]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:2]([CH3:1])[CH:6]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(=O)n(CCOc2ccccc2)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Oc1cc(C)nn1CCOc1ccccc1

Procedure:
0.1 mol (21.8 g) of 3-methyl-1-(β-phenoxyethyl)-5-pyrazolone was heated with 0.2 mol (20.4 g) of acetic anhydride in the presence of 0.11 mol (8.2 g) of sodium acetate for 2 hours.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH:35]([C:37]1[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:35][C:37]4[CH:38]=[C:39]([CH2:43][CH:44]([CH3:47])[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=4)[CH2:16][CH2:17]3)[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:10](=[O:25])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1cccc(F)c1
Reactant: CC(C#N)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C#N)Cc1cccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)c1
Reaction time: 0.17 h

Procedure:
To a 20 mL dichloroethane solution of 0.35 g (0.92 mmol) 4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one and 0.25 mL (1.4 mmol) DIEA went 0.16 g (0.92 mmol) 3-(3-formylphenyl)-2-methylpropanenitrile (9-3). The suspension was allowed to stir for 10 min then 0.4 g (1.9 mmol) sodium triacetoxyborohydride was added and the reaction was allowed to stir at rt overnight. HPLC/MS showed no starting material so the reaction was quenched with 100 mL sat NaHCO3 and diluted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 5% MeOH+0.5M NH3 in CH2Cl2 at 25 mL/min over 30 min. The product eluted second.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:2]([CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH3:1])=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)OCCc1ccc(Cl)cc1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1ccc(Cl)cc1)CCN1c2ccccc2COc2ccccc21
Temperature: 70 °C
Reaction time: 22 h

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol), 4-chlorophenethyl mesylate (352 mg, 1.50 mmol), sodium carbonate (160 mg, 1.50 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (25 ml), and they were heated at 70° C. under stirring for 22 hours and then at 90° C. under reflux for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (100:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5-[2-[N-(4-chlorophenethyl)-N-methyl-amino]ethyl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (171 mg, 44%).
Reaction SMILES: [C:1]([C:3](=[CH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:9][C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:14][CH:15]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5])#[N:2]
Reactant: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To a 25 ml one necked round bottom flask 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide (0.1 g, 0.000182 mole) was taken in CH2Cl2 (10 ml). To this reaction mixture TFA (2.0 ml) was added dropwise at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and then stirred for 16 hrs. After completion of the reaction, CH2Cl2 was distilled out and set pH 8 to 9 using saturated NaHCO3 solution (20.0 ml) at 5° C. Reaction mixture was stirred for 15 min. The solid was filtered, washed with methanol followed by n-pentane and dried under vacuum to yield 40 mg of 2-cyano-N,N-dimethyl-3-(6-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)pyridin-3-yl)acrylamide.
Reaction SMILES: C([O:5][P:6]([O:39]C(C)(C)C)([O:8][CH:9]([CH3:38])[CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[P:6]([O:8][CH:9]([CH3:38])[CH2:10][O:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[C@@:16]([C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])([F:27])[C:15]1=[O:37])=[O:13])([OH:7])([OH:39])=[O:5]
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCC(C)OP(=O)(O)O)c2cc(C(F)(F)F)ccc21
Yield: 57.4 %

Procedure:
A solution of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid 2-(di-tert-butoxy-phosphoryloxy)-propyl ester ((S)-VII, n=2) (540 mg, 0.82 mmol) in dichloromethane (30 mL) was stirred with trifluoroacetic acid (0.6 mL) at room temperature for 3 hours. LC-MS indicated the completion of the reaction. After removal of the solvent the residue was dissolved in methanol and the crude product was purified by prep. HPLC, affording the title compound 255 mg (57%) as white solid after lyophilization. 1H NMR (CDCl3, 500 MHz) δ 8.27 (s, 1H), 7.73 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 6.75 (d, 1H), 4.50 (b, 6H, containing some H2O as solvate), 4.54 (m, 2H), 4.17 (b, 2H), 3.49 (s, 3H), 2.1 (m, 2H); MS (m/e) 539.92 (M+−1); LC-MS, 542 (MH+, 98.5%); 31P NMR (CDCl3, 500 MHz) δ 2.03; 19F NMR (CDCl3, 500 MHz) δ−63.4, 153.8; Anal. Calcd. for C20H17ClF4NO8P: C=44.34%, H=3.16%, N=2.58%; Found: C=44.01%, H=3.11%, N=2.45%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:20]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](=O)[CH2:33]Br)=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C(#N)C>[C:20]([N:23]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 70 °C
Yield: 54.8 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (0.750 g, 4.03 mmol) in dry acetonitrile (20 mL) grounded potassium carbonate (0.486 mL, 8.05 mmol) was added followed by the product mixture from Example 38a (1.134 g) and the reaction was heated at 70° C. under argon over night. The acetonitrile was evaporated and DCM and water was added. The layers were separated and the aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude mixture was purified by flash chromatography (heptane/EtOAc 75/25 to 0/100) to give 0.823 g (55%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.ClC1C=C([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:9]2[C:4](=[C:5]([CH3:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1C
Product: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Yield: 50 %

