Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:25]C(=O)C)[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:29])[CH2:12][C:11]1=[O:30].[OH-].[Na+].Cl>CO>[OH:25][C@@H:17]([C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])/[CH:16]=[CH:15]/[C@@H:14]1[C@@H:10]([CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])[C:11](=[O:30])[CH2:12][C@H:13]1[CH3:29]
Reactant: CCCCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 20 h

Procedure:
A solution of optically active (5Z,11alpha,13E,15R)-15-acetyloxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid methyl ester (3.2 g) in methanol (32 mL) was treated with 4N NaOH (6.4 mL) and stirred under argon for 20 hours. The solution was acidified with 2N HCl and the product recovered by ethyl acetate extraction. There was thus obtained 3.0 g (~100%) of crude optically active (5Z,11alpha,13E,15R)-15-hydroxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].NN>C(O)C>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: CCO
Product: NCCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A suspension of 62.6 g of 2-[4-(4-nitrophenoxy)butyl]-1H-isoindole-1,3(2H)-dione (Example 33) in one liter of ethanol is treated with 6.5 ml of hydrazine, and the mixture then stirred at reflux for 18 hours. After cooling to room temperature, the precipitate is collected, washed with 250 ml of hot 2.5N HCl, and 200 ml of hot H2O. The combined acid and water washes are taken to dryness to obtain the hydrochloride salt of the title compound. Mass spectrometry shows the presence of the title compound. The compound is utilized directly without further purification.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][O:5][CH2:6][C:7]1[S:8][C:9]([C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:31][Si](C(C)(C)C)(C)C)[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:39])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:10][C:11]=1[CH3:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH2:14]([C:13]([C:9]1[S:8][C:7]([CH2:6][O:5][CH2:4][C:3]([OH:40])=[O:2])=[C:11]([CH3:12])[CH:10]=1)([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[C:20]([CH3:39])[CH:19]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(COCC(=O)OC)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(COCC(=O)O)s1
Yield: 49.1 %

Procedure:
A solution of 2-[5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophen-2-ylmethoxy]-acetic acid methyl ester (0.33 g, 0.57 mmol), 1.0 M TBAF/THF (0.62 m L, 0.62 mmol) and THF (4 mL) is refluxed for 3 h. The mixture filtered through silica gel, washed with EtOAc and concentrated. The resulting residue is hydrolyzed using a procedure analogous to Example 47 to give the title compound (0.13 g, 0.28 mmol) in an overall yield of 49%. 1H NMR (CDC3), δ 0.71 (t, J=7.4 Hz, 6H), 1.02 (s, 9H), 2.01-2.10 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 2.21 (bs, 2H), 3.72 (dd, J=8.8, 2.9 Hz, 1H), 3.87 (t, J=8.8 Hz, 1H), 4.08-4.12 (m, 2H), 4.16 (s, 1H), 4.66 (s, 1H), 5.24 (s, 1H), 6.54 (d, J=3.4 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 7.01-7.08 (m, 2H). LC/MS (m/z): calcd for C26H37O5S (M−H)−: 461.7; found: 461.2.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[C:6](=O)[CH:5]=1)C.[Mg].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:28]([CH3:36])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:29])[CH:24]=[CH:25][C:26]=1Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([C:28]([CH3:36])([CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=[CH:25][C:26]=1[C:6]1[CH:7]([CH3:10])[CH2:8][CH2:9][C:4](=[O:3])[CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: CCOC1=CC(=O)C(C)CC1
Agent: [Mg]
Product: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2C)c(OCc2ccccc2)c1

Procedure:
Similarly, 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-methylcyclohex-2-enone was prepared as an oil (4.12 g., 77%) using 3-ethoxy-6-methyl-2-cyclohexen-1-one (1.98 g., 12.9 mmoles), magnesium (0.61 g., 25.7 mmoles) and 12.9 mmoles (5.0 g.) of 2-(3-benzyloxy-4-bromophenyl)-2-methyloctane.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:16]=[C:6]2[C:5]1=[O:22]>O.C(O)C>[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:6]2[C:5]1=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)n(C)c3ccccc3n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c2cc(C(=O)O)cn2c2ccccc21
Yield: 94.1 %

Procedure:
A solution of 0.9 g of sodium hydroxide in 50 ml of water was added to a suspension of 1.66 g of ethyl 5-methyl-4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline-2-carboxylate in 30 ml of hot ethanol and the mixture was warmed on a water bath for one hour after which thin layer chromatography showed no ester present. The resulting solution was filtered hot and the filtrate was acidified to a pH of 1-2 with concentrated hydrochloric acid. The mixture was cooled and filtered and the recovered product was rinsed with water and dried over P2O5 under vacuum to obtain 1.40 g (95% yield) of 5-methyl-4,5-dihydro-4-oxo-pyrrolo[1,2-a]quinoxaline-2-carboxylic acid melting at 330°-333° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.Cl.[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[C:27](O)=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:13]([CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[C:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)=[O:28])[CH2:24][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C(=O)O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: Cl
Solvent: CCOCC
Product: CC(C(=O)Nc1ccc2c(c1)CC(=O)N2)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-amino-1,3-dihydro-indol-2-one and 2-(4-benzyl-piperidin-1-yl)-propionic acid hydrochloride (Example 161b) according to the method described in Example 161c. Melting Point: 153-155° C. (diethylether).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:16]1(C)C=CC=C[CH:17]=1>>[Br:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1Br
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Cl)cc1Br
Temperature: 90 °C
Yield: 100 %

