Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[Cl:15][C:16]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([OH:22])=[O:21].Cl>C(=S)=S>[Cl:15][C:16]1[C:26]([Cl:27])=[C:25]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: O=C(O)COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a mixture of 12.5 g of aluminum chloride and 45 ml of carbon disulfide there is added dropwise 7.1 g of 2-fluorobenzoyl chloride while maintaining the temperature below 0° C. This low temperature is maintained for 1.5 hours. While maintaining this same low temperature, 5 g of 2,3-dichlorophenoxyacetic acid is added incrementally. After addition is complete, the reaction mixture is maintained at low temperature for 30 minutes and then permitted to reach ambient temperature after which it is refluxed for 28 hours. The carbon disulfide is decanted from the refluxed solution leaving a dark orange residue which is poured onto a mixture of 500 ml of ice/water and 100 ml of concentrated hydrochloric acid. The resulting pink precipitate is collected by filtration, rinsed with 300 ml of warm water (50° C.) and dried in vacuum oven. The dried product is recrystallized twice from aqueous ethyl alcohol to form the product 2,3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid having a melting point of 153° to 156° C.
Reaction SMILES: [Cl:1][S:2]([CH2:5][C:6](Cl)=[O:7])(=[O:4])=[O:3].[CH3:9][OH:10]>CCOCC>[CH3:9][O:10][C:6](=[O:7])[CH2:5][S:2]([Cl:1])(=[O:4])=[O:3]
Reactant: O=C(Cl)CS(=O)(=O)Cl
Reactant: CO
Solvent: CCOCC
Product: COC(=O)CS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of chlorosulfonylacetyl chloride (419 μL, 3.955 mmol, 1 eq.) in Et2O (4 mL), at 0° C. was added MeOH (160 μL, 3.955 mmol, 1 eq.). The reaction mixture is stirred at 0° C. for 3 h, then concentrated in vacuo to give chlorosulfonyl-acetic acid methyl ester.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:13]=O>C(O)(=O)C>[C:5]12([OH:13])[CH2:10][C:1]3([OH:12])[CH2:8][CH:7]([CH2:9][C:3]([OH:11])([CH2:2]3)[CH2:4]1)[CH2:6]2
Reactant: O=O
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: CC(=O)O
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2
Yield: 80 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of 1,3-adamantanediol, 1 mmol of NHPI and 0.05 mmol of acetylacetonatovanadium (III) (V(AA)3), and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 6 hours. And, as a result, the 1,3-adamantanediol was converted into a 1,3,5-adamantanetriol (yield: 80%) with a conversion of 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(N)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A mixture of (2-methyl-6-nitrophenyl)phenylamine (981 mg, 4.3 mmol) and 10% Pd/C (981 mg) in EtOAc (20 mL) was degassed with a stream of nitrogen and then stirred at RT under a hydrogen atmosphere for 4 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 3-Methyl-N2-phenylbenzene-1,2-diamine as a yellow solid (852 mg, 100%). LCMS: RT 3.02 min [M+H]+ 199.0
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([CH3:16])[NH:11]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:11]2[C@H:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C@@H:10]2[CH3:9])[N:3]=[CH:4][N:5]=1
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: Clc1cc(Cl)ncn1
Product: C[C@@H]1CCC[C@H](C)N1c1cc(Cl)ncn1
Reaction time: 10 h
Yield: 27.7 %

Procedure:
0.5 g of 4,6-dichloropyrimidine and 0.76 g of cis-2,6-dimethylpiperidine were mixed and stirred for 10 hours at 90%. The reaction mixture was subjected to silica gel column chromatography to obtain 0.21 g of 4-chloro-6-(cis-2,6-dimethylpiperidino)pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH2:9]O)[CH:6]=[CH:7][CH:8]=1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[O:14]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][N:23]2[CH:24]=[C:20]([B:15]3[O:14][C:13]([CH3:25])([CH3:12])[C:17]([CH3:19])([CH3:18])[O:16]3)[CH:21]=[N:22]2)[CH:4]=1
Reactant: CN(C)c1cccc(CO)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(C)c1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Reaction time: 8 h

