Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[N:6]([CH2:34][O:35][C:36](=[O:42])[C@@H:37]([NH2:41])[CH:38]([CH3:40])[CH3:39])[N:5]=1)(=[O:3])[CH3:2].C(Cl)Cl.CCN(CC)CC.Cl[C:54]([O:56][CH3:57])=[O:55]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][N:12]([CH2:28][C@H:29]([C:31]([OH:33])=[O:32])[OH:30])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:18][CH:19]=2)=[O:10])[N:6]([CH2:34][O:35][C:36](=[O:42])[C@@H:37]([NH:41][C:54]([O:56][CH3:57])=[O:55])[CH:38]([CH3:39])[CH3:40])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)n(COC(=O)[C@@H](N)C(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)OCn1nc(C(C)=O)cc1C(=O)NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 3 %

Procedure:
(S)-2-Amino-3-methylbutyric acid 3-acetyl-5-[N′-((R)-2-carboxy-2-hydroxyethyl)-N′-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazinocarbonyl]pyrazol-1-ylmethyl ester (21.0 mg, 35 μmol) was combined with DCM (134 μL, 2.1 mmol) and Et3N (15 μL, 0.1 mmol). Methyl chloroformate (2.7 μL, 35 μmol) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was purified by preparative HPLC to yield the title compound (0.7 mg). MS m/z [M+H]+ calc'd for C30H33ClFN5O9, 662.20. found 662.1.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][NH2:5].S([O-])([O-])(=O)=O.[Mg+2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([CH:24]2[NH:5][CH2:4][CH2:3][C:2]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[O:1]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: NCCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: c1ccc(C2NCCC(c3ccccc3)(c3ccccc3)O2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the stirred mixture of 133.4 g of 3-hydroxy-3,3-diphenylpropylamine, 36 g of anhydrous magnesium sulfate and 250 ml of methylene chloride, the solution of 15.6 g of benzaldehyde in 50 ml of methylene chloride is added. The suspension is stirred for 15 hours at room temperature, heated to the boil and filtered. The residue is washed 3 times with 100 ml of methylene chloride, the combined filtrates evaporated and the residue recrystallized from ethanol, to yield the corresponding cyclic Schiff's base, i.e. the 2,6,6,-triphenyl-tetrahydro-1,3-oxazine melting 163°-165°.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:11]1([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:6][CH2:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CBr)N1CCN(C2CCCC2)CC1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C2CCN(CC(=O)N3CCN(C4CCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-cyclopentyl-piperazin-1-yl)-ethanone (1.2 mmol), 4-piperidin-4-yl-benzonitrile (1.2 mmol) and potassium carbonate (2.4 mmol) in acetonitrile (10 mL) is stirred at rt overnight. The solvent is removed in vacuo and to the residue is added DCM (40 mL) and aqueous sodium bicarbonate (15 mL). The layers are separated and aqueous layer is extracted with DCM (15 mL). The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound. 1H NMR (CDCl3) δ 7.59 (2H, d), 7.32 (2H, d), 3.64 (4H, br,), 3.22 (2H, s), 3.01 (2H, br), 2.40˜2.62 (6H, m), 2.21 (2H, dt), 0.80˜1.95 (12H, m); LC-MS (M+1) 381.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:16]([N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)CCl
Solvent: CCO
Product: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 140 °C
Yield: 80 %

Procedure:
To a stirred solution of ethyl chloroacetate (1.0 g, 8.16 mmol) in EtOH (5.0 mL), dibenzylamine (2.09 g, 10.6 mmol) was added and the mixture heated at 140° C. in a microwave reactor for 20 min. After evaporation of the solvent, the crude was dissolved in CH2Cl2 and washed with a 1.0 M KOH solution and brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (98:2), gave the title compound (1.85 g, 80%), as a white solid. MS (ESI) m/z: 284 [M−H]+[1H NMR as previously reported in literature: Synthesis, 1985, 9, 850-855].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:24](O)=O>C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: O=C(OCC1CCNCC1)N1CCN(c2ccc(Cl)cc2)CC1
Agent: C=O
Product: CN1CCC(COC(=O)N2CCN(c3ccc(Cl)cc3)CC2)CC1
Temperature: 95 °C
Yield: 30.7 %

