Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([N:3]1[CH2:4][CH2:5][C:6]2=[CH:10][N:9]=[CH:8][N:7]2[C:2]1=[O:1])[CH3:15]
Reactant: CCI
Reactant: O=C1NCCc2cncn21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2cncn2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 mg (3.6 mmol) of 5,6,7,8-tetrahydro-5-oxoimidazo[1,5-c]pyrimidine dissolved in 5 mL of DMF are added cautiously at room temperature 173 mg (4.32 mmol) of sodium hydride. The reaction medium is stirred for 1 hour at room temperature, and 0.35 mL (4.32 mmol) of iodoethane is then added dropwise. The reaction medium is stirred for 2 hours at room temperature and the solvents are then evaporated off. The residue is treated with 1N NaHCO3 solution and extracted with chloroform. The combined organic phases are dried with MgSO4, filtered and evaporated. The oil obtained is used directly in the following step.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2].C(N(CC)CC)C.[CH3:33][N:34](C)[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:37]2[CH2:38][CH2:39][C@H:35]([NH:34][CH3:33])[CH2:36]2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]=1[CH3:25])#[N:2]
Reactant: Cc1c(-c2cccc(F)c2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3cccc(F)c3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
4-Cyano-7-fluoro-6-(3-fluorophenyl)-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-184) (75 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (3.5 ml), then at room temperature, triethylamine (40 μl, 0.29 mmol) was added. The solution was heated at 150° C., a solution of (3S)-3-(dimethylamino)pyrrolidine (30 μl, 0.29 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. The solution was stirred under nitrogen atmosphere at the same temperature for 1 hour. After cooling to room temperature, the solvent was evaporated away under reduced pressure. The residue was fractionated with chloroform and an aft aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified first by preparative TLC (eluent, chloroform:methanol=9:1) to obtain a roughly-purified form (54 mg). This was further purified by preparative TLC (eluent, chloroform:7 N ammonia-containing methanol solution=95:5), then recrystallized from diisopropyl ether to obtain the entitled compound (12 tag, 13%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][C:11]([CH3:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([CH3:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1cc(C)nn1-c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.8 %

Procedure:
To a 100 mL flask, methyl 1-(3,5-dichloropyridin-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (1.00 g, 3.49 mmol), tetrahydrofuran (10 mL), water (10 mL) and sodium hydroxide (0.14 g, 3.49 mmol) were added sequentially. After being stirred for 40 minutes at room temperature, all of the starting materials had disappeared. Then water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL) and the aqueous layer was acidified with concentrated hydrochloric acid to pH of 2˜3, and extracted with ethyl acetate (3×80 mL), the organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated by rotary evaporator to give the product (0.91 g) as a white solid in 96% yield. Melting point: 227-228° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl.[I-].[Na+].O.[Cl-].[Na+].O>CN(C)C=O.C(N(CC)CC)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:1]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: ClCCOCCCl
Reactant: Cc1cc(C)nc(N)c1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CCOCC2)c1
Temperature: 150 °C
Yield: 56 %

Procedure:
2-Amino-4,6-dimethylpyridine (50 g), bis(2-chloroethyl)ether (57.5 mL), sodium iodide (6.13 g) and triethylamine (137 mL) were mixed in dry N,N-dimethylformamide (1 L) under argon and heated to 150° C. for 16 hours. Water/brine/saturated aqueous sodium bicarbonate (2:1:1, 750 mL) were added to the cooled reaction mixture and it was extracted with ethyl acetate (5×200 mL). The combined organic phases were concentrated in vacuo to app. 500 mL. Water (500 mL) and concentrated aqueous hydrochloric acid (35 mL) were added, the phases separated and the aqueous phase washed with ethyl acetate (200 mL). The aqueous phase was made basic with the addition of concentrated aqueous sodium hydroxide (50 mL) and extracted with isopropyl acetate (5×200 mL). The organic phases was dried over magnesium sulfate and concentrated in vacuo to furnish 44.0 g (56% yield) of the title compound as a black oil. The crude product was used without further purification. GC-MS (m/z) 192 (M+); tR=5.60. 