Procedure:
A mixture of 2-bromo-4-chlorobenzoic acid (235 mg, 1 mmol) and thionyl chloride (238 mg, 146 ul, 2 mmol) in toluene (5 ml) was heated at 90° C. for 1 hour. The reaction mixture was cooled and the solvent evaporated. The residue was dissolved in THF (1 ml) and treated with ethanol (1 ml). The solution was evaporated to dryness leaving the title compound as a yellow oil 263 mg 100%
Reaction SMILES: COC1C=C(C=CC=1OC)C[C@@H](C)N.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.[N+:27]([CH2:30][CH3:31])([O-:29])=[O:28]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:30]([N+:27]([O-:29])=[O:28])[CH3:31])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC[N+](=O)[O-]
Agent: COc1ccc(C[C@@H](C)N)cc1OC
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC

Procedure:
According to the present invention, (R)-3,4-dimethoxyamphetamine (3) is prepared according to the synthesis depicted in following Scheme I whereby the starting material 3,4-dimethoxy-benzaldehyde (veratric aidehyde) (10), which is a cheap raw material available from the market, is condensed with nitroethane (Henry's reaction), to form 3,4-dimethoxy-phenyl-2-nitropropene (11), which is then suitably reduced to an intermediate, i.e., 3,4-dimethoxy-phenyl-acetone (12) by means of a catalytic hydrogenation. The intermediate (12) is then reacted with an optically active amine, (R)-α-methyl-benzyl-amine (13) to form the corresponding chiral imine (14). In a key step of the present synthesis, the chiral amine (14) is diastereo-selectively reduced to the intermediate product, (R,R)-N-phenylethyl-3,4-dimethoxy-amphetamine (15) hydrochloride by catalytic hydrogenation with Raney-Nickel. The intermediate (15) is finally debenzylated by hydrogenation, to form (R)-3,4-dimethoxyamphetamine (3) hydrochloride. ##STR12##
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:13])=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:27]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:13])=[O:12])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[ClH:27]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Yield: 81 %

Procedure:
24.0 g (66.5 mmoles) of Z-Ile-Pro-NH2 are dissolved in 470 ml of methanol, and 30 ml of a 2.4 n hydrochloric acid solution in methanol and 4 g of a 10% palladium-on-carbon catalyst are added to the solution. Hydrogen is bubbled through the mixture for one hour, thereafter the catalyst is filtered off and the filtrate is evaporated. The residue is triturated with ether, and the resulting 20 g of crude product is recrystallized from a mixture of methanol and ether. 16.05 g (81%) of H-Ile-Pro-NH2.HCl are obtained; m.p.: 135°-140° C., Rf4 =0.15.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][N:3]=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(CC)CC.O>C(Cl)Cl>[S:1]1[C:5]([CH2:6][CH2:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cncs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCc1cncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
At 0° C., to a solution of 2-thiazol-5-yl-ethanol (0.154 g, 1.19 mmol) in CH2Cl2 (10 mL) was added MsCl (0.150 g, 1.31 mmol) and Et3N (0.180 g, 1.79 mmol). The mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×30 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (EtOAc), affording methanesulfonic acid 2-thiazol-5-yl-ethyl ester as a pale yellow liquid (0.246 g, 100%). 1H NMR (CDCl3) δ 2.99 (s, 3H), 3.33 (t, 2H, J=6.3 Hz), 4.42 (t, 2H, J=6.3 Hz), 7.73 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[CH:21]1([C:24]#[C:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([C:26]([OH:31])([C:25]#[C:24][CH:21]2[CH2:22][CH2:23]2)[C:27]([F:28])([F:29])[F:30])=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: O=C(C#CC1CC1)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (−50° C.) solution of 643 mg(2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.9 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at −50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO3, then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg(56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH3—CI): 391((M+H)+, 100%); 291((M+H-t-Boc)+, 49%). 1H NMR(300 MHz, CDCl3) δ 9.08(br. s, 1H); 8.29(br. s, 1H); 7.59(s, 1H); 1.50(s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([CH2:16][N+:17]([O-:19])=[O:18])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>C(O)C>[N+:17]([CH2:16][S:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2)(=[O:14])=[O:15])([O-:19])=[O:18]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])CS(=O)(=O)c1ccc2c(c1)CCN2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1-Acetyl-5-(nitromethylsulphonyl)indoline (5.41 g, 19 mM) was added in one portion to a boiling mixture of 2M hydrochloric acid (60 ml) and ethanol (20 ml). The mixture was heated at reflux until a clear solution formed, and then for a further 5 minutes. The hot reaction mixture was poured into ice-cold saturated sodium hydrogen carbonate solution (100 ml) and then extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent was removed by evaporation. The resultant yellow oil was purified by vacuum flash chromatography on silica, eluting with dichloromethane, to give 5-(nitromethylsulphonyl)indoline as a pale yellow solid, m.p. 139° C.; NMR(d6 -DMSO): 3.0(2H,t), 3.6(2H,t), 6.3(2H,s), 6.5(2H,s), 6.9(1H,s), 7.4-7.5(2H,m); microanalysis, found: C,44.5; H,4.1; N,11.4%; C9H10N2O4S requires: C,44.6; H,4.1; N,11.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:12][CH2:13]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(F)c4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(3-fluoro-4-(piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg. 0.192 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.23 mmol), DIPEA (50 mg, 0.384 mmol) and ethanol (5 mL) to get 100 mg (76.9% yield) of the titled compound. MS: m/z=683.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)(=[O:10])[CH3:9].Br[CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])[C:31]([CH:33]1[CH2:35][CH2:34]1)=[O:32].[ClH:43]>C(N(CC)CC)C>[ClH:43].[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:31]([CH:33]2[CH2:34][CH2:35]2)=[O:32])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[N:21][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:23]=1)(=[O:10])[CH3:9]
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Reactant: COC(=O)Cn1cc(/C=C2\CNCCC2SC(C)=O)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)nn1
Yield: 56 %

