Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][C:12](N)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:12]1[CH:11]=[N:10][C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:16])=[CH:14][CH:13]=1)[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)OC(C)(C)C)nc1
Temperature: 110 °C

Procedure:
A mixture of 12-3 (6.0 g, 20.9 mmol), ethyl acrylate (6.3 mL, 62.7 mmol), triethylamine (17 mL, 125.5 mmol), tri-o-tolylphosphine (1.3 g, 6.2 mmol) and Pd(OAc)2 (0.5 g, 2.1 mmol) in 50 mL CH3CN was purged with argon for 5 min and subsequently refluxed at 110° C. for 20 hr. The mixture was cooled and concentrated. The residue was purified using silica gel flash chromatography (EtOAc/hexanes 1:3) to afford the desired product 12-4 as an oil.
Reaction SMILES: [C:1]([N:4]1[CH:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2].[N+](=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N-]>C1(C)C=CC=CC=1.[Cu]>[C:1]([N:4]1[CH:9]2[CH:8]([CH:21]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6](=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C=CN(Cc2ccc(F)cc2)C(=O)C1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C2C1N(Cc1ccc(F)cc1)C(=O)CN2C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one (5.0 g, 20.0 mmol; Example 2, Step 3) and copper bronze (320 mg, 5.0 mmol) in anhydrous toluene (50 mL) under nitrogen at 120° C. (oil bath) was added ethyl diazoacetate (6.4 mL, 60.0 mmol) via a syringe pump at a speed of 2.5 mL/h. After 3 h, TLC (eluted with ethyl acetate) showed no starting material left. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate and methanol as eluents to give both exo and endo diastereomers.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]#[N:7])C.Cl.Cl.[CH:13]1([NH:16][NH2:17])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([N:16]2[C:6]([NH2:7])=[CH:5][CH:4]=[N:17]2)[CH2:15][CH2:14]1
Reactant: NNC1CC1
Reactant: CCOC(CC#N)OCC
Agent: Cl
Solvent: CCO
Product: Nc1ccnn1C1CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A 100-mL round-bottom flask was charged with 3,3-diethoxypropanenitrile (0.600 g, 4.19 mmol), cyclopropylhydrazine di-hydrochloride (0.610 g, 4.21 mmol) and ethanol (20 mL), and the resulting solution stirred for 18 h at 80° C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-cyclopropyl-1H-pyrazol-5-amine (0.206 g, 36%) as light yellow oil. MS (ESI, pos. ion) m/z 124 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1.NC1C=NC(C)=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:34]([NH:33][C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:35])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Agent: Cc1ccc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cc4)c3)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5) and phenyl 6-methylpyridin-3-ylcarbamate (123 mg, 0.541 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-methylpyridine) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (50-100% EtOAc:CH2Cl2) to afford the title compound (220 mg) as a white solid. MS APCI M+ 468.2, 375.2, 334.1 M− 466.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.41-2.45 (m, 2H) 2.46 (s, 3H) 2.54 (td, J=5.90, 1.26 Hz, 2H) 3.50-3.55 (m, 2H) 3.58-3.65 (m, 2H) 6.43 (s, 1H) 6.91-6.96 (m, 2H) 7.06-7.12 (m, 3H) 7.20 (d, J=8.52 Hz, 1H) 7.35-7.42 (m, 1H) 7.59-7.68 (m, 2H) 7.77 (dd, J=8.45, 2.62 Hz, 1H) 8.43 (d, J=2.78 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:35](C(OCC)=O)=NC(OCC)=O.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[NH2:35][C@H:10]1[C@@H:11]([O:13][CH3:14])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@H]1CN(Cc2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.6 g (25 mmol) of trans-1-benzyl-3-hydroxy-4-methoxypyrrolidine and 8.6 g (33 mmol) of triphenylphosphine are initially introduced into 40 ml of absolute tetrahydrofuran and a solution of 6 g (34 mmol) of diethyl azodicarboxylate in 40 ml of absolute tetrahydrofuran is added dropwise at 0° C. 3.9 g (27 mmol) of phthalimide are then added in small portions at 0° C. in the course of one hour. The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 80 ml of ethyl acetate and 80 ml of petroleum ether are added. The mixture is left to crystallize out overnight and the crystals (triphenylphosphine oxide and diethyl hydrazinedicarboxylate) are filtered off. The filtrate is concentrated and the residue is heated under reflux with 60 ml of concentrated hydrochloric acid overnight. The undissolved residues are decanted and the solution is concentrated. The residue is taken up in a little water and the solution is rendered alkaline with solid potassium carbonate and extracted five times with 50 ml of chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:30])[NH:6][C:7]1[N:8]([C:16]2[N:17]=[CH:18][N:19]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.C(C1C=C(NC([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=[O:30])[N:8]([C:16]2[N:17]=[CH:18][N:19]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH:20]=2)[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cn(CCOC3CCCCO3)cn2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOC3CCCCO3)cn2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 119c using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 5.52 min, m/z 723 [MH+].
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])=[CH:30][CH:29]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OCCCN(C)C)cc3)nc(=O)c1-2
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.03 g, 9.14 mmol), 4-[3-(dimethylamino)propoxy]benzaldehyde (2.76 ml), and xylenes was heated at 120° C. for 1 hour, then at 160° C. for 6 hours. p-Toluenesulfonic acid (300 mg) was added and the mixture was heated at 160° C. until the reaction was complete. The reaction mixture was cooled to room temperature, and a creamy white solid formed, which was collected by filtration, washed with methanol and recrystallized from ethyl acetate to afford 1-cyclopentyl-3-ethyl-6-[4-[3-(dimethylamino)propoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 175°-178° C.
Reaction SMILES: C1(C)C=CC(C2C=CC=CN=2)=CC=1.[Br:14]Br.[Br:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1>ClC1C=CC=CC=1>[Br:16][CH:17]([Br:14])[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: BrCc1ccc(-c2ccccn2)cc1
Agent: Cc1ccc(-c2ccccn2)cc1
Solvent: Clc1ccccc1
Product: BrC(Br)c1ccc(-c2ccccn2)cc1
Temperature: 115 °C
Yield: 60.7 %

