Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:39](OCC)=[O:40].C(N(C(C)C)CC)(C)C>CO>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:39]=[O:40])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC=O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 48 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in methanol (0.5 mL) was added ethyl formate (3 mL) followed by diisopropylethylamine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 48° C. for 18 h and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-formyl -3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (0.092 g, 58%). MS: 569.1 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[C:10]([C:11]#[N:12])=[C:6]2[N:5]=[C:4]([CH3:14])[C:3]=1[CH2:15][CH2:16]Cl.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(Cl)(Cl)Cl>[C:18]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][C:10]([C:11]#[N:12])=[C:6]3[N:5]=[C:4]([CH3:14])[C:3]=2[CH2:15][CH2:16]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: Cc1nc2c(C#N)c(C)nn2c(Cl)c1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2c(C#N)cnn2c2c1CCN2C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of 88.9 g of Compound (VI) [R2 =H, R3 =CN], 33.0 g of tert-butylamine, 89 g of anhydrous potassium carbonate, and 700 ml of anhydrous dimethylformamide were stirred at room temperature overnight. To the reaction solution was added 500 ml of chloroform to remove insoluble substances by filtration. The filtrate was condensed under reduced pressure to dryness. The residue was dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. The residue from which the solvent was evaporated was recrystallized in benzene to produce 73.6 g of 8-tert-butyl-3-cyano-6,7-dihydro-5-methyl-8H-pyrrolo [3,2-e]pyrazolo[1,5-a]pyrimidine [R1 =C(CH3)3, R2 =H, R3 =CN in formula (I)] having a melting point of 220°-224° C. at a yield of 82.8%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[OH-].[Na+].C([Br:17])(=O)C>>[Br:17][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CC(=O)Br
Reactant: CCc1cc([N+](=O)[O-])ccn1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Br)ccn1
Temperature: 75 °C
Yield: 62 %

Procedure:
A mixture of 2-ethyl-4-nitro-pyridine (2.3 g, 15.1 mmol) and acetyl bromide (9 mL) were heated together at 75° C. for 16 hours. More acetyl bromide (10 mL) was added and the reaction was heated to 100° C. for 5 hrs. The reaction mixture was poured into ice, made basic with 20% NaOH and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to a black oil. Purification by flash silica gel chromatography (0% to 25% EtOAc) gave the product as an oil (1.72 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J=7.6 Hz, 3 H), 2.81 (d, J=7.6 Hz, 2 H), 7.28 (dd, J=5.3, 1.8 Hz, 1 H), 7.35 (d, J=1.8 Hz, 1 H), 8.34 (d, J=5.3 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3.C1(C=CC(O)=CC=1)O.[Na].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH2:34])=[CH:29][N:28]=1>CS(C)=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:34][CH2:33][C:30]1[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][CH:31]=1)[C:6]1[CH2:11][CH:12]3[NH:16][CH:15]([C:5]2=1)[CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCC(C3)N1
Reactant: C=Cc1ccc(C)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCC1N2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A suspension of 2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole (170 mg, 0.80 mmol; Example 4A), hydroquinone (9 mg, 0.08 mmol), and -32% sodium in paraffin (79 mg, 1.1 mmol; Aldrich) in anhydrous dimethyl sulfoxide (800 μL) was sealed in a septum-capped reaction tube. After thoroughly evacuating and purging the vessel with nitrogen, 2-methyl-5-vinylpyridine (143 mg, 1.2 mmol, International Publication No. WO2001/017968) was added, and the reaction was stirred at 100° C. for 48 hours. The thick mixture was cooled to room temperature, poured into water (5 mL), and extracted with ethyl acetate (3×). The combined organic phases were washed with water, filtered through diatomaceous earth, dried (Na2SO4), concentrated, and purified by chromatography on silica (0-5% gradient of concentrated aqueous ammonium hydroxide in acetonitrile). The resulting material was purified further by reverse-phase HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.10-1.26 (m, 1H), 1.84-2.06 (m, 4H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86 (dd, J=16, 4.6, 1H), 2.97 (ddd, J=14, 5.4, 5.4, 1H), 3.09 (ddd, J=14, 9.0, 6, 1H), 3.75-3.86 (m, 1H), 4.14 (ddd, J=15, 9.0, 5.4, 1H), 4.30 (ddd, J=15, 6, 5.4, 1H), 4.44 (d, J=4.6, 1H), 6.90 (d, J=8.3, 1H), 7.10 (d, J=7.9, 1H), 7.17 (d, J=8.3, 1H), 7.20-7.25 (m, 2H), 7.75 (d, J=2.1, 1H); MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c(N=C=O)c(I)c1
Solvent: ClCCl
Product: Cc1cc(F)c(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude 1-fluoro-3-iodo-2-isocyanato-5-methylbenzene from description D2, 4-amino-1-N-Boc piperidine (200 mg, 1 mmol), and dichloromethane (3 ml) was stirred at room temperature for 1 h then directly purified by chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. Further purification by MDAP (mass-directed auto-purification) gave the title compound 300 mg.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7].O>C(O)(=O)C>[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: CCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCON=C(C(=O)CCl)C(=O)OCC
Yield: 93.1 %

