Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:41]([O-:44])([O-])=[O:42].[Cs+].[Cs+].[C:47](Cl)(=[O:57])[C:48]1[CH:56]=[CH:55][CH:54]=[C:50]([C:51](Cl)=[O:52])[CH:49]=1>C1COCC1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=3[N:15]([C:47](=[O:57])[C:48]3[CH:56]=[CH:55][CH:54]=[C:50]([C:51]([N:15]4[C:16]5[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:41]([O:44][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:42])[CH3:6])[CH3:10])[CH2:14]4)=[O:52])[CH:49]=3)[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2cccc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
To a stirred solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (300 mg, 0.49 mmol) in THF (10.0 mL) was added Cs2CO3 (320 mg, 0.98 mmol) and stirred at RT for 3 h. The mixture was cooled to 0° C., isophthaloyl dichloride (49 mg, 0.24 mmol) was added, the cooling bath was removed and the mixture was stirred at RT. After 18 h, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was evaporated and the residue purified by preparative reverse phase HPLC to afford tert-butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[3-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]benzoyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (18 mg, 3%). LC-MS: 1353.8 (M+H), 1370.8 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4](Cl)[N:3]=1.[H][H]>C(O)(=O)C.O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:11][CH2:10]2)=[CH:4][N:3]=1
Reactant: COc1ccc(N2CCC(c3c(N)nc(N)nc3Cl)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCC(c3cnc(N)nc3N)CC2)cc1
Yield: 45.1 %

Procedure:
21.5 g of 2,4-diamino-6-chloro-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine were dissolved in 350 ml of a mixture of acetic acid and water (1:1) and hydrogenated in the presence of 7 g of 10% palladium/carbon catalyst until the hydrogen uptake ceased or the reaction was complete in accordance with thin-layer chromatography. The catalyst was filtered off over a filter aid and the filtrate was evaporated to dryness. The residue was suspended in water and the pH was adjusted to 9 by addition of aqueous ammonium hydroxide. Filtration yielded a crude product which was chromatographed on silica gel with chloroform/methanol (19:1). There were obtained 8.7 g of 2,4-diamino-5-[1-(4-methoxyphenyl)-4-piperidinyl]pyrimidine of melting point 224°-225° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[N:50]1([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[CH:58][N:57]=2)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH3:21])[C:10](=[O:12])[N:53]1[CH2:54][CH2:55][N:50]([C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[CH:58][N:57]=2)[CH2:51][CH2:52]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccc1CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution containing 2-tert-Butoxycarbonylamino-3-(4-chloro-2-methyl-phenyl)-propionic acid (200 mg, 0.64 mmol) in 30 mL of DMF was added HOBT (0.12 g, 0.76 mmol), EDCI (0.15 g, 0.76 mmol) and NMM (0.19 g, 1.9 mmol) under a nitrogen atmosphere. After stirring for 10 minutes, 4-Piperazin-1-yl-quinazoline (200 mg, 0.93 mmol) was added and stirring continued overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 10% MeOH/DCM gave [1-(4-Chloro-2-methylbenzyl)-2-oxo-2-(4-quinazolin-4-yl-piperazin-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.31 g, 95%.) LCMS (APCI+) m/z 510 [M+H]+; Rt: 2.54 min.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([CH3:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH:24][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:19]([CH3:25])[CH:18]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2,6-dimethyl phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:14]=[CH:15][C:8]=12.[C:26]([NH:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O.[OH-].[Ba+2].[OH-]>COCCOC.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>[NH:13]1[C:9]2=[N:10][CH:11]=[CH:12][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:37]3[CH:36]=[CH:35][C:34]([NH:33][C:26](=[O:27])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:39][CH:38]=3)=[C:8]2[CH:15]=[CH:14]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sccc4Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2-c2ccnc3[nH]ccc23)cc1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 4-(3-bromo-2-thienyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (5.3 mmol) in 40 mL of 1,2-dimethoxyethane was added 4-(N-Boc-amino)phenyl boronic acid (13.8 mmol), tetrakis(triphenylphosphine)palladium(0), (0.17 mmol), water (16 mL) and barium hydroxide (21.2 mmol). The reaction was heated at 80° C. for 36 h. The 1,2-dimethoxyethane was evaporated and the residue taken up in ethyl acetate and washed with water (50 mL). The crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to give the title compound (40%). ESMS [M+H]+: 392.2
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[N:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[C:24]=2[CH:23]=[CH:22]1.C(=O)([O-])O.[Na+].C(O)C>O.C1(C)C=CC=CC=1>[N:15]1([C:4]2[C:5]3[O:10][C:9]4[N:11]=[CH:12][CH:13]=[CH:14][C:8]=4[C:6]=3[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][N:28]=[C:29]4[NH:21][CH:22]=[CH:23][C:24]=34)[N:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)c2oc3ncccc3c2n1
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1cnc2oc3c(N4CCOCC4)nc(-c4ccnc5[nH]ccc45)nc3c2c1
Temperature: 120 °C

Procedure:
Under Ar(g) to a mixture of compound 5 (20 mg, 0.069 mmol), 7-azaindole-4-boronic acid pinacol ester (18.5 mg, 0.076 mmol), dichloro-bis(triphenylphosphine)palladium (II) (2.4 mg, 0.003 mmol) and sodium hydrogen carbonate (17.4 mg, 0.21 mmol) was added ethanol (1 mL) followed by toluene (1.6 mL) and then water (0.5 mL). The reaction mixture was then heated in a microwave at 120° C. (300 W) for 1 h, and was subsequently cooled to rt; the mixture was then partitioned between CH2Cl2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 30-90% EtOAc/Hex) furnished D (20 mg, 0.054 mol, 78%) as an off-white solid.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:25]([F:26])=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[O:27]1[C:31]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[O:30][CH2:29][CH2:28]1>CCCCCC.O.O1CCCC1>[Cl:16][C:17]1[C:18]2[C:19](=[O:21])[O:20][C:34]3([CH2:35][CH2:36][C:31]4([O:30][CH2:29][CH2:28][O:27]4)[CH2:32][CH2:33]3)[C:22]=2[CH:23]=[N:24][C:25]=1[F:26]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(O)c1ccnc(F)c1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1OC2(CCC3(CC2)OCCO3)c2cnc(F)c(Cl)c21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
At −60° C., n-butyllithium (1.50 M hexane solution) (75.9 mL) was dropwise added to tetrahydrofuran (100 mL) solution of 2,2,6,6-tetramethylpiperidine (12.5 g), and stirred at −78° C. for 30 minutes. At −78° C., 3-chloro-2-fluoroisonicotinic acid (5.00 g) was added to the reaction liquid, and stirred at −78° C. for 2 hours. Then, at −78° C., tetrahydrofuran (50 mL) solution of 1,4-dioxaspiro[4.5]decan-8-one (5.78 g) was added to the reaction liquid, and stirred for 30 minutes at −78° C. The reaction liquid was warmed up under cooling with ice, and water and hexane were added thereto in that order. The aqueous layer and the organic layer were separated from each other, then the aqueous layer was made acidic (pH of 1 to 2) with 2 M hydrochloric acid added thereto and the stirred at room temperature for 2 hours. The formed solid was taken out through filtration, washed with water, and dried under reduced pressure to obtain the entitled compound (4.39 g, 49%) as a pale brown solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](O)=[O:30])[N:20]2[C:19]1=[O:32])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:33]([NH2:36])[CH2:34][CH3:35].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[O:32]=[C:19]1[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29](=[O:30])[NH:36][CH2:33][CH2:34][CH3:35])[N:20]12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Reactant: CCCN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)OC(C)(C)C)C(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
