Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26]C[CH2:24][CH2:23]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:36]([N:39]1CCC(N([C@H]2CC[C@H](C)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CC1)(=O)C.CN1CCNCC1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([N:22]3[CH2:27][CH2:26][N:39]([CH3:36])[CH2:24][CH2:23]3)=[O:28])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: CN1CCNCC1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCN(C)CC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea using {2-[3-(1-acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and N-methylpiperazine.
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]=1[N+:29]([O-])=O.[N:32]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)=[C:33]=S>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]=2[N:29]=[C:33]1[NH:32][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1
Reactant: COCCNc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(N=C=S)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2cc(-c3ccccc3)ccc21
Yield: 55.6 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 200 mg, 1.44 mg) is added to a solution of N-(2-methoxyethyl)-3-nitrobiphenyl-4-amine (119 mg, 0.48 mmol) and methyl 4-isothiocyanatobenzoate (83 mg, 0.43 mmol) in tetrahydrofuran. The reaction may reflux for an appropriate time period, such as 2 hours and cooled. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-5-phenyl-1H-benzo[d]imidazol-2-ylamino)benzoate (96 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.5 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was dried in vacuum at 50° C. to obtain the title compound (25 mg, yield 14%). LC-MS (ESI) m/z: 362 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.58 (s, 3H), 4.52-4.54 (d, J=7.2 Hz, 1H), 4.94-4.97 (m, 1H), 6.69-6.70 (m, 1H), 6.96-6.97 (m, 1H), 7.04-7.08 (m, 3H), 7.18-7.22 (m, 2H), 7.36-7.38 (m, 2H), 7.51-7.55 (t, J=8.0 Hz, 1H), 12.2 (s, 1H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(F)cc3)c3ccc(F)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-fluorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32]Cl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1=[O:41]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[C:36](=[O:41])[CH2:37]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: CN1CCNCC1=O
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)C(=O)C4)c(OC)cc23)c2c1OCO2
Yield: 79 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (250 mg, 0.51 mmol) and 1-methylpiperazin-2-one (290 mg, 2.54 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (229 mg, 79%) as a pale brown solid; NMR Spectrum: ()MSOd6) 1.98 (quintet, 2H), 2.56 (t, 2H), 2.69 (t, 2H), 2.82 (s, 3H), 3.01 (s, 2H), 3.30 (t, 2H), 3.35 (s, 3H), 3.93 (s, 3H), 4.19 (t, 2H), 4.37 (s, 2H), 6.16 (s, 2H), 7.15 (s, 1H), 7.18 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.52 (s, 1H); Mass Spectrum: M+H+ 566/568.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][CH:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.O>C(#N)C.[Cu](Br)Br>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:21])=[CH:8][C:9]=1[CH2:10][CH2:11]2
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2O
Agent: Br[Cu]Br
Solvent: O
Solvent: CC#N
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
43.55 g of 11β-fluoro-4-estren-17-ol-3-one (150 mmol, Tetrahedron Letters 1995, 2611) is suspended in 1500 ml of acetonitrile, 50 g of copper(II) bromide is added, and it is stirred at room temperature. After 16 hours, additional copper(II) bromide is added in three portions (25 g, 12 g, 6 g) within 6 hours, and finally stirred for another 6 hours at room temperature. The reaction mixture is cooled in an ice bath, mixed with 500 ml of water and extracted with ethyl acetate. The organic phase is mixed with a little methanol, washed with saturated bicarbonate solution and common salt solution and dried with sodium sulfate. After concentration by evaporation, the substance crystallizes out, yield 30.8 g (71% of theory), flash point 233-234° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=Cc1cccnc1
Product: CN(Cc1cccnc1)Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Yield: 71 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with pyridine-3-carbaldehyde using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-pyridin-3-ylmethyl-amine as a solid (71% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 427 as a solid (99% yield). NMR (CDCl3, 400 MHz), 2.34 (3H, s), 3.67 (2H, s), 3.88 (2H, s), 3.92 (414, t, J=5.2), 4.06 (4H, t, J=5.2), 5.25 (2H, s), 7.30-7.33 (2H, m), 7.73-7.75 (2H, m), 8.55-8.57 (1H, m), 8.66-8.67 (1H, m), 9.30 (2H, s). MS: (ESI+): MH+=449
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[CH3:28]>>[CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[O:13][N:23]=[C:21]([C:20]3[CH:25]=[C:26]([CH3:27])[C:17]([OH:16])=[C:18]([CH3:28])[CH:19]=3)[N:22]=2)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Product: COc1cc(CC(C)C)nc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)c1

