Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][NH:25][C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>O1CCCC1>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:18]2[CH:27]=[CH:26][NH:25][C:19]=2[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Reactant: CN(C)CCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
A mixture of Example 36e (0.15 g, 0.326 mmol), 2-(dimethylamino)ethanol (0.029 g, 0.326 mmol), and triphenylphosphine (0.128 g, 0.490 mmol) in tetrahydrofuran (3 mL) was stirred at ambient temperature for 10 minutes. To this solution was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (0.113 g, 0.490 mmol). The solution was stirred for three hours at ambient temperature. The solvent was removed, and the residue was purified by preparative HPLC (10-80% acetonitrile in 0.1% TFA water) to give the title compound (0.055 g, 0.104 mmol, 31.8% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.06 (s, 1H), 7.51 (d, J=2.44 Hz, 1H), 7.41-7.47 (m, 1H), 7.35-7.37 (m, 2H), 7.23-7.31 (m, 2H), 7.06-7.11 (m, 1H), 6.85 (d, J=8.85 Hz, 1H), 3.57 (t, J=6.71 Hz, 2H), 3.56 (s, 3H), 3.17 (q, J=7.32 Hz, 1H), 2.25 (m, 2H), 2.13 (s, 6H), 1.25 (q, J=7.48 Hz, 3H). MS (ESI+) m/z 531.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)=[O:17].CN(C1C=CC=CN=1)C>CC#N>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:16]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[O:17])[CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: O=C1CN(C(=O)n2ccnc2)CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-fluorobenzyl)piperazin-2-one (2.17 grams, 10.4 mmol) in 50 ml MeCN was added 1,1′-carbonyldiimidazole (2.03 g, 12.5 mmol) and dimethylaminopyridine (64 mg, 0.52 mmol). The solution was stirred at room temperature for 1 hour, concentrated under vacuum, and then dissolved in a mixture of CH2Cl2/CHCl3. The organic solution was washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and filtered to provide the title product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.27 (t, J=6.9 Hz, 2H), 7.21 (t, J=1.4 Hz, 1H), 7.13 (s, 1H), 7.05 (t, J=8.6 Hz, 2H), 4.60 (s, 2H), 4.34 (s, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.40 (t, J=5.4 Hz, 2H); ES MS (M+1)=303.
Reaction SMILES: N[C@@H]1C2C=C(C#N)C=CC=2OC(C)(C)C1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[CH2:24][C@@H:23]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:22]=2[CH:43]=1)#[N:17].CO>O>[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[CH2:24][C@H:23]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[C:30]3[C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:22]=2[CH:43]=1)#[N:17]
Reactant: CCOC(=O)c1nc2ccccc2n1[C@@H]1CC(C)(C)Oc2ccc(C#N)cc21
Agent: CC1(C)C[C@H](N)c2cc(C#N)ccc2O1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1nc2ccccc2n1[C@H]1CC(C)(C)Oc2ccc(C#N)cc21

Procedure:
The title compound was prepared from (S)-4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (compound of title F, Example 4) by the same procedure as described for (R)-1-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzopyran-4-yl)-1H-benzimidazole-2-carboxylic acid, ethyl ester in example 4, parts G-J. [a]D =-111° (c=0.5, MeOH). Microanalysis calculated for C20H16N3ClO2.0.3 H2O: C, 64.71; H, 4.51; N, 11.32, Cl, 9.55. Found: C, 65.08; H, 4.72; N, 10.76, Cl, 9.26. Further elution of the column also provided (R)-4-[3-Chloro-2-oxo-1(2H)-quinoxalinyl]-3,4-dihydro-2,2-dimethyl-2H-benzopyran-6-carbonitrile, m.p. 174°-175° C. [a]D =+92.1° (c=0.42, MeOH). Microanalysis calculated for C22H21N3O2.0.7 H2O: C, 68.10; H, 5.82; N, 10.83. Found: C, 68.07; H,5.55; N, 10.65.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([Cl:31])=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@@H:6]([CH3:35])[CH2:5]1)[CH:2]=[CH2:3].[CH2:36]([NH:43][CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N)(=O)C1C=CC=CC=1.C.Cl>C(O)C>[ClH:31].[CH2:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29]([N:43]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:44])=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@@H:6]([CH3:35])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CNCc1ccccc1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Agent: C
Agent: Cl
Agent: NC(=O)c1ccccc1
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)Cc3ccccc3)c2)CC1C

Procedure:
This compound was prepared from 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride and N-benzyl-N-methylamine by the Benzamide Formation Method described in Example 9. NMR (300 MHz, DMSO-d6, 121° C.): δ 0.93 (d, J=6.2 Hz, 3H); 1.06 (d, J=6.2 Hz, 3H); 1.96 (dd, J1 =6.7 Hz, J2 =11.0 Hz, 1H); 2.12 (dd, J1 =7.0 Hz, J2 =11.0 Hz, 1H); 2.58 (dd, J1 =2.9 Hz, J2 =11.4 Hz, 1H); 2.67-2.84 (m, 3H); 2.86 (s, 3H); 2.89 (dd, J1 =6.6 Hz, J2 =13.5 Hz, 1H); 3.18 (dd, J1 4.0 Hz, J2 =14.1 Hz, 1H); 4.58 (s, 2H); 4.98 (s, 1H); 5.08 (d, J=10.2 Hz, 1H); 5.16 (d, J=17.3 Hz, 1H); 5.74-5.89 (m, 1H); 6.62-6.74 (m, 3H); 7.10 (t, J=7.8 Hz, 1H); 7.21-7.50 (m, 9H); 8.76 (s, 1H). Mass spectrum (CI--CH4) m/e: 484 (M+1,88%), 330 (33%), 153 (100%). [α]D20 =+14.3° (ethanol, c=1.25). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.4 followed by precipitation with diethyl ether from dichloromethane to give (+)-3-((αR)-α-((2S,SR)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-benzyl-N-methylbenzamide monohydrochloride as a hygroscopic light yellow powder. Calc. for C31H37N3O2HCl 0.75 H2O: C, 69.78; H, 7.46; N, 7.87; Cl, 6.64 Found: C, 69.76; H, 7.48; N, 7.69; Cl, 6.74.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:14]([O:13][C:12]([NH:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:21]=[CH:20]/[C:19]([O:23][CH3:24])=[O:22])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)CCC2NC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
A mixture of 25 g (80.1 mmol) of tert-butyl (5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate, 975 mg (3.20 mmol) of tris(2-methylphenyl)phosphine, 179 mg (797 μmol) of palladium(II) acetate and 8.9 g (103 mmol) of methyl acrylate in 150 ml of triethylamine was stirred at 150° C. for five hours. The precipitate was filtered off, and chromatographic purification afforded 19 g (59.9 mmol) of methyl (2E)-3-[1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]acrylate (75%).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1)=[O:5].[CH3:12][C@@H:13]1C[C@H:14]1C(=O)CC=C>>[O:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[C:4](=[O:5])[CH2:14][CH:13]=[CH2:12]
Reactant: C=CCC(=O)[C@@H]1C[C@H]1C
Reactant: CON(C)C(=O)[C@@H]1CCCO1
Product: C=CCC(=O)[C@@H]1CCCO1

Procedure:
(2S)—N-Methoxy-N-methyltetrahydrofuran-2-carboxamide (C92) was converted to the product using the method described for the synthesis of 1-[(1R,2R)-2-methylcyclopropyl]but-3-en-1-one (C80) in Example 20. The resulting product was used in the next step without further purification. Yield: 19 g, ≦0.14 mol, ≦87%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:29])[C:23]2[C:18](=[CH:19][C:20]([C:24](=O)[CH3:25])=[CH:21][CH:22]=2)[C:17]([CH3:28])([CH3:27])[CH2:16][CH2:15]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1.CCCCCC>[CH3:13][C:14]1([CH3:29])[C:23]2[C:18](=[CH:19][C:20]([C:24]#[CH:25])=[CH:21][CH:22]=2)[C:17]([CH3:28])([CH3:27])[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.1572 g (11.4359 mmol) of diisopropylamine in 20 ml of dry tetrahydrofuran under argon at -78° C. was added dropwise via syringe, 7.2 ml of 1.6M (11.52 mmol) n-butyllithium in hexane. This mixture was stirred at -78° C. for 1 hour and then treated dropwise with a solution of 2.635 g (11.4391 mmol) of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-6-acetylnaphthalene in 6 ml of dry tetrahydrofuran. After stirring at -78° C. for 1 hour, the mixture was treated with 1.97 g (11.4175 mmol) of diethyl chlorophosphate. The cooling bath was then removed and the mixture stirred at room temperature for 3.5 hours. This mixture was then transferred using a double ended needle to a solution of lithium diisopropylamide [prepared using 2.31 g (22.83 22 mmol) of diisopropylamine and 14.5 ml of 1.6M (23.2 mmol) n-butyllithium in hexane] in 60 ml of dry tetrahydrofuran at -78° C. Stirring was commenced at room temperature and continued for 20 hours. The reaction was then quenched with 50 ml water and acidified with 25 ml of 3N hydrogen chloride. Reaction product was recovered by extracting with 5×50 ml pentane. Organic extracts were combined and washed with 3N hydrogen chloride, water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was then removed and residue purified by flash chromatography (silica, 5% ethylacetate in hexane) followed by kugelrohr distillation (60° C., 0.2 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ1.25 (6H, s), 1.27(6H, S), 1.66 (4H, s), 2.98 (1H, S, 7.24 (2H, s), 7.46 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[CH:3]1[C:14]([OH:16])=[O:15].[C:18]([CH:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[CH:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[CH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:15]
