Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[CH3:44][S:45]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:33](=[O:34])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][CH:23]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-[2-(Hydroxymethyl)phenyl]-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 654, 0.23 g, 0.51 mmol) was suspended in dichloromethane (5 mL), treated with diisopropylethylamine (0.20 mL, 1.1 mmol, 2.2 equiv) and cooled to −78° C. Methanesulfonyl chloride (60 μL, 0.77 mmol, 1.5 equiv) was added and the mixture was stirred at −78° C. for 30 minutes. The dry ice/acetone bath was removed, the mixture was warmed to ambient temperature and stirred for an additional 45 minutes. The mixture was poured into ammonium chloride (20 mL, aqueous saturated) and extracted with dichloromethane (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the title compound.
Reaction SMILES: [CH3:1][OH:2].[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10](Cl)=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:3]([N:8]([C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])[C:9](=[O:13])[C:10]([O:2][CH3:1])=[O:11])[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Reactant: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)OC
Yield: 97.9 %

Procedure:
0.64 g (0.02 mole) of methanol are added to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene, and 2.02 g (0.02 mole) of triethylamine are then added dropwise, while cooling with ice. After the precipitate has been filtered off, the filtrate is washed with water, dried over sodium sulphate and freed from the solvent under a high vacuum. 5 g (98% of theory) of methyl N-neopentyl-N-2-propinyloxycarbonyl-oxamate of refractive index nD20 =1.4634 are obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([CH:14]([OH:44])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[C:23]([C:24]([N:26]=[CH:27][N:28]=3)=[NH:25])=[N:22][C:21]2=[SiH2:30])[C@H:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:16]1[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:13])([CH3:12])[CH3:11].N1CCOCC1>N1C=CC=CC=1>[C:10]([CH:14]([OH:44])[C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[C:23]([C:24]([N:26]=[CH:27][N:28]=3)=[N:25][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][C:21]2=[SiH2:30])[C@H:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:16]1[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCN1
Product: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=NC(=O)c2ccccc2)O[C@@H]1C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzoyl chloride (8 ml, 68.86 mmol) was added dropwise to a stirred suspension of (50) (17.89 g, 34.28 mmol) in anhydrous pyridine (100 ml) at 0° C. After 5 min the reaction was warmed to room temperature and stirred for 2.5 hr. After that the mixture was cooled to 0° C. and morpholine (12 ml, 137.9 mmol) was added slowly with stirring. After 45 min at 0° C. the reaction mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization from acetonitrile (100 ml) furnished (51) as crystalline material. Yield 16.47 g (76.8%).
Reaction SMILES: [NH2:1][C@@:2]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH3:28])[C@@:3]([NH:12][C:13](=O)[C:14]1[C:19]([O:20][CH2:21][CH3:22])=[CH:18][C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16][CH:15]=1)([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[CH3:4].P(Cl)(Cl)(Cl)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:2]2([CH3:28])[C@:3]([C:5]3[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=3)([CH3:4])[NH:12][C:13]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][C:17]([C:23]([CH3:25])([CH3:24])[CH3:26])=[N:16][CH:15]=3)=[N:1]2)=[CH:30][CH:31]=1
Reactant: CCOc1cc(C(C)(C)C)ncc1C(=O)N[C@@](C)(c1ccc(Cl)cc1)[C@](C)(N)c1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Temperature: 25 °C

Procedure:
rac-N-[(1S*,2R*)-2-Amino-1,2-bis-(4-chloro-phenyl)-1-methyl-propyl]-6-tert-butyl-4-ethoxy-nicotinamide (200 mg, 0.4 mmol) was dissolved in toluene (8 mL) and phosphorus oxychloride (0.2 mL, 0.83 mmol) was added. The reaction mixture was refluxed under nitrogen overnight. It was allowed to cool to room temperature and poured into ice water, basified with saturated solution of sodium sulfate (10 mL). Reaction mixture was extracted with ethyl acetate (2×20 ml) and methylene chloride (2×10 mL). The combined organic layers were washed with brine and water, dried with magnesium sulfate, filtered and evaporated. Purification was by chromatography (silica gel, eluting with 0-30% ethyl acetate/methylene chloride, then 5% methanol/methylene chloride) to give rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyridine as a solid. (20 mg). LR-MS: 496 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.[N+]([O-])(O)=O.[C:27]1([NH:33][C:34]([NH2:36])=[NH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:35]=3)=[C:4]2[CH:3]=1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Reactant: N=C(N)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 150 °C
Yield: 35.8 %