Procedure:
The title compound is prepared in analogy to Example 2 starting from 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid and 4,N-dihydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=1.01 min, [M+H]+=354.28; 1H NMR (CDCl3): δ 0.99 (d, J=6.8 Hz, 6H), 2.19-2.28 (m, 1H), 2.35 (s, 6H), 2.78 (d, J=7.5 Hz, 2H), 3.98 (s, 3H), 4.96 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.88 (s, 2H).
Reaction SMILES: ClC1N=C(NC2C=CC=C(C3NN=NN=3)C=2)C(F)=CN=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([F:29])=[CH:24][N:23]=1.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:21][C:22]1[N:27]=[C:26]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[C:32]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[C:25]([F:29])=[CH:24][N:23]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to, the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-trifluoromethylaniline gave 2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91 (dd, 1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H); 19F NMR (CDCl3): −17892 and −44402; LCMS: purity: 93%; MS (m/e): 326 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14](N3CCOCC3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:32].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:32])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Yield: 80 %

Procedure:
The [4-(3-bromo-4,5-dimethoxy-phenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine was hydrolyzed to the lactol by heating 160 mg of crude solid in a mixture of acetic acid (2 ml) and water (2.4 ml) at 50° C. for 20 min. The reaction mixture was slowly added to saturated NaHCO3. It was extracted with dichloromethane (100 ml) and washed with brine (10 ml). The extract was dried over sodium sulphate and the solvent was evaporated. The crude product was passed through a bond-elute (hexane:ethyl acetate=9:1 and 4:1), yielding the title compound (110 mg; 80%). 1H NMR (CD3OD): 6.96 and 6.91 (two broad signals, 1H), 6.82 and 6.80 (two broad signals, 1H), 6.58 and 6.51 (d each, J=8.6 Hz, 1H), 6.28-6.34 (m, 1H), 6.23 and 6.22 (d each, J=2.1 Hz, 1H), 5.47 (broad signal) and 5.37 (d, J=8.9 Hz) (1H), 4.11-4.17 (m, 1H), 3.795, 3.793, 3.785 and 3.782 (s each, 6H), 2.871 and 2.868 (s each, 6H), 1.87-2.15 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:3].[NH:19]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:20]([C@H:25]([CH2:27][C:28](O)=[O:29])[OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:19]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:20]([C@H:25]([CH2:27][C:28]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C@H:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[OH:13])[CH2:8][CH:9]([CH3:10])[CH3:11])=[O:5])[CH3:3])=[O:29])[OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)N
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
960 mg of H-Ala-Sta-OMe, 1 g of Boc-Sta-OH, 420 mg of HONSu and 750 mg of DCCI are dissolved successively in 50 ml of CH2Cl2 at RT. A white precipitate appears very quickly. The mixture is stirred at RT and, after 7 h, the DCU formed is filtered off and washed with CH2Cl2. The organic solution is washed successively with KHSO4 --K2SO4 (5% solution in H2O) and NaHCO3 (5% solution in H2O). It is dried over MgSO4 and filtered and the solvent is evaporated off. The product is solubilized in the minimum quantity of a chloroform/MeOH mixture (97.5/2.5, vol/vol) and deposited on the top of a column of silica gel; elution is carried out with the same mixture and the eluate is fractionated.
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([Cl:3])[C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: OC(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccc(CC(Cl)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of of thionyl chloride in toluene is cooled to 0° C., and a catalytic amount of pyridine is added. A solution of 1,2-di(4-chlorophenyl)ethan-1-ol in toluene is then added drop wise. Upon completion addition of addition, the reaction mixture is allowed to warm to ambient temperature where it stirs for about 30 minutes. The reaction mixture is washed with water, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding the subject compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH3:22])[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>CN(C=O)C.C(Cl)(Cl)Cl>[F:81][C:76]1[CH:75]=[C:74]([CH:79]=[C:78]([F:80])[CH:77]=1)[CH2:73][C@H:59]([NH:58][C:9](=[O:10])[C:8]1[CH:12]=[C:13]([C:15]2[O:16][CH:17]=[CH:18][N:19]=2)[CH:14]=[C:6]([C:4]([N:3]([CH2:1][CH3:2])[CH2:20][CH2:21][CH3:22])=[O:5])[CH:7]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCN(CC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[Ethyl(propyl)amino]carbonyl}-5-(1,3-oxazol-2-yl)benzoic acid (290 mg, 0.96 mmol) is dissolved in DMF (5 mL), and diisopropylethylamine (668 μL, 3.8 mmol), HATU (438 mg, 1.15 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method of EXAMPLE SP-272 (391 mg, 0.96 mmol) are added. The reaction stirred at room temperature 5 h. The reaction mixture is diluted with chloroform, washed with water, 1N hydrochloric acid (aq), saturated sodium bicarbonate, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9% methanol/methylene chloride) provides the title compound. ESI MS m/z 619.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cl)c2cccnc2c1O
Temperature: 170 °C
Yield: 23.8 %

