Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6](=[O:14])[CH:7](OCC)OCC.OS(O)(=O)=O>>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:3]=1[CH:4]=[N:5][C:6]([OH:14])=[CH:7]2
Reactant: CCOC(OCC)C(=O)NCc1ccccc1Br
Agent: O=S(=O)(O)O
Product: Oc1cc2cccc(Br)c2cn1
Temperature: 15 °C
Yield: 92 %

Procedure:
N-(2-Bromobenzyl)-2,2-diethoxyacetamide (Description 52; 15.6 g, 49 mmol) was carefully added to concentrated H2SO4 (78 ml) with stirring at 10-20° C. The reaction mixture was stirred at room temperature for 16 hours, poured into ice water and filtered. The filtrate was neutralised with 33% aqueous ammonium hydroxide and the resulting precipitate was filtered and dried to give the title compound (10.1 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH3:38][O:39][C:40]([NH:42][CH:43]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:44](=[O:45])[CH:43]([NH:42][C:40]([O:39][CH3:38])=[O:41])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)C(NC(=O)OC)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 1-{[4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (600 mg, 1.115 mmol) in CH3CN (20 mL) was 2-methoxycarbonylamino-3,3-dimethyl-butyric acid (317 mg, 1.673 mmol), DIEA (0.97 mL, 5.575 mmol) and the coupling reagent HOBt (256 mg, 1.673 nunol) and HBTU (634 g, 1.673 mmol). The solution was stirred at rt. overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give yellowish oil. It was then purified by Prep. HPLC column to give a yellowish oil as product. (410 mg, 47% yield).1H NMR (400 MHz, CD3OD) δ1.03 (s, 9H), 1.22 (t, J=7.09 Hz, 3H), 1.41 (dd, J=9.41, 5.26 Hz, 1H), 1.71 (dd, J=8.19, 5.26 Hz, 1H), 2.17 (m, 1H), 2.50 (m, 1H), 2.77 (m, 1H), 3.33 (s, 3H), 4.03 (s, 3H), 4.04–4.14 (m, 3H), 4.18 (s, 1H), 4.61–4.69 (m, 2H), 4.86 (m, 1H), 5.08 (dd, J=10.27, 1.71 Hz, 1H), 5.25 (d, J=17.11 Hz, 1H), 5.72–5.82 (m, 2H), 7.39 (dd, J=9.29, 2.20 Hz, 1H), 7.51 (m, 1H), 7.63 (m, 1H), 7.69–7.77 (m, 3H), 8.06 (m, 2H), 8.35 (d, J=9.29 Hz, 1H), 8.75 (s, 1H). LC-MS (retention time: 2.857 min.), MS m/z 673 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[Na+].Cl>CO>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([CH2:11][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:22])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(OCc2ccnc3ccccc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(OCc2ccnc3ccccc23)c1
Yield: 97.1 %

