Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[C:1]([NH:5][S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([Cl:6])[CH:8]=1)(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(Cl)c1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution of t-butylamine (0.6 g) and 3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from toluene to give 1.03 g of N-t-butyl-3-chloro-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 18). M.P., 123°-127.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([Cl:39])[CH:33]=1>>[Cl:39][C:34]1[CH:33]=[C:32]([CH2:31][CH2:30][NH:29][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:37]=[CH:36][C:35]=1[OH:38]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CCC4CCNCC4)c3)n2)cc1Cl

Procedure:
Intermediate 94 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure Q. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 437. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (d, 1H), 8.05 (s, 1H), 7.99 (m, 1H), 7.46 (d, 2H), 7.35 (d, 1H), 7.24 (d, 1H), 7.03 (d, 1H), 6.80 (d, 1H), 3.70 (m, 2H), 3.35 (m, 2H), 2.78 (m, 6H), 1.99 (d, 2H), 1.66 (m, 3H), 1.37 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].C(O[C:19](=[O:29])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C>C(O)C>[CH2:11]([CH:10]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:19](=[O:29])[C:20]([OH:28])=[C:21]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=O
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CCCCC1C(c2ccccc2)=C(O)C(=O)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and pentanal (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-3-phenyl-propionic acid ethylester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[O:15][CH2:16][C:17](Cl)=[O:18].Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=1[CH3:12]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1ccccc1OCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1OCC(=O)Nc1c(C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
3-Methylanthranilic acid 1.0 g (6 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this soulution, 2-methylphenoxyacetyl chloride 1.3 g (7.3 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 5 minutes and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration, washed with hot water and recrystallized from ethanol to obtain 3-methyl-N-(2-methylphenoxyacetyl)anthranilic acid (melting point: 133° to 136° C.) 1.7 g (yield: 83%).
Reaction SMILES: CCC[CH2:4][CH2:5][CH2:6][CH3:7].[CH2:8]1CC[CH2:11][CH2:10][CH2:9]1.[CH3:14][CH:15]([CH2:24][CH2:25][CH3:26])[CH2:16][O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22].[Mg:27]>CCCCCCC>[CH3:23][CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][O:17][CH2:16][CH:15]([CH3:14])[CH2:24][CH2:25][CH3:26].[Mg:27].[CH2:8]([Mg:27][CH:6]([CH2:5][CH3:4])[CH3:7])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC
Reactant: C1CCCCC1
Agent: CCCC(C)COCC(C)CCC
Agent: [Mg]
Product: CCCC[Mg]C(C)CC

Procedure:
A 10 ml portion of the heptane-cyclohexane solution of magnesium 2-methyl-1-pentyloxide (6.6 mmoles) of Example I is mixed with 6.1 ml of 1.085M DBM solution in heptane. A clear solution of the 1:1 Molar complex of magnesium 2-methyl-1-pentyloxide and n-butyl-sec-butylmagnesium is obtained. Assuming total scrambling of alkyl and alkoxy groups, this complex can be represented as (n,s)-butylmagnesium 2-methylpentyloxide. The complex can also be prepared by the addition of 13.2 mmoles (1.63 ml) of neat 2-methyl-1-pentanol to 13.2 mmoles (12.2 ml) of 1.085M DBM solution in heptane.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:20])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19]
Reactant: CN(C)CCOc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 85 %

Procedure:
To a stirred solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-dimethylamino-ethoxy)-phenylamine (0.033 g, 0.10 mmol) in CH2Cl2 (2.0 mL) was added 4-chlorophenyl isocyanate (0.017 g, 0.11 mmol, 1.1 equiv.). The solvent was removed after the completion of the reaction and it was purified by the HPLC. The pure fractions were collected and CH3CN was evaporated under vacuum. The residue was diluted with EtOAc and neutralized with saturated NaHCO3, the EtOAc phase was washed with brine, dried over MgSO4, filtered and evaporated. Compound 69 was obtained in 85% yield. LCMS m/z (%)=492 (M+H79Br35Cl, 78), 494 (M+H81Br35Cl, 100), 496 (M+H81Br37Cl, 28). 1H NMR (400 MHz, acetone-d6) δ: 8.27 (s, 1H), 8.20 (1H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.48 (s, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.29 (d, J=8.9 Hz, 2H), 7.14 (d, J=9.0 Hz, 1H), 3.98-4.20 (m, 2H), 3.73 (s, 1H), 2.48-2.68 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: ClCCCN1CCN(Cc2ccc(Br)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1CCCc2c(OCCCN3CCN(Cc4ccc(Br)cc4)CC3)cccc21
Yield: 50 %