Procedure:
5-Chloro-8-hydroxyquinoline (5.00 g) and potassium carbonate (11.54 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is dissolved in 800 mL water. The insoluble material is filtered and partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.481 g of the title product as a brown solid.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([C:6]([O:8]C)=[O:7])[CH2:3]1.[OH-].[Na+]>CO.O.C1COCC1>[F:17][C:2]1([F:1])[CH2:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)([C:6]([OH:8])=[O:7])[CH2:5]1
Reactant: COC(=O)C1(c2ccc(F)cc2)CC(F)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(c2ccc(F)cc2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
To a stirred solution of Intermediate 308D (400 mg, 1.638 mmol) in MeOH (5 mL), water (2 mL) and THF (2 mL) was added NaOH (197 mg, 4.91 mmol) and stirred for 12 h at RT. The reaction mixture was concentrated under vacuo and the pH of the residue was adjusted to 2.0 using 1.5 N HCl and the compound was extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford Intermediate 308E as a pale yellow solid (250 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (bs, 1H), 7.33-7.43 (m, 2H), 7.21 (m, 2H), 3.32-3.37 (m, 2H), 2.99-3.15 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([Br:11])[CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[C:6]([Br:11])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(Br)c1
Temperature: 80 °C

Procedure:
The crude 3-bromo-4-fluorobenzoic acid methyl ester is dissolved in 120 mL of N,N-dimethylformamide, 4.32 g (43.1 mmol, 2 eq.) of N-methylpiperazine and 4.46 g (32.3 mmol, 1.5 eq.) of potassium carbonate were added and the reaction mixture heated at 80° C. for 8 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/Cl)=[C:5](\[O:7][CH3:8])/[CH3:6].[OH-].[Na+].[CH:13](=O)[CH:14]([CH3:16])[CH3:15].[NH3:18]>>[CH:13](=[C:6]1/[C:5]([O:7][CH3:8])=[CH:4][C:3](=[O:2])[NH:18]/1)\[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)/C(Cl)=C(/C)OC
Reactant: N
Reactant: CC(C)C=O
Agent: [Na+]
Agent: [OH-]
Product: COC1=CC(=O)N/C1=C\C(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
120 g of (E)-2-chloro-3-methoxybut-2-enoic acid methyl ester was instilled in 200 ml of concentrated aqueous ammonia solution at 65° to 70° C. with constant passing through of ammonia gas within 3 hours. The reaction mixture was stirred another 1.5 hours at this temperature and then refluxed another 0.5 hour. After cooling to room temperature, 450 ml of 1M sodium hydroxide solution was added and the pH was brought to greater than 13 by the further addition of 33 percent sodium hydroxide solution. Then 50 g of isobutyraldehyde was added and the reaction mixture was heated to 60° C. with stirring for 6 hours. After cooling to room temperature, the precipitated product was filtered off, washed with cold water and dried in a vacuum drying cabinet. The yield of the title compound was 93.2 g (80 percent of theory). The title compound had a melting point of 140.5° to 141.1° C. (from diethyl ether).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:12])[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)[CH3:3].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:12])[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[S:14]([CH3:13])(=[O:16])=[O:15])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1S(C)(=O)=O

Procedure:
In 200 ml of pyridine was placed 19.56 g (0.1 mol) of (2S,4R)-4-hydroxyproline ethyl ester hydrochloride, and 12.03 g (0.105 mol) of methanesulfonyl chloride was slowly added dropwise to the mixture under agitation and ice-cooling. After stirring the mixture under ice-cooling for 6 hours, the mixture was further stirred overnight at room temperature. After distilling off the pyridine under reduced pressure, 10% hydrochloric acid was added to the reaction mixture under ice-cooling. The mixture was extracted three times with 200 ml of ethyl acetate in each case and the ethyl acetate extracts were combined, washed with 40 ml of a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The extract was concentrated under reduced pressure and dried until dryness whereby a solid substance having a melting point of 111°-113° C. was obtained in a yield of 18.7 g (78.9%) which, after recrystallization from ethyl acetate, showed a melting point of 118°-120° C.