Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:30][N:31]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([CH:9]2[NH:10][C:11]3[C:12]4[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:24]=1)[CH3:32]
Reactant: CNC
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.21 mmol), dimethylamine (47 mg, 1.04 mmol) and acetic acid (62 mg, 1.04 mmol) in methanol (50 mL) was stirred at room temperature for 60 min. Then the mixture was cooled to 0° C. Sodium cyanoborohydride (20 mg, 0.3 mmol) was added. After the addition, the mixture was stirred at room temperature for overnight. Methanol was removed under reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((dimethylamino)methyl)phenyl)-9-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (21 mg, yield 24%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.82 (s, 6H), 4.26 (s, 2H), 4.32 (d, J=8.0 Hz, 1H), 4.77 (d, J=8.0 Hz, 1H), 6.93-6.95 (m, 2H), 7.10-7.11 (m, 2H), 7.23 (m, 1H), 7.40-7.41 (m, 4H), 7.59 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H). 19F-NMR (400 MHz, CD3OD) δ (ppm): −77.09, −118.00; LC-MS (ESI) m/z: 415 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4([C:49]#[N:50])[CH2:48][CH2:47][CH2:46][CH2:45]4)=[C:40]([F:51])[CH:39]=3)[CH2:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[O:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4([C:49]#[N:50])[CH2:45][CH2:46][CH2:47][CH2:48]4)=[C:40]([F:51])[CH:39]=3)[CH2:33][C:32]([OH:34])=[C:31]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)[C:30](=[O:35])[O:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1
Reactant: Cc1cnc2nc(C=O)nn2c1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCCC5)c(F)c4)(C4CCCC4)OC3=O)nn2c1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile (Example A(189) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.35–2.16 (m, 16 H), 2.42–2.82 (m, 7 H), 3.33 (s, 3 H), 3.74 (d, J=16 Hz, 1 H), 3.84 (d, J=16 Hz, 1 H), 7.14–7.19 (m, 2 H), 7.36–7.41 (m, 1 H), 8.71 (s, 1 H), 9 (s, 1 H), 10.9 (s, 1 H). Anal. Calcd. For C31H34FN5O3.0.75H2O: C, 66.83; H, 6.42; N, 12.57. Found: C, 66.93; H, 6.18; N, 12.45. MS (ESI): 544 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([NH2:10])[CH:7]=[N:6]2)[CH2:2]1.C(OC([NH:18][C:19]1[S:23][C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:21][C:20]=1[C:32](O)=[O:33])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:18][C:19]1[S:23][C:22]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:21][C:20]=1[C:32]([NH:10][C:8]1[CH:7]=[N:6][N:5]([CH:3]2[CH2:4][O:1][CH2:2]2)[CH:9]=1)=[O:33]
Reactant: Nc1cnn(C2COC2)c1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2COC2)c1
Yield: 9 %

Procedure:
Following the procedures as described in Example 113, 1-(oxetan-3-yl)-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 138 as a white solid (10 mg, 9%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.36 (s, 1H), 7.86 (s, OH), 7.67-7.41 (m, 1H), 7.28 (t, J=8.4, 1H), 5.46-5.26 (m, 2H), 4.90 (s, 1H), 4.40 (d, J=5.7, 2H). ESIMS m/z=378.0 (M+1)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:20].[Cl:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=1[O:12][C:13]1[N:18]=[CH:17][C:16]([NH:19][S:33]([C:28]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=2)(=[O:35])=[O:34])=[CH:15][C:14]=1[Cl:20]
Reactant: Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccccc2-c2nc3ccccc3s2)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared by reacting 6-(2-(benzo[d]thiazol-2-yl)phenoxy)-5-chloropyridin-3-amine (obtained as per procedure described in preparation 4) and 3,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]([N:18]([CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CN([CH:35]=[O:36])C.C[N:38]1[CH2:43][CH2:42][O:41]CC1.[CH2:44](Cl)[CH2:45]Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([N:18]([CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2].[NH2:38][C@H:43]([C:42]([O:36][CH2:35][CH:44]=[CH2:45])=[O:41])[CH:5]([CH3:6])[CH3:4]
Reactant: CN1CCOCC1
Reactant: CN(C)C=O
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Agent: O=C(O)CN(C(=O)OCC1c2ccccc2-c2ccccc21)C1CCc2ccccc21
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](N)C(C)C
Reaction time: 0.75 h