Procedure:
From 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-bromobenzyl)-piperazine; yield 50% of theory; m.p. of the dihydrochloride (recrystallized from 1N hydrochloric acid) 256°-259°C (decomposed);
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:28][N:29]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1)[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reactant: CNCC(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26B (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. MS (ESL) m/z 438 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)=[O:36])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)=[O:36])[CH2:32][CH2:33]1
Reactant: CN1CCN(CC(=O)Nc2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(CC(=O)Nc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methylpiperazinomethylcarbonylamino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[CH:15][N+:16]([O-:18])=[O:17]>N1C=CC=CC=1>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:15]([N+:16]([O-:18])=[O:17])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCNC1=C[N+](=O)[O-]
Reactant: ClSc1ccccc1
Solvent: c1ccncc1
Product: CN1CCNC1=C(Sc1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
14.6 g of phenylsulfenyl chloride was added dropwise to a cooled, stirred solution of 14.3 g of Compound 1A in 250 ml of pyridine. The mixture was allowed to stand overnight at room temperature, then excess pyridine was recovered on a rotary evaporator. The residue was treated with 250 ml of water and the mixture was extracted with methylene chloride. The combined extracts were dried and the solvent was evaporated to give a crystalline solid which was triturated with ethyl acetate, then ethanol, to yield 1-methyl-2-(nitro(phenylthio)methylene)imidazolidine (1B) as a yellow solid, melting point: 170°-173°.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH3:22])=[O:20])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[NH2:24][O:25][CH2:26][CH2:27][OH:28].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>>[F:23][C:14]1[CH:15]=[C:16]([C:19]([NH:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:3]1[C:2]([F:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=1[C:5]([NH:24][O:25][CH2:26][CH2:27][OH:28])=[O:7]
Reactant: NOCCO
Reactant: CNC(=O)c1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: CNC(=O)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 45 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-{2-fluoro-4-[(methylamino)carbonyl]anilino}benzoic acid with 2-(aminooxy)ethanol and DMT-MM by the general procedure of Example 3, Step B, then purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a crystalline cream solid (45%); m.p. (acetone) 197-200° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.86 (br s, 1 H), 8.31 (br q, J=4.3 Hz, 1 H), 7.65 (dd, J=12.6, 1.8 Hz, 1 H), 7.55 (dd, J=8.4, 1.8 Hz, 1 H), 7.47-7.41 (m, 1 H), 7.27 (dd, J=16.9, 9.5 Hz, 1 H), 6.84 (ddd, J=8.6, 8.6, 4.8 Hz, 1 H), 4.72 (v br s, 1 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.8 Hz, 2 H), 2.76 (d, J=4.5 Hz, 3 H). Anal. calcd. for C17H16F3N3O4: C, 53.3; H, 4.2; N, 11.0. Await Found.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:8]=[C:9]([OH:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].C(Cl)Cl.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.Cl.C([N:31](CC)CC)C>>[C:21]([CH2:22][CH2:23][C:24]([NH:31][C:8]1[C:9]([OH:17])=[C:10]([CH:15]=[CH:16][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:25])([OH:26])=[O:27]
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: O=C1CCC(=O)O1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)CCC(=O)O)c1O
Reaction time: 8 h

Procedure:
Methyl 4-aminosalicylate bisulfate (5 g) is placed in a 50-mL round bottom flask. The flask is charged with 20 mL of methylene chloride and 15 mL of triethylamine. Finally, succinic anhydride (2.75 g) is added. The reaction mixture is then allowed to stir at ambient conditions overnight. Solvents are removed under reduced pressure, yielding a viscous residue, to which 1 N HCl is added. Methyl (3-carboxy-propionylamino)-2-hydroxybenzoate is yielded as tan powder. The powders are collected by filtration, washed with water, and dried.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:37]=[CH:36][C:16]([CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]3[CH:20]=[CH:21][C:22]([OH:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2-hydroxybenzoate in MeOH (400 mL) and water (40 mL) was added an aqueous solution of NaOH (6.0 mL, 5N). The reaction mixture was sired at 60° C. overnight. Then an aqueous solution of HCl (10 mL, 5N) was added and the solvents were removed under reduced pressure. The residue was taken up in water and extracted with Et2O (3×). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to give a yellow solid. Precipitation from a DCM/MeOH mixture gave 2.17 g (53%, stop e and f) of the title compound as a beige powder. HPLC, Rt: 4.8 min purity: 99.7%). LC/MS, M+(ESI): 484.4, M−(ESI): 482.2. 1H NMR (CDCl3/CD3OD (15/1)) δ: 7.39 (m, 4H), 7.18-7.09 (m, 5H), 6.87 (dd, J=9.0, 3.0 Hz, 11), 6.78 (d, J=9.0 Hz, 1H), 4.38 (s, 2H), 3.22 (t, J=7.5 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H), 1.55 (m, 4H), 1.34-1.21 (m, 8H), 0.90-0.75 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN1CCOCC1.[N:18]1([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>ClC(Cl)C.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:25]2[CH2:26][CH2:27][C@H:23]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:24]2)=[O:8])=[CH:9][CH:10]=1
Reactant: C1CCN([C@H]2CCNC2)C1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of 4-fluorobenzoic acid (1.5 g, 10.71 mmol) in dichloroethane:DMF (4:1) was treated with O-benzotriazol-1-yl-N,N,N′N′-tetramethlyuronium tetrafluoroborate (4.13 gm 12.85 mmol) and N-methylmorpholine (5.41 g, 53.55 mmol) followed by a solution of (3′S)-1,3′-bipyrrolidine (2.52 g, 11.77 mmol) in dichloroethane:DMF (4:1). The reaction mixture was stirred at room temperature for 3 h and quenched with saturated sodium hydrogen carbonate. The phases were separated. The aqueous phase was extracted with ethyl acetate. The organic phase and the extracts were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash column chromatography to provide (3′S)-1′-(4-fluorobenzoyl)-1,3′-bipyrrolidine (57%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2].O.[NH2:24][NH2:25]>>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: NN
Reactant: CCc1ncn(-c2ccc(C(=O)CCC(=O)O)cc2)c1CC
Solvent: O
Product: CCc1ncn(-c2ccc(C3=NNC(=O)CC3)cc2)c1CC

