Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH:4]([OH:28])[C@@H:5]([NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH3:7])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:5]([CH2:6][CH3:7])[CH:4]([OH:28])[CH:2]([CH3:3])[CH3:1]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(O)C(C)C
Reaction time: 1 h

Procedure:
To a stirred solution of (3RS,4S)-2-methyl-4-(trityl-amino)-hexan-3-ol (0.36 g, 1 eq, 0.97 mmol) in DCM (20 mL) under an argon atmosphere at room temperature, was added trifluoroacetic acid (5 mL) dropwise, and the solution was stirred at this temperature for 1 h. The solvent was evaporated in vacuo, the residue was precipitated from ether (10 mL) with hexane (90 mL) with string to give a yellow oil. The solvent was decanted from the oil, and the oil was washed with hexane (20 mL) and dried in vacuo to afford the title compound as a light yellow oil; Yield: 0.13 g (100%). (50% de 3R,4S: 50% de 3S,4S), 1H-NMR (d6-DMSO, 250 MHz): δ 0.85-1.01 (m, 9H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 1.44-1.76 (m, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 2.94 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.17 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 3.40 (m, 1H, NH2CH(CH2CH3)CH(CH(CH3)2)OH), 7.54 (bs, 2H, NH2CH(CH2CH3)CH(CH(CH3)2)OH).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5]C.[CH2:19](C1C=CC2OCC(=O)COC=2C=1)C=C.CC(C)CCC1C=CC2OCC(=O)COC=2C=1>>[CH3:19][CH:4]([CH3:5])[CH2:3][CH2:2][CH2:1][C:7]1[CH:18]=[CH:17][C:10]2[O:11][CH2:12][C:13](=[O:16])[CH2:14][O:15][C:9]=2[CH:8]=1
Reactant: CCCCCCc1ccc2c(c1)OCC(=O)CO2
Reactant: C=CCc1ccc2c(c1)OCC(=O)CO2
Agent: CC(C)CCc1ccc2c(c1)OCC(=O)CO2
Product: CC(C)CCCc1ccc2c(c1)OCC(=O)CO2

Procedure:
Odor: Marine, floral-aldehyde odor. -IR (film): ν=1502/1418/1466/1580 cm−1 (ν C═C, Ar), 1265/1304/1201 cm−1 (ν ring), 1050 cm−1 (ν C—O—C), 1741 cm−1 (ν C═O). -1H-NMR (CDCl3): δ=0.88 (2d, J=6.4 Hz, 6H, 4′-Me2), 1.18-1.24 (m, 2H, 3′-H2), 1.53-1.61 (m, 4H, 2′-H2, 4′-H), 2.50 (t, J=7.8 Hz, 2H, 1′-H2), 4.69 (d, J=8.0 Hz, 4H, 2-,4-H2), 6.78 (dd, J=8.0, 4.0 Hz, 1H, 8-H), 6.82 (d, J=4.0 Hz, 1H, 6-H), 6.90 (d, J=8.0 Hz, 1H, 9-H). -13C-NMR (CDCl3): δ=22.44 (2q, 4′-Me2), 27.74 (d, C-4′), 29.07 (t, C-2′), 35.14 (t, C-1′), 38.39 (t, C-3′), 75.35/75.63 . (2t, C-2,-4), 120.30/120.48 (2d, C-6,-9), 123.50 (d, C-8), 138.86 (s, C-7), 146.03/147.83 (2s, C-5a,-9a), 204.76 (s, C-3). -MS (EI): m/z (%)=77 (13) [C6H5+], 91 (8) [C7H7+], 135 (7) [M+-C5H11—C2H2O], 149 (16) [M+-C5H11—CO], 177 (100) [M+-C5H11], 191 (1) [M+-C4H9], 205 (3) [M+-C3H7], 248 (38) [M+].
Reaction SMILES: [CH:1]([N:4]1[C:28](=[O:29])[C:27]2[N:12]3[CH2:13][CH2:14][C:15]4[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:20]=4[C:11]3=[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:9]=2[CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O>[C:35]([N:7]1[CH2:8][C:9]2[C:10]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)=[C:11]3[C:20]4[CH:19]=[C:18]([O:21][CH:22]([CH3:23])[CH3:24])[C:17]([O:25][CH3:26])=[CH:16][C:15]=4[CH2:14][CH2:13][N:12]3[C:27]=2[C:28](=[O:29])[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCNC3
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)C)CCN(C(C)=O)C3
Reaction time: 0.5 h