1H NMR (500 MHz, DMSO-d6): 2.08 (s, 3H), 2.26 (s, 3H), 3.39 (m, 4H), 3.68 (m, 4H), 6.05 (s, 1H), 6.44 (s, 1H).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][NH:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]1[C:11]2[CH2:21][CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:12]=2[N:13]=[C:14]([NH2:16])[N:15]=1.C=O.[BH3-][C:29]#N.[Na+].Cl>CC#N>[CH3:29][N:6]1[CH2:7][CH2:8][CH:9]2[CH2:1][N:2]([C:10]3[C:11]4[CH2:21][CH2:20][CH2:19][C:18]5[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=5[C:12]=4[N:13]=[C:14]([NH2:16])[N:15]=3)[CH2:3][CH:4]2[CH2:5]1
Reactant: Nc1nc2c(c(N3CC4CCNCC4C3)n1)CCCc1ccccc1-2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CN1CCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC2C1
Reaction time: 1 h
Yield: 45 %

Procedure:
The product from Example 79B (20.4 mg, 0.061 mmol) was treated with 0.091 M formaldehyde in CH3CN (0.80 mL, 0.073 mmol), diluted with CH3CN (2.24 mL), treated with NaCNBH3 (7.6 mg, 0.12 mmol), treated dropwise with a solution of 0.48 M HCl in CH3CN to keep the reaction at approximately a pH of 6 and then stirred for 1 hour. The mixture was directly purified by chromatography on silica gel (2, 3.5 and 5% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide 9.6 mg of the title compound. The 0.48 M HCl in CH3CN was prepared by diluting 1 mL of concentrated HCl to 25 mL with CH3CN. The 0.091 M formaldehyde solution was prepared by diluting 37% aqueous formaldehyde with CH3CN. 1H NMR (CDCl3) δ 1.63-1.76 (m, 1H), 1.76-1.89 (m, 1H), 2.10-2.21 (m, 2H), 2.21-2.36 (m, 3H), 2.28 (s, 3H), 2.37-2.55 (m, 5H), 2.65 (t, J=6.78 Hz, 2H), 3.55 (dd, J=10.85, 5.43 Hz, 1H), 3.62-3.75 (m, 3H), 4.77 (s, 2H), 7.18-7.23 (m, 1H), 7.29-7.39 (m, 2H), 7.75-7.79 (m, 1H); MS (M+H)+ m/z 350.
Reaction SMILES: [CH:1]([C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1)=O.[NH2:20]O.Cl>CO>[C:1]([C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1)#[N:20]
Reactant: NO
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a flask containing a solution of methyl 2-formyl-1-((2-(trimethylsilyl)-ethoxy)-methyl)-1H-imidazole-4-carboxylate (9 g, 31.6 mmol) in MeOH (200 ml), 50% aqueous NH2OH.HCl solution (2.5 ml) was added and stirred at RT for 3 h. The reaction mixture was concentrated and extracted with EtOAc. The organic layer was concentrated and the resulting residue was dissolved in DCM (200 ml). Pyridine (12 ml) and trifluoroacetic anhydride (18 ml) were added to the above mixture and stirred for 12 h. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with DCM. The organic layer was concentrated and purified with flash chromatography. Yield 4.1 g. 1H-NMR (400 MHz; DMSO-d6): δ −0.04 (s, 9H), 0.87 (t, 2H), 3.56 (t, 2H), 3.81 (s, 3H), 5.29 (s, 2H), 8.28 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(#N)C>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4]1
Reactant: FC1(F)CCNC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CCC(F)(F)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
900 mg of 3,3-difluoropyrrolidine hydrochloride (6.27 mmol, 1 equivalent) were initially charged in 62 ml of acetonitrile, 1475 mg of tert-butyl (2-bromoethyl)carbamate (6.58 mmol, 1.05 equivalent) and then 3.28 ml of N,N-diisopropylethylamine (2.43 g, 18.81 mmol, 3 equivalents) were added and the mixture was stirred at 80° C. overnight. 0.5 equivalent of 3,3-difluoropyrrolidine hydrochloride (450 mg, 3.14 mmol) was then added, and stirring of the reaction solution was continued at 80° C. overnight. The reaction solution was concentrated and purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate gradient: from 5/1 to pure ethyl acetate). This gave 431 mg (28% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[NH:26][C:25]([CH:27]=O)=[CH:24][N:23]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:27][C:25]3[NH:26][C:22]([CH3:21])=[N:23][CH:24]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: Cc1ncc(C=O)[nH]1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1ncc(CNc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)[nH]1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 2-methyl-3H-imidazole-4-carbaldehyde using decaborane yielded the title compound as a white solid. MS (ESI): m/z=373.2 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
