Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26](N1C=CN=C1)([N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:27]>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:26]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[O:27])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)n1ccnc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (0.492 g, 1.37 mmol) in THF (8 mL) was added 1,1′-carbonyl diimidazole (0.266 g, 1.64 mmol). After stirring at 75° C. for 2 hours, the reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane (20 mL). The solution was washed with HCl (0.5 M), dried over Na2SO4 and concentrated to provide the crude product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[CH2:20][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C@H:18]([N:28]([C:30](=[O:48])[C:31]([C:34]3[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=3)([CH3:33])[CH3:32])[CH3:29])[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:47][C:44]([F:45])([F:46])[C:36]1[CH:35]=[C:34]([C:31]([CH3:32])([CH3:33])[C:30]([N:28]([C@H:18]2[C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:20][N:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:17]2)[CH3:29])=[O:48])[CH:39]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:37]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)N2CCNCC2)C[C@H]1c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of rac-4-[(3S,4R)-3-{[2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-(4-fluoro-phenyl)-pyrrolidine-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (21 mg, 0.30 mmol) in CH2Cl2 (4 ml) at RT, was added TFA (1 ml). After 1 hour, the reaction mixture was neutralized by addition of an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 to yield the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH:9]=[CH:10][CH2:11]Cl)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][NH:40][CH:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C.[I-].[K+]>[C:23]([O:27][C:28]([N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH2:39][N:40]([CH2:11]/[CH:10]=[CH:9]\[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:13])[C@@H:41]1[C:50]2[N:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:44][CH2:43][CH2:42]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC=CCCl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC/C=C\CN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)[C@H]1CCCc2cccnc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 161.1 %

Procedure:
(4-Chloro-but-2-enyl)-carbamic acid tert-butyl ester (1.81 g, 7.47 mmol), potassium iodide (59 mg, 0.36 mmol) and diisopropylethylamine (1.80 mL, 10.3 mmol) were added to a solution of 2-[(5,6,7,8-tetrahydroquinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylic acid tert-butyl ester (2.57 g, 6.79 mmol)) in acetonitrile (70 mL) and warmed to 60° C. and stirred for 17 h under nitrogen. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with methylene chloride (2×150 mL). The combined organic layers were dried (Na2SO4) and concentrated. The crude mixture was purified by column chromatography on silica gel (150 g) to afford 2-{[(S)-((Z)-4-tert-butoxycarbonylamino-but-2-enyl)-5,6,7,8-tetrahydro-quinolin-8-yl-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (5.99 g, 88%) as a white foamy solid. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.72 (s, 9H), 1.95-2.08 (m, 4H), 2.09-2.20 (m, 1H), 2.61 (d, 1H, J=16.2 Hz), 3.28 (dd, 1H, J=14.1, 5.4 Hz), 3.62 (dd, 1H, J=13.7, 7.2 Hz), 3.69-3.85 (m, 2H), 4.29 (dd, 1H, J=9.2, 6.6 Hz), 4.42 (d, 1H, J=14.9 Hz), 4.48 (d, 1H, J=14.9 Hz), 5.43-5.63 (m, 2H), 6.19 (s, 1H), 6.87 (dd, 1H, J=7.5, 4.8 Hz), 7.17 (d, 1H, J=7.7 Hz), 7.23-7.28 (m, 1H), 7.65-7.71 (m, 1H), 7.75-7.80 (m, 1H), 8.34 (d, 1H, J=4.4 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:22]=[CH:21][C:13]2[C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][O:16][C:12]=2[C:11]=1[CH2:23][CH2:24][CH3:25])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:32]1[CH2:39][CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34]>CN(C=O)C>[CH2:23]([C:11]1[C:12]2[O:16][N:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[C:13]=2[CH:21]=[CH:22][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][N:32]1[CH2:39][CH2:38][C:36](=[O:37])[NH:35][C:33]1=[O:34])[CH2:24][CH3:25]
Reactant: CCCc1c(CCCCOS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CCNC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(CCCCN2CCC(=O)NC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
A mixture of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl methanesulfonate (60 mg, 0.16 mmol), from this Example step 5, Cs2CO3 (206 mg, 0.63 mmol) and 5,6-dihydrouracil (54.2 mg, 0.48 mmol) in dry DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. Combined organic extracts were washed with water and brine, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by preparative TLC using ethyl acetate to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].Cl>[OH-].[Na+]>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
In a 2 N-aqueous solution of sodium hydroxide (500 ml) was dissolved 11-aminoundecanoic acid (30.2 g, 0.15 mol) under mild heating (50° C.). With intense stirring, carbobenzoxy chloride (30.7 g, 0.18 mol) was added in 4 installments over a period of 30 minutes, after which the mixture was stirred for 2 hours. The reaction mixture was cooled with ice, adjusted to pH 2 with 6 N-hydrochloric acid and extracted with ethyl acetate (600 ml). The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and petroleum ether was added to the crystalline residue. After cooling, the crystals were recovered by filtration. By the above procedure there was obtained 36.0 g of N-carbobenzoxy-11-aminoundecanoic acid. m.p. 96°-97° C.; Rf1 =0.67.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15](O)=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1.[Cl-].[NH4+:31]>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=4)[OH:19])=[C:13]([C:15]([NH2:31])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:28]=1
Reactant: [NH4+]
Reactant: O=C(O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C(O)c1cc(F)cc(F)c1)CCOc1cc(F)c(Br)cc1-2
Yield: 45 %

