Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: C1COCCO1
Product: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of 4-(4-chloro-6-methoxy-3-nitroquinolin-7-yl)-3,5-dimethylisoxazole (for a preparation, see Intermediate 8) (1 g, 3.00 mmol) in 1,4-dioxane (6.5 mL) was added (R)-1-(pyridin-2-yl)ethanamine (0.549 g, 4.49 mmol) and the mixture stirred at room temperature for 5 h. A further portion of (R)-1-(pyridin-2-yl)ethanamine (0.255 g, 2.25 mmol) was added and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified by chromatography (50 g column, cyclohexane/EtOAc gradient) to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N—((R)-1-(pyridin-2-yl)ethyl)quinolin-4-amine (1.15 g, 2.74 mmol, 92% yield) as an orange solid. LCMS: (Formate, 2 min), Rt 0.98 mins, MH+ 420.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 88 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 88%). 1H NMR (200 MHz, CDCl3): δ 3.31 (s, 4H), 3.84 (s, 4H), 4.15 (s, 3H), 7.03-7.10 (m, 2H), 7.25-7.61 (m, 5H), 7.82 (dd, J=8.7 and 5.7 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2([CH2:12]O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:16].[ClH:18]>C1(C)C=CC=CC=1.CCOCC>[ClH:16].[Cl:18][CH2:12][C:7]1([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(Cl)Cl
Reactant: OCC1(NC2CCCC2)CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: ClCC1(NC2CCCC2)CCCC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane (Method B1c; 140 g, 0.76 mol, 1.0 equiv.) in toluene (1.4 L). was added SOCl2 (84 mL) over a period of 15 min. After the addition of SOCl2 was complete the reaction mixture, which had already warmed to 40° C., was heated at 60° C. overnight. The resulting solution was cooled to room temp. and treated with HCl (4N in p-dioxane, 100 mL), and the reaction was heated to 60° C. for 3 h then stirred at room temp. overnight. The resulting mixture was concentrated to half of the original volume under reduced pressure, at which time a precipitate began to form. The resulting slurry was diluted with Et2O and allowed stir for 4 h. The resulting precipitate was filtered and washed with Et2O (2×50 mL) to yield 1-(chloromethyl)-1-(cyclopentylamino)cyclopentane HCl salt as an off-white powder (125 g, 70%): 1H NMR (CDCl3) δ1.53-1.66 (m, 4H), 1.76-1.94 (m, 2H) 1.95-2.22 (m, 10H), 2.28-2.34 (m, 2H), 3.40 (s, 2H), 3.63-3.73 (m, 1H).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:23].[NH:24]1[CH:28]=[CH:27][C:26](B(O)O)=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:28]4[CH:27]=[CH:26][NH:25][N:24]=4)=[C:3]([CH3:23])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(-c3cc[nH]n3)sc2n1
Temperature: 100 °C
Yield: 10.4 %

Procedure:
To a solution of N-(2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 77) (80 mg, 0.185 mmol), 1H-pyrazol-3-ylboronic acid (20.73 mg, 0.185 mmol) and bis(triphenylphosphine)palladium(II) chloride (13.01 mg, 0.019 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added potassium carbonate (90 mg, 0.649 mmol) and the mixture heated to 100° C. using a microwave reactor for 30 min. The mixture was then evaporated to dryness and purified by MDAP (acidic conditions), followed by MDAP (basic conditions), to afford the title compound (8.07 mg). LCMS (A) m/z: 417 [M−1]−, Rt 0.99 min (acidic).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[C:26]([F:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:31])#[N:20].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:27][C:26]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:23]=[C:22]([F:31])[C:21]=1[C:19]#[N:20]
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2CCOC[C@H]2C(C)C)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C(C)C)n1
Temperature: 100 °C
Yield: 69.9 %

Procedure:
4-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (1.70 g, 6.28 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (1.72 g, 9.42 mmol, 1.5 equiv), tricyclohexylphosphine (0.264 g, 0.94 mmol, 0.15 equiv), Pd2(dba)3 (0.431 g, 0.47 mmol, 0.075 equiv), and K3PO4 (2.27 g, 10.67 mmol, 1.7 equiv) were charged into a 250 mL RB flask, followed by addition of 1,4-dioxane (30 mL) and water (10 mL). The mixture was degassed and back flushed with argon (5×). The mixture was heated in an oil bath at 100° C. for 20 hours. LCMS showed complete conversion. The mixture was filtered through celite and rinsed with EtOAc (150 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (150 mL) and brine (40 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, to afford the title compound (1.64 g) as a yellow foam. LC-MS (ES) m/z=374 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3OC(=O)[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:23](#[N:27])[C:24]([CH3:26])=[O:25]>C1(C)C(C)=CC=CC=1>[CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:27]=[C:23]([C:24](=[O:25])[CH3:26])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)C#N
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3nsc(=O)o3)s2)cc1
Solvent: Cc1ccccc1C
Product: CC(=O)c1nc(-c2cnc(Oc3ccc(OC(C)C)cc3)s2)ns1
Yield: 84 %

