Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3cccs3)ccc2C)cc1
Reaction time: 18 h
Yield: 106 %

Procedure:
A mixture of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (280 mg) and thiophene-2-carbonyl chloride (161 mg) in dichloromethane (5 ml) containing triethylamine (222 mg) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (425 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([O:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([O:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCN(CCOC(C)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CC(OCCN1CCNCC1)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Preparation 8(b), but using 4-{2-[1,1-bis(4-fluorophenyl)ethoxy]ethyl}-1-ethoxycarbonylpiperazine [prepared in a similar manner to that described in Preparation 8(a)], potassium hydroxide and ethylene glycol, the title compound was obtained in a yield of 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.C([Li])CCC.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([F:8])[C:5]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:6][CH:7]=1
Reactant: Fc1cccc(Cl)n1
Reactant: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-fluoropyridine (500 mg, 3.8 mmol) was taken up in tetrahydrofuran (19 mL) and cooled to −78° C. n-Butyllithium (2.4 mL, 3.8 mmol) was added dropwise over 10 minutes. The solution was stirred for 30 minutes and methanesulfonyl chloride (0.3 mL, 3.8 mmol) was added dropwise over 15 minutes. The resulting mixture was stirred at −78° C. for 2 hours and then warmed to 0° C. and stirred for 2 hours followed by an additional 2 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-75% ethyl acetate/hexanes) to afford the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:22])[F:23])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:12]
Reactant: O=C1NC(Cc2ccccc2C(F)(F)F)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Yield: 74.7 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((2-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (10.95 g, 32.3 mmol) in ethanol (200 ml) was added 8N aqueous sodium hydroxide solution (20 ml, 160 mmol) and the mixture was heated under reflux for 4 hrs. The reaction solution was concentrated, diluted with water (200 ml) and extracted with ethyl, acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (7.56 g, 75%).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N:16]([S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:17][C:18](=[O:22])[N:19]([CH3:21])[CH3:20])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:21][N:19]([CH3:20])[C:18]([CH:17]1[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:8])[C:9]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=2)[N:16]1[S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:24])=[O:25])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)C2CCCCC2)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)N2c3ccc(Cl)cc3C(O)(C3CCCCC3)C2C(=O)N(C)C)cc1

Procedure:
1.5 g of the product obtained in step C are treated with 950 mg of DBU in 10 ml of DCM for 24 hours at RT. The reaction medium is then chromatographed on silica using a DCM/AcOEt mixture (95/5, v/v) as the eluent to give the other isomer (cis isomer). It is recrystallized from isopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([NH2:30])[CH:24]=2)=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][NH:30][C:25]2[CH:24]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:28]=[CH:27][C:26]=2[CH3:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2ccc(F)cc2)cc1N
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(F)cc2)cc1NCC(=O)Nc1ccc(Cl)cc1C(=O)O
Yield: 20 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid, 1.78 g (8.9 mmol) of 4′-fluoro-4-methylbiphenyl-3-amine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 3 mL of DMF at 90° C. for 5.5 hours. Thereafter, the reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography. The separated fractions containing a target compound were combined and condensed. Ethyl acetate was added to the residue, and solids were collected by filtration. The resulting solids were recrystallized using ethyl acetate/n-hexane, thereby giving 334 mg of the target 5-chloro-2-{[N-(4′-fluoro-4-methylbiphenyl-3-yl)glycyl]amino}benzoic acid (yield: 20%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.Br[C:11]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[CH:20]4[CH2:26][CH2:25][N:23]([CH2:24][C:14]=3[C:13]=2[CH:12]=1)[CH2:22][CH2:21]4>>[CH3:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:11]2[CH:19]=[CH:18][C:17]3[NH:16][C:15]4[CH:20]5[CH2:26][CH2:25][N:23]([CH2:24][C:14]=4[C:13]=3[CH:12]=2)[CH2:22][CH2:21]5)=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc(/C=C/c2ccc3[nH]c4c(c3c2)CN2CCC4CC2)cn1

