Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[CH:12][CH:13]=1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)Cl.C(OCC)(=O)C>[Br:22][C:12]1[CH:13]=[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:9]=[N:10][C:11]=1[NH2:14]
Reactant: Cc1cnccc1-c1ccc(N)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnccc1-c1cnc(N)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To an ice cold solution of 3′-methyl-3,4′-bipyridin-6-amine (250 mg, 1.350 mmol) in DCM (4499 μL) was added NBS (264 mg, 1.485 mmol) in two portions. The reaction mixture was stirred at 0° C. for 2 h. Reaction mixture was diluted with ethyl acetate, and was washed with water, brine, dried and concentrated. Residue was treated heptane, the solid filtered to give 5-bromo-3′-methyl-3,4′-bipyridin-6-amine (350 mg, 1.325 mmol, 98% yield) as brown color solid, used in next step reaction without purification. LCMS (m/z): 264.4/266.4 (MH+), 0.32 min; 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.12 (d, J=5.1 Hz, 1H), 5.06 (br. s., 2H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A solution of methyl 2-amino-6-chloropyrimidine-4-carboxylate (0.2 g, 1.07 mmol) and phenylboronic acid (0.16 g, 1.3 mmol) in THF (10 mL) was treated with saturated aqueous NaHCO3 (1.6 mL). Nitrogen was bubbled through the solution for 5 min then tetrakis(triphenylphosphine)palladium(0) (0.04 g) was added and the mixture refluxed under nitrogen overnight. The mixture was treated with aqueous LiOH (1-M, 1 mL), heated at 90° C. for 2 h, concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 1 with 2-N HCl, the resulting suspension centrifuged, the liquors decanted and the resulting solid dried to give the title compound (0.17 g, 72%) as a white powder which was used directly in the next step without further purification; M/Z 216 (M+H)+; retention time 1.60 min (Method AM).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1.Cl.[CH3:40][NH2:41].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:41][CH3:40])=[O:7])=[CH:4][C:3]=1[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[O:21][C:22]([NH:25][CH:26]([CH3:27])[CH3:28])=[N:23][N:24]=3)[CH:18]=2)[N:13]([S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(C(=O)O)ccc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccc(F)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)benzoic acid (500 mg, 0.936 mmol) and methylamine hydrochloride (97 mg, 1.40 mmol) in pyridine (10 mL) was added POCl3 (0.13 mL, 1.40 mmol). The reaction was stirred at RT for 1 h, then quenched with ice cold water (20 mL) to get a precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried. The crude product was purified with basic alumina chromatography (eluting with EtOAc) to give 4-fluoro-3-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylbenzamide (250 mg, 48%). MS (ESI, pos. ion) m/z: 548.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 1.00 g Boc-1-pyrrolidine-3-carboxylic acid in 10 ml toluene were added 0.61 ml benzyl bromide and 0.76 ml DBU. After stirring for 12 h the reaction mixture was washed with water and the crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 1:3 as eluent.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29](=[O:44])[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH:43][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2N)c1
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccc(-c2ccccc2NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.3 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (61 mg, 0.32 mmol) and Et3N (44 μL, 0.32 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (55 mg, 0.23 mmol) and DMAP (2 mg, 0.02 mmol) and stir the resulting solution for 15 min. Add (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) (50 mg, 0.21 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with water, separate layers and extract aqu. layer with DCM (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain {2′-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-biphenyl-3-yl}-acetic acid methyl ester (72) (46 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3): 2.50 (t, 2H, J=7.6 Hz); 2.90 (t, 2H, J=7.7 Hz); 3.64 (s, 2H); 3.65 (s, 3H); 3.77 (s, 6H); 3.78 (s, 3H); 6.38 (s, 2H); 7.09-7.18 (m, 3H); 7.19-7.28 (m, 3H); 7.34 (d, 1H, J=8.1 Hz); 7.38 (d, 1H, J=7.8 Hz); 8.31 (br.d, 1H, J=7.8 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:36][CH2:37][N:38]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:39][CH2:40]1
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(c3cc(F)ccc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title E compound, 1-(2,5-difluorophenyl)piperazine hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,5-difluorophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=465.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.64 (m, 4H), 2.76 (t, 2H, J=64 Hz), 3.01 (m, 4H), 4.28 (t, 2H, J=6.4 Hz), 6.60 (d, 1H, J=3.2 Hz), 6.72 (m, 1H), 6.75 (m, 1H), 6.80-6.85 (m, 1H), 7.12 (m, 1H), 7.18 (m, 2H), 7.51 (br s, 2H), 7.91 (s, 1H). Anal. calculated for (C23H22F2N8O): C, 59.48; H, 4.77; F, 8.18; N, 24.12; O, 3.44. Found C, 59.45; H, 4.70; N, 24.19.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)=[O:11].[C:18](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:18][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1ccc(O)c(NC(=O)c2ccsc2Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)NC(=O)c1cc(C)sc1O2
Temperature: 145 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
To a solution of N-(2-hydroxy-5-methylphenyl)-2-bromo-3-thiophenecarboxamide (2.9 g) in dimethyl sulfoxide (24 ml) was added potassium carbonate (2.4 g) and the mixture was stirred at 140-150° C. for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue and the above-mentioned crystals were combined and purified by silica gel column chromatography (chloroform:methanol=20:1). The obtained solid was collected by filtration from hexane to give 2,7-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.0 g).