Procedure:
Following a procedure similar to that described in Example 150-(g), (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (550 mg) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone and triethylamine, and the free base that was obtained by chromatographic purification on silica gel was treated with hydrogen chloride to yield the title compound (380 mg, yield: 56%) as a pale yellow amorphous solid.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][O:11][Na]>CO>[CH3:10][O:11][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CO[Na]
Solvent: CO
Product: COc1ncccc1C#N

Procedure:
2-Methoxy-nicotinonitrile was prepared according to the literature by reaction of the 2-chloro-nicotinonitrile with MeONa in MeOH according to Dunn, A. D.; Norrie, R.; Heterocycl. Chem.; EN; 24; 1987; 85-89.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.Cl.[OH:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:35])[C:25]=2[N:24]=[C:23]1[CH2:36][CH2:37][CH3:38].[OH-].[Na+].C(=O)(O)[O-].[Na+].O>ClCCl>[NH2:35][C:26]1[C:25]2[N:24]=[C:23]([CH2:36][CH2:37][CH3:38])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:17]([OH:16])[C:5](=[O:7])[CH3:6])[C:34]=2[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(O)C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (0.490 mL, 5.14 mmol) and triethylamine (2.86 mL, 20.6 mmol) were added to a solution of 1-[4-(hydroxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (1.80 g, 5.14 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours, then 10% aqueous sodium hydroxide was added. The mixture was stirred for 1 hour, then was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient elution with 10-20% methanol in dichloromethane). The appropriate fractions were combined and concentrated under reduced pressure to afford a solid that was slurried in 1:1 saturated aqueous sodium bicarbonate/water, filtered, washed with water, and dried to yield N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-hydroxyacetamide as brown needles, mp 191-193° C.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate (Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24.0 mg (43%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[O:24])[C:5]1=[O:35].[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[O:24])[C:5](=[O:35])[N:4]3[CH2:3][CH2:2][NH:1][C:42]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:43])=[N:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 4-morpholinecarbonyl chloride employing methods similar to those described in Example 450 and was obtained as an orange solid: ES+ MS: 595 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH3:26][C:23]1[C:22]([CH2:27][N:32]2[CH:31]=[C:30]([CH3:29])[CH:34]=[N:33]2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:14][CH:13]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: Cc1cn[nH]c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1cnn(Cc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-methyl-1H-pyrazole.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([CH:29]3[CH2:31][CH2:30]3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C2CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-cyclopropyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.1093 g, 0.0002593 mol) was dissolved in ethanol (2.00 mL, 0.0342 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (1.00 mL, 0.00420 mol) was added and the reaction was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The solvent was removed under reduced pressure. Methylene chloride and water were added and the layers were separated. The combined organic layer was concentrated to dryness and purified by HPLC to give 41.0 mg of the title compound (40% yield). MS; m/z=379.33 [M−16]+. 1H NMR (MeOD) δ: 8.52 (d, J=9.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.57 (dd, J=9.2, 2.1 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 4.26-4.36 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.18-2.27 (m, 2H), 1.85-1.95 (m, 3H), 1.80 (s, 3H), 1.43-1.57 (m, 2H), 1.08-1.28 (m, 5H), 0.92 (s, 9H), 0.68-0.75 (m, 2H)