Procedure:
(1-piperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (4.07 g, 12.0 mmol) was dissolved in formic acid (20 mL) and 35% aqueous formaldehyde solution (20 mL). The reaction mixture was heated at 95° C. for 90 minutes, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto 1M aq Na2CO3 solution (200 mL), basified to pH10 with 1M aq KOH solution (30 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 97:2:1 mixture of DCM:MeOH:DIPEA) followed by reverse phase column chromatography (gradient eluting with MeOH in water, 0-80%) to give (1-methylpiperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (1.30 g, 30.7%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH:47]([CH:58]([CH3:60])[CH3:59])[C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:47]([CH:58]([CH3:60])[CH3:59])[C@@H:48]([NH:50][C:51]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:57])[CH3:49])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(O)[C@H](C)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: CC(C)C(OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.6 %

Procedure:
p-Nitrobenzoic acid (10.6 g), triphenylphosphine (20.8 g), and DIAD (42 ml) were added to a THF (50 ml) solution containing tert-butyl ((2S)-3-hydroxy-4-methylpentan-2-yl)carbamate (11.5 g) obtained in the 2nd step, followed by stirring at room temperature for 15 hours. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=1:0 to 5:1). Yellow oily matter of (2S)-2-((tert-butoxycarbonyl)amino)-4-methylpentan-3-yl 4-nitrobenzoate (10 g) was thus obtained.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([N:16]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:17]([O:19][CH3:20])=[O:18])[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]1[C:40](OC(CC)C)=[O:41])=O)C.[BH4-].[Na+].O>CO>[CH3:20][O:19][C:17](=[O:18])[N:16]([CH2:21][C:22]1[CH:23]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH:14]1[C:13]2[C:8](=[CH:9][C:10]([O:38][CH3:39])=[C:11]([O:36][CH3:37])[CH:12]=2)[N:7]2[C:40](=[O:41])[O:3][CH2:4][CH:6]2[CH2:15]1
Reactant: CCOC(=O)[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CC2COC(=O)N2c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of cis 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 5) (100 mg, 0.15 mmol) in 8.5 mL methanol at 0° C. was added sodium borohydride (57 mg, 1.5 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed using 80% ethyl acetate/hexanes to afford the title product (70 mg). 1H NMR (CDCl3) δ 1.8 (br, 1H), 2.4 (br, 1H), 3.6 (s, 3H), 6.5 (br, 1H), 7.6 (br, 2H), 7.9 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>O>[Cl:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:17]2[C:16]=1[N:15]=[C:3]([C:2]([F:13])([F:1])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[NH:20][C:18]2=[O:19]
Reactant: NC(=O)c1cccc(Cl)c1N
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(Cl)cccc12
Temperature: 115 °C
Yield: 92.1 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (51 mg, 0.24 mmol) and 2-amino-3-chloro-benzamide (34 mg, 0.20 mmol) were combined with polyphosphoric acid (1.0 g) and the mixture was heated at 115° C. for 20 h with vigorous stirring. The mixture was allowed to cool to rt and then water (3 mL) was added, resulting in a precipitate that was separated washing with DCE (2×8 mL). The combined DCE extracts were washed with brine (3 mL) and separated using Biotage Phase Separators. The organic fraction was concentrated using a Savant Speed Vac to afford 8-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4(3H)-one as an off-white solid (60 mg). LCMS (ESI) m/z 326 (M+H)+
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[S:11]1C2CCCC(=O)C=2C=C1>>[S:11]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: NC1CCCc2occc21
Reactant: O=C1CCCc2sccc21
Product: NC1CCCc2sccc21