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was added N-phenylguanidine nitrate (1.0 g, 5.0 mmol) and anhydrous potassium carbonate (0.7 g, 5.0 mmol). The resulting mixture was heated at 150° C. for 12 hours and concentrated in vacuo to a syrup. Ethyl acetate and water were added and the phases separated. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was crystallized from acetonitrile to give 500 mg (36%) of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-phenyl-2-pyrimidinamine as a yellow solid. 1H-NMR (CDCl3): δ 8.48 (d, 1H), 8.45 (d, 1H), 8.23 (d,1H), 7.64 (m, 4H), 7.42 (t, 2H), 7.1–7.25 (m, 4H), 6.93 (dd, 1H), 6.52 (d, 1H); 19F-NMR (CDCl3): δ−112.29; MS m/z 416 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH3:13].C(O)(=O)C.[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C@H:7]([NH:23][CH2:22][CH:19]1[CH2:21][CH2:20]1)[C@@H:8]2[CH3:13]
Reactant: COc1cccc2c1CCC(=O)C2C
Reactant: NCC1CC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc2c1CC[C@H](NCC1CC1)[C@@H]2C
Temperature: 80 °C

Procedure:
To a solution of 5-methoxy-1-methyl-2-tetralone (2.0 g) in absolute ethanol (50 ml) are added acetic acid (1.9 g), cyclopropylmethylamine (2.0 g) and 4 Å molecular sieves. The mixture is heated in a closed flask at 80° C. for one hour. The molecular sieves are filtered off and the solution is hydrogenated (PtO2) at atmospheric pressure. The catalyst is filtered off (Celite) and the volatiles are evaporated. Dilute hydrochloric acid (50 ml) is added to the solid residue. The resulting acidic solution is washed with ether, made basic 5% sodium hydroxide and extracted twice with ether. The ether extracts are combined, dried (sodium sulfate) and evaporated. The resulting crude base is eluted through an alumina column with ether-light petroleum (1:4).
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)CC1)C1C=CC=CC=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([NH:14][C:15](=[O:32])[CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][N:23]=[C:24]([N:27]4[CH:31]=[N:30][CH:29]=[N:28]4)[CH:25]=3)[NH:20][CH:19]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(CCc1c[nH]c2cnc(-n3cncn3)cc12)NN1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)CCc2c[nH]c3cnc(-n4cncn4)cc23)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl) propionic acid (0.34 g, 1.3 mmol) (prepared as described in Example 53 Step 7) in anhydrous DMF (5 ml) was added 1-tert-butyloxycarbonylpiperazine (0.5 g, 2.7 mmol), 1-hydroxybenzotriazole (225 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45 g, 2.3 mmol) and triethylamine (0.23 ml, 1.7 mmol). The mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue partitioned between ethyl acetate (25 ml) and water (20 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The combined organic layers were dried (Na2 SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (90:10) to afford the title compound, with some impurities, as a pale yellow foam.
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:12]([O-])=O)=[C:5]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[NH2:6].N1C=CC=CC=1.[C:21](Cl)(=O)[CH:22]([CH3:24])[CH3:23].C(O)C>Cl.[Pd]>[OH:2][C:3]1[C:4]2[NH:12][C:21]([CH:22]([CH3:24])[CH3:23])=[N:6][C:5]=2[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: COc1cc(N)c([N+](=O)[O-])c(OC)c1
Reactant: CC(C)C(=O)Cl
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)c1nc2cc(O)cc(O)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dimethoxy-2-nitroaniline (55.0 g, 321 mmol) and pyridine (400 mL) was added isobutyryl chloride (41.0 mL, 391 mmol). After stirring for 16 hours, the reaction mixture was concentrated in vacuo. The resulting oil was partitioned between H2O (200 mL) and ethyl acetate (200 mL). The aqueous layer was extracted with more ethyl acetate (2×200 mL). The organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated. The solid was recrystallized from hexane/ethyl acetate at 5° C. to afford yellow crystals. To a slurry of the yellow crystals, 4N HCl (200 mL) and ethanol (250 mL) was added 10% Pd/C (1.30 g). The slurry was placed under 50 psi of H2 (g) and shaken for 4 hours. The mixture was then filtered and concentration of the filtrate afforded a white solid. The white solid was dissolved in 2N HCl (200 mL) and refluxed for 4 hours. The reaction mixture was concentrated. The resulting solid was dissolved in 48% HBr (100 mL) and H2O (100 mL) and refluxed for 15 hours. The reaction was then cooled to ambient temperature and concentrated. The solids were dissolved in H2O (200 mL) and neutralized (KHCO3). The aqueous layer was then extracted with n-butanol (3×500 mL). The organic layer was washed with brine (50 mL), treated with activated charcoal and concentrated to afford 4,6-dihydroxy-2-isopropylbenzimidazole, a compound of formula (11).
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH3:12])[CH2:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])=[C:2]=[O:3].[CH2:13]([CH:15]([NH:18][OH:19])[CH2:16][CH3:17])[CH3:14]>ClCCl>[CH3:12][CH:5]([CH2:6][CH2:7][CH2:8][NH:9][C:10]([N:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[OH:19])=[O:11])[CH2:4][NH:1][C:2]([N:18]([OH:19])[CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:3]
Reactant: CCC(CC)NO
Reactant: CC(CCCN=C=O)CN=C=O
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NCCCC(C)CNC(=O)N(O)C(CC)CC
Yield: 34.7 %