Reactant: CC1(C)C(/C=C\C(=O)OCC(F)F)C1C(=O)O
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C#C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47°±1.5° (c=1% in CHCl3).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:7]1[S:8][C:9]([CH3:12])=[CH:10][N:11]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[Br:20][C:15]1[CH:14]=[C:13]([CH:6]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][N:11]=2)[CH2:5][C:4]([OH:21])=[O:3])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: CCOC(=O)CC(c1cc(Cl)cc(Br)c1)c1ncc(C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(C(CC(=O)O)c2cc(Cl)cc(Br)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
17 g (43.73 mmol) of 3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid ethyl ester are dissolved in 30 ml of a THF/MeOH/H2O=2:1:1 mixture and LiOH (2Eq) is added. After stirring overnight at RT, the solvent is removed in vacuo and the crude material is treated with 30 ml of EtOAc and 30 ml of water with pH=4. The organic phase is separated, dried over Na2SO4 and the solvent removed in vacuo. The crude material is recrystallized from heptane/EtOAc mixtures delivering 9.2 g (Yield=58%) of 3-(3-Bromo-5-chloro-phenyl)-3-(5-methyl-thiazol-2-yl)-propionic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:12])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:12][C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)sc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
4-Methyl-2-thiophenecarboxylic acid ethyl ester (3.4 g) synthesized in accordance with the method of Reference Example 140 was dissolved in acetonitrile (30 ml), and sulfuryl chloride (2.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room-temperature for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g). 5-Chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) was dissolved in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml), and 1N aqueous sodium hydroxide (40 ml) was added. The mixture was stirred at 60° C for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) as crystals.
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][CH:31]([OH:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[S:29][CH2:30][CH:31]([OH:33])[CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CC(O)CS
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(C)O)cc(C(C)(C)C)n1C
Yield: 67.9 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 1-mercaptopropan-2-ol (277 mg, 3 mmol) and potassium carbonate (415 mg, 3 mmol) in DMF (10 mL) was heated at 50° C. for 16 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography afforded 320 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.3 Hz, 3H), 1.15-1.24 (m, 3H), 1.27-1.44 (m, 11H), 1.54-1.79 (m, 2H), 2.68-3.07 (m, 2H), 3.76-3.94 (m, 4H), 4.27-4.45 (m, 2H), 4.94 (d, J=4.8 Hz, 1H), 6.83 (s, 1H), 7.42-7.52 (m, 1H), 7.54-7.66 (m, 1H), 8.24 (d, J=1.6 Hz, 1H). MS (DCI/NH3) m/z 472 (M+H)+. Anal. calculated for C23H32F3N3O2S: C, 58.58 H, 6.84 N, 8.91. Found: C, 58.57 H, 6.96 N, 8.77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH:18]=2)[CH2:21][CH2:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: NCc1ccccc1
Product: COc1cc(-c2cc(CN3CCC(NCc4ccccc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and benzylamine (0.51 g) was condensed in the same manner as described in Preparation Example 37 to give the title compound as yellow amorphous.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](O)=[O:31])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:30](=[O:31])[CH2:29][O:28][C:27]3[CH:33]=[CH:34][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccncc3)sc2n1
Reactant: O=C(O)COc1ccc(Cl)cc1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccncc3)sc2n1
Yield: 43 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-4-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 43%, according to the procedure for the synthesis of example 50.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COC(=O)C=Cc1c(C)cccc1[N+](=O)[O-]