Procedure:
A solution of 35 mg of 14e in 250 μl of pyridine was treated with 30 μl of acetic anhydride and a catalytic amount of DMAP. After stirring ½ hr the reaction mixture was diluted with 400 μl of water and stirred for an additional 1 h. The precipitate was filtered, washed with water and dried to give 31 mg of crystalline white 14f;
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13]CC)=O)[C:6](OCC)=[O:7])[CH:3]=[CH2:4].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C>[CH2:2]([C:5]1[C:11]([OH:13])=[N:21][CH:20]=[N:22][C:6]=1[OH:7])[CH:3]=[CH2:4]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCc1c(O)ncnc1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
Sodium metal (4.5 g) was added slowly into ethanol (100 mL) in a 500 mL round bottom flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature until all the sodium metal dissolved, before being cooled to 0° C. Diethyl 2-allylmalonate (12 g) was added into the reaction mixture, followed by formamidine acetate (6.24 g) under nitrogen atmosphere at 0° C. The reaction was stirred at room temperature for 24 hours under nitrogen atmosphere, before being quenched by acetic acid (20 mL), followed by water (100 mL). The white precipitate was filtered, washed with water (4×50 mL), methanol (2×50 mL) and dried under vacuum to afford 5-allylpyrimidine-4,6-diol (4 g) as white solid. 1H NMR (DMSO-d6): δ 2.96 (d, 2H), 4.85 (dd, 1H), 4.91 (dd, 1H), 5.76 (dd, 1H), 7.89 (s, 1H), 11.64 (bs, 2H).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][CH:24]([F:48])[O:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[NH2:49][CH2:50][C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1>>[F:48][CH:24]([F:23])[O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:37][C:38]([C:42]([NH:49][CH2:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 65 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-(difluoromethoxy)benzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 65% yield: mp 166-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.55-8.40 (m, 3H), 7.67 (d, J=7.8 Hz, 1H), 7.43-6.94 (m, 6H), 4.45-4.35 (m, 4H), 3.97 (t, J=8.1 Hz, 2H), 3.39 (t, J=8.1 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.8, 155.5, 151.7, 150.7, 149.3, 148.4, 135.6, 133.8, 130.0, 123.9, 120.1, 119.4, 117.9, 115.0, 46.6, 42.4, 42.0, 40.8, 17.5; MS (ES+) m/z 474.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].Br[C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1O.C(=O)([O-])[O-:26].[K+].[K+]>CO.O>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C@@H:16]3[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:23][C@H:15]3[OH:26])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O

Procedure:
A mixture of 4.4 g (25 mmol) 3-formyl-8-hydroxy-2-methyl-imidazo[1,2-a]pyridine, 10.7 g (50 mmol) (trans)-2-bromo-1-indanol and 13.8 g of potassium carbonate is stirred in 120 ml of methanol/water (4:1) for 16 hours at 40° C. The mixture is worked up analogously to Example 21 and the yield of the title compound m.p. 200°-202° C. (from methanol) is 4.8 g (62%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:14][C:15]([Si](C)(C)C)([F:17])[F:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:13])[C:15]([F:17])([F:16])[F:14])=[CH:10][N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc(N2CCCC2)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(N2CCCC2)nc1)C(F)(F)F
Yield: 93.9 %

Procedure:
According to Reference Example 8-12, by use of 6-(pyrrolidin-1-yl)-3-pyridinecarboxaldehyde (173 mg, 0.982 mmol), (trifluoromethyl)trimethylsilane (174 μL, 1.18 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 98.0 μL, 0.098 mmol) and tetrahydrofuran (5.0 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Then, slurry purification was performed using hexane, to give 2-(pyrrolidin-1-yl)-5-(2,2,2-trifluoro-1-hydroxyethyl)-pyridine (Compound DH) (227 mg, yield: 94%).
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])=[O:21])[CH:16]=[N:15]2)[N:12]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:20](=[O:21])[NH:19][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:11]2[N:12]=[C:8]([CH2:6][OH:5])[S:9][CH:10]=2)[CH:18]=1
Reactant: CCOC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Nc1cnn(Cc2csc(CO)n2)c1)OCc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-[4-(2-chloro-benzyloxycarbonylamino)-pyrazol-1-ylmethyl]-thiazole-2-carboxylic acid ethyl ester (912 mg, 2.17 mmol) in THF (20.0 mL) at −78° C. was treated with DiBAL (8.70 mL of a 1M solution in toluene, 8.70 mmol). The reaction mixture was stirred at −78° C. for 1 h, then allowed to reach rt before being quenched with Rochelle's salt (100 mL). The resulting mixture was stirred for 2 h at rt, extracted with EA (2×50 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as a yellow foam. TLC: rf (19:1 CH2Cl2-MeOH)=0.11. LC-MS-conditions 02: tR=0.83 min; [M+H]+=379.04.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([N:7]([CH2:10][CH3:11])CC)C.Cl[C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:23])[CH3:22])[CH:16]=[CH:17]C=1Cl>>[C:10]([C:11]1[CH:17]=[CH:16][C:15]([CH2:20][C:21](=[O:23])[CH2:22][O:3][C:1](=[O:4])[CH3:2])=[CH:14][CH:13]=1)#[N:7]
Reactant: CCN(CC)CC
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Product: CC(=O)OCC(=O)Cc1ccc(C#N)cc1
Yield: 25 %

