Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]([F:34])([F:33])[S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.CN(C=O)C>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:22][C:23]([S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1)([F:34])[F:33]
Reactant: FC(F)(F)Sc1ccccc1CBr
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3SC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.7 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 60 mg, 0.30 mmol) was dissolved in THF (1.5 mL). K2CO3 (41 mg, 0.30 mmol) and tetrabutylammonium iodide (15 mg, 0.04 mmol) were added. 2-(Trifluoromethylthio)benzyl bromide (available from Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA; 88 μL, 0.30 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. DMF (100 μL) was added and the mixture was heated at 45° C. for 4 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and H2O (5 mL). The organic layer was evaporated and the residue was purified by chromatography (35-50% EtOAc/hexanes) to give 3-[4-(2-trifluoromethylsulfanyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (60 mg, 52%) as a white solid. HRMS Calcd. for C18H14F3N2O3S (M+H)+, 395.0672. Found: 395.0688.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:23][O:24][C:25]([CH2:27]P(OC)(OC)=O)=[O:26]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:27][C:25]([O:24][CH3:23])=[O:26])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1sc(COc2ccc(C=O)cc2)nc1-c1ccccc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)c(C)s2)cc1

Procedure:
According to the method described for Reference Example 22, 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to give methyl 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)cinnamate. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.142°-143° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: CC(C)CN
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Product: CC(C)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.150 g, 0.265 mmol) and isobutylamine (1.052 mL, 10.58 mmol) the title compound was obtained as an off-white solid (108 mg, 0.166 mmol, 62.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.44-7.64 (m, 3H), 7.31-7.44 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 5.68-6.07 (m, 1H), 3.83-3.96 (m, 2H), 3.38-3.55 (m, 2H), 3.21-3.32 (m, 1H), 2.87-3.18 (m, 2H), 1.92-2.06 (m, 2H), 1.61-1.92 (m, 3H), 0.74-0.99 (m, 6H). MS (ESI): 604.20 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[NH:10]2)=[CH:6][CH:5]=1)[CH3:3].[OH-].[K+]>>[CH3:3][N:2]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10]2)=[CH:6][CH:5]=1)[CH3:1]
Reactant: COC(=O)c1cc2ccc(N(C)C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Product: CN(C)c1ccc2cc(C(=O)O)[nH]c2c1

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 6-(N,N-dimethylamino)indole-2-carboxylate (PREPARATION 88, 0.80 g), potassium hydroxide (0.25 g), the title compound is obtained, NMR (300 MHz, CD3OD) 7.62, 7.13, 7.11, 7.01, and 3.11 δ.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](CCl)[C:9]1=[O:20])C1C=CC=CC=1.[Na].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.CO.ClCCl>CN(C=O)C>[N:22]1([CH2:1][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:20])[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=c1c(CCl)cc2ccccc2n1Cc1ccccc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1Cn1cncn1

Procedure:
React 1-benzyl-3-chloromethyl-2(1H)-quinolone with the sodium salt of 1,2,4-triazole in DMF at 25° C. for 18 hours, following the procedure of example 22. Chromatograph the crude product using 5% methanol-dichloromethane to obtain the major product, 1-Benzyl-3-(1H-1,2,4-triazol-1-ylmethyl-2(1H)-Quinolone.
Reaction SMILES: O.[NH2:2][NH2:3].N[O:5][C:6](=O)[CH2:7][N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1=[O:16]>CCO.[Cl-].[Na+].O>[O:16]=[C:9]1[CH2:10][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:12][N:8]1[CH2:7][C:6]([NH:2][NH2:3])=[O:5]
Reactant: NN
Reactant: CCCC1CC(=O)N(CC(=O)ON)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC1CC(=O)N(CC(=O)NN)C1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, hydrazine hydrate (5.78 g, 0.18 mol, 3 eq) is added to a solution of 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one x40 (11.99 g, 60.29 mmol) in EtOH (125 ml). The mixture is heated 4 h at reflux, cooled down to room temperature, diluted with brine and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and evaporated to afford 11.0 g of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].O.[CH2:13]([NH2:16])[CH2:14][NH2:15].C(N)CN.Cl>>[ClH:1].[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH2:13][NH2:16])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: NCCN
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCN
Yield: 87 %

Procedure:
51.45 g (0.3 mole) of 2-chloro-5-nitro-toluene is added to 200 cm3 (2.5 moles) ethylenediamine hydrate. The mixture is heated at reflux for 5 hours, and the excess of ethylene diamine is then eliminated under vacuum. The residue is treated with 300 cm3 of a 5N solution of hydrochloric acid, Drying yields 60.5 g of 4-nitro-2-methyl-N-(β-aminoethyl)aniline monohydrochloride, which is washed with acetone.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:10][C:5]2[N:6]([C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Reactant: C1CCNCC1
Product: Clc1ccc(-c2cc3nnc(N4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (22 mg, 0.06 mmol) in piperidine (0.5 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, 100% B hold for 7 min, (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was lyophilized in acetonitrile to afford 12 mg (48%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=3.82 min, (M+H)+=424.1. 1H NMR (CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.29-7.39 (m, 4H), 7.21 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.56 Hz, 2H), 3.66 (s, 4H), 1.72-1.81 (m, 4H), 1.69 (d, J=4.89 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:36]=[C:37]([C:45]([F:48])([F:46])[F:47])[CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: FC(F)(F)c1cc(Sc2ccc(Br)cc2)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Yield: 37.8 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-bis-trifluoromethyl-benzene (0.29 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-bis-trifluoromethyl-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.115 g, 37%) as a solid.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:17])[NH:9][C:10]1([C:14](=O)[CH3:15])[CH2:13][CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[I:18][C:19]1[CH:20]=[C:21]([CH:26]=O)[C:22]([NH2:25])=[N:23][CH:24]=1>CCO>[C:3]([O:7][C:8](=[O:17])[NH:9][C:10]1([C:14]2[CH:15]=[CH:26][C:21]3[C:22](=[N:23][CH:24]=[C:19]([I:18])[CH:20]=3)[N:25]=2)[CH2:13][CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Nc1ncc(I)cc1C=O
Reactant: CC(=O)C1(NC(=O)OC(C)(C)C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(I)cnc3n2)CCC1
Reaction time: 72 h
Yield: 83.8 %

Procedure:
Freshly ground NaOH (0.32 g, 7.9 mmol) was dissolved in absolute EtOH (25 mL). To this solution was added (1-acetyl-cyclobutyl)-carbamic acid tert-butyl ester (0.84 g, 3.95 mmol) and 5-iodo-2-aminopyridine-3-carboxaldehyde (0.932 g, 3.76 mmol) simultaneously as a solution in EtOH (25 mL). The reaction was allowed to stir for 72 h and the volatiles were removed in vacuo. This crude residue was diluted with CH2Cl2, absorbed onto SiO2 by removal of solvent in vacuo and purified via SiO2 flash chromatography (20-75% EtOAc-hexane) to afford the title compound as a white solid (1.34 g, 84%), m/z=366.4.
Reaction SMILES: [C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[C:1]1([N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 73% of theory, C28H29N5O3 (483.6); Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=484; (M+H+Na)++=253.7.
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:19]=[C:18]1[NH2:32])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:19]=[C:18]1[NH2:32])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc3ccccc3c2)nc1N

Procedure:
Analogously to Example 2, 0.3 g of Raney nickel is added to a mixture of 1.0 g (2.13 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(2-naphthyl)-imidazole dihydrochloride in 120 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, the filtrate is acidified to pH 3 with 3N methanolic hydrochloric acid, and concentration is carried out by evaporation in vacuo. Recrystallization of the residue from ethanol with the addition of a small amount of methanol yields the title compound, m.p. >280° C., 1H-NMR (DMSO/D2O): δ=8.31 (d, 1H); 8.18 (s, 1H); 8.05 (s, 1H); 7.92-8.03 (m, 3H); 7.79-7.86 (m, 2H); 7.52-7.69 (m, 3H); 3.35 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17](C3C=CC=CC=3)=[O:18])[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.[C:29]1([CH2:35]C(O)=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:18])[CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)c4ccccc4)CC3)c12
Reactant: O=C(O)Cc1ccccc1
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(C(=O)Cc4ccccc4)CC3)c12