Procedure:
To a solution of (3-(dimethylamino)phenyl)methanol (0.100 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.167 g) and cyanomethylenetributylphosphorane (0.208 g) were added and stirred together in toluene (1 mL) at room temperature. After stirring overnight the reaction was loaded directly onto silica gel and eluted using a gradient of 5% to 35% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:25]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH2:15]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccccc3)CC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A solution of 20 mg (0.06 mmol) of 3-(RS)-((4-phenyl)-piperidin-1-yl)methyl-4-(SR)-phenylpyrrolidine (from Example 30, Step A), 19 mg (0.19 mmol) of TEA and 6 mg (0.05 mmol) of 4-DMAP in 2 mL of CH2Cl2 (2 mL) was treated with 28 mg (0.16 mmol) of nicotinoyl chloride·HCl and was stirred at rt for 2 h. The reaction was concentrated in Vacuo. Preparative thin layer chromatography (silica gel GF, 20×20 cm, 1000 microns) using 92:8 v/v MeOH/CH2Cl2 +0.5% NH4OH as the eluant afforded 20 mg (71%) of the title compound as a yellow foam. 1H NMR (500 MHz, CDCl3): δ7.17-8.88 (9H), 1.27-4.24 (22H). Mass Spectrum (NH3 -CI): 426 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[NH:7][CH2:6][CH:5]=[CH:4][NH:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[N:16]=[C:17]=[O:18]>CN(C=O)C.O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1)=[O:18]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: NC1NC=CCN1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1=NCCCN1)Nc1c(Cl)cccc1Cl

Procedure:
A solution of 4.20 g (0.0424 mol) of 2-aminotetrahydropyrimidine in 30 ml of dry DMF was warmed to 70° C. and with stirring there was added 7.16 g (0.0381 mol) of 2,6-dichlorophenyl isocyanate in 25 ml of dry DMF over a period of 0.5 hours. After stirring for 2 hours at 70° C., the reaction mixture was cooled, diluted with H2O and filtered. The filter cake was washed well with H2O and air dried. The crude product, 5.1 g (47%) was dissolved in CH2Cl2, dried over K2CO3, filtered through a prewashed pad of filter aid and hexane was added to the cloud point. The resulting crystals were filtered, washed with hexane and dried in vacuo for 3 hours (50° C.; 5 mm Hg) to give pure N-(2,6-dichlorophenyl)-N'-(1,4,5,6-tetrahydropyrimidin-2-yl)urea, 4.71 g (43%); m.p. 179°-180.5° C. TLC: 5×20 cm silica gel; toluene-ether-MeOH (8:4:1) or CHCl3 --MeOH-NH4OH (90:10:1) indicated homogeneity; IR (KBr) 3421,1628 cm-1 ; UV max. (MeOH) 222 nm (ε=28300) and 239 nm (inflection) (ε=18,000).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Br)(=[O:7])[CH3:6].[CH:9]([NH:11][C:12]([CH3:21])([CH3:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10]>ClCCCl>[CH:9]([NH:11][C:12]([CH3:21])([CH3:20])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](=[O:7])[CH3:6])=[CH:16][CH:15]=1)=[O:10]
Reactant: CC(C)(Cc1ccccc1)NC=O
Reactant: CC(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CC(C)(C)NC=O)cc1

Procedure:
This was prepared in an identical manner to the compound described in Description 10 using aluminum chloride (26 g), acetyl bromide (115 ml) and N-formyl-2-phenyl-1, 1-dimethylethanamine (101.5 g) in 1,2-dichloroethane, (850 ml). τ(CDCl3). 8.62 (6H, s), 7.45 (3H, s), 7.1+6.85 (2H, s+s), 3.85 (1H, broad) 2.7 (2H, d, J=8 Hz) 2.1 (2H, d, J=8 Hz), 1.9 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:22])=[C:14]([C:16](=O)[C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].Cl[Sn]Cl>CCO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:22])=[C:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCc2sc(CC(F)(F)F)c(Br)c2CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
The product of step (a) (73 mg, 0.18 mmol) was stirred in 3 mL EtOH and treated with NaBH4 (20 mg, 0.5 mmol). After stirring for 20 minutes, the reaction was quenched with HOAc until no bubbling was observed. The reaction was diluted with water (5 mL) and the crude product was extracted into DCM (3×5 mL). The combined organic extracts were concentrated and the residue was dissolved in HOAc (2 mL) and concentrated HCl (1 mL). SnCl2 (225 mg, 1 mmol) was added and the reaction was heated to 80° C. for 2 hours. The crude reaction was diluted with water (10 mL) and the product was extracted into DCM (3×5 mL). The combined organic extracts were concentrated to dryness and used without further purification.
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][C:11](=[O:18])[C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH2:29]([NH2:32])[CH2:30][CH3:31].Cl>O.CO>[CH2:29]([N:32]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][C:11](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: CCOC(=O)c1c(-c2ccccc2)oc(-c2ccccc2)cc1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Yield: 36 %