Procedure:
This crude material was reacted with acetic acid (1.42 mL, 1.49 g, 24.8 mmol) and triethylamine (3.46 mL, 2.51 g, 24.8 mmol), as described above for the synthesis of 3-(3,4-dichlorophenyl)propan-2-one. Flash chromatography over silica gel (10-30% ethyl acetate in hexanes) gave pure product (0.71 g, 25% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.09 (s, 3H) 3.96 (s, 2H) 4.88 (s, 2H) 7.40 (d, J=8.34 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H).
Reaction SMILES: N1C=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[N:18]1C=CC(B(O)O)=C[CH:19]=1>>[N:18]1[CH:19]=[CH:2][C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: OB(O)c1ccncc1
Product: O=Cc1ccc2c(-c3ccncc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting pyridin-4-ylboronic acid (27 mg, 0.22 mmol), the title compound was obtained as a beige solid (3.7 mg, 9%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1H), 8.69 (d, J=6.3 Hz, 2H), 8.32 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J=6.3 Hz, 2H), 7.84 (d, J=6.3 Hz, 1H); MS ESI 224.0 (100) [M+H]+, calcd for [C13H9N3O+H]+ 224.07.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:34][C:33]([CH3:40])([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:32]2)[N:3]=1.CC(O)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:32][C:33]([CH3:40])([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[CH2:34]2)[N:3]=1
Reactant: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C1
Solvent: O
Solvent: CC(=O)O
Product: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (145 mg) in 4:1 AcOH:water (20 mL) was stirred at room temperature overnight. LCMS indicated ˜45% completion of the deprotection. Another portion of the mixed solvents (4:1 AcOH:water, 20 mL) was added, and stirring continued overnight. The solvents were then removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (45 mg, 36%). LCMS: (M+H)+: 498.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)(=[O:22])=[O:21])=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[C:4](Cl)[N:3]=1.CS(C)=O.C[O-].[Na+].[C:40](O)(=[O:42])C>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)(=[O:22])=[O:21])=[N:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[C:4]([O:42][CH3:40])[N:3]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(Cl)nc(Cl)c2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(Cl)n1
Temperature: 100 °C

Procedure:
To a crude product of N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide (1.24 g) prepared using procedures similar to those for Example 151, was added anhydrous DMSO (10 mL), followed by sodium methoxide (273 mg). The resulting mixture was heated at 100° C. for 3 days. The mixture was diluted with EtOAc and water, and the pH was adjusted to about 4 by adding acetic acid. The product was extracted with EtOAc (3×). The combined extracts were washed with brine to give the crude product. A portion of the crude product was purified by prep HPLC to give N-(3-{[2-chloro-6-(methyloxy)pyridin-4-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.90 (s, 1H), 8.50 (d, 1H), 8.42 (d, 1H), 7.88-7.84 (m, 2H), 7.77 (s, 1H), 7.74 (s, 1H), 7.64 (d, 1H), 7.45-7.38 (m, 2H), 3.82 (s, 3H); MS (EI) m/z for C20H15ClN6O5S: 496.94 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH:34]1[CH2:38][NH:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH:34]5[CH2:35][CH:36]([CH2:39][OH:40])[NH:37][CH2:38]5)[CH3:32])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CNC(CO)C1
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)C1CNC(CO)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-hydroxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and (4-Methylamino-pyrrolidin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[N:14]1([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=3[CH2:21]2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:17]3[CH2:16][CH2:15][N:14]([CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=5[CH2:21]4)[CH2:19][CH2:18]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1)C2
Reactant: O=CCc1ccc2c(c1)COC2=O
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)COC4=O)CC1)C2

Procedure:
The above product was prepared following similar procedure of EXAMPLE 38 from (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde and 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 402 [M+1]+. (0.050 μM)
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([NH:13][CH3:14])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([N:13]([CH3:14])[C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: CNc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Reaction time: 2.5 h