Procedure:
10-bromo-3-((3,5-difluorophenyl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid was reacted with ammonium chloride and purified by flash chromatography to afford 57 mg (45% yield) of the title compound.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]([OH:20])(=[O:19])[CH3:18]>>[C:17]([O:20][CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:19])[CH3:18]
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CC(=O)O
Product: CC(=O)OC1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 57.5 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.30 g, 1.28 mmol) was refluxed in 50 ml of acetic acid for 10 min. Activated carbon (100 mg) was added and the reaction mixture was filtered and evaporated in vacuo to about 3 ml, and 20 ml of water was added. The precipitate was filtered off and washed with water and dried to give 229 mg of the crude compound, which was recrystallized from acetic acid-water to yield 190 mg (57.5%) of the title compound. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 2.13 (s, 3H), 6.36 (s, 1H), 7.15 (t, 1H), 7.29 (d, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 12.0 (s, 1H), 12.4 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([C:13]1[CH:22]=[CH:21][C:16]2[C:17](=[O:20])[O:18][CH2:19][C:15]=2[C:14]=1[CH3:23])[CH2:3][N:4]1[CH:9]2[CH2:10][NH:11][CH2:12][CH:5]1[CH2:6][O:7][CH2:8]2.[CH3:24][C@@H:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH:35]3[CH2:37][O:36]3)[CH:32]=2)[C:27](=[O:38])[O:26]1>>[OH:36][CH:35]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:38])[O:26][C@H:25]([CH3:24])[CH2:34]2)[CH2:37][N:11]1[CH2:12][CH:5]2[N:4]([CH2:3][C@H:2]([OH:1])[C:13]3[C:14]([CH3:23])=[C:15]4[C:16](=[CH:21][CH:22]=3)[C:17](=[O:20])[O:18][CH2:19]4)[CH:9]([CH2:8][O:7][CH2:6]2)[CH2:10]1
Reactant: Cc1c([C@@H](O)CN2C3CNCC2COC3)ccc2c1COC2=O
Reactant: C[C@@H]1Cc2cc(C3CO3)ccc2C(=O)O1
Product: Cc1c([C@@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2)C[C@@H](C)OC4=O)C3)ccc2c1COC2=O

Procedure:
(3R)-6-(1-Hydroxy-2-(9-((R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)ethyl)-3-methylisochroman-1-one was prepared initially as a mixture of two diastereomers from 5-[(1R)-1-hydroxy-2-(3-oxa-7,9-diazabicyclo[3.3.1]non-9-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one [INTERMEDIATE 17] and (3R)-3-Methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one [INTERMEDIATE 23, STEP B] in an analogous fashion to that described for the synthesis of EXAMPLE 1. The mixture of diastereomers was separated by preparative SFC-HPLC using a Chiralcel® OD column (30×250 mm) to afford the title single isomers.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:15][NH2:16]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:15][NH2:16])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2[nH]ccc2c1