Chlorosulfonic acid (9.7 mL, 0.147 mole) was added dropwise to 4-chlorophenoxybenzene (12.6 mL, 73.4 mmole) at room temperature with stirring. When addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, dried in the air, and recrystallized from petroleum ether and ethyl acetate to give 4-(4-chlorophenoxy)benzenesulfonylchloride (7.43 grams, 33%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5](O)=[O:6].Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC(OC)(C)C.CN(C=O)C>[CH3:19][O:18][N:17]([CH3:16])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1C(F)(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)c(C)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-methyl-4-trifluoromethyl-benzoic acid from step 6 (14.1 g, 69.1 mmol), N,O-dimethylhydroxylamine hydrochloride (10.78 g, 111 mmol), N-methylmorpholine (12.14 mL, 111 mmol) and 4-DMAP (844 mg, 691 mmol) in DCM (230 mL) at 0° C. were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (15.98 g, 82.9 mmol) and DMF (85 mL). The mixture was warmed up to 23° C. and was stirred for 18 h under nitrogen atmosphere. The mixture was diluted with TBME, washed with water and twice brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a brown oil (16.92 g, 99%), which was used without further purification. MS (ISP) 248.0 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([C:14]1[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=1)=[O:13])[NH:7][CH:6]=[CH:5]2.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:24]=[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=[C:14]1[C:12]([NH:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:13]
Reactant: O=C(Nc1cc2[nH]ccc2cc1Br)c1c[nH]c2ccccc2c1=O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(Nc1cc2[nH]ccc2cc1-c1ccccc1)c1c[nH]c2ccccc2c1=O
Temperature: 180 °C
Yield: 8.8 %

Procedure:
A mixture of N-(5-bromo-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide (B-27-I) (38 mg, 0.1 mol), phenyl boronic acid (18 mg, 0.15 mmol), (dppf)PdCl2 (cat.), and K2CO3 (100 μL, 2M solution) in DMF (1 mL) was heated in the microwave at 180° C. for 10 min. The reaction was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product, 4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide (158) (5 mg, 13%). HPLC ret. time 3.05 min, 10-99% CH3CN, 5 min run; ESI-MS 380.2 m/z (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1>[Pd].CCO.CCOC(C)=O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)c1ccc(N)cn1
Reaction time: 16 h

Procedure:
Palladium on carbon (200 mg) was added to a solution of N,N-dimethyl-5-nitropyridin-2-amine (1.29 g, 7.75 mmol) in EtOH (40 mL) and EtOAc (40 mL). The resulting mixture was stirred for 16 h under a H2 atmosphere, filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: ClC1C(Cl)=CC=CC=1N1CCCN([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)CC1.[Na+].[I-].[O:34]1[CH2:39][CH2:38][O:37][C:36]2[C:40]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=[CH:43][C:35]1=2.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:34]1[CH2:39][CH2:38][O:37][C:36]2[C:40]([N:44]3[CH2:45][CH2:46][N:47]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:48][CH2:49]3)=[CH:41][CH:42]=[CH:43][C:35]1=2
Reactant: O=c1ccc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4OCCO5)CC3)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of intermediate 4 (100 mg, 0.34 mmol) and NaI (102 mg, 0.68 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 61 (112 mg, 0.51 mmol) and anhydrous K2CO3 (188 mg, 1.36 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH 30:1) to give 7-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (compound 40) (125 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 7.88 (s, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.80-6.77 (m, 1H), 6.61-6.51 (m, 3H), 6.31 (d, J=1.8 Hz, 1H), 4.33-4.24 (m, 4H), 3.96 (m, 2H), 3.10 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.66-2.59 (m, 6H), 2.50-2.46 (m, 2H), 1.81-1.71 (m, 6H). HPLC: 99%, RT 2.468 min. MS (ESI) m/z 438.2 