Procedure:
3,3-Dimethylacryloyl chloride (3 mL, 27 mmol) was added to a solution of 4-bromo-N-methyl-aniline (4.55 g, 25 mmol) in 150 mL of dichloromethane followed after 5 minutes by triethyl amine (5 mL, 33 mmol). After 2.5 h at ambient temperature, the reaction mixture was washed with water and the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title product as a brown oil in quantitative yield.
Reaction SMILES: [CH:1]1([C:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+].C(Cl)Cl.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:4]([CH:1]2[CH2:3][CH2:2]2)[OH:5])=[CH:9][CH:10]=1)#[N:15]
Reactant: N#Cc1ccc(CCC(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1ccc(CCC(O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 30.9 g of 4-cyanophenylethyl cyclopropyl ketone in 90 ml of absolute ethanol was added 1.48 g of sodium borohydride, and the mixture was stirred at room temperature for three hours. The product isolated from the reaction still contained unreacted starting material, so the material was redissolved in 90 ml of ethanol and treated with 0.7 g additional sodium borohydride for three hours. The product obtained by evaporation of the solvent, trituration of the residue with methylene dichloride and water, and isolation of the product from the organic phase, gave 31.0 g of 4-cyanophenylethyl cyclopropyl carbinol as an oil which crystallized to a colorless solid, m.p. 70°-71° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([NH:44][CH:45]1[CH2:47][CH2:46]1)=O>>[CH:45]1([NH:44][CH2:42][CH2:41][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:47][CH2:46]1
Reactant: O=C(CCl)NC1CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNC3CC3)c(F)c2)C(C)C)c1
Yield: 39.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 2-chloro-N-cyclopropylacetamide (13 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].Cl.[F:8][C:9]1[CH:14]=[C:13](SC)[CH:12]=[CH:11][C:10]=1[C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.[CH3:24]C(C)=O>O>[F:8][C:9]1[CH:14]=[C:13]([S:3]([CH3:24])(=[O:5])=[O:2])[CH:12]=[CH:11][C:10]=1[C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1
Reactant: CC(C)=O
Reactant: CSc1ccc(-c2ccc(O)cn2)c(F)c1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Oxone® (9.05 g, 14.7 mmol) was added to a solution of 6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinol hydrochloride (prepared as in Example 176, Step 1, 2 g, 7.4 mmol) in acetone (45 mL) and water (15 mL) at room temperature. The mixture was stirred at room temperature overnight. The reaction was filtered to remove the solid, and washed by CH2Cl2. The filtrate was brought to pH=7 with 2M Na2CO3 and was extracted with CH2Cl2. The organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was treated with a small amount of CH2Cl2 and sonicated, and then the solid was collected by filtration and washed with a small amount of CH2Cl2. The filtrate was evaporated to dryness again, treated with a small amount of CH2Cl2 and sonicated. The resulting solid was collected and washed by a small amount of CH2Cl2. The solids were combined to give 1.35 g (65%) of 6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinol as a pink solid.
Reaction SMILES: N1C=CC=C(C)C=1.Cl.C(C(CCCC)CO)C.[CH:18](=[C:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])[CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>>[CH2:18]([C:23]1[C:24](=[O:28])[CH2:25][CH2:26][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC=C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccnc1
Solvent: CCCCC(CC)CO
Product: CCCCCC1=CCCC1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
5.44 g (0.058 mol) of 3-picoline and 5.54 g (0.053 mol) of a 35% hydrochloric acid were mixed with 100.0 g of 2-ethylhexanol and heated to 140° C. Then, 100.0 g (0.53 mol) of 2-pentylidene cyclopentanone were added dropwise thereto for 2 hours at the same temperature. After this dropping addition was finished, the resultant mixture was stirred for 2 hours under heating at the same temperature. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 1. As the result, 69.2 g of 2-pentyl-2-cyclopentenone were obtained (yield: 86.0%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:42])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:29]=3)([CH3:27])[CH3:26])=[CH:15][CH:14]=2)[N:7]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:43]4[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:42])=[CH:14][CH:15]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)(C)c3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)(C)c3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a suspension of the tert-butyl carbamate (62) (780 mg, 1.18 mmol) in DCM (10 mL) was added TFA (8.0 mL) and the resulting dark green solution stirred at RT for 2 hr. The mixture was evaporated in vacuo and the residue was taken up in MeOH (10 mL) and subjected to SCX capture and release to afford the title compound (Intermediate L) (690 mg, 100%): m/z 563 (M+H)+ (ES+).