Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][OH:39])[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH2:40]([O:42][C:43](=[O:59])[CH2:44][CH:45]([N:49]1[C:57]2[C:52](=[CH:53][C:54](O)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1)[CH2:46][CH2:47][CH3:48])[CH3:41].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:20]([O:24][C:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([CH2:37][CH2:38][O:39][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[N:49]([CH:45]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:59])[CH2:46][CH2:47][CH3:48])[CH:50]=[CH:51]4)[N:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCO)nc21
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Triphenylphosphine (0.20 g, 0.77 mmol) was added to a solution of 7-(2-hydroxy-ethyl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.16 g, 0.58 mmol) and 3-(5-hydroxy-indol-1-yl)-hexanoic acid ethyl ester (0.10 g, 0.38 mmol) in THF (4 mL) at 0° C. Diisopropylazodicarboxylate (0.15 g, 0.77 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The solution was then concentrated. The residue was purified by flash chromatography on silica gel (30% ethyl acetate in hexane) to give the title compound (13% yield). 1H NMR (CDCl3) δ 7.30 (m, 2H), 7.09 (m, 2H), 6.96 (d, 1H, J=7.6 Hz), 6.86 (m, 1H), 6.41 (d, 1H, J=3.2 Hz), 4.78 (m, 1H), 4.39 (t, 2H, J=6.9 Hz), 3.98 (q, 2H, J=7.1 Hz), 3.75 (m, 2H), 3.21 (t, 2H, J=6.9 Hz), 2.86 (m, 2H), 2.77 (m, 2H), 1.85 (m, 4H), 1.50 (s, 9H), 1.20 (m, 2H), 1.06 (t, 3H, J=7.1 Hz), 0.85 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[O:15][C:14]3[C:13](SC)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1.O.[NH3:25]>[Cl-].[NH4+].O1CCOCC1>[CH3:1][N:2]1[C:6]([C:7]2[O:15][C:14]3[C:13]([NH2:25])=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[CH:3]1
Reactant: N
Reactant: CSc1ncnc2cc(-c3c(-c4ccccc4)ncn3C)oc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2o1
Temperature: 170 °C
Yield: 84 %

Procedure:
A mixture of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)furo[3,2-d]pyrimidine (Intermediate 87) (50 mg) and saturated aqueous ammonium chloride solution (2 drops) in concentrated aqueous NH3 (1 mL) and 1,4-dioxane (2 mL) was heated under microwave conditions (CEM explorer, 170° C., 150 minutes). Water (10 mL) was added, and the mixture extracted into EtOAc (2×20 mL). The combined organic phases were dried and concentrated in vacuo. Purification by flash chromatography on silica (0-5% MeOH in EtOAc) afforded the title compound as an off-white solid (38 mg, 84%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[OH-].[Na+].Cl>CO>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)c1cc2c(C(=O)Nc3c(Cl)cncc3Cl)ccc(OC)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Ethyl 4-[(3,5-dichloro-4-pyridyl)carbamoyl]-7-methoxybenzofuran-2-carboxylate (6.1 g) was dissolved in methanol (80 ml), 1 N aqueous NaOH (40 ml) was added thereto under cooling on ice, and the mixture was returned to room temperature and stirred for 2 hours. The reaction mixture was acidified by dropwise adding 1 N aqueous HCl under cooling on ice, and the precipitated crystals were collected by filtration and washed with water to give Compound K (5.6 g, 98%).
Reaction SMILES: [CH2:1]([N:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:2]=[CH2:3].[H-].[Na+].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.O>C1COCC1>[CH2:1]([N:4]([CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: C=CCN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C)CCCCCCOc1ccc(C(C)=O)cn1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
490 mg of 6-(allyl-methyl-amino)-hexan-1-ol (Ex. 42.B) in 5 ml of THF are treated over a period of 1.5 h. with 240 mg of NaH (55-60% dispersion in mineral oil) and with 410 mg of 1-(6-chloro-pyridin-3-yl)-ethanone (Ex. 42.D.a) in 4 ml of THF. The solution is stirred at RT, treated with water and filtered and the residue is washed with methylene chloride. The phases are separated and the inorganic phase is extracted with methylene chloride and then with ethyl acetate. The organic phases are concentrated, taken up in methylene chloride and extracted with 1M HCl. The acidic-aqueous phase is washed with methylene chloride, made basic with NaOH and extracted with methylene chloride. The organic phase is washed with NaHCO3 solution and saturated sodium chloride solution and dried. The crude product is purified on silica gel with methylene chloride:methanol (9:1). 177.8 mg of 1-[6-[6-(allyl-methyl-amino)-hexyloxy]-pyridin-3-yl]-ethanone are obtained as an oil. 176.4 mg of this are converted with 70 mg of fumaric acid into 1-[6-[6-(allyl-methyl-amino)-hexyloxy]pyridin-3-yl]-ethanone.fumarate (1:1), MS: m/e 291 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:19].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:19][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: [I-]
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: Cc1oc(-c2ccc3ccccc3c2)nc1CI