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.09, 7.02, 3.95, 2.79, 2.03, 1.85, 1.62; 13C NMR (100 MHz, CDCl3) δ 140.51, 137.18, 126.77, 122.66, 47.96, 34.24, 25.48, 21.48;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([S:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38](Br)[N:37]=2)=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:35])[N:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=S(c1ccccc1)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(S(=O)c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-benzenesulfinyl-6-bromo-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH3:26][C:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][N:29]2[C:28](=[O:33])[C:27]([CH3:26])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:31][C:30]2=[O:32])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CC1(c2ccccc2)NC(=O)NC1=O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)NC(C)(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.158 g, 0.44 mmol), 5-methyl-5-phenylhydantoin (0.102 g, 0.53 mmol), and triphenylphosphine (0.141 g, 0.53 mmol) in THF (3 mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.53 mmol), and the reaction was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([NH:15][N:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH3:2].S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:24])[C:13]([N:15]([CH3:29])[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a 25 mL volume two-necked flask, 500 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(phenylmethylidene)hydrazine ((40-a)-(14)-6), 2.3 ml of toluene, 345 mg of dimethyl sulfate and 315 mg of potassium carbonate were added and the mixture was stirred at 5° C. for 24 hours. To the reaction mixture, 2 ml of water and 2.3 ml of toluene were added and the resultant was extracted. Further, the aqueous layer was extracted with 2.5 ml of toluene two times. The organic layers were combined, concentrated under reduced pressure and subjected to column chromatography (hexane:ethyl acetate=5:1) to give 411 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([N+:16]([O-:18])=[O:17])[C:3]=1[F:10]
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(F)c(Br)c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cooled (1.3° C.) mixture of 1-bromo-2,4,6-trifluorobenzene (30.0 g, 142 mmol) and H2SO4 (115 mL) was added HNO3 (68%, 102 mL) over 1.5 h at such a rate that the internal temperature was <8° C. After stirring at 0° C. for 2 h, the resulting mixture was poured into ice water (1850 mL), stirred vigorously for 30 min and extracted with CH2Cl2 (3×600 mL). The combined organic layers were washed with water (2×600 mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a clear yellow oil (35.0 g, 99% yield). 1H NMR (CDCl3) δ 7.01 (ddd, J=2.4, 7.8, 9.3 Hz, 1H); 19F NMR (CDCl3) δ −116.20 to −116.10, −107.73 to −107.71, −93.80 to −93.70.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([Cl:31])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Clc1cccc(Cl)c1CBr
Product: Cc1nc2c(ccn2Cc2c(Cl)cccc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,6-dichlorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.37 (m, 3 H), 7.28-7.21 (m, 2 H), 6.91 (t, J=8.3 Hz, 1 H), 6.83-6.78 (m, 1 H), 6.19-6.13 (m, 1 H), 5.83-5.68 (m, 2 H), 5.62-5.56 (m, 1 H), 4.27 (t, J=5.2 Hz, 2 H), 2.94-2.77 (m, 2 H), 2.75 (s, 3 H), 2.12-2.06 (m, 2 H), 0.97 (s, 9 H); LC/MS (m/z) ES+=553.30 (M+1).
Reaction SMILES: O=S(Cl)Cl.[OH:5][C:6]1[C:11]2[CH2:12][C@@H:13]3[C:18]([CH3:20])([CH3:19])[C@:17]([CH3:21])([C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:15][N:14]3[C:22]([C@@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1)=[O:23]>C(O)(C)(C)C>[C:10]([C:7]1[CH:8]=[CH:9][C:10]2[C@@:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:13]([N:14]([C:22]([C@@H:24]4[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[O:23])[CH2:15][CH2:16]3)[CH2:12][C:11]=2[C:6]=1[OH:5])([CH3:17])([CH3:11])[CH3:9]
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: CC(C)(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1O)C[C@H]1N(C(=O)[C@H]3CC[C@@H](C(=O)O)CC3)CC[C@]2(C)C1(C)C
Temperature: -10 °C
Reaction time: 8 h