Procedure:
The product of Example 1C (133 mg, 1.11 mmol) and the product of Example 8A (180 mg, 0.62 mmol) were processed as described in Example 1D to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 2.03-2.14 (m, 4 H), 2.52 (s, 3 H), 2.98-3.04 (m, 1 H), 3.08 (dt, J=14.0, 6.9 Hz, 2 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.05 (d, J=16.2 Hz, 1 H), 7.27 (d, J=8.2 Hz, 2 H), 7.33 (d, J=16.2 Hz, 1 H), 7.35-7.38 (m, 1 H), 7.49 (s, 1 H), 7.94 (dd, J=7.9, 2.1 Hz, 1 H), 8.50 (d, J=1.8 Hz, 1 H); MS (APCI) m/z 330 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:32][CH2:31][N:30](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:29][CH2:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][CH2:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:23][CH2:22][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:20][CH2:19][CH2:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:16][CH2:15][N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:13][CH2:12][CH2:11]2)(=O)=O)=CC=1.S(=O)(=O)(O)O.O>C(OCC)C>[NH:10]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: C1CNCCNCCCNCCNCCNCCNCCNC1
Temperature: 90 °C
Yield: 53.9 %

Procedure:
63.3 g (0.045 mol) of the 1,5,8,12,15,18,21-Heptakis(p-tolylsulfonyl)-1,5,8,12,15,18,21-heptaazacyclotricosane was mixed with 300 ml of 98% sulfuric acid and 8 ml of water, and then the mixed solution was heated at a temperature of 90° C. for 3 days and then cooled. The mixed solution was added to 2000 ml of diethylether and then diethylether was subjected to decanting, and the residual was dissolved in 200 ml of water. A pH of the resultant solution was controlled to be pH 13 by using a NaOH aqueous solution, and the solution was filtered and extracted with ethanol. The ethanol used was evaporated from the extraction product and impurities were removed therefrom under vacuum conditions according to a kugelrohr distillation method to produce 8 g of 1,5,8,12,15,18,21-heptaazacyclotricosane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.Cl.Cl.[N:15]1([CH2:21][CH2:22][CH2:23][N:24]2[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:27]2[CH2:28][CH2:29][C:30](=[O:31])[N:24]([CH2:23][CH2:22][CH2:21][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:25][CH2:26]2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1cccc(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of (E)-3-(3-Chloro-phenyl)-acrylic acid acid (26 mg, 0.12 mmol), 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4) (24 mg, 0.1 mmol), O-(7-azabenotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in DMF (1 ml) was added Et3N (21 ul, 0.15 mmol) and the mixture shaken for 1 h. The reaction was then directly purified by preparative HPLC affording the title product (28 mg, 69%) as a white powder. MS: 404.2 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]([CH:12]([CH3:14])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH:12]([CH3:14])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-valinamide (0.730 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.018 g) in 2-propanol (10 mL) was added piperidinium acetate (0.436 g) under ice-cooling. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.050 g).
Reaction SMILES: [C:1]([C:3]1([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1)#N.C[Mg]Br.C1(C)C=CC=CC=1.C1COCC1>O1CCCC1>[OH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:3]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]2)[CH2:14][CH2:15]1
Reactant: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.6 %

Procedure:
To a stirred solution of ethyl 3-cyano-3-(4-hydroxy-1-piperidyl)pyrrolidine-1-carboxylate (1.0 gm, 3.74 mmol) in tetrahydrofuran (25 mL) was added a 1.4 M solution of methyl magnesium bromide in toluene/THF (5.35 mL, 7.48 mmol) at 0° C., and the mixture was allowed to warm to room temperature. The mixture was stirred for another 12 h at room temperature, the reaction was quenched with saturated ammonium chloride solution (5 mL) at 0° C. and diluted with ethyl acetate (25 mL). The layers were separated and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a pale solid (830 mg), which was used for the subsequent step without further purification. MS (M+1): 257.16.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(Cl)cc2)c(C(N)=O)cc1OC

Procedure:
As shown in scheme Q, 2-amino-4,5-dimethoxybenzamide is reacted with 4-chlorobenzoyl chloride in presence of triethyl amine and THF to give 2-((4-chlorophenyl)carbonylamino)-4,5-dimethoxybenzamide. Which is cyclised using NaOH and then treated with thionyl chloride to give 4-chloro-2-(4-chlorophenyl)-6,7-dimethoxyquinazoline (McKee, R. L. et. al., J. Am. Chem. Soc., 1946, 68, 1902-1903). The 4-chlorocompound is treated with 5-(tert-butyl)selenophene-2-carboxamide in the presence of NaOH/DMF to give 3-(2-(4-chlorophenyl)-6,7-dimethoxyquinazolin-4-ylamino)-5-tert-butylselenophene-2-carboxamide.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:38][CH2:37][C:26]3[N:27]=[C:28]([C:30]4([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.93-6.84 (m, 4H), 6.69 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.06 Hz), 3.22 (d, 1H, J=13.68 Hz), 3.09 (d, 1H, J=13.06 Hz), 2.98 (t, 2H, J=6.06 Hz), 2.31 (s, 3H), 2.17-2.09 (m, 2H), 1.57-1.50 (m, 4H), 1.45-1.37 (m, 4H), 1.35 (s, 3H), 1.31 (s, 3H); MS (ES+) calcd for C29H35NO5F: Found m/e 496.3 (M+1, 100%).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]1.CN1CCOCC1>CN1CCCC1=O>[CH:23]([C:21]1[CH:22]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:26]5[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:27]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:18]=[N:19][CH:20]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 120 °C

