Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCOCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(N3CCOCC3)c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A mixture of tert-butyl 9-(morpholin-4-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.449 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (97.5 mg, 70.8%) as a solid.
Reaction SMILES: [N:1](=[CH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[N:6][CH:5]=1)O>C(OC(=O)C)(=O)C>[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([C:3]#[N:1])=[CH:5][N:6]=1
Reactant: ON=Cc1cnnc2ccccc12
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cnnc2ccccc12

Procedure:
A stirred solution of 0.173 g of 27B in 5 ml of acetic anhydride was refluxed overnight under nitrogen. The mixture was stripped under reduced pressure, and the residue was recrystallized from hexane to give cinnoline-4-carbonitrile (27C), as a yellow crystalline solid, m.p.: 140° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:28])[C:26]=1[F:27]>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:23]3[CH:22]=[C:21]([F:20])[C:26]([F:27])=[C:25]([F:28])[CH:24]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (37 mg, 40%), MS (ISP) m/z=370.4 [(M+H)+], mp 306° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [CH:1]12[NH:17][CH:5]([CH:6]([C:8]3[CH:9]=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][CH:13]=3)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([CH:6]2[CH2:7][CH:1]3[N:17]([C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:5]2[CH2:4][CH2:3][CH2:2]3)=[CH:13][N:12]=1
Reactant: CN(C)c1ccc(C2CC3CCCC2N3)cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(C2CC3CCCC2N3C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
217 mg (0.94 mmol, 1 eq) of (−)-[5-(8-aza-bicyclo[3.2.1]oct-6-yl)-pyridine-2-yl]-dimethylamine (VII-1) are dissolved in 1 ml of chloroform. 195 μL (1.4 mmol, 1.5 eq) of TEA and 274 mg (0.98 mmol, 1.05 eq) of tritylchloride are added. After stirring for 1 and 2.5 h at RT 195 μL (1.4 mmol, 1.5 eq) of TEA and 274 mg (0.98 mmol, 1.05 eq) of tritylchloride are added. After stirring for a total of 4 h at RT it is diluted with EE. It is washed once with water, the aqueous phase is re-extracted twice with EE. The combined organic phases are dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (EE:hex=1:3). 158 mg (0.33 mmol, 35%) of a colorless foam is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18](O)=[O:19])[CH:13]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:19])[CH:13]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)ccn1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
174 mg (1.27 mmol) 5-fluoro-2,3-dihydro-1H-indole were added to 200.0 mg (1.27 mmol) 4-chloropyridine-2-carboxylic acid, 351 μL (2.50 mmol) triethylamine and 434.0 mg (1.35 mmol) TBTU in 3 mL DMF. The reaction mixture was stirred overnight at RT. Purification was carried out by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[Li+].CC([N-]C(C)C)C.C1C(=O)N([Cl:27])C(=O)C1>C1COCC1>[Cl:1][C:2]1[C:3]([Cl:27])=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(=O)c1ccnc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(=O)c1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methyl-isonicotinamide (12-2, 1.19 g, 6.98 mmol) was dissolved in 20 mL anhydrous THF and the solution was cooled to −78° C. LDA (2M, 7.33 mL, 14.7 mmol) was added dropwise and the reaction turns orange. After 15 min NCS (1.02 g, 7.67 mmol) was added and the reaction was allowed to warm to RT. After 1 h at RT HPLC shows ˜3:1 starting material/product. The reaction was quenched with water, extracted 3× w/ EtOAc, and the organic phases were dried over Na2SO4, filtered, and concentrated. The residue vias purified by preparative reverse phase HPLC to afford the pure titled compound. 1H NMR (CDCl3) δ8.36 (d, 1H, J=4.8 Hz), 7.41 (d, 1H, J=4.8 Hz), 6.10 (bs, 1H), 3.05 (d, 3H, J=4.9 Hz).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:9][C:7]=3[CH:8]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1