Procedure:
SOCl2 (1 mL) is added dropwise to a solution of cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid (100 mg) in tert-butanol (5 mL) cooled to −10° C. Then, the cooling bath is removed and the resulting solution is stirred at ambient temperature overnight before another portion of SOCl2 (1 mL) is added. After stirring for additional 12 h more SOCl2 (2 mL) is added and the solution is heated to 50° C. The solution is stirred at this temperature for 48 h before HCl in 1,4-dioxane (1 mL) is added. The resulting solution is stirred at reflux temperature overnight and then treated with concentrated H2SO4 (3 mL). After stirring at reflux temperature for additional 3 h, the solution is cooled to ambient temperature and concentrated under reduced pressure. The residue is treated with water and the precipitate is separated by filtration. The precipitate is taken up in ethyl acetate and washed with water and dried (MgSO4). After removing the solvent, the residue is purified by HPLC (water/MeCN/F3CCO2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:16][C:15]2[CH2:14][CH2:13][CH2:12][NH:11][C:10](=[O:17])[C:9]=2[CH:8]=1)=[O:6].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1>>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]([C:7]4[S:16][C:15]5[CH2:14][CH2:13][CH2:12][NH:11][C:10](=[O:17])[C:9]=5[CH:8]=4)=[O:6])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCCCl)c1cc2c(s1)CCCNC2=O
Agent: Cl
Product: O=C(CCCN1CCC(c2noc3cc(F)ccc23)CC1)c1cc2c(s1)CCCNC2=O
Yield: 11.8 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.1 g of 2-(4-chlorobutyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.21 g of 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, m.p. 142°-143° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>CCOCC>[CH2:15]([NH:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[S:19])[CH3:16]
Reactant: NCCCCCCCCCCCCN
Reactant: CCN=C=S
Solvent: CCOCC
Product: CCNC(=S)NCCCCCCCCCCCCN

Procedure:
22 grams (.110 mole) of 1,12-diaminododecane in 300 cc ether was reacted via dropwise addition with 5 grams (0.058 mole) ethyl isothiocyanate. The precipitate was filtered, washed with ether and recrystallized from alcohol yielding 6 grams of the thiourea derivative.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CO.C1COCC1>[C:12]([C:8]1[N:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)#[CH:13]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(C#C[Si](C)(C)C)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2n1
Temperature: 23 °C
Reaction time: 23 h

Procedure:
To a solution of 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetic acid (183 mg, 490 μmol, Example 19 (b)) in MeOH (5 mL) and THF (5 mL) was added potassium carbonate (339 mg, 2450 mmol), and the reaction mixture was stirred at 23° C. for 23 hours. The mixture was acidified with concentrated HCl, and filtered. The filter cake was washed with water (10 mL), Et2O (10 mL) and DCM (10 mL), and dried in vacuo to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 302 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.22-10.52 (m, 1 H), 8.43 (d, J=8.0 Hz, 1 H), 7.54 (d, J=8.2 Hz, 1 H), 4.74 (s, 1 H), 4.14 (d, J=5.5 Hz, 2 H), 3.64 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]([CH3:14])[CH3:13])=[C:4]([C:7]([OH:11])=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]([F:31])([F:30])/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH:12]([CH3:14])[CH3:13])=[C:4]2[C:7](=[C:8]([CH3:10])[CH:9]=1)[O:11][CH:23]([C:22]([F:21])([F:31])[F:30])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:5]2
Reactant: Cc1cc(Cl)c(C(C)C)c(C=O)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(c(C)cc(Cl)c2C(C)C)OC1C(F)(F)F
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 3-chloro-6-hydroxy-2-isopropyl-5-methylbenzaldehyde (1.83 g, 8.6 mmole), K2CO3 (2.38 g, 17.3 mmole) and ethyl 4,4,4-trifluorocrotonate (2.17 g, 12.9 mmole) in anhydrous DMF (10.0 mL) was heated to 90° C. under a dry N2 atmosphere for 18 hrs. The mixture was then cooled, poured into 0.5 N HCl (50 ml) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give a dark oil which was subject to flash chromatography (silica gel) and eluted with 50% CH2Cl2/hexanes to give a yellow oil (2.1 g, 68%): GCMS m/z 362.0 (M+). 1H NMR (CDCl3/400 MHz) 8.07 (s, 1H), 7.02 (s, 1H), 5.64 (q, 1H, J=7.0 Hz), 4.23 (m, 2H), 3.39 (s, 3H), 3.23 (m, 1H), 1.26 (m, 3H), 1.12 (m, 6H).