Procedure:
4.0 gms of 2,6-diphenyl-3-ethoxycarbonyl-pyr-4-one, 50 mls of glacial acetic acid were mixed. 8.1 gms of n-propylamine and 6 mls of water was added slowly at room temperature. After 3 hours an additional 14 mls of water, 12 mls of 6% HCl and enough methanol to bring everything into solution, was added. The next day this acidic reaction mixture was poured into water and extracted with methylene chloride (2×100 mls). Evaporation of the organic extracts yield 4.4 gms of crude nicotinate ester which was suspended in 50 mls of 5% aqueous NaOH and heated at 85° for 4 hours. The resulting solution was acidified with HCl and extracted with methylene chloride (2×50 mls). Evaporation of the solvent yielded a solid mass. recrystallization from ether provided 1.5 gms of 1-propyl-2,6-diphenyl-4-oxonicotinic acid. mp=166°-167°.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[C:14]([C:19](O)=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=4)=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[F:52][C:53]1([F:57])[CH2:56][NH:55][CH2:54]1>CN(C)C=O.C(OCC)(=O)C>[F:52][C:53]1([F:57])[CH2:56][N:55]([C:19]([C:14]2[C:13]([NH:12][C:10]([C:4]34[CH2:5][CH:6]5[CH2:9][CH:2]([CH2:1][CH:8]3[CH2:7]5)[CH2:3]4)=[O:11])=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:20])[CH2:54]1
Reactant: O=C(O)c1ncccc1NC(=O)C12CC3CC(CC1C3)C2
Reactant: FC1(F)CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ncccc1NC(=O)C12CC3CC(CC1C3)C2)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 332B (0.1 g, 0.35 mmol) in dimethylformamide (5 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.1 g, 0.52 mmol), 1-hydroxybenzotriazole hydrate (0.07 g, 0.52 mmol), triethylamine (0.11 g, 1.05 mmol) and 3,3-difluoro-azetidine hydrochloride (0.07 g, 0.52 mmol). The reaction was stirred at room temperature for 16 hours, diluted with ethyl acetate (50 mL) and the organics were washed with sodium bicarbonate solution, brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (20% ethyl acetate in hexane) afforded the title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ ppm 1.50-1.73 (m, 4H) 1.73-1.93 (m, 4H) 1.95-2.19 (m, 2H) 2.33 (s, 2H) 2.67 (t, J=6.61 Hz, 1H) 4.53 (t, J=12.37 Hz, 2H) 5.03 (t, J=12.54 Hz, 2H) 7.57 (dd, J=8.65, 4.58 Hz, 1H) 8.30 (dd, J=4.41, 1.36 Hz, 1H) 8.98 (dd, J=8.65, 1.53 Hz, 1H) 11.82 (s, 1H). MS (ESI+) m/z 362.1 (M+H)+
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH:23]=[CH:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC=C3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,3-Dip-tolylpyrido[2,3-b]pyrazine (Intermediate E, step 1) (6.74 g, 21.65 mmol) in THF (130 ml) was added dropwise at room temperature 2.4 M LiAlH4 in THF (4.51 ml, 10.82 mmol). To the reaction mixture cooled to 0° C. was added dropwise and successively water (0.409 ml), 15% aqueous NaOH (0.409 ml) and water (1.227 ml). The mixture was stirred at 0° C. for 15 min and allowed to warm to RT. Anhydrous MgSO4 was added and the mixture was stirred for 15 min and filtered. The residue was washed with EtOAc (×5) and the filtrate was concentrated in vacuo to afford the title compound:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH2:15]Cl)=[N:13][N:14]=3)[C:5]=2[CH:4]=1.[I-].[K+].[CH3:29][CH:30]=[CH:31][CH2:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH2:15][NH:33][CH2:32][CH2:31][CH:30]=[CH2:29])=[N:13][N:14]=3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)-n1c(CCl)nnc1CN=C2c1ccccc1
Reactant: CC=CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1cc(C(F)(F)F)ccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 9-(trifluoromethyl)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and methylallylamine in tetrahydrofuran are reacted to give 9-(trifluoromethyl)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 48 8-Chloro-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: OCC(C1C=CC=CC=1)CC(OCC)=O.C[O:17][C:18](=[O:47])[CH2:19][CH:20]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[C:41]1([CH:20]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:33][CH2:34]3)=[CH:27][CH:28]=2)[CH2:19][C:18]([OH:47])=[O:17])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)CC(COc1ccc(N2CCN(c3ccncc3)CC2)cc1)c1ccccc1
Agent: CCOC(=O)CC(CO)c1ccccc1
Product: O=C(O)CC(COc1ccc(N2CCN(c3ccncc3)CC2)cc1)c1ccccc1
Yield: 10 %