Procedure:
A mixture of Example 100B (2.0 g, 0.0057 mol) and excess pyruvonitrile (2 mL) in xylene was heated at reflux in a pressure tube overnight. The solvent was removed and the residue was purified on silica gel (5˜30% ethyl acetate in hexane) to give 1.74 g of product as a light yellow solid (84% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 2.77 (s, 3H) 4.46-4.61 (m, 1H) 6.89-6.99 (m, 2H) 7.18-7.25 (m, 2H) 8.03 (s, 1H). MS (ESI), M/Z: 394.0 (M+33)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[CH:15]=1>C(O)C.C1COCC1>[CH3:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(C)ccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
Na metal (425 mg, 21.3 mmole) was dissolved in 50 mL of ethanol. To 5 mL of this solution, diethyl malonate (32 mg, 199 μmole) in 5 mL of THF was added, and the mixture was refluxed for 1 hour. 2-bromomethylanthraquinone (Compound 4.1) (50 mg, 166 μmole) in 5 mL of THF was then added to the refluxing reaction mixture. The reaction was refluxed for 8 hours, cooled to room temperature, and then quenched with 5 mL of saturated NH4Cl solution. The mixture was concentrated under vacuum, and redissolved in 20 mL of ethyl acetate for H2O extraction. The organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography to yield 41 mg (54 %). 1H NMR (300 MHz, CDCl3) δ 8.11 (2H, m), 7.96 (1H, s), 7.88 (1H, d), 7.64 (1H, d), 7.37 (2H, m), 4.61 (2H, d), 4.20 (5H, m), 1.21 (6H, t).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:41])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:41])[C:23]2[CH:28]=[N:27][C:26]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[N:25][C:24]=2[N:33]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:34]=1)=[O:20])[CH3:17]
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (from Example 27(A), 54 mg, 0.26 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e) above, 100 mg, 0.26 mmol). The title compound was obtained as a white solid (77 mg, 59%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.28 (s, 1H), 8.46 (s, 1H), 7.98 (br, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 5.04 (m, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.67 (t, J=4.6 Hz, 4H), 2.76 (m, 2H), 2.54 (m, 2H), 2.47 (m, 4H), 1.99 (m, 4H), 1.78 (m, 1H), 1.61 (m, 2H), 1.46 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.23 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:27][CH3:28])[CH:4]=1
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of ethyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (5.60 g) in tetrahydrofuran (100 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.26 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless crystals (5.22 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 108-109° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:30]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)[N:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=3)=[O:27])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:26]([NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:16][CH:17]=2)=[O:27])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Temperature: 22 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of 4-{4-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-isoquinolin-1-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (820 mg, 1.37 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (15 mL). Stir the reaction mixture at 22° C. for 1.5 hours. After removal of solvent, treat the residue with 1N sodium hydroxide saturated with NaCl (50 mL) and extract five times with dichloromethane (50 mL each). Dry the combined organic phases over sodium sulfate. Filter the mixture and subject residue to silica gel chromatography eluting with dichloromethane and methanol to provide a white solid (515 mg, 75% yield, LCMS ES+ (m/z) 499.5 [M+H]).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6](O)=O)=[CH:4][C:3]=1[CH3:12].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:24][C:25]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>C(Cl)Cl.C1COCC1>[Br:34][C:31]1[CH:30]=[C:26]2[C:25](=[CH:33][CH:32]=1)[N:24]=[C:6]([C:5]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH3:12])[CH:4]=1)[NH:29][C:27]2=[O:28]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: NC(=O)c1cc(Br)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccc(Br)cc3c(=O)[nH]2)cc(C)c1O
Reaction time: 1.25 h
Yield: 94.8 %