Procedure:
Sulfuryl chloride (35.2 g.) was added all at once to the stirred solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) (48.9 g.) in acetic acid (49 ml.) at room temperature, and stirred at the same temperature for an hour. After adding the resultant solution into water (200 ml.), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (53.8 g.), pale yellow oil.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1.CI.C([O-])([O-])=O.[K+].[K+]>O>[Br:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[C:11]([Br:13])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(=O)c(Br)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cc1c(Br)cc(Br)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (50 mL), 327c (10.0 g, 37.5 mmol), CH3I (5.3 g, 37.5 mmol), and K2CO3 (7.8 g, 56.2 mmol). The mixture was stirred at room temperature for 5 h. Water (100 mL) was added and the resulting white solid was collected to afford 327d (8.2 g, 78%) as a white solid. MS-ESI: [M+H]+ 280.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][CH:8]([NH2:23])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[O:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[C@@H:6]([CH3:24])[CH2:7][C@H:8]([NH:23][C:30](=[O:31])[CH2:29][CH2:28][C:27]([OH:32])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Reaction time: 2 h
Yield: 10.8 %

Procedure:
To a stirred solution of (S)-4-Amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloric acid salt (200 mg, 0.52 mmol) and dihydrofuran-2,5-dione (68 mg, 0.68 mmol) in 8 ml CH2Cl2 was added pyridine (0.17 ml, 2.1 mmol) and the solution was stirred for 2 hours. The reaction mixture was acidified to pH=3 with 1M HCl. Solvent was removed under reduced pressure and the residue was purified by preparatory HPLC (DAICEL CHIRALCEL OD-H 21×250 mm column, 18 ml/min, 90% heptane 10% EtOH+0.1% TFA), collected a peak at 5.7 minutes, to give 25 mg (2S,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. MS m/z 446.3 (M+H), 444.3 (M−H). LC/MS (Condition A): 1.52 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][N:14]([CH3:30])[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C:19]([CH3:24])=[C:18]2[CH2:25][C:26]([O:28]C)=[O:27].CC(C)([O-])C.[K+]>COCCOC.CCOCC>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[C:20]2/[C:19]([CH3:24])=[C:18]([CH2:25][C:26]([OH:28])=[O:27])[C:17]3[C:21]/2=[CH:22][CH:23]=[C:15]([N:14]([CH3:30])[CH3:13])[CH:16]=3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)CC1=C(C)Cc2ccc(N(C)C)cc21
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1=C(CC(=O)O)c2cc(N(C)C)ccc2/C1=C\c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
p-Methylsulfonylbenzaldehyde (1.5 g) is added to a solution of methyl 5-dimethylamino-2-methyl-3-indenylacetate (2.5 g) from Example 3 Part B in 1,2-dimethoxyethane (1.5 ml) at 0° C. followed by the addition of potassium t-butoxide (1.1 g). The reaction mixture is kept in the ice-bath for 4 hours and at room temperature for 18 hours. The mixture is diluted with ether (15 ml), and the potassium salt is filtered off. The salt is dissolved in 30 ml of water and neutralized with dilute hydrochloric acid to pH 6-6.5. The crude acid precipitates, is collected by filtration and is recrystallized to give pure (Z)-1-(p-methylsulfonylbenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[Cl:23]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:23])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 28a (6.38 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL). N-chlorosuccinimide (2.36 g, 17.70 mmol) is added as a solid and the reaction mixture is stirred at room temperature under N2 until the reaction is complete (5-6 days). The reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution to give a suspension. The resulting solids are collected by filtration, washed with water and diethyl ether and dried under reduced pressure to yield 6.07 g (87%) of the pure desired product as a beige solid. MS ESI (+) m/z 398, 400 (M+ Br pattern) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([F:15])[C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]([C@@H:20]1[O:22][CH2:21]1)=[O:19].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[F:15][C:13]1[C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:21][C@@H:20]([OH:22])[C:18]([O:17][CH3:16])=[O:19])[CH:14]=1
Reactant: CC(C)n1c(=O)oc2cc(N)cc(F)c21
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C(C)C

