Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.[C:13]1(OC)C=CC=CC=1.[F:21][C:22]([F:29])([F:28])[S:23]([O:26]C)(=[O:25])=[O:24]>C(OCC)(=O)C>[F:21][C:22]([F:29])([F:28])[S:23]([O-:26])(=[O:25])=[O:24].[CH3:1][O:2][CH:3]1[NH+:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]1[CH3:13]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COc1nc2cccccc-2n1
Reactant: COc1ccccc1
Solvent: CCOC(C)=O
Product: COC1[NH+]=C2C=CC=CC=C2N1C
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
First, 0.9 g of 2-methoxycycloheptimidazole was added to 5 ml of anisole, and 1.1 g of methyl trifluoromethanesulfonate was added dropwise. After being stirred at room temperature for one hour, 30 ml of ethyl acetate was added, and deposited crystals were collected by filtration and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](C=O)=[C:9]2[C:13]=1[N:12]([CH3:14])[N:11]=[CH:10]2)=[O:4].Cl.[NH2:18][OH:19].[C:20]([O-])(=O)C.[Na+]>C(O)(C)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](=[N:18][OH:19])[C:9]2[C:13]=1[N:12]([CH3:14])[NH:11][C:10]=2[CH3:20])=[O:4]
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc(C=O)c2cnn(C)c12
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(=NO)c2c(C)[nH]n(C)c1-2
Reaction time: 4 h
Yield: 99.4 %

Procedure:
A solution of 4-formyl-1-methyl-1H-indazole-7-carboxylic acid methyl ester (1.4 g) in isopropyl alcohol (30 ml) and water (20 ml) was treated with hydroxylamine hydrochloride (0.62 g) and sodium acetate (0.72 g) and stirred for 4 h. Isopropyl alcohol was removed and the remaining mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give 4-(hydroxyimino-methyl-1-methyl-1H-indazole-7-carboxylic acid methyl ester (1.5 g). 1H-NMR (400 MHz, DMSO): 10.1 (s, 1H), 8.5 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H), 7.1 (d, 1H), 4.20 (s, 3H), 4.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1.[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12>C1(C)C=CC=CC=1>[O:25]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:26])[N:1]1[C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(N2C(=O)c3ccccc3C2=O)cc1C
Yield: 68.4 %

Procedure:
A solution of 2.8 g (10 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) and 1.5 g (10 mmol) of phthalic anhydride in 100 mL of toluene is stirred at reflux beneath a phase separating head for 2 hours. The solvent is removed and on standing a red brown oil crystallizes. Recrystallization from isoctaneisopropyl ether with the addition of charcoal affords 2.8 g of the title compound as pale pink crystals; mp 109°-111° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:36][CH2:35][C:24]4([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:36][CH2:35][C:24]4([CH2:25][NH:26][CH2:27]4)[CH2:23]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:38])[F:37])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC2(CNC2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
(Z)-tert-Butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (0.05 g) was dissolved in DCM (20 mL), cooled to 0° C. and CF3COOH (0.5 mL) was added. The reaction mixture was stirred at room temperature for 4 h, concentrated under reduced pressure (35° C., 20 mmHg) to give (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(2,6-diazaspiro[3.4]octan-6-yl)prop-2-en-1-one 2,2,2-trifluoroacetate (0.03 g, 95% yield). 1H NMR (400 MHz, DMSO) δ=9.25 (s, 1H), 8.77 (brs, 1H), 8.59 (s, 2H), 8.30 (s, 1H), 7.39-7.37 (d, 1H, J=10.4 Hz), 6.15-6.12 (d, J=10.4 Hz, 1H), 3.86-3.65 (brs, 4H), 2.14 (s, 2H), 1.49 (s, 2H), 0.85-1.23 (m, 2H); LCMS calcd. for C19H18F6N5O [M+H]+ 446.36. found 446.12 at retention time 2.161 min.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].O[CH2:74][CH2:75][P:76](=[O:81])([O:79]C)[O:77]C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH2:74][CH2:75][P:76](=[O:77])([OH:81])[OH:79])=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: COP(=O)(CCO)OC