Procedure:
2-Chloro-8-methyl-7-methoxy-4-(4-methoxy-benzyloxy)-quinoline 221b was synthesized from compound 220b as a white powder in 50% yield, following the procedure as described for compound 221d. 1H NMR (CDCl3, 376 MHz) δ (ppm) 2.60 (s, 3H), 3.85 (s, 3H), 3.97 (s, 3H), 5.18 (s, 2H), 6.69 (s, 1H), 6.97 (d, J=8.57 Hz, 1H), 7.19 (d, J=8.57 Hz, 1H), 7.42 (d, J=8.57 Hz, 1H), 8.02 (d, J=8.57 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)[CH2:7][NH2:8])[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:19])[NH:5][C@@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)[CH2:7][NH:8][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:2]
Reactant: CCOC(=O)N[C@H](CN)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N[C@H](CNCc1ccc(OC)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Crude (S)-[2-amino-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester from above is dissolved in anhydrous EtOH (100 mL). p-Anisaldehyde (2.07 g, 15.2 mmol) is added into the solution and stirred at room temperature for 5 h before the addition of NaBH4 (0.82 g, 21.8 mmol) at 0° C. The mixture is then warmed up to room temperature and stirred for 14 hr. After the solvent is removed under vacuum, the residue is treated with saturated NH4Cl aqueous solution (50 mL) and extracted with EtOAc (3×150 mL). The combined organic layer is washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated to provide the crude (S)-[2-(4-methoxy-benzylamino)-1-(3-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester as colorless oil (˜6.0 g) which is used directly for next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[C:10]([CH3:24])([CH3:23])[N:9]=1.[H-].[Na+].[C:27]([NH:30][NH2:31])(=O)[CH3:28]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:27]([CH3:28])=[N:30][N:31]=[C:11]2[C:10]([CH3:24])([CH3:23])[N:9]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: CC(=O)NN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1F)=NC2(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
55.25 g (0.16 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one, dissolved in 800 ml of tetrahydrofuran, are treated portionwise and while stirring at room temperature with 9.7 g of a 55 to 60 percent sodium hydride dispersion and the mixture is stirred at 50° C. for a further 60 minutes. 100 g (0.39 mol) of dimorpholinochlorophosphate are added to the cooled solution and the mixture is stirred at room temperature for 24 hours. After the addition of 50 g (0.67 mol) of acetic acid hydrazide, the mixture is stirred at room temperature for a further 45 hours and concentrated in vacuo. The residue is taken up in methylene chloride; the organic phase is washed with water and the solvent is removed. The residue is treated with 1.2 liters of n-butanol and heated to boiling under reflux. After distilling off 350 ml of solvent, the mixture remaining is heated at reflux for a further 1 hour and concentrated in vacuo. The residue is dissolved in 250 ml of hot ethanol. After cooling to -10° C., there is obtained crystalline 6-(o-fluorophenyl)-1,4,4-trimethyl-8-nitro-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 195° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:20])=[CH:17][CH:16]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N[C@@H](CO)C(=O)O)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
L-Serine (100 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), potassium carbonate (131.5 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), and water 1 L were placed into a recovery flask (egg plant flask), followed by stirring vigorously. p-Methylbenzoyl chloride prepared in Step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries, Ltd.), which was added dropwise to this solution for 30 minutes. During this process, pH was maintained in the vicinity of 8 while additionally adding potassium carbonate. After the completion of the dropwise addition, the agitation was performed for 1 hour. The reaction solution was added to water 1 L which was prepared in a distinct vessel, and then pH was adjusted to not more than 3 with hydrochloric acid, followed by being cooled to 4° C. Precipitated crystals were filtrated, followed by being recrystallized with a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.)/water=6/4. An objective substance was obtained in an amount of 106.0 g (yield: 64.7%).
Reaction SMILES: [ClH:1].[CH2:2]([NH:10][C:11](=[O:25])[C@H:12]([C@H:21]([CH2:23][CH3:24])[CH3:22])[NH:13]C(OC(C)(C)C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCCCCC>CCOC(C)=O>[ClH:1].[CH2:2]([NH:10][C:11](=[O:25])[C@H:12]([C@H:21]([CH2:23][CH3:24])[CH3:22])[NH2:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@H](C)[C@H](N)C(=O)NCCc1ccccc1
Yield: 100 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of N-t-butoxycarbonyl-L-isoleucine-phenethylamide (3.1 g, 9.3 mmol) in EtOAc (200 mL) at -20° C. in a dry ice-acetone bath until TLC (EtOAc: hexane, 1:3) indicated complete loss of starting material. The solution was concentrated to dryness to give 2.5 g (100%) of the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:21](=O)[C:20]2[C:19]([C:31]([O:33]CC)=O)=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[NH:14][C:15]2[C:20]3[C:21](=[N:37][NH:38][C:31](=[O:33])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:22]1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1Cc1ccccc1)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1nccn1Cc1ccccc1)C2c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of ethyl 2-(1-benzyl-1H-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (280 mg, 0.59 mmol) and hydrazine monohydrate (2 mL, 85%) in methanol (4 mL) was stirred at 40° C. for 2 hr, and then evaporated to half of the original volume. The mixture was filtrated and washed the solid with ethyl acetate to obtain the title compound (200 mg, yield 96%). LC-MS (ESI) m/z: 437 (M+1)+.