Procedure:
Prepared from 6-amino-4-fluoro-3-isopropyl-1,3-benzoxazol-2(3H)-one (Step 2, 0.77 g, 3.66 mmol), methyl (2R)-glycidate (0.374 g, 3.66 mmol) and lithium trifluoromethanesulfonate (0.57 g, 3.66 mmol) in acetonitrile (10 ml) according to the method of EXAMPLE 86, Step 8 (0.89 g, 78%); MS for C14H17FN2O5 m/z 313 (M+H)+.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:11][C@H:12]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: N[C@@H]1CC[C@@H]2N[C@@]1(c1ccccc1)C[C@H]2S(=O)(=O)c1ccccc1
Yield: 97 %

Procedure:
(1R*,2R*,5S*,6R*)-2-benzylamino-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octane (Description 4; 1.73 g, 3.3 mmol) was dissolved in a mixture of methanol (30 mL) and acetic acid (20 mL), then treated with 10% palladium on charcoal (500 mg). The suspension was hydrogenated at 50 psi hydrogen for 16 hours, then filtered and concentrated. The residue was basified with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (2×100 mL). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the title compound as a gum (1.10 g, 3.2 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]=1[CH2:11][CH3:12]
Reactant: O=C(O)c1ccccc1
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)c2ccccc2)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A solution of the amine of Example 43 (98 mg, 0.30 mmol) in dimethylformamide (3.75 ml) was treated with benzoic acid (41 mg, 0.33 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64 mg, 0.33 mmol) and 4-dimethylaminopyridine (81 mg, 0.66 mmol) and stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic extract was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (48 mg) as a white solid, m.p. 115–117° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[CH3:19][C:20]1[C:28]([SH:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]>>[CH3:19][C:20]1[C:28]([S:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH3:18])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: Cc1c(S)cccc1C(=O)O
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2cccc(C(=O)O)c2C)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and methyl 3-mercaptobenzoic acid using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.93 (s, 3H) 6.79 (s, 1H) 7.62-7.73 (m, 3H) 7.76-7.88 (m, 3H) 7.94 (d, J=8.18 Hz, 1H) 8.12 (d, J=8.26 Hz, 1H) 10.30 (s, 1H) 13.11 (bs, 1H); ESI-MS: m/z calc'd for C20H15N3O3S 377.08. found 378.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3]1.[NH2:28][CH:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1.C(OCC)C>O1CCOCC1>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:29]([NH:28][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(OS(=O)(=O)C(F)(F)F)nc1-2
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)C3)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 1.5 g (3.7 mmol) of ethyl 1-methyl-8-{[(trifluoromethyl)sulfonyl]oxy}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in 150 mL of anhydrous dioxane, 756 mg (4.1 mmol) of tert-butyl 3-aminopyrrolidine-1-carboxylate were added. The reaction mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated. 1.2 g (88% yield) of the title compound was collected by filtration after trituration with diethylether.