Procedure:
reacting 4-[2-(2-hyd roxyethyl)-1-benzofuran-5-yl]benzonitrile with para-toluenesulfonyl chloride and N,N-dimethylaminopyridine, in the presence of a base, such as triethylamine, to provide 2-[5-(4-cyanophenyl)-1-benzofuran-2-yl]ethyl 4-methylbenzenesulfonate; and
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]=2[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]1=2.[NH2:30][CH2:31][CH2:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38]>>[CH3:38][N:37]([CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH2:32][CH2:31][NH:30][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1)[CH2:39][CH2:40][NH:41][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3ccccc3c3c2C(=O)c2ccncc2-3)cc1
Reactant: CN(CCN)CCCN(C)CCN
Product: CN(CCCN(C)CCNc1nc2ccccc2c2c1C(=O)c1ccncc1-2)CCNc1nc2ccccc2c2c1C(=O)c1ccncc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 6c-1) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[S-:11][C:12]#[N:13].[K]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH:10][C:12]([NH2:13])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: N#C[S-]
Agent: [K]
Solvent: O
Product: NC(=S)NNc1ccc(Cl)c(Cl)c1
Yield: 95 %

Procedure:
A mixture of 3,4-dichlorophenylhydrazine (18.8 mmol) and thiocyanate of potassium (55.7 mmol) was dissolved in water (1 L) and heated for 17 hours. After cooling the product the solid was filtered and dried in vacuo to give 3,4-dichlorophenylthiosemicarbazide (4.20 g, yield=95%). H1NMR (300 MHz, DMSO, 25° C.) δ: 9.37 (s, 1H); 8.30 (s, 1H); 7.84 (s, 1H); 7.60 (s, 1H); 7.40 (d, J=8.7 Hz, 1H); 6.37 (d, J=2.52 Hz. 1H); 6.60 (dd, J=8.67 Hz, J=2.5 Hz. 1H) ppm. EM (ES+) m/z=236 (100%) [M+H]+.
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:1].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(N)ccc1NC1=NCCCC1
Agent: Cl
Product: CCOC(=O)Nc1ccc(NC2=NCCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 21 using 30.5 mmole of ethyl chloroformate and 1.0 g (3.6 mmole) of the product compound of Example 14. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:14]3=[N:15][CH:16]=2)=[NH:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:21])=[O:22])[C:14]3=[N:15][CH:16]=2)[NH2:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
To a flask was added (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanimine (1.36 g, 3.35 mmol, Preparation #AF.1) and NaBH4 (0.127 g, 3.35 mmol) in MeOH (20 mL). The mixture was stirred for about 30 min at rt. The mixture was concentrated in vacuo, DCM (10 mL) was added to the residue and the insoluble material was removed via filtration. The filtrate was loaded on a 40 g silica column and product was eluted with 50 to 100% EtOAc/DCM to provide (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine (0.595 g, 44%): 1H NMR (d-DMSO) δ 8.56 (s, 1H), 8.29-8.24 (m, 1H), 8.02-7.96 (m, 2H), 7.43 (dd, J=8.3, 0.9 Hz, 2H), 7.36-7.31 (m, 2H), 6.96 (d, J=4.1 Hz, 1H), 6.84 (m, 2H), 5.22 (s, 1H), 3.68 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]#[N:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C#N)C(c2cccc(Br)c2)NC(=O)N1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(Br)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-(2H)-pyrimidine (0.29 g, 1 mmol) in THF (5 mL) chilled to −78° C. was added LDA (0.55 mL, 1.1 mmol, 2.0 M in THF). The resulting yellow suspension was stirred for 0.5 h, warmed to −20° C. for 0.5 h and recooled to −78° C.; then ethyl chloroformate (0.14 mL, 1.5 mmol) was added via syringe. The reaction mixture was stirred for 20 min, warmed to room temperature and quenched with EtOAc. This mixture was washed with aqueous NaHCO3 solution and with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash column chromatography (10% to 30% EtOAc/hexanes) to give, after evaporation of solvent, 6-(3-bromophenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl ester as a colorless solid (0.29 g; 80%): 1H NMR (CDCl3, 400 MHz) δ 7.48 (m, 2H), 7.28 (m, 2H), 5.87 (s, 1H), 4.33 (m, 2H), 2.22 (s, 3H), 1.33 (t, 3H, J=7.0 Hz); LC/MS (ES+) 364 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([O:6][CH2:7][C@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (12 mL, 0.15 mol) was added to a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (28 g, 0.13 mmol) in CH2Cl2 (172 mL) and triethylamine (23.4 mL, 0.17 mol) at 0° C. The resulting mixture was stirred at a temperature of from 0° C. to room temperature over 1.5 hr. The mixture was then diluted with water (35 mL), and the phases were separated. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and filtered on a pad of silica gel, which was rinsed with CH2Cl2. The filtrate was concentrated under reduced pressure to the title product (37.7 g, 99%) as an oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.55 (s, 9H), 2.77-2.91 (m, 1H), 2.97-3.09 (m, 1H), 3.14-3.15 (m, 3H), 3.57-3.67 (m, 1H), 3.73-3.81 (m, 1H), 3.85-4.10 (m, 3H), 4.31 (d, J=4.79 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccc(F)c2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2cccc(F)c2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.3 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL), and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and crystallized from ethyl acetate-diisopropyl ether to give 2-[[3-(aminomethyl)-4-(3-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.12 g, 92.3%) as crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methoxyphenol: MS (ESI) m/z 433 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH:8]([NH2:16])[CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])[C:5](O)=[O:6])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[OH:1][CH:2]([CH:4]1[CH:8]([CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])[NH:16][C:5]1=[O:6])[CH3:3]
Reactant: CCOC(=O)C(C)C(N)C(C(=O)O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: CCOC(=O)C(C)C1NC(=O)C1C(C)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The thus obtained (2SR,3RS,4RS)-2-[1(SR)-hydroxyethyl]-3-amino-4-ethoxycarbonylpentanoic acid was suspended in dry acetonitrile (5 ml), and N,N'-dicyclohexylcarbodiimide (266 mg) was added thereto, and the resultant mixture was stirred at room temperature for 10 minutes and at 60° C. for 2 hours. After removal of the solvent under reduced pressure, ethyl acetate (5 ml) was added to the residue, followed by stirring at room temperature. The suspension was allowed to stand at 5° C. for 5 hours, and insoluble materials were collected by filtration and washed with cold ethyl acetate. The filtrate and the washings were combined together and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (3SR,4SR)-3-[1(SR)-hydroxyethyl]-4-[1-(RS)-ethoxycarbonylethyl]-2-azetidinone.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:6]=1[Cl:21])C=C.CCN([C:27]1[CH:28]=CC=C[CH:32]=1)CC>>[CH2:28]([C:10]1[C:9]([Br:11])=[CH:8][C:7]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[C:6]([Cl:21])[C:5]=1[OH:4])[CH:27]=[CH2:32]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(Br)cc(Cc2ccc(OC)cc2)c1Cl
Product: C=CCc1c(Br)cc(Cc2ccc(OC)cc2)c(Cl)c1O
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 1-(allyloxy)-5-bromo-2-chloro-3-(4-methoxybenzyl)benzene (1.20 g, 3.26 mmol) in diethylaniline (3 mL) was heated in a sealed tube at 200° C. for 24 h under nitrogen atmosphere. The mixture was cooled to room temperature and quenched by slow addition of 1 M HCl (50-100 mL). The mixture was extracted with ethyl acetate (100-150 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 216 (1.10 g, 2.99 mmol, 92%).