DIPEA (0.033 mL, 0.19 mmol) was added to a cold (0° C.) mixture of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (50 mg, 0.15 mmol), propan-1-amine (10.3 mg, 0.174 mmol) and 1-hydroxy-7-azabenzotriazole (23.7 mg, 0.174 mmol) in DMF (0.3 mL). Then, EDC (33.4 mg, 0.174 mmol) was added. The reaction was stirred at rt for 8 hr. The crude mixture was purified by RP prep-HPLC (Method B) to give tert-butyl (4S,7S,10aS)-5-oxo-7-(propylcarbamoyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (56 mg, 0.15 mmol, 100% yield) as a white solid. Anal. Calcd. for C18H31N3O4S m/z 385.5. found: 386.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.02 (br s, 1H), 5.27 (br s, 1H), 5.02 (br s, 1H), 4.77 (m, 1H), 3.23 (m, 2H), 2.89 (m, 1H), 2.36 (m, 1H), 2.41 (m, 2H), 2.05 (m, 2H), 1.53-1.50 (m, 6H), 1.50 (s, 9H), 0.90 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1[C:33](=O)C2C(=CC=CC=2)C1=O.FC1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:8]([C:7]2[CH:11]=[C:3]([CH:4]=[CH:5][C:6]=2[N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)[C:1]#[N:2])=[O:10])[C@@H:19]1[CH2:24][NH:25][C:33]1[N:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1
Reactant: Fc1ncc(C(F)(F)F)cn1
Reactant: N#Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Product: C[C@@H]1CCCN(C(=O)c2cc(C#N)ccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-cyano-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-fluoro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[N:14]=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1.[OH-].[Na+]>CCOC(C)=O>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:10][C:11]1[N:15]([CH2:16][CH2:17][OH:18])[N:14]=[C:13]([C:19]([CH3:22])([CH3:20])[CH3:21])[CH:12]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.8 %

Procedure:
2,2,2-Trichloroethyl chloroformate (3.24 mL, 23.5 mmol) was added dropwise over 5 min to a solution of Intermediate 110a (4.11 g, 22.4 mmol) in NaOH (1M in water, 33.6 mL, 33.6 mmol) and EtOAc (35 mL) cooled at 0° C. under argon atmosphere. The reaction mixture was stirred at RT for 5 h. Additional 2,2,2-trichloroethyl chloroformate (462 μL) was added and stirring at RT was continued for 16 h. Additional NaOH (1M in water, 15 mL) and 2,2,2-trichloroethyl chloroformate (462 μL) were added and stirring at RT was continued for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was dissolved in cyclohexane (100 mL) and left to stand for 5 days. The resulting suspension was filtered and the solid collected by filtration washing with additional cyclohexane affording the title compound (3.64 g, 45%) as a white solid. The filtrate was concentrated in vacuo and the resultant residue was purified by FCC on silica, using a mixture of 50% EtOAc in cyclohexane, then partitioned between DCM and water. The organic layer was dried through a phase separator and concentrated in vacuo to afford additional title compound (1.43 g, 18%) as an orange gum. LCMS (Method 3): Rt 3.72 min, m/z 358 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][C@H:18]([C:22](=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>ClCCl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:43]([C:39]3[O:38][CH:42]=[CH:41][CH:40]=3)=[O:44])[C@H:18]([C:22](=[O:28])[NH:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCN[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)[C@H](C(=O)NC(C)(C)C)C3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
A mixture of 0.243 g of the above intermediate 3A, 0.17 ml of diisopropylethylamine, 0.08 ml of 2-furoyl chloride in 10 ml of dichloromethane was stirred at room temperature for 10 hours. The solution was diluted with dichloromethane (10 ml), washed with water (4×10 ml), 2N NaOH (4×10 ml), water (4×10 ml), dried (Na2SO4) and evaporated to dryness. The residue was purified by flash chromatography eluting with petroleum ether:ethyl acetate 100:2 to give 0.2 g (68%) of the title compound as an ivory solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=1[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28]>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH2:27]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=1[Br:7])[CH3:28]