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[CH:12]=2)[C:3]([OH:24])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A solution of 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid methyl ester (1.28 g, 3.52 mmol) in tetrahydrofuran (12 mL) was treated with a 0.8M aqueous lithium hydroxide solution (4.9 mL, 3.88 mmol). The reaction mixture was stirred at 25° C. for 24 h and then concentrated in vacuo to remove tetrahydrofuran. The resulting yellow oil was partitioned between water (50 mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous hydrochloric acid solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromethanesulfonyl-phenyl)-propionic acid (1.09 g, 99%) as a viscous yellow oil that solidified upon sitting to a white solid: mp 86–88° C.; EI-HRMS m/e calcd for C15H17F3O4S (M+) 350.0800, found 350.0792.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:19])C.[NH3:21]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7]([CH3:19])=[C:6]([CH2:5][C:4]([NH2:21])=[O:3])[C:10]=2[CH:11]=1)[CH3:18]
Reactant: N
Reactant: CCOC(=O)Cc1c(C)oc2ccc(CN(C)C)cc12
Solvent: CO
Product: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Temperature: 70 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
A solution of (5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (744 mg, 2.70 mmol) in a mixture of methanol (5 mL) and liquid ammonia (40 mL) is stirred for 3 days in an autoclave at 70° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as beige solid (662 mg, 2.42 mmol, 90%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=7.48 (bs, 1H), 7.42 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.93 (bs, 1H), 3.45 (s, 2H), 3.38 (s, 2H), 2.38 (s, 3H), 2.15 (s, 6H). MS (ES+): 247 (M(C16H14O4)+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15])O)=[O:4].[OH-].[Na+].Cl[C:19]([O:21]CC)=[O:20]>O1CCOCC1>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:7]=1[N:5]1[C:3](=[O:4])[N:2]([CH3:1])[C:19](=[O:20])[O:21]1
Reactant: CNC(=O)N(O)c1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(=O)on(-c2cc(Cl)c(Cl)cc2Cl)c1=O
Reaction time: 0.5 h

Procedure:
1-Methyl-3-(2',4',5'-trichlorophenyl)-3-hydroxyurea (8 g; 0.03 mole) was dissolved in cooled (10° C.) 2 N aqueous sodium hydroxide solution (18 ml.) and mixed with dioxane (80 ml.). Ethyl chloroformate (3.3 ml; 0.034 mole) was added dropwise to the reaction mixture at 10°-15° C. with stirring. The stirring was continued for about 1/2 hour after the addition was completed. The dark, oily product was separated and recrystallized from methanol and boiled with powdered charcoal to yield 2-(2',4',5'-trichlorophenyl)-4-methyl-1,2,4-oxadiazolidine-3,5-dione as tan needle-like crystals melting 112°-114° C. and having the following elemental analysis as calculated for C9H5Cl3N2O3 :
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2].Cl.[OH-].[NH4+:22]>>[C:1]([CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH2:22])=[O:14])=[C:11]([OH:19])[CH:10]=1)=[O:7])([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NC(=O)c1ccc(NC(=O)CCC(=O)O)cc1O
Reaction time: 16 h

Procedure:
Methyl 4-(3-carboxy-propionylamino)-2-hydroxybenzoate (1 g) from Example 2 is dissolved in 5 mL of 28% ammonium hydroxide solution. The reaction mixture is stirred at ambient conditions for 16 hours. In an ice-water bath, the solution is carefully acidified using concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried.