Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:20]3[N:19]=[N:18][C:17]([Cl:16])=[CH:22][CH:21]=3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1ccc(CN2CCC(Nc3ccc(Cl)nn3)CC2)cc1
Temperature: 120 °C

Procedure:
A solution of 1-(4-chlorobenzyl)-piperidin-4-yl amine (1 g, 4.45 mmol) (prepared by a procedure similar to that described in WO2001098273), 3,6-dichloropyridazine (670 mg, 4.45 mmol) and sodium carbonate (940 mg, 8.90 mmol) in dimethylacetamide (5 ml) was heated at 120° C. in a microwave reactor (Emrys Optimizer; 0-9 Barr) for 40 minutes. After this period, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and the solvents evaporated in vacuo. Purification by reverse phase HPLC (conditions as previously described) gave E16 (228 mg, 15%). C16H18Cl2N4 requires 336; Found 337 (MH+). 1H NMR (360 MHz, CDCl3) δ1.52 (qd, J=11.5, 3.5 Hz, 2H), 2.08 (d, J=12.5 Hz, 2H), 2.16 (t, J=11.3 Hz, 2H), 2.82 (d, J=11.5 Hz, 2H), 3.48 (s, 2H), 3.77-3.87 (m, 1H), 4.55 (d, J=7.8 Hz, 1H), 6.59 (d, J=9.3 Hz, 1H), 7.14 (d, J=9.3 Hz, 1H), 7.25 (d, J=7.7 Hz, 2H), 7.29 (d, J=7.7 Hz, 2H)
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21].[OH-].[Na+]>ClCCl>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:23]([N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[O:24])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCN(CCC)C1CCc2cccc(CNC(=O)N(CC)CC)c2C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of dichloromethane under nitrogen. 0.81 g (6 mmol) of diethylcarbamoyl chloride was then added dropwise at a maximum of +25° C. The batch was then stirred for 26 h at room temperature. The batch was then stirred into 160 ml of ice water. The mixture was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was subsequently removed by distillation. The residue was purified by column chromatography. Diisopropyl ether/isopropanol/triethylamine, 80:19.5:0.5, was used as eluent. The final product could be crystallized from petroleum ether 30-50 and was dried at +40° C. in vacuo.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH2:13][CH3:14])[CH3:11]>N1C=CC=CC=1.ClCCl>[CH2:13]([N:12]([CH2:10][CH3:11])[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:22][CH:23]=1)[CH3:14]
Reactant: CCN(CC)CCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)CCCc1ccc(NC(=O)c2ccccc2)cc1

Procedure:
Benzoylchloride (6.33 g, 45 mmol) in pyridine (50 mL) was added over a 15-minute period to a solution of N,N-diethyl-3-(p-nitrophenyl)-propylamine (9.4 g, 45 mmol) in pyridine (50 mL). The solution was refluxed for 1.5 hours. The solvent was evaporated, giving a brown oil. The oil was dissolved in dichloromethane (300 mL) and washed with 1N NaOH (200 mL). The dichloromethane layer was dried and evaporated. Toluene (100 mL) was added to the resulting oil and re-evaporated. The semi-solid residue was washed with pentane, then recrystalized from cyclohexane (125 mL) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].O.[OH-].[Li+]>CCO>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
26 g of the crude product described in 3d) were dissolved in 200 mL EtOH, combined with 2.3 g (55 mmol) of lithium hydroxide hydrate and stirred overnight at RT. The reaction solution was concentrated by evaporation in vacuo, the residue was taken up with water, extracted with diethyl ether, acidified with citric acid solution and exhaustively extracted with EtOAc. The combined organic phases were dried over MgSO4 and evaporated down in vacuo.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:22]=[CH:21][C:10]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>C1COCC1>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][O:11][C:10]1[CH:21]=[CH:22][C:7]([B:27]([OH:32])[OH:28])=[CH:8][C:9]=1[C:23]([F:26])([F:25])[F:24]
Reactant: FC(F)(F)c1cc(Br)ccc1OCCOC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCOC2CCCCO2)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
BuLi (2.5M, 6 ml) was added dropwise to a solution of 2-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethoxy)tetrahydro-2H-pyran (5 g) in THF (50 ml) at −78° C. under N2 during 3 minutes. After stirring at −78° C. for another 10 minutes, triisopropyl borate (3.8 ml) was then added dropwise during 2 minutes at −78° C. The mixture was stirred at −78° C. for further 30 minutes, then slowly warmed up to room temperature and stirred at room temperature for 30 minutes. The mixture was then quenched with acetic acid (10% in water, 20 ml), extracted with EtOAc (300 ml), washed with water (200 ml×3), dried over sodium sulphate, solvent removed under reduced pressure, the residue was taken in to toluene and then solvent removed under reduced pressure to take out traces of acetic acid (repeat 3 times) (4.5 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:32])[CH2:17][C:18]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)(O)[C:19]([F:22])([F:21])[F:20])=[CH:8][CH:7]=1.Cl>C1(C)C=CC=CC=1>[Br:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:32])[CH:17]=[C:18]([C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)[C:19]([F:21])([F:22])[F:20])=[CH:8][CH:7]=1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)c2ccccc12
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of thionyl chloride (0.5 g, 4.46 mmol) in toluene (2 mL) was added dropwise to the product of Step A (1.1 g, 2.23 mmol) in toluene (10 mL) at 65° C. The mixture was cooled to ambient temperature and then poured into 1N hydrochloric acid (50 mL). The resulting mixture was extracted with ethyl acetate (2×25 mL). The combined extracts were dried and evaporated to give the title product as an oil (1.0 g, 95% yield).
Reaction SMILES: Cl.C(O[C:5](=[O:23])[CH2:6][CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)C.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27]C)[CH3:25]>C(OC(C)C)(=O)C>[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]2[N:22]([CH2:27][N:26]3[CH2:29][CH2:30][CH2:25][CH2:24]3)[C:5](=[O:23])[CH2:6][CH2:7]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1CN1CCCC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl ester hydrochloride [10-a, R5=Et] (86 g) in isopropyl acetate (1 L) is added triethylamine (43 g). The mixture is then stirred at about 55° C. for 1 h and then filtered. The filtrate is heated at reflux for 24 hours. To the mixture is added saturated ammonium chloride solution and the phases are separated. The organic layer is concentrated to dryness and crystallized from isopropyl acetate to yield (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)]. Spectroscopic data agree with data provided above.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C[Si]([N:33]=[C:34]=[O:35])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:34]([NH2:33])=[O:35])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: C[Si](C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (9.00 mg, 0.0213 mmol), trimethylsilyl isocyanate (5.31 μL, 0.0392 mmol), DMF (0.5 mL, 0.005 mol), and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 3 h. The solution was taken directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.85-1.92 (m, 3H), 2.51 (br, s, 2H), 3.60-3.68 (m, 2H), 4.10 (br, s, 2H), 6.27 (d, J=3.5 Hz, 1H), 6.52 (q, J=6.8 Hz, 1H), 7.18-7.27 (m, 1H), 7.36-7.44 (m, 1H), 7.63-7.70 (m, 1H), 8.13-8.17 (m, 1H). MS (ES+): m/z 465.02 [MH+]. HPLC: tR=2.49 min (ZQ2, polar—5 min). The title compound was also converted to its mesylate and maleic acid salts by precipitation from ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[NH:6][C:5](=[O:7])[CH:4]([NH:8]C(=O)OC(C)(C)C)[CH2:3]1.[ClH:17].O1CCOCC1>C(Cl)Cl>[ClH:17].[NH2:8][CH:4]1[CH2:3][C:2]([CH3:16])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)CC(NC(=O)OC(C)(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)CC(N)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl N-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)carbamate (which may be prepared as described in Description 36) (1307 mg, 5.73 mmol) in DCM (5 mL) was added 4 M HCl in dioxane (2.86 mL, 11.45 mmol). The solution (which immediately started to evolve gas) was stirred at room temperature over 1 hour. The reaction mixture heavily precipitated. It was diluted with ether (approximately 50 mL) and the solid filtered under vacuum, washed with ether and dried in the vacuum oven to afford 3-amino-5,5-dimethyl-pyrrolidin-2-one hydrochloride (D37) (917 mg, 5.5701 mmol, 97.3% yield) as a white solid;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([CH3:35])=[N:22][O:23][C:24]=3[NH:25][C@H:26]([C:31]([O:33]C)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([CH3:35])=[N:22][O:23][C:24]=3[NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CC(C)C)Nc1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(N[C@@H](CC(C)C)C(=O)O)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 8 h

Procedure:
To methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucinate (450 mg, 0.926 mmol) in MeOH (15 mL) was added an aqueous solution of LiOH (2.0 M, 2.3 mL, 4.6 mmol) and the reaction mixture was stirred overnight. The reaction was acidified (pH=4–5) with aqueous 10% HCl, the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH(EtOAc/Hex, 1/29/70) to afford N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)leucine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12])[C:15]#[CH:14]
Reactant: O=C1NCCN1c1cccnc1
Reactant: C#CCBr
Product: C#CCN1CCN(c2cccnc2)C1=O

Procedure:
The starting material, 1-(2-propynyl)-3-(3-pyridyl)-2-imidazolidinone was synthesized similarly to Referential example 1, using 1-(3-pyridyl)-2-imidazolidinone as material and using 3-bromopropyne in place of 4-fluoronitrobenzene.
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Mg].II.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>O1CCCC1.O>[N:20]1[CH:21]=[CH:22][C:17]([C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:11])=[CH:9][CH:8]=2)=[CH:18][CH:19]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Brc1ccncc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A solution of 6.93 g of 4-bromobenzaldehyde dimethyl acetal in 40 ml of tetrahydrofuran was dropwise added to a mixture comprising 0.80 g of magnesium powder, a catalytic amount of iodine and 10 ml of tetrahydrofuran under stirring at a temperature in the bulk of 40° to 50° C. in a nitrogen atmosphere to prepare a Grignard reagent. This Grignard reagent was dropwise added to a solution of 4.46 g of 4-bromopyridine and 0.4 g of bis(1,3-diphenylphosphinopropane)nickel (II) chloride in 100 ml of tetrahydrofuran at a room temperature in a nitrogen atmosphere. The obtained mixture was refluxed for 4 hours and allowed to cool to a room temperature, followed by the addition of water. The obtained mixture was distilled to remove the tetrahydrofuran Ethyl acetate was added to the residue. The obtained mixture was extracted with dilute hydrochloric acid thrice. The extracts were combined, allowed to stand for a short time, made alkaline with concentrated aqueous ammonia and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform/methanol) to obtain 3.28 g of the title compound as a pale yellow crystal (yield: 64%).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][CH2:40][CH3:41])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH2:40]([NH:39][S:36]([C:32]1[CH:31]=[C:30]([NH:29][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:35]=[CH:34][CH:33]=1)(=[O:38])=[O:37])[CH3:41]
Reactant: CCNS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(OCC)c4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-ethyl-benzenesulfonamide [CAS 56445-08-0] according to general procedure II. Yellow solid. MS (ISP) 582.0 [(M−H)−]; mp 222° C.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCBr
Reactant: OCCCCCCO
Product: CC(C)CCOCCCCCCO

Procedure:
Using 1,6-hexandiol and isopentylbromide, the above compound is produced. B.P.: 164°-170°/12 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17].O>CO>[NH:16]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[NH2:17]
Reactant: NN
Reactant: COC(=O)CCCNC(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC(=O)NN
Temperature: 65 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)butanoate (21.0 g, 96.8 mmol) in MeOH (180 mL) was added NH2NH2.H2O (28.0 g, 483 mmol) at rt. The mixture was stirred at 65° C. for 12 hrs then concentrated under reduced pressure. The crude material was dissolved in DCM (400 mL). The organic layer was washed with water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford tert-butyl 4-hydrazinyl-4-oxobutylcarbamate (18.9 g, 90%) as a white solid. ESI-MS (EI+, m/z): 240 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:18])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[C:3]([NH2:13])=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=[N+]([O-])c1c(Cl)ccc2c1ccc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Chloro-5-nitroquinoline 1-oxide (4 g) was added to phosphorus oxychloride (15 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 12 hours. The excess phosphorus oxychloride was evaporated in vacuo and the residue dissolved in water (100 mL)/dichloromethane (100 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The residue was dissolved in ethanol/water (1:1, 80 mL), ammonium chloride (2.8 g) and iron (2.8 g) added. The mixture was stirred at 65° C. for 4 hours, cooled to room temperature and filtered. The resulting solid was suspended in dimethylsulfoxide (50 mL), methanol (50 mL) and aqueous hydrochloric acid added (2M, 100 mL). The resulting solid was removed by filtration and then treated with ether (50 mL) and isohexane (50 mL). Evaporation of the mixture afforded the sub-title compound as a solid (1 g).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][N:25]([CH2:3][C:4]2[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=2)[CH2:24][CH2:23]3)=[CH:18][CH:19]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: Clc1ccc(-c2ccc3c(c2)CCNC3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCc3cc(-c4ccc(Cl)cc4)ccc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 75.5 %

Procedure:
A suspension of 1.69 g (0.0087 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 95 ml of dimethylformamide was treated with 2.035 g (0.00726 mol) of 6-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride and 3.35 ml (0.0;24 mol) of triethylamine and stirred at room temperature under argon for 66 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water. 16 ml of a 1N aqueous sodium hydroxide solution were added dropwise thereto, the mixture was extracted and chromatographed over silica gel with ethyl acetate/isopropyl alcohol 9:1 as the eluent and digested in diethyl ether. 2.0 g (63%) of 5-[6-(4-chlorophenyl)-3,4-dihydro-1H-isoquinolin-2-ylmethyl]-2-methyl-pyrimidin-4-ylamine were obtained as a white solid. An analytical sample was recrystallized from ethyl acetate and gave white crystals; m.p. 205°-208°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][O:16][C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=2)=[O:24])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of 4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate. 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Procedure M to give 550 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 429 (M)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[CH:6][CH:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O>[O:11]1[CH:12]=[N:13][N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=1
Reactant: COC(OC)c1ccc(-c2nnco2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To the product from step B (175 mg, 0.80 mmol) in a 1:1 mixture of tetrahydrofuran/water (2 mL) at room temperature was added p-toluenesulfonic acid (50 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 1 h, and partitioned between dichloromethane and sat. aq. NaHCO3. The organic layer was dried with Na2SO4, and concentrated in vacuo to give 100 mg (72%) of the title product, which was used without further purification. MS 175 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:25](O)[CH3:26]>>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][NH:15][C:13]([C:7]1[C:8](=[O:12])[O:9][C:10]2[C:5]([C:6]=1[OH:20])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)=[O:14])[CH3:26]
Reactant: CCO
Reactant: O=C(O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O

Procedure:
A mixture of [(7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carbonyl)-amino]-acetic acid (3.209 g, 9.38 mmol) and thionyl chloride (2.05 mL, 28.1 mmol) in ethanol (75 mL) was refluxed for 2 h; then cooled, the precipitates were collected via filtration and washed with cold ethanol, air dried to give the desired product (3.153 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=17.5 (s, 1H), 9.5 (br, 1H), 7.88 (dd, 1H, J=0.6 Hz, 8.4 Hz), 7.5-7.2 (m, 2H), 4.32-4.18 (m, 4H), 1.32 (t, 3H, J=7.0 Hz).