Reactant: CCNc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (1.65 ml, 2.3 g, 18.3 mmol) was added dropwise to a solution of 2-bromo-5-nitrobenzoic acid (3 g, 12.2 mmol) in dichloromethane (12 ml). N,N-Dimethylformamide (0.01 ml) was added to the reaction mixture via syringe, the reaction mixture was stirred at 23° C. for 4 hour. The reaction mixture was concentrated in vacuo, and the residue was taken up in dichloromethane (24 ml), and DMAP (10 mg) and triethylamine (3.4 ml, 2.5 g, 24.3 mmol) were added. N-Ethylaniline (1.8 ml, 1.8 g, 14.6 mmol) was added over a 10 min period. After 18 hours at this temperature, 1:1 ethyl acetate/hexanes (30 ml) was added, and the organics were washed with 1N HCl (2-30 ml portions) and saturated aqueous sodium chloride (30 mL). The organics were dried over anhydrous sodium sulfate and concentrated. Purification of the residue by recrystallization from ethyl acetate/hexanes afforded N-ethyl-2-bromo-5-nitro-N-phenyl-benzamide (3.8 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([C:12]3[N:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=3)[C:7]=2[CH:19]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](=[O:36])[CH3:35]>C1COCC1>[NH2:18][C:14]1[N:15]=[CH:16][N:17]=[C:12]([N:8]2[C:7]3[CH:19]=[C:3]([C:1]#[C:2][C:34]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][N:28]=4)([OH:36])[CH3:35])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[CH3:11])[N:13]=1
Reactant: C#Cc1ccc2nc(C)n(-c3ncnc(N)n3)c2c1
Reactant: CC(=O)c1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(C#CC(C)(O)c3cnccn3)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.9 %

Procedure:
To a solution of 4-(6-ethynyl-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (80 mg, 0.29 mmol) in THF (0.5 mL) at −78° C. under N2 (g) was added 2M LDA in THF (0.43 mL, 0.86 mmol). After 5 min 1-pyrazin-2-yl-ethanone (105 mg, 0.86 mmol) in THF (0.5 mL) was added. After 20 min, the mixture was allowed to warm to RT and was stirred for 1 hr. The reaction mixture was quenched by addition of sat aq NH4Cl (0.5 mL). The volatiles were removed by evaporation under reduced pressure. The mixture was diluted with EtOAc (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by Biotage chromatography (100% DCM to 8% MeOH/DCM) gave the title compound (15 mg, 14% yield); 1H NMR (250 MHz, DMSO) delta 1.86 (3H, s), 2.89 (3H, s), 6.63 (1H, s), 7.32 (1H, dd, J=8.22, 1.52 Hz), 7.58 (1H, d, J=8.22 Hz), 7.96 (1H, s), 7.98 (1H, s), 8.39 (1H, d, J=1.22 Hz), 8.59-8.63 (1H, m), 8.63-8.67 (2 H, m), 9.02 (1H, d, J=1.37 Hz); LC-MS: m/z+373.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: O=C(O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Yield: 49.1 %

Procedure:
The title compound (1.43 g, 49% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-8-(trifluoromethyl)quinoline (2.12 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 384 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[C:12]([CH3:22])[O:11][C:10]=12)=[O:5])C.O.[OH-].[Li+].CO.O>O.C(O)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:9]2[N:8]=[C:7]([CH2:23][CH3:24])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][C:12]=1[CH3:22]
Reactant: CCOC(=O)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
Temperature: 25 °C

Procedure:
A suspension containing 3-(2,4-dichloro-phenyl)-6-ethyl-2-methyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid ethyl ester (1.80 g, 4.90 mmol) and lithium hydroxide monohydrate (1.0 g, 24.51 mmol) is heated at 70° C. in a 3/1 mixture of methanol/water (32 ml) for 2 hrs. The resulting solution is cooled to RT, diluted with water (60 ml) and glacial acetic acid added (approx. 3 ml) to adjust the pH to 4-5. The resultant suspension is stirred for 1 h and filtered and washed with water. The product is dried in vacuo at 50° C.; MS: m/z 339.03 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:34][CH2:35][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:31][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Reactant: Cc1cccc(N2CCNCC2)c1
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(C)c4)CC3)c(OC)nc2cc1OC
Yield: 56 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl) piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 56%) H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.25-3.30 (m, 4H), 3.76-3.80 (m, 4H), 3.98 (s, 3H), 4.02 (s, 3H), 4.16 (s, 3H), 6.74-6.78 (m, 3H), 7.14-7.26 (m, 4H).