Procedure:
A 100 mL round bottomed flask was charged with methyl 1H-indole-5-carboxylate (1.6 g, 9.13 mmol) and ethanol (20 mL). To this was added hydrazine monohydrate (10 g) and the mixture was placed under reflux for 7 days. The reaction mixture was concentrated to dryness and chloroform (80 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (1.54 g, 96%) was dried en vacuo and 1H NMR analysis was consistent with the solid compound. 1H NMR (DMSO d6, 400 MHz) δ 10.7 (br s, 1 H), 9.6 (br s, 2H), 8.21-8.15 (m, 1 H), 7.71 (dd, J=8.6 and 1.7 Hz, 1 H), 7.50 (d, J=8.6 Hz, 1 H), 7.44-7.39 ( m, 1 H) and 6.58-6.53 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].Cl.Cl.[NH2:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[N:38]([CH3:40])[CH3:39]>CCCCCCC.C(OCC)(=O)C>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([N:38]([CH3:40])[CH3:39])=[C:31]([NH:30][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)[CH:36]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CN(C)c1ccc(Cl)cc1N
Agent: Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(Cl)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate), (2-amino-4-chlorphenyl)dimethylamine dihydrochloride (commercially available, CAS RN 183251-88-9), using 5 mole equivalents of base and using a gradient of n-heptane:ethyl acetate (100:0 to 50:50) for the chromatographic purification. White solid (72%). MS (ESI): m/z=436.038 [M+H]+.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([N+:13]([O-])=O)[C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]>C(O)C.[Fe]>[F:10][C:9]1[C:4]([F:3])=[C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:6]([NH2:13])=[C:7]([O:11][CH3:12])[CH:8]=1
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 25 °C
Yield: 89 %

Procedure:
Ammonium chloride (1.18 g, 20.16 mmol) and iron powder (1.15 g, 21.44 mmol) were added to a stirred solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (0.57 g, 1.34 mmol) in ethanol (20 mL). The mixture was stirred at reflux for 16 hours, cooled to room temperature, filtered over celite and the filtrate concentrated to dryness. The resulting residue was taken into ethyl acetate, washed with water, dried over sodium sulfate and further purified by crystallization from ethanol to provide the product as an off-white solid (0.47 g, 90.3%). M−H+: 393.2. 1H NMR (DMSO, 300 MHz): 3.76 (s, 311); 6.1 (t, 1H); 6.8-7.0 (m, 1H); 7.2 (d, 1H); 7.35 (s, 1H); 7.42 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][CH:14]=[C:15]([Br:17])[N:16]=1>CN(C=O)C>[Br:17][C:15]1[N:16]=[C:12]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: Brc1csc(Br)n1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(Sc2nc(Br)cs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Fluorothiophenol (0.48 mL, 4.5 mmol) was dissolved in DMF (10 mL) and then chilled to 0° C. in an ice bath. NaH (0.14 g, 5.8 mmol) was added slowly to the mixture and it was allowed to stir under inert atmosphere. After 1 hour, 2,4-dibromothiazole (1.0 g, 4.1 mmol) was added to the mixture and the ice bath was removed. The resulting mixture was allowed to stir 3 hours under an inert atmosphere. The mixture was quenched with 1N NaOH and diluted with DCM. The aqueous layer was extracted three times with 4:1 DCM/MeOH, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (1-10% EtOAc/hexanes) to give 4-bromo-2-(4-fluorophenylthio)thiazole (1.0 g, 84% yield) as a white solid. MS (ESI pos. ion) m/z: 290 (MH+, 79Br), 292 (MH+, 81Br). Calculated exact mass for C9H5BrFNS2: 289 (79Br), 291 (81Br).
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][C:22]2([C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[CH2:25]2)[CH2:21][CH2:20]1)=[O:18])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)C.[C:35]([NH:42][C:43]([CH3:48])([C:45]([OH:47])=O)[CH3:44])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[O:33]=[C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]2([CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][C:45](=[O:47])[C:43]([NH:42][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])([CH3:44])[CH3:48])[CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])=[O:18])[CH2:24][CH2:23]2)[CH2:25]1
Reactant: CC(c1ccccc1)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Product: CC(c1ccccc1)C(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Yield: 64.8 %