Procedure:
In a 100 ml four neck flat were placed 2-(4-tolyl)pyridine (5.0 g, 29.6 mmol) and chlorobenzene (18 ml), and bromine (9.4 g, 59.1 mmol) was added dropwise while heating the mixture at 110-120° C. over 12 hours. The reaction mixture was stirred with heating at a temperature in the above-mentioned range for 1 hour and analyzed by HPLC. As a result, 2-(4-bromomethylphenyl)pyridine was confirmed to have been produced in a 60.7% yield. The obtained reaction mixture was cooled and the precipitated 2-(4-bromomethylphenyl)pyridine salt was collected by filtration. The filtrate was neutralized with 5% aqueous sodium hydroxide solution. After washing with water, the mixture was dried over anhydrous magnesium sulfate. Chlorobenzene was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-hexane) to give 2-(4-dibromomethylphenyl)pyridine in a 1.2 g yield. From the 1H-NMR analysis, the product was found to be 2-(4-dibromomethylphenyl)pyridine. [2-(4-dibromomethylphenyl)pyridine]
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1F)Nc1ccccc1C(=O)O
Yield: 85.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), ortho-fluoroaniline (7.48 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.54 (broad s, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=8, J=1.4, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (t, J=7.6, 1H), 7.05 (dd, J=11.6, J=8.0, 1H), 6.94 (t, J=7.6, 1H), 6.58 (m, 2H), 6.37 (broad s, 1H), 3.90 (d, J=5.6, 2H); 13C NMR (DMSO-d6) δ 170.30, 169.19, 151.02 (J=238.1), 140.56, 136.00 (J=11.3), 134.20, 131.12, 124.77 (J=3.1), 122.71, 119.35, 116.80 (J=6.8), 114.52 (J=18.2), 111.81 (J=3.1), 48.23.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.[CH2:15](O)[CH3:16]>>[CH2:15]([O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1)[CH3:16]
Reactant: Cc1ccc2c(O)cc(=O)oc2c1
Reactant: CCO
Agent: Cl
Product: CCOc1cc(=O)oc2cc(C)ccc12
Yield: 72 %

Procedure:
Dry hydrogen chloride was passed through a solution of 4-hydroxy-7-methylcoumarin (14 g; 0.08 mole) in ethanol (300 ml) for 15 mins and the resulting solution was refluxed for 30 minutes. After cooling, the solvent was removed in vacuo and the residue recrystallized from ethanol to give 11.74 g (72%) of product of m.p. 142°-143° C.; (Found; C, 70.24; H, 5.95; C12H12O3 requires; C, 70.60; H, 5.88%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(C)ccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2cc(CBr)ccc2c1
Temperature: 35 °C
Yield: 69.5 %

Procedure:
A solution of 2-methyl-6-methoxynaphthalene (4.lg, 23.8 mmole) and azoisobutyronitrile (80 mg) in dry carbon tetrachloride (30 ml) was heated to reflux with stirring. A slurry of N-bromosuccinimide (4.6 g, 25.8 mmole) and azoisobutyronitrile (20 mg) in dry carbon tetrachloride (10 ml) was added gradually over 2 hours. The resulting solution was heated under reflux for 30 minutes and then cooled to 35° C. The succinimide was filtered off and washed with carbon tetrachloride (5 ml). The filtrate was evaporated to dryness to afford a creamy coloured solid which was dried under vacuum at 40° C. It weighed 5.8 g and contained 70.3% 2-bromomethyl-6-methoxynaphthalene giving an activity yield of 69.5%.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:8]1[NH:12][N:11]=[N:10][N:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([N:10]1[N:11]=[N:12][C:8]([C:2]([CH3:1])([CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:9]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(C)c1nnn[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)c1nnn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred mixture of α,α-dimethyltetrazole-5-acetic acid, ethyl ester (J. Med. Chem. 1996, 39, 2354-2366.) (6.87 g, 37.3 mmol) and K2CO3 (12.3 g, 89.0 mmol) in acetone (200 mL) was added benzyl bromide (4.45 mL, 37.4 mmol) at ambient temperature. The resulting mixture was stirred at 50° C. for 18 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (10:1) to give 6.14 g (60%) of the title compound as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C(OC([N:35]1CCCC1COC1C=CN=CC=1)=O)(C)(C)C>>[N:35]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]3=[O:27])(=[O:15])=[O:16])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccncc1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3ccncc3)cc2C1=O
Yield: 55 %