Procedure:
1,5-Diisocyanato-2-methylpentane (3.2 ml, 20 mmol) was added dropwise to a solution of N-(1-ethylpropyl)hydroxylamine (4.4 g, 43 mmol) in dichloromethane (200 ml). The reaction was maintained overnight and then concentrated (in vacuo) to a volume of approximately 20 ml. Purification of the sample by flash column chromatography (96:4 dichloromethane.backslash.methanol, Rf 0.26) followed by recrystallization from N,N-dimethylformamide.backslash.water provided 2.6 g of the desired product as a white powder: MP: 124.0-125.0° C.; 1H NMR (300 MHz, DMSO): δ 8.70 (s, 1H), 8.66 (s, 1H), 6.73 (t, J=6.0 Hz, 1H), 6.68 (t, J=7.0 Hz, 1H), 3.81-3.72 (m, 2H), 3.02-2.78 (m, 4H), 1.60-0.98 (m, 13H), 0.83-0.77 (m, 15H); 13C NMR (75 MHz, DMSO): δ 160.95, 160.92, 59.9, 45.4, 39.6, 33.1, 31.2, 27.5, 24.5, 17.5, 11.1; IR (KBr): 3428, 3177, 2969, 2930, 2876, 1639, 1540, 1462, 1378, 1266, 1167, 1142, 1062, 1034, 929, 770 cm-1 ; MS (FAB): m/e 375.2957 (375.2971 calc'd for C18H39N4O4, M+H); Anal. calc'd for C18H38N4O4 : C, 57.73; H, 10.23; N, 14.96. Found: C, 57.90; H, 10.19; N, 14.93.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[CH:2][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Reaction time: 15 h
Yield: 57.3 %

Procedure:
To a 0.35M solution of 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.53 mmol) in THF was added pyridine (Aldrich, 0.21 mL, 2.63 mmol) followed by 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 122 mg, 0.58 mmol). The resulting mixture was stirred for 15 hours. A 1M aqueous solution of HCl (20 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 140 mg (58%) of 94 as a pale yellow solid.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH2:11]>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:10][CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: C=C
Product: CCC(C)(C)c1ccccc1

Procedure:
Particular preference is given to the reaction of toluene with ethene or propene to give propylbenzene or isobutylbenzene, the reaction of cumene with ethene to give tert-amylbenzene and the reaction of xylenes with butadiene to give 5-tolylpentenes, and the reaction of p-xylene with 1-butene or 2-butene to give 1-tolyl-2-methylbutane.
Reaction SMILES: Cl.Cl.[CH2:3]1[CH:7]2[CH2:8][NH:9][CH2:10][CH:6]2[CH2:5][N:4]1[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[S:23][C:24]4[C:25]([N:30]=3)=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][C:15]=2[O:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[O:48]1[CH2:52][CH2:51][CH:50]([C:53](O)=[O:54])[CH2:49]1>CN(C=O)C>[O:48]1[CH2:52][CH2:51][CH:50]([C:53]([N:9]2[CH2:10][CH:6]3[CH:7]([CH2:3][N:4]([CH2:11][C:12]4[C:16]5[CH:17]=[CH:18][C:19]([O:21][C:22]6[S:23][C:24]7[C:25]([N:30]=6)=[N:26][CH:27]=[CH:28][CH:29]=7)=[CH:20][C:15]=5[O:14][CH:13]=4)[CH2:5]3)[CH2:8]2)=[O:54])[CH2:49]1
Reactant: c1cnc2nc(Oc3ccc4c(CN5CC6CNCC6C5)coc4c3)sc2c1
Reactant: O=C(O)C1CCOC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C1CCOC1)N1CC2CN(Cc3coc4cc(Oc5nc6ncccc6s5)ccc34)CC2C1
Yield: 44.5 %