Procedure:
1.8 g of 4-chloromethyl-5-methyl-2-naphthalen-2-yloxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.7 g of 4-iodomethyl-5-methyl-2-naphthalen-2-yloxazole as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)#[N:13]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:17]1[CH:18]=[C:14]([C:12]#[N:13])[NH:15][CH:16]=1)=[O:4]
Reactant: N#Cc1ccc[nH]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Trichloracetyl chloride (44.4 g, 27.3 mL, 244 mmol) in dichloromethane (75 mL) was added over 20 min to a mechanically stirred suspension of aluminum trichloride (54.3 g, 407 mmol) in dichloromethane (150 mL). The resulting mixture was stirred for 30 min, and then 2-cyanopyrrole (15.0 g, 163 mmol) in dichloromethane (75 mL) was added over 30 min. The reaction was heated at reflux for 5 h and then allowed to cool. The reaction was diluted with ethyl acetate (600 mL) and then quenched slowly with water (300 mL). The layers were separated and then the organic layer was washed with water and brine, dried (magnesium sulfate) and evaporated under reduced pressure to afford a quantitative yield of desired product (39.0 g, 100%) containing trace impurities. This material was used in the next step without further purification. 1H NMR (DMSO-d6) δ 8.14 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:6]=1[NH2:7].[CH2:18]([N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=[C:21]1SC)[CH3:19].Cl>C(OCC)(=O)C.CN(C=O)C>[F:3][C:4]([F:16])([F:17])[C:5]1[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=[CH:8][C:6]=1[NH:7][C:21]1[N:20]([CH2:18][CH3:19])[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[N:22]=1
Reactant: CCn1c(SC)nc(C(F)(F)F)cc1=O
Reactant: Nc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Nc2ccc(C(F)(F)F)cc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Sodium hydride (60% in oil, 0.45 g, 11.4 mmol) was added to DMF (5 ml) solution of 2,4-bis(trifluoromethyl)aniline (2.00 g, 8.73 mmol), followed by stirring for 30 minutes. Then, 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (2.08 g, 8 .73 mmol) was added, followed by stirring at 60° C. for 2 hours. After completion of the reaction, 1 N hydrochloric acid (30 ml) and ethyl acetate (20 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with water (30 ml×2) and saturated brine (70 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=9:1˜7:3), white solid of 2-{2,4-bis(trifluoromethyl)phenyl}amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 33] was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[N:15]=[C:14](F)[CH:13]=[C:12]([F:17])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14]2[CH:13]=[C:12]([F:17])[N:11]=[C:10]([F:9])[N:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cc(F)nc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1cc(Nc2ccc(Cl)cc2)nc(F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloroaniline was added to a stirred solution of 2,4,6-trifluoropyrimidine (7.7 g), potassium carbonate (7.86 g) in ethanol (80 ml). The mixture was stirred at room temperature for 16 h, diluted with water, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 8.3 g cream solid
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][CH2:63][C:64]([NH:66][CH2:67][C:68](O)=[O:69])=[O:65])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][CH2:63][C:64]([NH:66][CH2:67][C:68]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:69])=[O:65])=[O:61])([CH3:58])([CH3:57])[CH3:56]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 76 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 76%. [α]D =+14.9° (c=1.05, dichloromethane).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][CH3:37])[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1OC
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1OC

Procedure:
The title compound, MS: m/e=515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,4-dimethoxy-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[C:4]([O:15][CH3:16])[CH:3]=1.[N:17]1([CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:14])[C:11]([N:20]2[CH2:21][CH2:22][N:17]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH2:18][CH2:19]2)=[O:13])=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(I)cc1NC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(I)cc1NC(C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.6 %

Procedure:
To a solution of 2-(4-chloro-5-iodo-2-methoxyphenylamino)propanoic acid (760 mg, 2.13 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (669 mg, 2.78 mmol), EDCI.HCl (818 mg, 4.26 mmol), HOBt (575 mg, 4.26 mmol) in DMF (8 mL) at 0° C., Et3N (861 mg, 8.52 mmol) was added. The resulting mixture was stirred at RT for 16 h and then partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1:1) to afford the desired product (673 mg, 55% yield) as a white solid. ESI-MS m/z: 579.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[N:6][CH:7]=1.[N:34]([C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1)=[C:35]=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[CH:38][C:37]([NH:34][C:35]([N:31]2[CH2:32][CH2:33][N:28]([C:3]3[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[CH:11][C:10]=4[N+:25]([O-:27])=[O:26])[N:4]=3)[CH2:29][CH2:30]2)=[O:36])=[CH:44][CH:43]=1)#[N:42]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)Nc2ccc(C#N)cc2)CC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 222 %