Procedure:
3-(4-Quinolinylmethoxy)benzoic acid methyl ester (10.25 g, 35 mmol) and 2.5N NaOH (aq) (70 ml, 175 mmol) were refluxed for 2 hours in MeOH (300 mL). Neutralization with conc. HCl (14.5 mL, 175 mmol) and filtration afforded 9.5 g (34 mmol, 97%) of air-dried 3-(4-quinolinylmethoxy)benzoic acid as a white solid. The free acid (9.0 g, 32 mmol) was refluxed in excess thionyl chloride (50 mL, neat) for 10 minutes. Dichloroethane and ether were added and the resulting precipitate filtered to afford 3-(4-quinolinylmethoxy)benzoyl chloride hydrochloride as a cream colored solid. The acid chloride (3.34 g, 10 mmol), resuspended in methylene chloride, was treated with 4-amino-1-benzylpiperidine (3.80 g, 20 mmol) and, after 0.5 hours, extracted with 1N NaOH (aq) and water. Evaporation of the organic phase, crystallization of the residue from methylene chloride-ether-hexane, and purification by flash column chromatography on silica gel afforded, after recrystallization from acetonitrile, 3.1 g (6.9 mmol, 69% yield) of the product as a pale yellow solid, m.p. 160°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:6]([NH2:18])[CH:5]=1.N1C=CC=CC=1.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[C:6]([NH:18][S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N+:26]([O-:28])=[O:27])(=[O:36])=[O:37])[CH:5]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 3-amino-4-tert-butoxycarbonylaminobenzoic acid methyl ester (817.3 mg, 3.07 mmol) in dichloromethane (10 ml), pyridine (0.373 ml, 4.60 mmol) and 2-nitrobenzenesulfonyl chloride (815 mg, 3.68 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 4 hours. Pyridine (0.050 ml) and 2-nitrobenzenesulfonyl chloride (135 mg) were added, and stirring was continued for 2 hours. The reaction mixture was concentrated under reduced pressure, water (30 ml) was added, and then extraction was performed with ethyl acetate (20 ml×3 times). The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the crystallized residue was suspended in n-hexane-ethyl acetate (4:1), filtered, and dried to obtain 4-tert-butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].[Cl-].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: Cc1ccc(F)cc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(5-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D55, 50 mg, 0.094 mmol), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 34 mg, 0.116 mmol) were dissolved in toluene (1.5 mL). Bis tritertbutylphosphine palladium (12.5 mg, 0.0244 mmol), followed by hexadecyltrimethylammoium chloride (204, 25% aq sol), and finally sodium hydroxide solution (0.11 mL, 50% aq sol) were added. The mixture was degassed for 5 minutes before heating at 90° C. for 2 hours. Reaction cooled to R.T., diluted with EtOAc, washed with sat NaHCO3 solution, dried (MgSO4). Filtered. Solvent evaporated to afford a yellow sticky solid. Used crude in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.CO[C:11](OC)([N:13]([CH3:15])[CH3:14])[CH3:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5](/[N:8]=[C:11](/[N:13]([CH3:15])[CH3:14])\[CH3:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: C/C(=N\c1ccc(Cl)nn1)N(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
In a 2 L round bottom flask combine 3-chloro-6-pyridazinamine (43.2 g, 333.5 mmol), toluene (500 mL), and N,N-dimethylacetamide dimethyl acetal (67.8 mL, 1.25 equiv.). Attach a reflux condenser then heat to reflux for 2 h. Let cool to RT. Concentrate in vacuo. Triturate the crude material with hexanes and filter to isolate the title compound (60.4 g, 91%) as a light tan solid. MS=199.0 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31](=[O:39])[NH:32][S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.C1COCC1>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31](=[O:39])[NH:32][S:33]([CH:36]4[CH2:37][CH2:38]4)(=[O:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C4CC4)cc3n2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 60 °C
Yield: 94.4 %

Procedure:
Methyl 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (1.0 g, 1.8 mmol) was dissolved into MeOH//THF (1:1, 24 mL) and treated with 1M aqueous NaOH (5 mL). The reaction mixture was stirred and heated at 60° C. for 1.5 h and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (5 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (1.0 g, 1.7 mmol, 94%) as a bright yellow solid (with 0.75 equiv. of THF) which was used without further purification. 1HNMR (300 MHz, CD3OD) δ 1.11-2.24 (m, 17H, 3H from THF), 2.81-2.96 (m, 1H), 3.17-3.28 (m, 1H), 3.69-3.79 (m, 3H, from THF), 3.94 (s, 3H), 4.07-4.33 (m, 1H), 5.55-5.81 (m, 1H), 7.14-7.24 (m, 2H), 7.55-7.64 (m, 2H), 7.88-7.94 (m, 2H), 8.20 (br s, 1H). LCMS: m/e 535 (M+H)+, ret time 3.73 min, column B, 4 minute gradient.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl>>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)cc4Cl)CC3)cccc2n1
Yield: 60 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Dichlorobenzyl Chloride (72.3 mg; 0.37 mmol) to obtain 48.3 mg. (60% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.49 (s, 1H), 7.60 (m, 3H), 7.44 (m, 1H), 7.16 (m, 2H), 3.66 (s, 2H), 3.02 (br d, J=10.8 Hz, 3H), 2.90 (m, 4H), 2.41 (m, 2H). ESIMS+403.5 m/z
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCOCC.CCCCCC.C(OCC)C>[Cl:11][CH2:12][CH2:13][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OCCCl
Reactant: Oc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxyindole (3.99 g, 30 mmol), 2-chloroethanol (6.03 ml, 90 mmol) and triphenylphosphine (23.6 g, 90 mmol) in tetrahydrofuran is treated with diethyl azodicarboxylate (14.1 ml, 90 mmol) under nitrogen at room temperature, stirred for 2 hr at room temperature and concentrated in vacuo to give a residue. Cooled diethyl ether is added to the residue and the solid triphenylphosphine oxide is precipitated and removed by filtration. The filtrate is concentrated and purified by flash chromatography (silica gel, EtOAc/hexane: 1.5/8.5) to give an oil. After trituration with Et2O/hexane (1/10), the title compound is obtained as a white solid, 4.8 g (82%) mp 60° C., identified by NMR and mass spectral analyses.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2)([O-])=O.N>CCO.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][CH2:9]2
Reactant: O=C1NCc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CNC2=O
Temperature: 95 °C