Reaction SMILES: CS(O[CH:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:18]1([NH:17][CH:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccccc1)c1cccs1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Ethyl 2-(methylsulfonyloxy)-2-(thiophen-2-yl)acetate (I87) (5.7 g, 21.6 mmol), aniline (2.16 mL, 23.7 mmol) and DIPEA (4.52 mL, 25.9 mmol) are dissolved in acetonitrile (20 mL) to give a yellow solution which is heated under microwave irradiation into a sealed vial at 100° C. for 15 minutes. Conversion complete by UPLC/MS-UV. Solvent is evaporated and the residue is dissolved in DCM and washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (Petroleum ether/EtOAc=85/15) to get desired compound as a yellow solid (4.33 g, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[NH:20][C:19]3=[O:27])[CH2:12][C:13]#[CH:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N+:28]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35])([O-:30])=[O:29]>>[NH2:1][C:2]1[CH:10]=[C:9]([N:11]([CH2:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([CH3:26])[NH:20][C:19]3=[O:27])[CH2:12][C:13]#[CH:14])[CH:8]=[CH:7][C:3]=1[C:4]([NH:35][CH2:34][C:33]1[CH:36]=[CH:37][CH:38]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=1)=[O:5]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)O)c(N)c1
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)c(N)c1
Yield: 64 %

Procedure:
Using the procedure described in Example 1, o-amino-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with 3-nitrobenzylamine to give o-amino-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(3-nitrobenzyl)benzamide in 64% yield, m.p. 86°-92° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1.[F-:17].[K+].C1OCCOCCOCCOCCOCCOC1>CN1CCCC1=O>[F:17][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:16])[N:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: Nc1nc2ccccc2c2ccc(Cl)nc12
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1nc2ccccc2c2ccc(F)nc12
Temperature: 25 °C

Procedure:
A solution of 3-chlorobenzo[f][1,7]naphthyridin-5-amine (Example 20) (1.0 eq.), potassium fluoride (3.0 eq.), and 18-crown-6 (0.2 eq.) in N-methylpyrrolidone (NMP) (0.4 M) was heated in a microwave reactor at 210° C. for 80 minutes. After cooling to room temperature, the crude reaction mixture was purified by HPLC using 10-50% acetonitrile in water to give 3-fluorobenzo[f][1,7]naphthyridin-5-amine. 1H NMR (acetone d-6): δ 11.40 (br, 2H), 9.38-9.42 (dd, 1H), 8.60 (d, 1H), 7.89-7.92 (dd, 1H), 7.81-7.83 (m, 2H), 7.59-7.66 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH:5]([CH:14]1[CH2:16][CH2:15]1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[OH-].[K+].[CH2:20](O)C>>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([CH:14]1[CH2:15][CH2:16]1)[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:20])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: CN(C)CCC(Oc1ccc(O)cc1)C1CC1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OC(CCN(C)C)C2CC2)cc1
Reaction time: 1 h

Procedure:
A mixture of 23.5 g of 1-dimethylamino-3-cyclopropyl-3-p-hydroxyphenoxy-propane, 100 ml of absolute ethanol and 200 ml of 0.5N ethanolic KOH is stirred for one hour at 20° and evaporated. The residue is dissolved in 250 ml of absolute DMF. 12.6 g of dimethyl sulphate is added in portions, with stirring. The mixture is boiled for two hours and evaporated; the residue is subjected to the customary working up; and 1-dimethylamino-3-cyclopropyl-3-p-methoxyphenoxy-propane is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:7]=3[C:6]=2[N:18]=1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:17][C:14]1[CH:15]=[CH:16][C:7]2[C:6]3[N:18]=[C:2]([NH:1][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:3]=[CH:4][C:5]=3[CH2:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1
Reactant: Brc1ccccc1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Cc2cnc(Nc3ccccc3)nc2-c2ccc(Cl)cc2N1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 2-amino-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-23) (148 mg, 0.568 mmol), 1-bromobenzene (0.072 mL, 0.681 mmol), Cs2CO3 (333 mg, 1.02 mmol), and BINAP (53 mg, 0.085 mmol) in 4 mL toluene was added Pd(OAc)2 (12.8 mg, 0.057 mmol), and the reaction was stirred at 100° C. for 12 h. The reaction mixture was then treated with H2O and extracted with CH2Cl2 (2×30 mL). The organic fractions were combined, filtered, dried over MgSO4 and concentrated in vacuo to give an orange oil which was purified by C-18 RP LC-MS chromatography to afford I-61 (0.9%): HRMS Calcd. for C18H13ClN4O: 337.0856, Found 337.0853.