Reaction SMILES: [OH:1][C@@:2]1([CH3:23])[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[F:24][C:25]([F:37])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH2:35])=[CH:32][N:31]=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:37][C:25]([F:24])([CH3:36])[CH2:26][O:27][C:28]1[C:33]([CH2:34][NH:35][C:11]2[N:10]=[C:9]([NH:8][C@@H:5]3[CH2:6][CH2:7][C@@:2]([OH:1])([CH3:23])[C:3]([CH3:22])([CH3:21])[CH2:4]3)[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:32][N:31]=[CH:30][N:29]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@]1(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CC[C@](C)(O)C(C)(C)C2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 4-(((1R,4S)-4-hydroxy-3,3,4-trimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (90 mg, crude) in THF (2.8 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (50 mg, 0.246 mmol) and DIEA (100 mg, 0.738 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 2 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (38.7 mg, 0.084 mmol, 34% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.90 (s, 1H), 8.57-8.54 (s, 1H), 8.34 (s, 1H), 4.92 (t, J=12.0 Hz, 1H), 4.81-4.78 (m, 2H), 4.34-4.28 (m, 1H), 2.04-1.95 (m, 3H), 1.92-1.68 (m, 6H), 1.47-1.45 (m, 3H), 1.09-1.01 (m, 6H). MS (ESI) m/z 462.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH2:33][N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:30]=[CH:29][C:28]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:25])[C:6]1=[O:39])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2cc(CBr)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2cc(CN3CCCC3)ccc2C(C)(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2-tert-butyl-5-(bromomethyl)phenyl]urea (330 mg, 0.56 mmol) in THF (tetrahydrofuran, 5 ml) is added pyrrolidine (362 mg, 5.09 mmol), and the mixture is stirred at room temperature for 3 hours. The mixture is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (5-10% methanol/chloroform) to give the title compound (234 mg, 0.42 mmol) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1cc(F)ccc1-c1nc(OCCNC(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 130 (1 g, 1.9 mmol) was dissolved in CH2Cl2 (8 mL) and stirred under Ar in an ice bath. A chilled solution of 25% TFA in CH2Cl2 (40 mL) was added, and the mixture was stirred for 45 min at 0° C. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and a saturated NaHCO3 solution. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% MeOH/CH2Cl2 gave the title compound as a white-amorphous solid. mp 96-99°, LC MS in/z=427 (MH+) Retention time=1.52 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NCCCCNC1C2C(=[CH:50][C:51]([O:55][CH2:56][C:57]3C=CC=CC=3)=CC=2)N=CC=1N)(C)(C)C.C(OCC(Cl)=O)C.COCCC(Cl)=O>>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13]2[C:22]3[CH:21]=[C:20]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:31]=[C:50]1[CH2:51][O:55][CH2:56][CH3:57])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCOCC(=O)Cl
Agent: COCCC(=O)Cl
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CCCCNC(=O)OC(C)(C)C

Procedure:
For Example 73, a modification of the general method described for Part C of Example 50 was followed using tert-butyl{4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (9.25 g, 21.2 mmol) in lieu of tert-butyl{4-[3-amino-7-(benzyloxy)quinolin-4-ylamino]butyl}carbamate and ethoxyacetyl chloride (2.86 g, 23.3 mmol) in lieu of methoxypropionyl chloride. After the cyclization reaction, the solvent was removed under reduced pressure, and the residue was dissolved in chloroform (400 mL). The resulting solution was washed with water (2×200 mL) and brine (1×200 mL), concentrated under reduced pressure, and dried under high vacuum to provide a brown oil. The crude product was purified by column chromatography on silica gel (400 g, eluting with 95:5 dichloromethane:methanol). The resulting solid was triturated with diethyl ether and isolated by filtration to provide 5.37 g of tert-butyl{4-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate as an off-white powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:16]Br>>[Br:16][C:7]1[CH:6]=[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCOC(=O)CCCc1ccc(O)cc1