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Product: CCn1c(C)c(C(=O)OCCP(=O)(O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1

Procedure:
9 was prepared from BM-957 and dimethyl (2-hydroxyethyl)phosphonate according general procedure V. MS (ESI): m/z 1173.42 (M+H)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([C:34](=[O:38])[CH:35]=[N+]=[N-])[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:40].C(O)(=O)C>ClCCl>[Br:40][CH2:35][C:34](=[O:38])[CH:25]([NH:24][C:22]([CH:18]1[N:15]2[C:16](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:12][C:13](=[O:39])[N:14]2[CH2:21][CH2:20][CH2:19]1)=[O:23])[CH2:26][C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 506a (2.27 g, 4.2 mmol) in dry dichloromethane (50 ml) was treated with 30% hydrobromic acid in acetic acid (1.84 ml, 9.2 mmol, 2.2 equiv) at 0° C., under nitrogen. After 10 min stirring at 0° C. the reaction was complete and a white solid crystallised in the medium. The solid was filtered and washed with ethylacetate and diethylether to afford 2.20 g (100%) of [3S(1S,9S)] 5-bromo-3-(9-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxamido)-4-oxopentanoic acid which was used without further purification: 1H NMR (D6-DMSO) δ8.87 (1H, d, J=7.3), 8.63 (1H, d, J=7.6), 7.91-7.87 (2H, m), 7.60-7.44 (3H, m), 6.92 (1H, bs), 5.14-5.09 (1H, m), 4.92-4.65 (2H, m), 4.43 (2H, AB), 4.41-4.35 (1H, m), 3.33-3.22 (1H, m), 2.98-2.90 (1H, m), 2.89-2.57 (2H, m), 2.35-2.15 (3H, m), 1.99-1.91 (2H, m), 1.75-7.60 (2H, m). A solution of the bromoketone (535 mg, 1 mmol) in dry DMF (10 ml) was treated with potassium fluoride (150 mg, 2.5 mmol, 2.5 equiv), under nitrogen. After 5 min stirring at room temperature, 2-mercaptothiazole (140 mg, 1.2 mmol, 1.2 equiv) was added. After overnight reaction ethylacetate (150 ml) was added and the organic solution was washed with brine, dried over magnesium sulphate and reduced in vacuo. The residue was crystallised in diethyl ether, filtered and purified on silica gel using a gradient of MeOH (0% to 5%) in dichloromethane. Evaporation afforded 344 mg (60%) of a white solid: mp. 90-9520 C. (decomp. ); [α]D20 −82° (c 0.2, CH2Cl2); IR (KBr) 3328, 2941, 1745, 1659, 1535, 1422, 1276, 1255, 1223, 1072; 1H NMR (D6-DMSO) δ8.92 (1H, d, J=7.6), 8.68 (1H, d, J=7.6), 7.98-7.90 (2H, m), 7.75-7.67 (1H, m), 7.64-7.50 (4H, m), 5.22-5.18 (1H, m), 4.95-4.74 (2H, m), 4,58-4.38 (3H, m), 3.52-3.19 (1H, m), 3.05-2.65 (4H, m), 2.40-1.50 (6H, m). Anal. Calcd for C25H27N5O4S2.H2O: C, 50.75; H, 4.94 N, 11.84. Found: C, 51.34; H, 4.70; N, 11.58. MS (ES+) 572.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:34]2[CH2:33][CH2:32][CH:31]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]3=[O:24])[CH2:36][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCCCN1C1CCNCC1
Product: CN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 108.2 %

Procedure:
A solution of (3S)-3-(3,4-Dichlorophenyl)-3-((1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.596 g) was treated with 4-(2-oxopiperidino)piperidine (0.311 g) as described in Example 8. The resulting material was not purified by chromatography but was transformed into the hydrochloride to afford the title compound (0.51 g); [α]D =28° (c=1.0 Ethanol); mp 150-160° C. (dec); MS: m/z=514(M+1); NMR(CD3SOCD3): 1.69 (broad,5), 2.23 (broad, 3), 3.06 (s,3), 4.57 (m,1), 4.87 (d,1, J=3.7), 6.75 (dd,1, J=8.4, 2), 6.96 (d,1, J=2), 7.33 (d,1, J=8), 7.50 (m,2), 7.62 (m,1), 7.92 (d,1, J=7.6). Analysis for C28H33Cl2N3O2.1.5 HCl.H2O: Calculated: C, 57.27; H, 6.26; N, 7.16; Found: C, 57.24; H, 6.15; N, 7.26.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[OH:33])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]>N1C=CC=CC=1.Cl>[CH2:13]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[O:33][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH3:14]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12CC