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][C:15](=[O:29])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH:7]([CH2:14][C:15]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)=[O:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1ccccc1)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl)phenylcarbamate (1.30 g) was dissolved in 50% trifluoroacetic acid in dichloromethane (26 mL) and the mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane-ethyl acetate (1:1, 15 mL). The crystals were collected by filtration and washed with n-hexane/ethyl acetate (1:1, 5 mL) to afford 2-anilino-N-[4-(4-pyridinyl)phenyl]acetamide bis(trifluoroacetate) (1.46 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Si:21]([O:28][CH2:29][CH2:30][CH2:31][NH2:32])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16])([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.5 g, 4.3 mmol) and 3-(tert-butyl(dimethyl)silyl)oxypropan-1-amine (0.98 g, 5.12 mmol). The title compound was obtained as a yellow solid (1.1 g, 49% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a 250 mL round bottom flask was added 4-bromophenol (16.5 g, 95.3 mmol), 3-bromopropanol (15.9 g, 114.4 mmol), N,N-dimethylformamide (50 mL) and potassium carbonate (22.4 g, 162.0 mmol). The reaction was allowed to stir at room temperature while being monitored by TLC (CH2Cl2). Upon the disappearance of 4-bromophenol the mixture was poured into a separatory funnel containing 50 mL of water. The product was extracted in diethyl ether and the organic layer was washed with 3×25-mL portions of cold water. The solvent was removed under reduced pressure. The product was purified by flash chromatography on silica gel eluting with dichloromethane. The solvent was removed under reduced pressure. Residual solvent and remaining 3-bromopropanol were removed in vacuo (14.2 g, 64.4%). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, 9.0 Hz), 6.77 (d, J=9.0 Hz, 2H), 4.06 (t, J=6.0 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.10 (q, J=6.0 Hz, 2H), 1.65 (s, 1H).
Reaction SMILES: C(OC(=O)[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([CH:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)(C)(C)C.[CH3:43][O:44][C:45]([C:47]1[S:51][C:50](Br)=[N:49][CH:48]=1)=[O:46]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][O:44][C:45]([C:47]1[S:51][C:50]([C:11]2[N:10]3[CH:27]=[CH:28][N:29]=[C:9]3[C:8]([NH:7][C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:34][CH:35]=3)=[N:13][CH:12]=2)=[N:49][CH:48]=1)=[O:46]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Reactant: COC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
In the same way as described for Compound 212, step 3, using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.25 g, 0.36 mmol), 2-bromo-thiazole-5-carboxylic acid methyl ester (0.159 g, 0.716 mmol), and Pd(PPh3)4 (0.041 g, 0.036 mmol) in DMF (4 mL). The reaction mixture is concentrated, treated with a mixture of (1:1) TFA-DCM and stirred at room temperature for 18 hours. The mixture is diluted with EtOAc and washed with a solution of sat. NaHCO3. The organic layers are dried over MgSO4, filtered and concentrated. Purification by silica gel column chromatography using 75:25 petroleum ether-EtOAc affords the title compound (90 mg, 57%). HPLC (254 nm): Rt 3.89 min (73%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:20][C:19]1[CH:18]=[C:17]([CH:34]=[CH:33][CH:32]=1)[CH2:16][O:10][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)c1cncc(O)c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-hydroxy nicotinic acid methyl ester (200 mg, 1.3 mmol) in DMF (3 mL) is added 60% sodium hydride emulsion (50 mg, 1.2 mmol) and this mixture is stirred 30 minutes. The free base of 2-(3-chloromethyl-phenoxymethyl)-quinoline hydrochloride (350 mg, 1.2 mmol, example 49) is prepard by partioning the material between ethyl ether and sodium bicarbonate and drying the organic phase with magnesium sulfate. A solution of this free base in DMF (2 mL) is added to the alcohol and this mixture is stirred at 25° C. for 16 hours. The solvent is removed in vacuo, dichloromethane (10 mL) and water (5 mL) is added, and this mixture is acidified to pH6 with acetic acid. The organic layer is dried over magnesium sulfate and the solvent removed in vacuo. The residue is purified by flash chromatography (silica, 4% methanol in dichloromethane) to give the title compound. MS (ESI) 401 (M+H)+.