Procedure:
Fmoc Indanylglycine (0.54 g, 1.315 mmol) was solvated in CH2Cl2 (5 mL) and DMF (1.8 mL) followed with the addition of L-Val allylester (0.437 g, 1 eq), 4-methylmorpholine (0.15 ml, 1.04 eq) and 4 min latter DMAP (14.5 mg, 0.09 eq) then EDC (0.265 g, 1.05 eq). The mixture was stirred for 1 hour 45 min. Then it was extracted using EtOAc/brine. The organic layer was dried over MgSO4, filtered off and concentrated to dryness.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[OH: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>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Reactant: Oc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cccc(O)c2)CC1
Yield: 76 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [CH:1]1[CH:2]=CC2N(O)N=[N:7][C:5]=2[CH:6]=1.C(Cl)CCl.N.C(OCC)(=[O:18])C.C[N:23]([CH:25]=[O:26])C>CO.C(Cl)Cl>[C:5]([NH2:7])(=[O:18])[CH2:6][CH2:1][CH2:2][C:25]([NH2:23])=[O:26]
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: NC(=O)CCCC(N)=O
Reaction time: 0.5 h

Procedure:
Part B. To a solution of 92 mg (0.19 mmol) of product from part A and 38 mg (0.28 mmol) HOBT in 0.5 mL DMF at 0° C. was added 36 mg (0.19 mmol) of EDC. After 30 minutes at 0° C., 0.25 mL of conc. aqueous ammonia was added. After 1 hour at 0° C. and 16 hours at RT, ethyl acetate was added, washed with 0.2N HCl , sat'd NaHCO3, brine, dried and concentrated to afford 72 mg of crude product. This was passed through a one-inch column of basic alumina with 10% methanol/methylene chloride to afford 53 mg of desired product, m/e=491 (M+H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]1[S:15][C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:17]([CH3:19])[N:18]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:31])[NH:13][C:14]1[S:15][C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([CH3:28])([CH3:27])[CH2:29][NH2:30])[CH:21]=2)=[C:17]([CH3:19])[N:18]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)CN)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
LiAlH4 (1M in THF, 3.06 mL, 3.06 mmol, 1.5 eq) is added to a solution of {5-[2-(cyanodimethyl-methyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 21.4) (0.73 g, 2.04 mmol) in THF (10 mL), under an argon atmosphere. The reaction mixture is stirred for 2 h at rt, quenched by addition of H2O (20 mL) and extracted with EtOAc (2×75 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 99:0:1→94:5:1) to afford 318 mg of the title compound as a brown solid: ESI-MS: 363.1 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH2:12][CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:7][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Clc1ccn2ncc(Br)c2n1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(Br)c2n1
Yield: 74 %

Procedure:
The reaction of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine and (S)-tert-butyl 2-(aminomethyl)pyrrol-idine-1-carboxylate under the amine displacement conditions described in example 5.6.5 afforded 74% product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH2:15])=[C:10]([CH3:16])[CH:9]=1.O>C(#N)C>[CH2:5]([O:4][C:2](=[O:3])[NH:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([Br:7])=[CH:9][C:10]=1[CH3:16])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 97 %