Procedure:
A solution of 2-[3-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-benzofuran-6-yloxy]-thiazolo[4,5-b]pyridine dihydrochloride (50 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbdiimide hydrochloride (21 mg, 0.11 mmol), 1-hydroxybenzotriazole (73 mg, 0.54 mmol), N-methylmorpholine (33 mg, 0.32 mmol), and tetrahydro-furan-3-carboxylic acid (13 mg, 0.11 mmol) in DMF (0.4 mL) was stirred at rt. Upon reaction completion, the mixture was concentrated, re-dissolved in DMF and purified using reverse phase HPLC to provide the title compound (24 mg, 45%). MS (ESI): mass calculated for C26H26N4O4S, 490.17; m/z found, 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=8.0, 1.5, 1H), 7.70 (dd, J=8.5, 2.9, 1H), 7.59 (dd, J=5.6, 3.4, 2H), 7.27-7.18 (m, 2H), 4.08-3.95 (m, 1H), 3.94-3.60 (m, 7H), 3.53-3.42 (m, 1H), 3.40-3.26 (m, 1H), 3.17-3.06 (m, 1H), 2.99-2.77 (m, 2H), 2.71-2.46 (m, 4H), 2.29-2.14 (m, 1H), 2.14-1.99 (m, 1H).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=CC=1)CCC.C[N:33](C=O)C.S(Cl)(Cl)=O>C1COCC1>[CH2:25]([N:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:31][C:19]=2[CH:20]=[C:21]([C:28]([NH2:33])=[O:29])[CH2:22][CH2:23]1)[CH2:26][CH3:27]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (8.0 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of 4-[3-(imidazol-1-yl)propyl]aniline (0.42 g) and triethylamine (2.1 ml) in THF (12.6 ml) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[imidazol-1-yl]propyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 287) (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][NH2:73])[CH:67]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([NH:73][CH2:72][C:68]4[CH:67]=[N:66][CH:71]=[CH:70][CH:69]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.11 g, 0.30 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added 1-hydroxybenzotriazole (HOBt) (0.08 g, 0.60 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.19 g, 0.60 mmol), N,N-diisopropylethylamine (0.23 g, 1.80 mmol) and pyridin-3-ylmethanamine (0.05 g, 0.45 mmol). The resulting mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was diluted in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-8% methanol in dichloromethane to afford the title compound as a colorless solid (0.09 g, 70%): mp 67-70° C. (hexanes/diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.57 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.40-7.34 (m, 3H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.1, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.1, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.5 (d, 1JC-F=244 Hz), 161.8, 157.2, 154.9, 151.2, 148.8, 148.0, 135.1, 135.1, 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 123.5, 117.6, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 40.4, 18.4, 17.1; MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([CH2:11][P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.Cl>O1CCOCC1.O>[CH2:18]([O:17][P:12]([CH2:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:5][C:4]([OH:20])=[O:3])([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)CC(CC(C)C)CP(=O)(OCC)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOP(=O)(CC(CC(=O)O)CC(C)C)OCC
Yield: 61.8 %

Procedure:
Lactam 6 (0.64 g, 3.87 mmol) was dissolved in 1,4-dioxane (4 mL) and hydrochloric acid (16 mL of a 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (2×15 mL). The aqueous layer was evaporated under reduced pressure to give acid 7 (0.67 g, 79%) as a white solid. Recrystallization using ethyl acetate/methanol gave Example 41 exclusively (0.26 g);δH (400 MHz; d6-DMSO) 7.98 (2H, br s, NH2), 3.13 (2H, s, CH2NH2), 2.70 (2H, s), 2.17–2.14 (4H, m), 1.85 (2H, dd, J 13.3, 8.0), 1.63 (2H, m), 1.55 (2H, dd, J 12.9, 5.1); m/z (ES+) 184 (M+H, 100%); LCMS (Prodigy C18, 50 mm×4.6 mmid column, 5–50% Acetonitrile/water) Retention Time=2.40 minutes, 98% purity.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([OH:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:12][S:13]([O:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCc2cccnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CCCc2cccnc21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.0 g (13 mmol) of 5,6,7,8-tetrahydroquinolin-8-ol and 3.3 g (27 mmol) of 4-(dimethylamino)pyridine in 30 mL of dichloromethane was added 1.3 mL (16 mmol) of methanesulfonyl chloride under an atmosphere of nitrogen. The reaction mixture was stirred for 8 h and then diluted with 30 mL water. The aqueous phase was then extracted with dichloromethane (3×30 mL) and the combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a light orange gum that was used without further purification. LC/MS: m/z (ES) 172.0 (MH)+.