Procedure:
Similarly, the reaction of 4-(4,5-diethyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(4,5-diethyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3h).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[CH3:13][O:14][S:15]([O:18]C)(=[O:17])=[O:16]>>[CH3:13][O:14][S:15]([O-:18])(=[O:17])=[O:16].[CH3:13][N+:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: COS(=O)(=O)OC
Product: COS(=O)(=O)[O-]
Product: Cc1ccc2cc(F)ccc2[n+]1C
Yield: 86 %

Procedure:
6-Fluoro-2-methylquinoline, 4 (25 g, 0.15 mol) was alkylated with dimethylsulphate (1.89 g, 0.15 mmol) as above to give the title compound (37.5 g, 0.13 mol, 86%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:41][CH2:40][CH2:39][C@@H:35]1[C:36]([OH:38])=[O:37]>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:41][CH2:40][CH2:39][CH:35]5[C:36]([OH:38])=[O:37])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)[C@H]1CCCN1
Agent: OC1CCNC1
Product: O=C(O)C1CCCN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (D)-proline. A yellow solid 121 was obtained (0.035 g, 70%). MS (APCI) m/z 503 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 94 %

Procedure:
Synthesized from pivalic acid (S)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (59 mg) and (4-formylphenyl)acetic acid (126 mg) according to an analogous synthetic method to Example 212, the title compound (77 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:13]O>Cl[Ti](Cl)(Cl)Cl>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([OH:11])=[C:9]([I:12])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)c1cc(I)c(O)c(I)c1
Yield: 76 %

Procedure:
To a stirring solution of 3,5-diiodo-4-hydroxybenzoic acid (10.00 g, 25.65 mmol) in dry methanol (250 mL) was added TiCl4 (1.41 mL, 12.82 mmol) in one lot. The reaction was stirred at reflux for 6 h and was then stirred at room temperature for 24 h. The mixture was concentrated down and the residue was taken up in diethyl ether and filtered through a plug of silica gel. The filtrate was concentrated down and the residue was recrystallized from hot methanol to give 7.84 g (76%) of the ester as white crystalline needles. 1H NMR (DMSO-d6) δ10.41 (br s, 1H), 8.22 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=1)#[N:2].[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:26][N:25]=[C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:28]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Temperature: 70 °C
Reaction time: 3 h
Yield: 8.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl (6-cyanopyridin-3-yl)carbamate (263 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:7) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (26.1 mg, 8.2%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:27][C:28]1[N:29]=[C:30]([C:8]2[CH:7]=[CH:6][C:5]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[CH:4][C:3]=2[O:2][CH3:1])[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) CsF (350 mg, 2.3 mmol), Pd(Ph3P)4 (65 mg, 0.057 mmol), and 2-bromopyridine (140 mg, 0.57 mmol) were combined in a 2-neck flask. The flask was evacuated and filled with argon and DME (5 mL) was added. The suspension was deoxygenated with a stream of argon for 10 min. The reaction mixture was stirred under argon at 80° C. for 24 h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using and EtOAc/hexanes gradient to afford the desired 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.08–8.05 (d, 1H), 7.98–7.95 (m, 2H), 7.89 (s, 1H), 7.84–7.79 (m, 1H), 7.63–7.60 (m, 1H), 7.45–7.38 (m, 3H), 4.02 (s, 3H). MS (ESI) 382 (M+H)+.