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Add decanoyl chloride (1.9 g.) to 13β-ethyl-17β-hydroxy-gon-4-en-3-one (1.3 g.) in pyridine (12.5 cc.) and allow the mixture to stand at room temperature overnight. Pour the mixture in 2N hydrochloric acid and extract with ether. Wash, dry and evaporate the extracts and recrystallize the residue from benzene-hexane to give the title compound (1.0 g.), m.p. 97°-97.5°; ultraviolet absorption peak at 239 mμ (ε16,500); infrared absorption peaks at 5.74, 5.99, 6.17 μ.
Reaction SMILES: Cl.O1CCOCC1.[C:8]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C@H:25]([OH:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:22]=[CH:23][CH:24]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>C(Cl)Cl>[NH2:28][CH2:27][CH2:26][C@H:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([C:8](=[O:10])[CH3:9])[CH2:12][CH2:13]1)[OH:36]
Reactant: CC(=O)N1CCC(COc2cccc([C@H](O)CCNC(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)N1CCC(COc2cccc([C@H](O)CCN)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HCl/dioxane (4M, 2 mL) was added to a solution of (R)-tert-butyl (3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate (0.60 g, 1.40 mmol) in CH2Cl2 (10 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give after purification by triturating in diethyl ether Example 11 hydrochloride as a white solid. Yield (0.40 g, 88%); 1H NMR (400 MHz, DMSO-d6); δ 7.18 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.6 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 4.38 (d, J=14.8 Hz, 1H), 4.11 (s, 2H), 3.79 (d, J=6 Hz, 3H), 3.02 (t, J=11.2, 1H), 2.64 (d, J=3.2 Hz, 2H), 2.54 (s, 1H), 1.97 (s, 4H), 1.76 (t, J=16.0 Hz, 2H), 1.66-1.61 (m, 2H), 1.26-1.04 (m, 2H); MS: m/z 307.01 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[N:43]1([CH2:52][CH2:53]O)[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]1>>[OH:51][CH2:50][CH2:49][N:46]1[CH2:45][CH2:44][N:43]([CH2:52][CH2:53][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)[CH2:48][CH2:47]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OCCN1CCN(CCO)CC1
Product: COc1cc(C(=O)OCCN2CCN(CCO)CC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2,2′-(piperazine-1,4-diyl)diethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethyl ester. MS (ES+) m/z calcd. for C39H46Cl2F2N5O5: [(M+H)+]772. found: 772.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetate (5.5 g, 0.02 mol) in toluene (55 mL, 10 times), 3 M sodium hydroxide solution (9.09 mL) was added at 50° C. and the reaction mixture was stirred for 3 h at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, the contents were cooled to 0° C., the mixture was acidified with diluted HCl and the solid precipitated was filtered. The crude product 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetic acid obtained as an yellow colored solid (4.5 g, crude) was directly used for the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[H][H]>[Pd].C(O)C>[CH:14]1([NH:11][CH2:10][CH2:9][C:4]2([CH3:12])[CH:5]([CH3:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH:3]2[CH3:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: CC1CCN(C)C(C)C1(C)CCN
Reactant: O=C1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(C)C(C)C1(C)CCNC1CCCC1
Yield: 92.6 %

Procedure:
A mixture of 1,2,3,4-tetramethyl-3-piperidineethanamine (2.0 g, 10.7 mmol), ethanol (50 mL), cyclopentanone (950 μL, 10.7 mmol) and 10% palladium on carbon (1.0 g) was placed on a Parr hydrogenator under 50 psi of hydrogen pressure for four hours. The reaction mixture was filtered to remove the catalyst and the solvent was removed in vacuo to afford 2.5 g (93%) of N-cyclopentyl-1,2,3,4-tetramethyl-3-piperidineethanamine as a yellow oil. The product was dissolved in ether/ethanol and treated with ethereal HCl to afford the product as a dihydrochloride hemihydrate. The dihydrochloride hemihydrate was isolated as a white powder and had a melting point of 201°-202.5° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>CO>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)s1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