Procedure:
Iron powder (2.51 g, 45 mmol), water (0.97 ml) and HCl (37%, 0.74 ml), were added to a stirred suspension of the 5-nitroisoindolin-1-one (800 mg, 4.5 mmol) from step 2 of this example in EtOH (11.2 ml). The mixture was heated at 95° C. for 2 h. Ammonia (7N in MeOH) was added (1 mL) to make the pH of the mixture alkaline. The mixture was filtered to removed undissolved solids and the filter cake washed with EtOH (2×40 ml). The filtrate and organic washes were combined and concentrated in vacuum to give the titled compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([N:11]([CH3:20])[CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7]=2[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>Br>[N:14]1([CH2:13][CH2:12][N:11]([CH3:20])[C:8]2[C:7]3[CH:21]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COc1ccc2onc(N(C)CCN3CCOCC3)c2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(CCN1CCOCC1)c1noc2ccc(O)cc12
Temperature: 25 °C
Yield: 84.9 %

Procedure:
5-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (2.6 g) was dissolved in 48% hydrobromic acid (40 ml) and heated to reflux under nitrogen for 6 hours. The reaction was cooled to room temperature, neutralized with saturated Na2CO3 solution, and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM provided the pure product (2.1 g), 153°-154° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=C([Cl:48])C=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[C:22]([Cl:48])[CH:23]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1Cl

Procedure:
1-(4-(4-Bromo-2-chlorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-2-chlorobenzyl bromide. MS(FAB+): 403/405.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.OO.NC(N)=[O:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N+:4]([O-:14])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)n1
Reactant: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(Br)c(Cl)[n+]1[O-]
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a solution of 3-bromo-2-chloro-6-methylpyridine (1 g, 4.84 mmol) and urea hydrogen peroxide (911 mg, 9.69 mmol) in DCM (24 mL) at 0° C. was added trifluoroacetic anhydride (1.4 mL, 9.69 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM) yielding the title compound (1.1 g, quant.) as a white solid: LCMS (ES) m/z=223 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)=[CH:4][CH:3]=1.B.O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][CH2:8][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc(Cl)cc2)CC1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNCc2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 80.9 %

Procedure:
To a solution of 4-(N-(4-chlorobenzyl)aminocarbonyl)-1-t-butoxycarbonylpiperidine (1.76 g, 5.0 mmol) in dry tetrahydrofuran (20 mL) stirring under argon at room temperature, was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 20 mL, 20 mmol). The resulting solution was heated to 80° C. for 16 h before cooling to 0° C. Saturated aqueous ammonium chloride (20 mL) was added, and the resulting mixture was stirred for 30 min before extraction with ethyl acetate (25 mL three times). The combined extracts were dried (anhydrous sodium sulfate) and evaporated under vacuum to obtain a gum, which was purified by column chromatography (silica gel, 100% ethyl acetate) to provide 4-(N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.37 g, 81% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:23])([CH3:22])[CH2:16][CH:17]([C:18]([O:20]C)=[O:19])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.[OH-].[K+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:23])([CH3:22])[CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:11]2=[CH:10][C:9]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1
Reactant: COC(=O)C1CC(C)(C)Oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC(C(=O)O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Temperature: 70 °C

Procedure:
Product from Step A (66 mg, 0.14 mmol) was dissolved in THF (1 mL) and 10% KOH (1 mL) was added. The reaction was heated to 70° C. for 1 hr. The reaction was diluted with EtOAc and washed with 10% NaHSO4. The organic layer was separated, dried (Na2SO4), filtered and concentrated and used without any further purification
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)C.[OH-].[Li+]>O1CCCC1.O>[ClH:1].[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C@H:6]([O:24][CH2:25][CH3:26])[C:5]([OH:27])=[O:4])=[CH:9][CH:10]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Yield: 41.7 %

Procedure:
Water (200 ml) was added to a solution of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (15 g; 42 mmole) in tetrahydrofuran (100 ml). Lithium hydroxide (3.4 g; 84 mmole) dissolved in a small amount of water was added while stirring and then the reaction mixture was stirred at room temperature over night. Tetrahydrofuran was evaporated and the remaining residue was extracted twice with ethyl acetate. The water phase was acidified with hydrochloric acid (2 M) and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 6.4 g of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride. The acidic water phase, from above, was neutralized with sodium hydroxide to pH5 and extracted with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. This procedure gave 1.4 g more of the desired product. The total yield of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride was 7.8 g (50.8%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[F:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:33]1>C1COCC1>[F:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:42]=[CH:43][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:45][CH:46]=2)[CH2:33]1
Reactant: Nc1ccc(OCCCN2CCC(F)C2)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(OCCCN4CCC(F)C4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-[3-(3-Fluoro-pyrrolidin-1-yl)-propoxy]-phenylamine (prepared below, 59.3 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 39% (0.060 g, 0.097 mmol) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[C:33]([CH3:38])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (182 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (286 mg).