Procedure:
A mixture of 1-(6-fluoro-2-pyridyl)-6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridine (0.3032 mmol; 120.0 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (0.9095 mmol; 182.2 mg), and N-methylmorpholine (3.032 mmol; 310 mg; 0.337 mL) in 1-Methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then partitioned between EtOAc and water. The organic layer was concentrated to afford tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate, which was used without purification.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:17]([C:19]([C:33](=[O:35])[CH3:34])=[CH:20][NH:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:18])C>CCCCCC>[C:33]([C:19]1[C:17](=[O:18])[C:23]2[C:22](=[CH:32][CH:31]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=2)[NH:21][CH:20]=1)(=[O:35])[CH3:34]
Reactant: CCOC(=O)C(=CNc1ccc(C(=O)OCC)cc1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc2[nH]cc(C(C)=O)c(=O)c2c1
Temperature: 225 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Diphenyl ether (150 ml, 943 mmol) was heated to boiling and ethyl 4-((2-(ethoxycarbonyl)-3-oxobut-1-en-1-yl)amino)benzoate (6.84 g, 22.40 mmol) was added slowly. After the addition, the reaction was allowed to stir at 200-250° C. for another 30 min. After cooling, the reaction was diluted with hexane, filtered, and the precipitate was washed with hexane/diethyl ether, collected and dried to give ethyl 3-acetyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (5.74 g, 22.14 mmol, 99% yield) as tan solid. LCMS: (M+H)+: 260.0.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (324 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (590 mg, yield: 74%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CC(N(C)C)=O>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 29.2 h

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of dimethyl acetamide. The reaction mixture was then heated with stirring for 29.2 hr. at a bath temperature of 127° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (65.0% overall yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=[O:5])#[N:2].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([N:6]([C:4](=[O:5])[CH2:3][C:1]#[N:2])[NH2:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCC(=O)NN
Reactant: O=C(Cl)c1ccccc1
Product: N#CCC(=O)N(N)C(=O)c1ccccc1

Procedure:
in a second step treating the as-synthesized cyanoacetic hydrazide with benzoyl chloride in the presence of a buffer system to form an N-benzoylcyanoacetic hydrazide, and thereafter
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[C:3]#[N:4].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])[NH:1][C:16]=1[CH3:17])(=[O:14])[CH3:13]
Reactant: Cc1ccccc1C(N)C#N
Reactant: CC(=O)CC(C)=O
Solvent: CO
Product: CC(=O)c1c(C)[nH]c(-c2ccccc2C)c1N

Procedure:
Starting from 2-amino-2-(o-tolyl)acetonitrile and acetylacetone, the open-chain intermediate compound is obtained, b.p. 120° C./0.2 mm Hg. The title compound is obtained in a 77% overall yield, m.p. 258° C. (from methanol).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:6][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[NH:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([N:27]([CH3:28])[CH3:26])(=[O:20])=[O:19])=[CH:14][C:13]=3[O:22][CH3:23])=[N:6][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25]
Reactant: COc1cc(S(=O)(=O)Cl)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Reactant: CNC
Product: COc1cc(S(=O)(=O)N(C)C)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
Prepared analogously to Example 11 from 1,3-dimethyl-8-(2-methoxy-4-chlorosulfonyl-phenyl)-1H,3H-purin-2,6-dione and dimethylamine.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][C@H:10]1[O:21][CH2:22][CH:23]([F:25])[F:24])C1C=CC=CC=1>[Pd].CO>[F:25][CH:23]([F:24])[CH2:22][O:21][C@H:10]1[C@@H:9]([NH2:8])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:11]1
Reactant: O=C(N1CC[C@H](NCc2ccccc2)[C@H](OCC(F)F)C1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCN(C(=O)C(F)(F)F)C[C@H]1OCC(F)F
Yield: 95.3 %

Procedure:
The same operation as in Example (95b) was performed using cis(±)-N-benzyl-3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-amine obtained in Example (121d) (1.1 g, 3 mmol), 10% Pd/C (wet, 0.35 g) and methanol (10 mL), to obtain 0.79 g of the title compound as a colorless oily substance (95%).