Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2CC1
Temperature: 60 °C

Procedure:
A mixture of 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (4.0 g, 13.9 mmol), morpholine (1.8 ml, 20.8 mmol) and triethylamine (2.14 ml, 15.3 mmol) in tetrahydrofuran (120 ml) was heated at 60° C. for 3 h. The reaction mixture was then cooled, filtered and the filtrate evaporated in vacuo to give a yellow solid. Crystallisation from dichloromethane/n-hexane gave the title compound as an off-white solid (4.4 g, 94 Mass Spectrum AP+: Found 339 (MH+). C16H22N2SO4 requires 338.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH:13]1[C:26]2[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.[C:35]([NH2:52])([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36]>C(O)(=O)C>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:52][CH:13]3[C:26]4[CH:25]=[C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:23]=[CH:22][C:21]=4[O:20][C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CCCCOc1ccc2c(c1)C(O)c1ccccc1O2
Reactant: NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1ccc2c(c1)C(NC(=O)OCC1c3ccccc3-c3ccccc31)c1ccccc1O2
Reaction time: 14 h

Procedure:
A solution of p-toluenesulfonic acid (30 mg, 0.015 mmol) in glacial acetic acid (3 mL) was added dropwise at 25° C. over 15 minutes to a solution of 5-(9-hydroxyxanthen-2-oxy)valeric acid (0.2 g, 0.64 mmol) prepared as described above and Fmoc-NH2 (184 mg, 0.76 mmol) in glacial acetic acid (12 mL). This mixture was stirred continuously for 14 hours, filtered, and the resultant white solid washed with water (3×5 mL) and n-hexane (2×5 mL). The solid was dried in vacuo over P2O5 at 25° C. for 6 hours. Yield: 200 mg (69%), TLC-pure Rf : 0.53 EtOAc/MeOH 10:2. 1H-NMR (CDCl3, 300 MHz) δ7.76 (d, 7.4 Hz 2H), 7.59 (d, 7.4, 2H), 7.40 (t,J=7.4, 2H), 7.31 (t,J=7.4 2H), 4.69 (s, broad, 1H), 4.40 (d, J=6.9, 2H), 4.24 (t,J=6.9, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:5]1=2.Cl[CH2:19][C:20]1[O:24][CH:23]=[N:22][C:21]=1[CH3:25].O>COCCOC>[CH3:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[C:13](=[O:17])[N:14]([CH2:19][C:20]3[O:24][CH:23]=[N:22][C:21]=3[CH3:25])[CH2:15][CH2:16][C:5]1=2
Reactant: Cn1c2c(c3ccccc31)C(=O)NCC2
Reactant: Cc1ncoc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ncoc1CN1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 5 h
Yield: 13.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 600 mg) was added to a stirred suspension of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (1.5 g) in dry DME (150 ml) and then the mixture was stirred at 60° for 5 h under nitrogen. 5-Chloromethyl-4-methyloxazole (1.2 g) was added and the mixture was stirred overnight. A further quantity of sodium hydride (60% dispersion in oil; 600 mg) was added and the mixture was stirred at 60° for 4 h, then cautiously treated with water (100 ml). The mixture was extracted with dichloromethane containing methanol (ca. 1%) (3×100 ml) and the combined extracts were evaporated. The residue was purified by FCC eluting with System A (100:8:1) to give the title compound (300 mg) as a solid, t.l.c. (System A, 100:8:1) Rf 0.4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][NH2:18])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: NCCCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: NCCCc1ccc(O)cc1
Yield: 91.1 %

Procedure:
100% Palladium-carbon catalyst (water content 50%, 120 mg) was added to a solution of 3-(4-benzyloxyphenyl)propylamine (620 mg, 2.57 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred for 2 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 3-(4-hydroxyphenyl)propylamine (354 mg, 91.1%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=[O:10]>CO.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH2:9][OH:10]
Reactant: COc1c(C=O)cc(Br)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(CO)cc(Br)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Sodium borohydride (4 g) was added in portions to a stirring solution of crude 5-bromo-2-methoxy-3-nitrobenzaldehyde (20.5 g) in methanol (350 mL) and tetrahydrofuran (150 mL) at 0° C. After 1 h, the methanol was removed in vacuo. The residue was treated with cold water (150 mL) and extracted with diethyl ether (2×150 mL). The combined organic layer was evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in petroleum ether (10–40%) gave the title compound (17 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8][N:9]4[CH3:12])=[CH:4][CH:3]=3)=[O:25])=[C:22]([CH3:29])[N:21]=2)=[CH:16][CH:15]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: CN1CCCc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2c(c1)N(C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (31 mg, 0.19 mmol) in DCM (1 ml) was added 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (44 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 4-dimethylaminopyridine (11 mg, 0.09 mmol) and the reaction stirred at ambient temperature overnight. The crude reaction mixture was loaded directly onto a silica SPE column and eluted with 0-2% methanol/DCM to give the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.02 (dd, 2H), 7.84 (d, 1H), 7.57 (d, 1H), 7.35 (br, 1H), 7.17 (t, 2H), 7.00 (s, 1H), 6.93 (d, 1H), 6.74 (d, 1H), 3.25 (m, 2H), 2.93 (s, 3H), 2.80 (s, 3H), 2.74 (m, 2H), 1.96 (m, 2H)
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[CH3:11][C:12](=O)[CH2:13][C:14](=[O:17])[CH2:15][CH3:16]>CO>[NH2:4][C:3]1[C:13]([C:14](=[O:17])[CH2:15][CH3:16])=[C:12]([CH3:11])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CCC(=O)CC(C)=O
Solvent: CO
Product: CCC(=O)c1c(C)[nH]c(-c2ccccc2)c1N
Yield: 53 %

Procedure:
Starting from 2-amino-2-phenylacetonitrile and hexane-2,4-dione, the open-chain intermediate compound is obtained, b.p. 160° C./0.3 mm Hg. The title compound is obtained in an overall yield of 53%, m.p. 166°-168° C. (from methanol).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[C@H:16]([CH3:28])[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>[OH-].[Na+]>[CH2:21]([O:20][C:18]([NH:17][C@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:31])=[O:2])=[O:30])=[O:29])[CH3:28])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: 30 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To N-benzyloxycarbonyl-L-alanyl-L-prolyl-L-proline methylester (4.31 g, 10 m mole), 1.5 N aqueous sodium hydroxide (10 ml, 15 m mole) was added and the mixture was stirred for 2 hours at 30° C. The solution was adjusted to pH 2.5 with 1N hydrochloric acid, and then extracted with two 50 ml portions of 1,2-dichloroethane. The thus obtained 1,2-dichloroethane layer was concentrated under reduced pressure. The residue was recrystallized with acetone-water to give N-benzyloxycarbonyl-L-alanyl-L-prolyl-L-proline (3.68 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]1[N:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>CN(C=O)C>[Br:17][C:14]1[CH:15]=[N:16][C:11]([N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[S:19]([CH3:18])(=[O:21])=[O:20])=[N:12][CH:13]=1
Reactant: Brc1cnc(NCc2ccccc2)nc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (0.1 g, 60% disp. in oil) was added to a stirred solution of benzyl-(5-bromo-pyrimidin-2-yl)-amine (0.55 g) in DMF (8 ml) at 0° C. After 30 min methanesulphonyl chloride (0.286 g) was added and the mixture stirred at RT for 2 h then partitioned between ethyl acetate and water. The organics were separated washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with dichloromethane. Yield 0.41 g
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH2:13]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CC(Oc2ncccc2Br)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3Br)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (243 mg, 1 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and p-toluenesulfonyl chloride (380 mg, 2 mmol) was added dropwise. After 1 hour, the reaction mixture was warmed to room temperature, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide (318 mg, 0.8 mmol, yield 80%). ESI-MS (M+1): 397 calc. for C16H17BrN2O3S 396.
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>ClCCl>[CH2:1]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=O
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Solvent: ClCCl
Product: CCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
Pentylisocyanate (0.034 g, 0.30 mmol) was added slowly to a solution of [4-(5-aminopyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.050 g, 0.15 mmol) in dichloromethane (2 mL) at 0° C. The mixture was stirred at 25° C. for 16 h. After removal of dichloromethane, the residue was purified by column chromatography to yield the title compound as a light purple solid (24.5 mg, 35% yield). 1H NMR (300 MHz, CDCl3) δ 7.99, 7.71, 7.58, 7.33, 6.62, 6.28, 4.69, 3.91, 3.58, 3.43, 3.28, 3.18, 1.45, 1.27, 0.88. MS (ES+) m/z 464.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][C:33]1([CH3:44])[O:38][CH2:37][C:36]([CH2:42][OH:43])([N+:39]([O-:41])=[O:40])[CH2:35][O:34]1.[CH3:45][C:46]1[CH:51]=[C:50]([C:52]2[N:56]=[C:55]([C:57]3[S:64][C:63]([CH3:65])=[C:62]4[C:58]=3[CH2:59][C@H:60]3[C:66]([CH3:68])([CH3:67])[C@H:61]34)[O:54][N:53]=2)[CH:49]=[C:48]([CH3:69])[C:47]=1O>C1COCC1>[CH3:32][C:33]1([CH3:44])[O:34][CH2:35][C:36]([CH2:42][O:43][C:47]2[C:48]([CH3:69])=[CH:49][C:50]([C:52]3[N:56]=[C:55]([C:57]4[S:64][C:63]([CH3:65])=[C:62]5[C:58]=4[CH2:59][C@H:60]4[C:66]([CH3:67])([CH3:68])[C@H:61]45)[O:54][N:53]=3)=[CH:51][C:46]=2[CH3:45])([N+:39]([O-:41])=[O:40])[CH2:37][O:38]1
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1O
Reactant: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1([N+](=O)[O-])COC(C)(C)OC1
Reaction time: 168 h
Yield: 40.7 %

Procedure:
To a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF (2.5 mL) is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl-5-nitro-[1,3]dioxan-5-yl)-methanol (118 mg, 0.615 mmol) and 2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenol (150 mg, 0.410 mmol) is added. Stirring is continued for 7 days. The formed precipitate is collected, washed with isopropanol and dried under high vacuum to give 3-[4-(2,2-dimethyl-5-nitro-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (90 mg) as an almost colourless solid; LC-MS: tR=1.30 min, [M+1]+=540.28; 1H NMR (CDCl3): δ 7.77 (s, 2H), 4.50 (d, J=12.9 Hz, 2H), 4.29-4.21 (m, 4H), 3.10 (dd, J=6.4, 18.8 Hz, 1H), 2.93 (d, J=18.8 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2.00-1.91 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.15 (s, 3H), 0.76 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]2[C:12](CCCCCCCCCCCCCCCCC)=[N:11][N:10]=[C:9]2[CH2:30][OH:31])=[C:5]([C:32](=O)C2C=CC(C)=CC=2)[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH3:32][C:5]1[CH:6]=[CH:2][C:1]([C:3]2[S:7][C:6]3[N:8]4[CH:12]=[N:11][N:10]=[C:9]4[CH2:30][O:31][CH2:32][C:5]=3[CH:4]=2)=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCc1nnc(CO)n1-c1sc(CC)cc1C(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cc3c(s2)-n2cnnc2COC3)cc1

Procedure:
5-Ethyl-3-(4-methylbenzoyl)-2-(5-heptadecyl-3-hydroxymethyl-1,2,4-triazol-4-yl)thiophene (3 g) obtained in Example 22 was dissolved in ethanol (30 ml). Thereto was added sodium borohydride (0.1 g) with stirring and the mixture was stirred at room temperature for 1 hour. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added thereto and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (120 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromotography. The oily substance obtained was crystallized from hexane to give 0.9 g of 2-ethyl-9-heptadecyl-4-(4-methylphenyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine as white crystals, melting point 83°-84° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([C:2]2[S:3][C:4]([Br:7])=[CH:5][N:6]=2)[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Brc1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 160 °C
Yield: 68 %

Procedure:
A mixture of 24.7 mmol 2,5-dibromothiazole, 49.4 mmol tert-butyl 1-piperazinecarboxylate and 74.1 mmol triethylamine in 24 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 30 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 68%). MS (m/e): 350.2 ({81Br}M+H+, 100%), 348.2 ({79Br}M+H+, 98%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]1[C:7]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[N:4]1)[CH3:2]
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccncc2)nn1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
To a 25 ml flask was added ethyl 2-((S)-1-(1-ethyl-3-(pyridin-4-yl)-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 101.1.C (105 mg, 0.78 mmole), 0.5 ml of 1N-sodium hydroxide solution and 1.5 ml of methanol. The mixture was stirred at room temperature for 1 hour and at 50° C. for 1 hour. After then, 0.25 ml of 2N-hydrogen chloride solution was added to neutralize. The solvent was removed by rotary evaporation. The crude product was purified by silica gel chromatography to give 101.2 (79 mg, 81% yield) as colorless powder. LCMS ESI (pos.) m/e: 394 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (d, J=5.9 Hz, 2H), 7.72 (d, J=5.8 Hz, 2H), 7.34-7.22 (m, 5H), 6.79 (s, 1H), 3.89 (q, J=7.4 Hz, 2H), 3.66 (t, J=7.1 Hz, 1H), 3.30 (d, J=17.2 Hz, 1H), 3.24 (d, J=17.2 Hz, 1H), 3.04-2.93 (m, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[O:8][CH:7]=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:7]2[O:8][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][N:6]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: CC(C)c1cnco1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2ncc(C(C)C)o2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 5-isopropyl-oxazole (54 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (48 mg) as a yellow gum.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15]C(=O)C)[NH:13][CH:14]=2)=[CH:6][CH:5]=1>O.CO.S(=O)(=O)(O)O>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1nc(-c2ccc(OC(F)(F)F)cc2)c[nH]1
Yield: 94.9 %

Procedure:
N-[4-(4-Trifluoromethoxy-phenyl)-1H-imidazol-2-yl]-acetamide (0.7 g, 2.6 mmol, 1.0 eq) was dissolved in water (18 mL) and methanol (18 mL), and 20 drops of sulfuric acid were added. The reaction was refluxed for 2 days, then the mixture was dried; the residue was diluted with water, the pH adjusted to 8 with NaOH 2N, the product was extracted with DCM and concentrated under reduced pressure to give 0.6 g of the title compound (yield 98%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([CH3:42])[C:25]=1[C:26]1[CH:27]=[C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])[CH:29]=[CH:30][C:31]=1[OH:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:58][C@@H:59]([NH:61]C(=O)OC(C)(C)C)[CH3:60]>C1COCC1>[NH2:61][C@@H:59]([CH3:60])[CH2:58][O:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])=[CH:27][C:26]=1[C:25]1[N:24]([CH3:42])[N:23]=[CH:22][C:21]=1[Cl:20]
Reactant: Cc1cc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)no1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(OC[C@H](C)N)c(-c3c(Cl)cnn3C)c2)no1
Temperature: 65 °C
Yield: 21.34 %

Procedure:
Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq; 1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed with nitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in a rotary shaker for 2 minutes. N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide (30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly then DIAD (diisopropyl azodicarboxylate, 27.94 μl, 144.4 μmol) was added. After 30 minutes in a rotary shaker a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dry THF was added. The resulting suspension was heated to 65° C. and mixed overnight. LCMS showed that the reaction did not go to completion. A fresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to the reaction mixture and the suspension was heated to 65° C. and mixed overnight. The suspension was filtered and the resin washed with THF (3×3 mL). The filtrate and washings were combined and concentrated under vacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL), heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organic solvent was removed under vacuum and the crude residue was dissolved in acetonitrile (0.8 mL), neutralized with saturated NaHCO3 and subjected to purification by preparative LCMS. The desired fractions were pooled, frozen and lyophilized to afford the title compound as an off-white solid (21.34% yield). LCMS m/z=390.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3H), 2.54 (s, 3H), 3.46-3.57 (m, 1H), 3.66 (bs, 3H), 3.95-4.16 (m, 2H), 6.66 (s, 1H), 7.35 (dd, J=9.09, 2.53 Hz, 1H), 7.66 (s, 1H), 7.74 (d, J=2.53 Hz, 1H), 7.95 (dd, J=9.09, 2.53 Hz, 1H), 7.97-8.04 (bs, 2H), 10.76 (s, 1H).