Product: CCOC(=O)CCCc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To an ice cooled solution of ethyl 4-(4-hydroxyphenyl)butanoate (16.73 g, 80.32 mmol) in 200 mL of CHCl, was added bromine (4.15 mL, 80.8 mmol). The cooling bath was removed, and the reaction stirred at room temperature for 2 hours. The reaction mixture was then washed with water and brine, dried over sodium sulfate and concentrated to give 22.3 g (96.6%) of ethyl 4-(3-bromo-4-hydroxyphenyl)butanoate as a crystalline solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([S:35]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=4)(=[O:37])=[O:36])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(NC(C)=O)cc4)CC3)c(F)c21
Reaction time: 1 h
Yield: 92.4 %

Procedure:
2.80 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is suspended in 100 ml of pyridine. To this suspension is slowly added 7.76 g of 4-acetamidobenzenesulfonyl chloride in 20 ml of benzene under ice-cooling while stirring. Stirring is continued for 1 hour under ice-cooling and then for further 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure. To the residue is added 1N sodium hydroxide solution to dissolve. The pH of the solution is then adjusted to 4 with acetic acid. Precipitating crystals are collected by filtration, washed with water and recrystallized from dimethylformamide (DMF)-ethanol to give 4.10 g of the titled compound. Melting point: 276°-277° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.Cl.[CH2:27]([NH:34]N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH2:27]([N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NNCc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1Cc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.675 g, 2.0 mmol), benzylhydrazine dihydrochloride (1.56 g, 8.0 mmol), and Et3N (2.23 mL, 16 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (375 mg, 47% yield) as a white solid: mp 156-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 5.75 (2H, s), 6.70 (1H, d, J=7.9 Hz), 6.84-6.91 (2H, m), 7.18-7.24 (3H, m), 7.32-7.37 (1H, m), 7.47-7.53 (2H, m), 7.64-7.67 (2H, m), 7.70 (1H, d, J=1.9 Hz), 8.15 (1H, d, J=7.9 Hz). Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.63; H, 3.85; N, 14.16.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:50]#[N:51]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:47]2[CH2:48][CH2:49][NH:44][CH:45]([C:50]#[N:51])[CH2:46]2)=[O:13])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: N#CC1CNCCN1
Reactant: COc1cc(Cl)c(Cl)cc1NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(Cl)cc1NCC(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a mixture of 2-(4,5-dichloro-2-methoxyphenylamino)acetic acid (260 mg, 1.04 mmol), EDCI (273 mg, 1.43 mmol), HOBt (194 mg, 1.43 mmol) and Et3N (288 mg 2.85 mmol) in DCM (10 mL) at 0° C., piperazine-2-carbonitrile was added. The resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (108 mg, 30% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:13]=1[C:14]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (1.45 g, 4.09 mmol) in CH2Cl2 (40 mL) was added benzylamine (0.613 g, 5.73 mmol), EDC (1.254 g, 6.54 mmol), and DMAP (1.00 g, 8.18 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was then purified using silica gel chromatography (hexanes/EtOAc 8/2) to afford the title compound as an oil (720 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 4.63 (d, 2H, J=5.5 Hz), 5.09 (s, 2H), 5.97 (br s, 1H), 6.22 (d, 1H, J=15.6 Hz), 7.01 (dd, 1H, J=2.7, 8.6 Hz), 7.10 (d, 1H, J=2.8 Hz), 7.28-7.42 (m, 10H), 7.55 (d, 1H, J=9.0 Hz), 7.88 (d, 1H, J=16.0 Hz).