Procedure:
5-(2-(Pyridin-4-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (23) was prepared according to the same procedure for compound 10, except using compound 22, purified with ethyl acetate to afford 1.17 g (55%) of 23 as a yellow solid, mp 204.2-205.3° C. 1H NMR (300 MHz, CDCl3) δ 11.44 (s, 1H), 8.37 (d, J=5.7 Hz, 2H), 8.03 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.96 (d, J=6.0 Hz, 2H), 4.17-4.05 (m, 2H), 3.90 (m, 1H), 3.32 (m, 1H), 3.10 (m, 1H), 1.85 (m, 2H), 1.60 (m, 2H). LCMSm/e: 387.9 (M+H). Anal. Calcd for C18H17N3O5S.0.75H2O: C, 53.92, H, 4.65; N, 10.48. Found: C, 54.14, H, 4.39; N, 10.35.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:12]=[N:28][O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: COC(=O)C1(C=O)CCCCCC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(C=NOCc2ccccc2)CCCCCC1
Yield: 51 %

Procedure:
A mixture of 1-formyl-cycloheptanecarboxylic acid methyl ester from Preparation 34 (35.6 mmol theoretical), sodium acetate (5.84 g, 72 mmol) and O-benzylhydroxylamine hydrochloride (11.36 g, 72 mmol) were stirred in methanol (71 mL) for 2 h. The methanol was removed in vacuo and the residue partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (50 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. Purifiaction by flash column chromatography using an eluting sytem of hexanes/EtOAc (99:1) provided the title compound as a clear colorless oil (5.22 g, 51%). MH+290.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:29][C:2]([F:1])([F:28])[CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 17 h

Procedure:
To a solution of ethyl(+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoate (95 mg, 0.24 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) was added 1 N aq sodium hydroxide (1.2 mL, 1.2 mmol). After 17 hours, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 5 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (20 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzoic acid. 1HNMR (400 MHz, CD3OD) δ 8.50 (br. s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.80-7.73 (m, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.40-7.32 (m, 2H), 6.95 (d, J=2.5 Hz, 1H), 4.73-4.64 (m, 1H), 2.55-2.39 (m, 1H), 2.39-2.22 (m, 1H), 2.22-2.04 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[Cl:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([NH:28][CH3:29])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=4)[S:10][C:3]=23)[CH:21]=[CH:20][C:19]=1[CH2:25][C:26]([NH:28][CH3:29])=[O:27]
Reactant: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)Cc1ccc(O)cc1Cl
Product: CNC(=O)Cc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)cc1Cl

Procedure:
was prepared from coupling of 7-chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine and intermediate 63a following Method C. 1H NMR (300 MHz, CD3OD) δ 8.38 (d, 1H, J=5.65 Hz), 7.67 (s, 1H), 7.38 (d, 1H, J=8.48 Hz), 7.27 (d, 1H, J=2.44 Hz), 7.20 (s, 1H), 7.12–7.06 (m, 1H), 6.99 (s, 1H), 6.67 (d, 1H, J=5.47 Hz), 3.91 (s, 3H), 3.61(s, 2H), 2.66 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 413, found 413. Anal. (C20H17N4O2SCl.0.25CH2Cl2), C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20])([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (1 eq) and triethylamine (3 eq) in tetrahydrofuran (0.08M) at 0° C. was added isobutyl chloroformate (1.8 eq). After stirring at 0° C. for 2 hours, isopropylamine (5 eq) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[C:1]([CH:3]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)C(C)c1ccccc1

Procedure:
In another example, methyl cyanoacetate can be reacted with acetophenone in the presence of ammonium acetate and acetic acid in refluxing toluene solvent followed by hydrogenation with 5% Pd on C catalyst to yield methyl 2-cyano-3-phenylbutyrate. The latter compound can then be reacted with methyl bromacetate in the presence of potassium carbonate to provide the α-methylbenzyl substituted dimethyl cyanoethane-1,2-dicarboxylate starting 1,2-diester (See Example 8, below): ##STR10## The latter material can then be subjected to the aforesaid 1,2-ester transposition to provide the isomeric terminal diester (See Example 1, below.)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=O)[CH3:2].Cl.[Cl:20][C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2cccc(Cl)c2)n1
Yield: 22 %

Procedure:
Starting from 1 g (3.46 mmol) of 4-(2,4-dichlorophenyl)-2,4-dioxobutanoic acid ethyl ester from example 11A and 842.25 mg (4.7 mmol) of 3-chlorophenylhydrazine hydrochloride, 297.5 mg (0.75 mmol, 22% yield of theory) of product are obtained according to the method described in example 4A and after purification by preparative HPLC.