Procedure:
Ethyl chloroformate (0.55 g, 0.48 mL, 5 mmol) was added to a solution of 4-bromo-2,6-dimethyl-phenylamine (1.0 g, 5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at reflux for 16 hours. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.32 g, 97% yield).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[CH3:35][S-:36].[Na+]>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][S:36][CH3:35])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: C[S-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 0.17 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (0.11 g) was added to a solution of the product from Example 27 step b) (0.2 g) in DMF (2 ml), and the solution stirred for 10 min. Sodium thiomethoxide (43 mg) was then added and the mixture stirred for a further 3 hours. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. The residue was triturated with ether to give a solid, which was filtered and dried to yield the title compound as a white solid (40 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:73])([F:72])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:71])[C@@H:20]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1CCCCC1>C(#N)C>[CH2:6]([O:5][P:4]([C:9]([F:72])([F:73])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:71])[C@@H:20]([NH2:53])[CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-16-dodecanamido-1,1-difluoro-11-oxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonic acid diethyl ester in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the crude material was by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex, then 0-10% MeOH/DCM to give the title compound as an off-white solid.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)Cl.S(Cl)(Cl)=O.N[CH2:36][CH:37]([OH:40])[CH2:38][OH:39].[N:41]1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(COC)OC>[OH:40][CH:37]([CH2:38][OH:39])[CH2:36][C:21]1[CH:20]=[C:19]([NH:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:27]=[CH:26][C:22]=1[C:23]([NH2:41])=[O:25]
Reactant: c1ccncc1
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(N)=O)c(CC(O)CO)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A slurry of 8.0 g. of 4-(hexadecylamino)benzoic acid hydrochloride in 175 ml. of CH2Cl2 and 50 ml. of glyme containing 10 ml. of thionyl chloride was heated at reflux for 2 hours. The clear solution was concentrated in vacuo giving 9.5 g. of an amber oil. This oil was diluted with 50 ml. of pyridine containing 0.1 g. of 4-dimethylaminopyridine and 9.1 g. of 3-amino-1,2-propandiol. The reaction was stirred for two days at room temperature. The solution was partitioned between ether and water. The water phase was extracted twice more with 100 ml. of chloroform and ether. The combined organic layer was extracted with water, dried over MgSO4 and evaporated to a tacky solid. The solid was recrystallized from acetone-water and a second time from benzene. A small sample was recrystallized from acetonitrile, m.p. 121°-122° C.
Reaction SMILES: C(N=C=NC1CCCCC1)C1C=CC=CC=1.[CH3:17][O:18][CH2:19][C:20]([OH:22])=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]2[C:34]([CH3:45])=[N:35][NH:36][C:37]=2[CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:31]=1)[C:27]#[N:28]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][C:33]2[C:34]([CH3:45])=[N:35][NH:36][C:37]=2[CH2:38][N:39]2[CH2:40][CH2:41][N:42]([C:20](=[O:22])[CH2:19][O:18][CH3:17])[CH2:43][CH2:44]2)[CH:31]=1)[C:27]#[N:28]
Reactant: Cc1n[nH]c(CN2CCNCC2)c1Oc1cc(Cl)cc(C#N)c1
Reactant: COCC(=O)O
Agent: C(=NCc1ccccc1)=NC1CCCCC1
Solvent: ClCCl
Product: COCC(=O)N1CCN(Cc2[nH]nc(C)c2Oc2cc(Cl)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
N-Benzyl-N′-cyclohexylcarbodiimide polymer bound (624 mg of 1.3 mmol/g, 0.480 mmol) was added in one portion to a stirred solution of methoxyacetic acid (37 μL, 0.480 mmol) and the amine of Example 78 (80 mg, 0.240 mmol) in dichloromethane (5 ml) at room temperature under nitrogen. The reaction was stirred for 1 hour and the polymer bound reagent was removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (45 mg) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:23])(=[O:22])[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[C:6](N)[CH:5]=1.N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7]([S:10](=[O:22])(=[O:23])[NH:11][C:12]3[C:13]2=[CH:14][CH:15]=[C:16]2[C:21]=3[N:20]=[CH:19][CH:18]=[CH:17]2)=[CH:6][CH:5]=1)=[O:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 18.6 %

Procedure:
In a similar fashion using route 16 general procedure 61, 3-amino-4-(quinolin-8-ylsulfamoyl)-benzoic acid methyl ester (Intermediate 277) (340 mg, 0.95 mmol), t-butyl nitrite (0.17 ml, 1.4 mmol), AcOH (3.4 ml) and THF (3.4 ml), gave the title compound (60 mg, 18%) after purification by column chromatography with DCM/MeOH (99.8:0.2) as the eluent.
Reaction SMILES: [CH3:1][O:2][NH2:3].[N:4]([C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[C:5]=[O:6]>>[CH3:1][O:2][NH:3][C:5]([NH:4][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:6]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: CON
Product: CONC(=O)Nc1cc(C(C)(C)C)on1

Procedure:
8.5 g of methoxyamine was added slowly to a stirred solution of 15 g of 3A in 600 ml of tetrahydrfuran. The resulting mixture was filtered and the solid was triturated with ether to give 1-methoxy-3-(5-(1,1-dimethylethyl)-isoxazol-3-yl)urea (3B), m.p.: 145°-148° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14]O)[CH3:2].S(Cl)(Cl)=O.[F:33][C:34]([F:53])([F:52])[C:35]1[CH:36]=[C:37]([C@H:45]2[O:49][C:48](=[O:50])[NH:47][C@H:46]2[CH3:51])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:53][C:34]([F:33])([F:52])[C:35]1[CH:36]=[C:37]([C@H:45]2[O:49][C:48](=[O:50])[N:47]([CH2:14][C:5]3[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=3[N:3]([CH2:16][C@H:17]3[CH2:18][CH2:19][C@H:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:22]3)[CH2:1][CH3:2])[C@H:46]2[CH3:51])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of ethyl [trans-4-({ethyl[2-(hydroxymethyl)-4-(trifluoromethyl)phenyl]amino}methyl)cyclohexyl]acetate (Step B; 60 mg; 0.149 mmol) in toluene (1 mL) was added dropwise to a stirred solution of thionyl chloride (12.3 μL; 0.169 mmol) in toluene (300 μL) at 0° C. The reaction stirred at room temperature for 1.5 h. Pyridine (27 mL) was added and the reaction was partitioned between toluene (10 mL) and H2O (10 mL). The aqueous layer was re-extracted with toluene (10 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DMF (1 mL) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (intermediate 17; 56 mg; 0.179 mmol) and potassium tert-butoxide (23.5 mg; 0.209 mmol) were added successively. The reaction stirred for 72 h and was quenched with sat. NH4Cl. The reaction was partitioned between sat. NH4Cl (10 mL) and EtOAc (10 mL). The aqueous layer was re-extracted with EtOAc (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-20% EtOAc/hexanes gradient) and chiral HPLC (1.5% IPA/heptane; ChiralPak IA column) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl](ethyl)amino]methyl}cyclohexyl)acetate as a clear glass. LCMS=697.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.92 (s, 1 H), 7.81 (s, 2 H), 7.65 (s, 1 H), 7.58 (d, J=8.4 Hz, 1H), 7.30-7.27 (m, 1 H), 5.78 (d, J=8.1 Hz, 1 H), 4.88 (d, J=16.5 Hz, 1 H), 4.74-4.69 (m, 1 H), 4.11 (q, J=7.1 Hz, 2 H), 3.17-3.10 (m, 2 H), 3.05-2.97 (m, 2 H), 2.15 (d, J=6.8 Hz, 2 H), 1.80-1.68 (m, 4 H), 1.66-1.50 (m, 1 H), 1.46-1.39 (m, 1 H), 1.25 (t, J=7.1 Hz, 3 H), 1.07 (t, J=7.0 Hz, 3 H), 1.03-0.85 (m, 4H), 0.71 (d, J=6.6 Hz, 3 H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7]CC(Cl)=O)=[O:4].[CH2:12]([N:14](CC)CC)[CH3:13].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]([OH:36])[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=O)[CH:23]=[CH:24][C:25]=1[Cl:26].C([O-])(=O)C.[NH4+]>C(Cl)Cl.C(O)(=O)C>[CH3:13][C:12]1[O:36][C:27]([C:22]2[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:14]=1.[CH3:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2]
Reactant: CCN(CC)CC
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: O=C(c1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(=O)O
Product: Cc1nc(-c2ccccc2)c(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42287.2 %

Procedure:
5-(Methoxycarbonyl)pentanoyl chloride (2.82 g, 0.017 mol) and triethylamine (3.47 g, 0.034 mol) were added to a solution of 2-(3,4-dichlorophenyl)-2-hydroxy-1-[phenyl]ethanone (Step 1) (4.77 g, 0.017 mmol) in 40 mL of methylene chloride. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with 100 mL of methylene chloride. The organic solution was washed with water (1×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was dried under high vacuum, then ammonium acetate (4.6 g, 0.06 mol) and 30 mL of acetic acid were added. The reaction mixture was heated at 100° C. for 2.5 h. The reaction mixture was cooled to room temperature, and the excess acetic acid was removed under vacuum. The resulting residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (2×100 mL), saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash chromatography on silica gel (eluting with 1:9 ethyl acetate:hexane) to give 2.82 g (42.6%) of methyl [(4-phenyl)-5-(3,4-dichlorophenyl)oxazole]-2-butanoate as a yellow oil: HRMS calcd. for C20H17N1O3Cl2 390.0664. Found 390.0648.