Procedure:
Prepared according to a procedure analogous to that described for synthesis of [4-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-3,6-dihydro-2H-pyridin-1-yl]-phenylmethanone except using phenyl-acetic acid. 1H NMR (400 MHz, CDCl3): δ 2.03 (dd, J=8.08, 3.03 Hz, 1H) 2.11-2.25 (m, 1H) 2.41-2.60 (m, 5H) 2.74 (br. s., 1H) 3.68-3.78 (m, 2H) 3.84 (s, 2H) 3.93 (t, J=5.68 Hz, 1H) 4.17 (d, J=2.53 Hz, 1H) 4.35 (d, J=2.53 Hz, 1H) 5.78-6.08 (m, 1H) 6.81 (t, J=6.06 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.22-7.40 (m, 5H). MS (ES+): m/z 388.00 (100) [MH+]. HPLC: tR=2.19 min (OpenLynx, polar—5 min).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Br:18])[CH:12]=2.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl.CCOC(C)=O>[CH2:28]([O:27][C:25]([NH:7][C:8]1[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([Br:18])[CH:12]=2)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Pyridine (727.5 mg, 9.197 mmol) was added to a solution of ethyl 3-amino-7-bromoquinoline-2-carboxylate (Ark Pharm, 1069 mg, 3.622 mmol) in DCM (10.0 mL). The mixture was cooled to −10° C. A solution of benzyl chloroformate (816.5 mg, 4.547 mmol) in DCM (5.0 mL) was added slowly to the solution. The reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc (100 mL), washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as an off-white solid (1.54 g, 99%). LCMS calc. for C20H18BrN2O4(M+H)+: m/z=429.0. found 429.0.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([C:28]5[CH:29]=[C:30]([C:36]6[CH:41]=[CH:40][C:39]([C:42]([O:44]C)=[O:43])=[CH:38][C:37]=6[CH3:46])[CH:31]=[CH:32][C:33]=5[O:34][CH3:35])=[CH:26][C:25]([CH:47]([CH3:49])[CH3:48])=[C:24]([N:50]([CH3:52])[CH3:51])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Li+]>C1COCC1>[F:53][C:2]([F:1])([F:54])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([C:28]5[CH:29]=[C:30]([C:36]6[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][C:37]=6[CH3:46])[CH:31]=[CH:32][C:33]=5[O:34][CH3:35])=[CH:26][C:25]([CH:47]([CH3:49])[CH3:48])=[C:24]([N:50]([CH3:51])[CH3:52])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cc(C(C)C)c(N(C)C)nc3[C@@H]3CC[C@H]4[C@@H](c5cc(C(F)(F)F)cc(C(F)(F)F)c5)OC(=O)N34)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1cc(C(C)C)c(N(C)C)nc1[C@@H]1CC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To methyl 3′-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (24 mg, 0.033 mmol) in THF (1 mL) was added lithium hydroxide (9.51 mg, 0.397 mmol). The reaction was stirred overnight at room temperature. Reaction was incomplete. More lithium hydroxide (4.76 mg, 1.99 mmol) was added, and the reaction was heated to 50° C. for 5 hours. The reaction was purified by HPLC to yield 3′-[2-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-(dimethylamino)-5-(propan-2-yl)pyridin-3-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylic acid (10 mg, 0.012 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.6:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.94-8.10 (m, 2H), 7.90 (s, 1H), 7.84 (s, 2H), 7.48 (m, 2H), 7.42 (dd, J=8.5 Hz, J=2.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H, minor rotamer), 7.30 (d, 1H, merged with solvent peak, major rotamer), 7.14 (d, J=8.5 Hz, 1H, minor rotamer),7.07 (d, J=8.5 Hz, 1H, major rotamer), 5.98 (d, J=8.0 Hz, 1H, minor rotamer), 5.93 (d, J=8.0 Hz, 1H, major rotamer), 5.09 (t, J=7.5 Hz, 1H, minor rotamer), 5.01 (t, J=7.5 Hz, 1H, major rotamer), 4.76 (m, 1H), 3.93 (s, 3H, minor rotamer), 3.83 (s, 3H, major rotamer), 3.40 (m, 1H), 3.07 (s, 6H), 2.47 (s, 3H, major rotamer), 2.40 (s, 3H, minor rotamer), 2.35 (m, 1H), 2.05 (m, 1H), 1.60 (m, 1H), 1.29 (t, J=6.5 Hz, 6H), 1.08 (m, 1H). MS ESI calc'd. for C39H38F6N3O5 [M+H]+ 742.3. found 742.5. RTA (95% HS): 182 nM
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1ccc(N)cc1C(=O)OCC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(C)=O)cc1C(=O)OCC
Reaction time: 16 h

Procedure:
A solution of diethyl 4-aminophthalate (660 mg) in methylene chloride (40 mL) at 0° was treated with pyridine (0.25 mL) and acetyl chloride (0.22 mL). The reaction mixture was allowed to warm to 23° and stirred for 16 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was washed with water, 2N hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue was dissolved in ethyl acetate, which upon standing afforded the title compound as white crystals (350 mg). M.p. 118°-121°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:28]=1[C:29]([N:31]=[C:32]=[O:33])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:27]=2[F:26])=[N:9]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3F)[nH]c2=O)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 2-fluoro-4-(trifluoromethyl)benzoyl isocyanate (Intermediate-56, 0.10 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.030 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 4.48 (d, J=5.7 Hz, 2H), 6.13 (m, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.41-7.51 (m, 3H), 8.12 (t, J=7.9 Hz, 1H); MS (m/z): 489.20 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36]>CN(C)C(=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(Cc2ccc(C(=O)Cn3ccc(OCc4ccc(Cl)cn4)cc3=O)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 3b, 110 mg, 0.23 mmol) in N,N-dimethylacetamide (2 mL) is added Cs2CO3 (184 mg, 0.57 mmol) and N-ethylpiperazine (63 μL, 0.75 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).