Procedure:
The title compound (236 mg, 0.431 mmol) was prepared from 316 mg (0.665 mmol) of the intermediate from Step A and 148 mg (0.731 mmol) of Boc alpha methyl alanine according to the procedure described in Example 1 (Step A).
Reaction SMILES: O[CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.COCCN(S(F)(F)[F:32])CCOC>ClCCl>[F:32][CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2O
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2F
Yield: 82.1 %

Procedure:
Ethyl 4-hydroxy-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (400 mg, 1.00 mmol, 1.00 equiv) in dichloromethane (25 mL) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (442 mg, 2.00 mmol, 2.00 equiv) at 0° C. After 4 h at room temperature the resulting mixture was washed with brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10). It resulted in 330 mg (82%) of the titled compound as a yellow solid. LC-MS (ES, m/z) 403 [M+H]+.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][CH2:35][CH3:36])[NH2:32])=[O:16])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 80.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-norleucine N-benzylamide (234 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 210 mg (80%) of L-norleucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-Prolyl] benzylamide as a white foam.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)O1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:10]1[C:11]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:6]([OH:8])=[CH:5][CH:9]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Oc1ccnc2ccncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione (1.149 g, 4.63 mmol) in diphenyl ether was heated at 200° C. for 20 min, then cooled to RT. Hexane was added and the mixture was stirred at RT for 30 mins. The solid was filtered off and washed with hexane to furnish 1,6-naphthyridin-4-ol as an off-brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[N:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]1[NH:6][C:7](=[O:9])[CH:8]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[N:4]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C#N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccccc1-c1nc(-c2nnn[nH]2)cc(=O)[nH]1

Procedure:
A stirred solution of 4-cyano-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (325 mg), sodium azide (91 mg) and ammonium chloride (75 mg) in dimethylformamide (15 ml) was heated at 125° C. for 5 hours. Most of the dimethylformamide was removed under reduced pressure and water added to the oily residue which solidified. The mixture was cooled and the solid was collected, washed with water and recrystallized from glacial acetic acid to yield the title compound, 174 mg, m.p. 219°-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([CH2:12][CH3:13])=[C:5]([CH3:14])[N:4]=1
Reactant: CCc1cc([N+](=O)[O-])c(OC)nc1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(N)c(OC)nc1C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
A solution of 2-methoxy-3-nitro-5-ethyl-6-methylpyridine (535 mg, 2.72 mmol) in methanol (8 mL) and tetrahydrofuran (8 mL) containing 5% palladium on carbon (83 mg) was hydrogenated at atmospheric pressure for 5 hours. The catalyst was filtered off the solvent evaporated to yield 436 mg (98%) of oily product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]1[O:10][CH:8]1[CH3:9]>CO>[OH:10][CH:8]([CH3:9])[CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: Cc1ncc[nH]1
Reactant: CC1CO1
Solvent: CO
Product: Cc1nccn1CC(C)O

Procedure:
2-Methylimidazole (1 mol) and methanol as a solvent were charged into a stirring-type autoclave, and propylene oxide (1 mol) was reacted therewith at a reaction temperature of 80° C. to 140° C. Thereafter, by purification through distillation, 1-(2-hydroxypropyl)-2-methylimidazole was obtained.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH3:3].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(CC)=O>[CH2:17]([NH:21][C:22]([NH:16][S:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])(=[O:14])=[O:15])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CC(C)S(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[(1-methylethyl)sulfonyl]benzenesulfonamide (29 g, 0.11 mol), n-butylisocyanate (14.7 g, 0.15 mol) and anhydrous potassium carbonate (16.6 g, 0.120 mol) in methylethyl ketone (325 ml) was refluxed with stirring for 3 hours. The reaction mixture was cooled to 0° and then poured into ice-water. The aqueous solution was acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to give N-[butylaminocarbonyl]-2-[(1-methylethyl)sulfonyl]benzenesulfonamide, m.p. 164.5°-165.5°.