Procedure:
To a solution of 4-hydroxy-3,5-dimethylbenzoic acid (2.00 g, 12.0 mmol) in CH2Cl2 (60.2 mL) cooled to 0-5° C. was added oxalyl chloride (1.47 mL, 16.8 mmol) followed by dropwise addition of DMF (93.3 μL, 1.20 mmol). The mixture was stirred for 1.25 h, the volatiles were removed under vacuum to give crude acid chloride, which was used immediately without further purification. A mixture of 2-amino-5-bromobenzamide (1.99 g, 9.23 mmol) and the acid chloride (crude residue described above) in THF (92.3 mL) was stirred at room temperature for 17 h, then heated at reflux for 4 h. The volatiles were removed under vacuum, the residue was triturated with EtOAc, and filtered to afford the amide (3.02 g, 90%) as a yellow solid. A mixture of the amide (3.01 g, 8.29 mmol), 2 M NaOH (20.0 mL), water (40.0 mL), and MeCN (20.0 mL) was heated at reflux for 15 h, cooled to 5° C., and neutralized with 2 M aqueous HCl. After stirring for 30 min, the white solid was filtered, triturated with acetone, and filtered again to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.28 g, 80%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=2.29 Hz, 1H), 7.93 (dd, J=8.72, 2.42 Hz, 1H), 7.86 (s, 2H), 7.63 (d, J=8.70 Hz, 1H), 5.75 (s, 1H), 2.24 (s, 6H); MS (APCI) m/z 346 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S@@](C(C)(C)C)=O)[CH3:9])=[CH:4][C:3]=1[O:17][CH3:18].[ClH:19]>CO>[ClH:19].[NH2:10][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:17][CH3:18])[CH:4]=1)[CH3:9]
Reactant: COc1cc([C@@H](C)N[S@](=O)C(C)(C)C)ccc1O
Agent: Cl
Solvent: CO
Product: COc1cc([C@@H](C)N)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (R)—N—((R)-1-(4-hydroxy-3-methoxyphenyl)ethyl)-2-methylpropane-2-sulfinamide (4.10 g, 15.1 mmol) was added 10% hydrogen chloride in methanol (40 ml), and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was evapolated and dried in vacuo to give the title compound (crude 6.75 g) as a white solid. This crude amine was used for the next step without further purification. 1H NMR (270 MHz, DMSO-d6) δ ppm 1.48 (3H, d, J=6.6 Hz), 3.79 (3H, s), 4.27 (1H, m), 6.79 (1H, d, J=8.5 Hz), 6.88 (1H, d, J=8.0 Hz), 7.17 (1H, s), 8.35 (3H, br. s), 9.18 (1H, br. s). MS (ESI) m/z 151 (M+H—NH2)+.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([F:40])[CH:39]=1)[C:34](O)=[O:35]>>[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([F:40])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:35]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc(F)cc(F)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-difluorobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-difluorobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 506 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:16]([F:19])([F:18])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH:32]([CH3:34])[NH:31][CH:30]([CH3:35])[CH2:29]2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].Cl>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C.O1CCOCC1>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH:32]([CH3:34])[NH:31][CH:30]([CH3:35])[CH2:29]5)=[CH:26][N:27]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: CC1CN(c2ccc(Cl)nc2)CC(C)N1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC1CN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC(C)N1
Temperature: 120 °C
Yield: 67 %

Procedure:
A 10 mL reaction vessel was charged with compound 245 (80.0 mg, 295 μmol), 1-(6-chloropyridin-3-yl)-3,5-dimethylpiperazine (66.6 mg, 295 μmol), tris(dibenzylideneacetone)dipalladium (0) (20.3 mg, 22.1 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (25.6 mg, 44.2 μmol), sodium t-butoxide (56.7 mg, 590 μmol), and dioxane (2.5 mL). The reaction was purged with argon and heated with microwave energy (300 W) for 3.5 hours at 120° C. The reaction was taken up in ethyl acetate (40 mL) and washed with water (30 mL) and brine (30 mL). The organic phase was dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution hexanes+2.5% TEA/0-100% ethyl acetate+2.5% TEA, then ethyl acetate+2.5% TEA, 0-8% methanol) afforded a yellow solid. This residue was taken up in 2 mL methanol (2 mL) and 1M ethanolic HCl (1 mL) was added, followed by the addition of diethyl ether (20 mL). The resulting precipitate was collected and dried in vacuo to give compound 289 as a yellow solid (91 mg, 67%) 1H NMR (500 MHz, DMSO-d6) δ 9.54-9.67 (m, 2 H) 9.47-9.54 (m, 1 H) 9.05-9.23 (m, 1 H) 8.19-8.30 (m, 1 H) 8.06-8.17 (m, 3 H) 7.94-8.04 (m, 1 H) 7.81-7.94 (m, 1 H) 5.45-5.58 (m, 1 H) 3.81-3.94 (m, 2 H) 3.34-3.48 (m, 2 H) 2.75-2.91 (m, 2 H) 2.23-2.35 (m, 2 H) 2.10-2.20 (m, 2 H) 2.05 (none, 2 H) 1.68-1.86 (m, 2 H) 1.34 (d, J=6.60 Hz, 7 H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-])=O)[S:7][C:6]=2[CH:26]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:26]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12

Procedure:
In addition, in the same manner as in Starting Material Synthesis Example 19 and using ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.