Procedure:
In a similar manner to Example 204ii), but starting from RS ethyl 4-hydroxy-3-phenylbutyrate was made RS methyl-3-phenyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate in 10% yield as an oil; NMR (d6DMSO+CD3COOD) δ 8.23(2H,d), 7.3(5H,m), 7.17(2H,d), 6.95(2H,d), 6.83(2H,d), 4.06(2H,m), 3.77(4H,t), 3.55(3H,s), 3.51(1H,m), 3.17(4H, t), 2.83(2H,m); m/e 432(M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9](SC)[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:29])[NH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.Cl>CN(C=O)C.C(Cl)Cl.CO.O1CCOCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)[N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:29])[NH:4][CH:3]=1
Reactant: CSc1nc(Nc2ccc(Oc3cccc(F)c3)cc2)c2c(=O)[nH]cc(Br)c2n1
Reactant: CN1CCC(N)CC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCC(Nc2nc(Nc3ccc(Oc4cccc(F)c4)cc3)c3c(=O)[nH]cc(Br)c3n2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A 40 mL reaction vial was charged with 238e (0.90 g, 1.90 mmol) in 15 mL DMF. The clear solution was cooled to −10° C. To this, was added m-CPBA (1.48 g, 6.00 mmol) at −10° C. The reaction was allowed to warm up to room temperature, and then stirred for additional 30 min at RT. To the mixture was added TEA (0.83 mL, 6.00 mmol) and 1-methylpiperidin-4-amine (685 mg, 6.00 mmol), and then it was stirred at room temperature for 1 hour with monitoring the reaction by LC-MS. The solvent was removed under reduced pressure yielding light brown oily residue. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to yield a solid. The solid was dissolved in a minimum amount of methylene chloride and treated with excess of n-hexanes yielding pale yellow solids. The resulted solids were collected by filtration, rinsed with n-hexanes and then dried in the air yielding a pale yellow solid. The solid was dissolved in the mixture of DCM and methanol. To the clear solution was added 4N HCl in dioxane (12.0 mL), then it was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure yielding the desired product (238, 90% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:38])=[C:6]([CH3:37])[C:7]2[N:8]([C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH3:2].CO.Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([CH3:38])=[C:6]([CH3:37])[C:7]2[N:8]([C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4([NH2:23])[CH2:20][CH2:21][CH2:22]4)=[CH:17][CH:18]=3)[N:12]=2)[N:9]=1)[CH3:2]
Reactant: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)c1C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1nn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of the tert-butyl {1-[4-(6-ethoxy-7,8-dimethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-36 (210 mg, 0.410 mmol, 1.0 eq) in DCM (2.64 mL) and MeOH (1.66 mL) was added a solution of 4 M hydrogen chloride in dioxane (2.05 mL, 8.19 mmol, 20.0 eq) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline, treated with DCM and filtered through a phase separator. The volatile components of the organic phase were removed in vacuo to give 145 mg (82% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19](Cl)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH:16]1[CH3:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:42]([NH2:45])([CH3:44])[CH3:43].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:8]([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:45][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[CH2:27][CH2:26]3)[N:21]=2)[CH:16]1[CH3:41])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)N
Reactant: CC1c2nc(Cl)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CCN1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(Cc1ccccc1)C2C

Procedure:
Combined 6-benzyl-3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazine TFA salt (280 mg, 0.467 mmol), isopropylamine (200 μL, 2.337 mmol), Pd2(dba)3 (42.8 mg, 0.047 mmol), BINAP (58.2 mg, 0.093 mmol), and sodium tert-butoxide (112 mg, 1.169 mmol) in toluene (2.34 mL) and heated at 100° C. for 30 min under microwave conditions. The reaction mixture was cooled, concentrated in vacuo, and purified by HPLC Method A to give 6-benzyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine as a TFA salt (175 mg) as a brown oil.
Reaction SMILES: [C:1]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:18][N:19]=[C:20]=[O:21]>C1(C)C=CC=CC=1.P([O-])(OCCCC)(OCCCC)=O>[CH3:18][NH:19][C:20]([N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: CN=C=O
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1cccc2ccccc12
Temperature: 100 °C
Yield: 80 %

Procedure:
0.5 mole of α-naphthyl-phenylamine was taken together with 0.53 mole of methyl isocyanate and 0.6 g of di-n-butyl phosphate in 150 ml of toluene. The mixture was warmed at 100° C. for 24 hours, with stirring, and then cooled to 10° C. After the product had been filtered off, washed with 150 ml of cold toluene and dried, 0.4 mole of N-methyl-N'-phenyl-N'-α-naphthyl-urea was obtained. Melting point: 146° C./yield: 80% of theory,