Procedure:
To a solution of 4-((5-methyl-4-(piperazin-1-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-nitrobenzamide (0.073 mmol) in DCM (1.5 mL) was added 4-isocyanatobenzonitrile (23 mg, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was filtered and washed with minimal volume of DCM and then hexanes to give the title compound (97 mg, 100%). MS (ES+) C30H34N10O4 requires: 598. found: 599 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C=O.[C:46](O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:46])[CH:19]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[C:18]3=[O:33])[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: Cc1cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To the solution of: (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid (3 mg) in methanol (0.5 mL) was added formaldehyde solution (20 μL, 37%), followed by acetic acid (10 μL) and sodium cyanoborohydride (12 mg). The mixture was stirred for 1 hour, and solvents were removed under reduced pressure. The remaining solid was dissolved with DMF/water (1 mL/0.5 mL), and was purified with reverse phase HPLC to give (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C33H35ClN5O4S: 632.2 (M+H+); Found: 632.2 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 8.0 (m, 1H), 7.82 (m, 1H), 7.68 (s, 1H), 7.62-7.40 (m, 6H), 5.21 (m, 1H), 4.70 (m, 1H), 4.6-4.3 (m, 2H), 4.08/4.05 (s, 3H), 3.5 (m, 2H), 2.57 (s, 3H), 2.40 (m, 3H), 0.93 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F:44][C:45]([F:54])([F:53])[C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:48][C:47]4[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=4[C:45]([F:44])([F:53])[F:54])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4C(F)(F)F)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 37 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-(trifluoromethyl)aniline yielded the title compound (37% yield) as a yellow foam. MS (ISP): m/z=734.4 [M+H]+.
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15](F)[N:14]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[CH2:22]([NH:29][C:15]1[C:16]([F:20])=[CH:17][C:18]([F:19])=[C:13]([NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])[N:14]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1nc(F)c(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 160 °C
Reaction time: 24 h
Yield: 119.2 %

Procedure:
To 20 ml of N-methylpyrrolidone were added 9.7 g of 2-(t-butylamino)-3,5,6-trifluoropyridine together with 15.5 g of benzylamine, and the mixture was stirred at 160° C. for one day and allowed to cool. After adding 50 ml of chloroform, the mixture was washed three times with 500 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 16.5 g of the title compound as a dark green oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([OH:22])=O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([NH:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]([CH2:19][C:20]([N:38]([CH2:39][CH2:40][CH3:41])[CH2:35][CH2:36][CH3:37])=[O:22])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc([N+](=O)[O-])cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A suspension of crude 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101 mole), 1,1'-carbonyldi imidazole (1.63 g, 0.0101 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for three hours with nitrogen bubbling through it and then refluxed under nitrogen overnight. The mixture was cooled to room temperature and a solution of dipropylamine (3.06 g, 0.0302 mole) in tetrahydrofuran (5 ml) was added. The suspension was refluxed over the weekend under nitrogen. The solvents were removed under reduced pressure and the solid residue was triturated in water (100 ml) overnight. The solid was collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice more with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and cooled to room temperature to precipitate a solid. Water was added and the solid was collected by filtration, rinsed with water and dried under high vacuum at 70° C. to give 1.23 g (32%) of title compound, mp. 205°-208° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][S:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.[C:33]([C:41]1[C:42](=[O:52])[N:43]([CH3:51])[C:44](=[O:50])[N:45]([CH3:49])[C:46]=1[CH2:47]Br)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CCO>[OH:4][CH2:3][C@H:2]([N:1]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:41]2[C:46]([N:45]([CH3:49])[C:44](=[O:50])[N:43]([CH3:51])[C:42]2=[O:52])=[CH:47]1)[CH2:5][S:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: N[C@@H](CO)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CO)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
(S)-2-Amino-3-(tritylthio)propan-1-ol (step 1) (1.58 g, 4.52 mmol), triethylamine (1.454 mL, 10.43 mmol) and 5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.173 g, 3.48 mmol) were combined in EtOH (60 mL) and the mixture heated at reflux for 1 hour. The reaction mixture was cooled to RT and evaporated under vacuum. The residue was partitioned between DCM and water and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated under vacuum to give the title compound which was used without further purification.