Temperature: 95 °C
Yield: 0.5 %

Procedure:
2-Bromo-3-nitrotoluene (0.5 g, 23 mmol), methyl acrylate (0.39 g, 46 mmol,), palladium acetate (29 mg, 1.3 mmol), triphenylphosphine (0.06 g, 0.23 mmol,) and TEA (0.4 mL) were combined in a sealed tube and heated to 95° C. for 24 h. The residue was dissolved in MeOH, the solvent was removed and the crude product was purified by column chromatography (EtOAc:hexane=7.5:92.5) to give 0.024 g (48% yield) of the title compound as a yellow oil:
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:9]([CH2:16][CH2:17][C@@H:18]([OH:48])[CH2:19][O:20][C:21]2[CH:47]=[CH:46][C:24]3[N:25]=[C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=5)[CH2:30][CH2:29]4)[S:27][C:23]=3[CH:22]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[N:12]=1.[Cl-].[NH4+]>CS(C)=O>[N+:13]([C:11]1[N:12]=[C:8]2[N:9]([CH:10]=1)[CH2:16][CH2:17][C@H:18]([CH2:19][O:20][C:21]1[CH:47]=[CH:46][C:24]3[N:25]=[C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=5)[CH2:30][CH2:29]4)[S:27][C:23]=3[CH:22]=1)[O:48]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cn(CC[C@@H](O)COc2ccc3nc(N4CCN(Cc5ccc(OC(F)(F)F)cc5)CC4)sc3c2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc3nc(N4CCN(Cc5ccc(OC(F)(F)F)cc5)CC4)sc3c1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.6 %

Procedure:
Sodium tert-butoxide (112 mg) was added to a dimethylsulfoxide solution (6 ml) of (R)-4-(2-chloro-4-nitroimidazol-1-yl)-1-{2-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]benzothiazol-6-yloxy}butan-2-ol (662 mg), and the mixture was stirred at room temperature for 3 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and precipitated solid was sequentially washed with water and diisopropyl ether. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1→ethyl acetate) to afford the title compound as a pale yellow powder (60 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][C:16](Br)=[O:17].O>ClCCl>[Br:14][CH2:15][C:16]([NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[O:17]
Reactant: Cc1cc(N)on1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC(=O)CBr)on1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
3-Methyl-isoxazol-5-ylamine (2.9 g) and potassium carbonate (9.8 g) were suspended in dichloromethane (100 mL) at room temperature and 2-bromoacetyl bromide (6 g) was added dropwise. The mixture was allowed to stir overnight. Water (0.3 mL) was added together with a further quantity of potassium carbonate (3 g) and the reaction mixture stirred for a further 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated in vacuo. The crude product was purifed by column chromatography on silica eluting with ethyl acetate/isohexane (50:50) to give sub-titled compound (4.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([N:14](CC2C=CC=CC=2)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C1CCC(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CCC(C(=O)OC(C)(C)C)CC1
Yield: 104.3 %

Procedure:
To a solution of 4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester (300 mg, 0.7433 mmol) in EtOH (10 mL) is added 10% Pd/C (wet) (40 mg). The mixture stirs under a blanket of hydrogen gas at atmospheric pressure for 12 h. The mixture is then filtered though celite. The celite is washed with MeOH (50 mL). The filtrated is concentrated to afford 243 mg of 4-(tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.98 (m, 2 H), 1.25 (m, 2 H), 1.36 (m, 9 H), 1.41 (m, 9 H), 1.81 (m, 4 H), 2.05 (m, 1 H), 2.28 (m, 1 H), 3.20 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:5].[CH:23](NC(C)C)(C)C.[Li].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:23])([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propionic acid methyl ester (1.23 g, 3.9 mmoles) from Example 14A in dry THF (3 mL) was added dropwise to a −65° C. solution of 1.8 N lithium diisopropylamine (LDA) in dry THF (2.4 mL) and stirred at this temperature for 1 hour. Methyl iodide (0.49 mL, 7.88 mmoles) was added and the mixture was allowed to slowly warm to room temperature and stir for 2 hours at room temperature. The mixture was quenched with ice/water and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts washed with water, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified (silica gel, 10-30% acetone in hexane) to provide the title compound as a yellowish solid.