5-Bromothiazol-2-amine (6.0 g, 23 mmol) and acetic anhydride (50 g, 490 mmol) were charged into a 250 mL round bottom flask. The suspension in the flask was heated to 100° C. After stirring for 3 hours, the reaction mixture was cooled and filtered to yield the crude product. The crude product was charged into a round bottom flask, 50 mL MeOH was added, and the mixture was heated to reflux. The mixture was cooled, and the product N-(5-bromothiazol-2-yl)acetamide (4.5 g, 93%) was obtained by filtration. The collected product was then washed with hexane. The product was used directly in the next step without further purification. LCMS (API-ES) m/z (%): 221.0 (100%, M++H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24].[OH-:26].[K+]>C(Cl)CCl>[CH:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:25][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:8]([O:26][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OC2CCCCC2)cc1
Reactant: NCCCCCCCN
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCCNC(=O)c1ccc(OC2CCCCC2)cc1)c1ccc(OC2CCCCC2)cc1

Procedure:
m.p. 144°-145° C., 27.3 g., was prepared as in Example 1 using 4-cyclohexyloxybenzoyl chloride (from 42.0 g. of the corresponding acid as in Example 6) in 100 ml. of ethylene dichloride, 11.7 g. of 1,7-heptanediamine, 200 ml. of 10% potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from acetonitrile using decolorizing charcoal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=O.ClCCCl.C(#[N:35])C.ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5]#[N:35]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CC#N
Agent: O=C=NS(=O)(=O)Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.222 g, 0.569 mmol) in 1,2-dichloroethane (1.5 mL, 19 mmol) and acetonitrile (1.5 mL, 29 mmol) under argon were added chlorosulfonyl isocyanate (0.074 mL, 0.853 mmol) and triethylamine (0.12 mL, 0.853 mmol). The reaction mixture was stirred at 90° C. for 18 h. The cooled reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 solution and brine; dried (MgSO4). ISCO purification (with 10% to 50% EtOAc/hexanes) afforded 3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzonitrile as an off-white solid. MS (ESI) m/z: Calculated: 371.1; Observed: 372.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]([Mg]Br)#[CH:12]>C1COCC1>[CH3:1][C:2]1[C:3]([C:8]([OH:10])([C:11]#[CH:12])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ncccc1C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1ncccc1C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure A. 1-(3-Methylpyridin-2-yl)ethan-1-one. (3.2 g, 23.68 mmol, 1.00 equiv) was dissolved in 6 mL of THF under inert nitrogen atmosphere in a 100-mL 3-necked round-bottom flask. Then ethynylmagnesium bromide (2M in THF, 61 mL, 1.30 equiv) was added dropwise into the solution at 0° C. The resulting solution was stirred for 10 min and then allowed to rise to room temperature and stirred for additional 2 h. The reaction was then quenched by the addition of 20 mL of sat. aqueous NH4Cl and the resulting solution was extracted with 2×25 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to get a residue, which was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to obtain 3.5 g (88%) of 2-(3-methylpyridin-2-yl)but-3-yn-2-ol as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:10]=1[OH:11])[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5]2.C(N(CC)CC)C.S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:10]2[O:11][C:13]([CH2:15][OH:32])([CH3:14])[CH2:12][C:9]=2[C:8]2[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=C(C)Cc1c(O)c(Br)cc2c1C(CCNC(=O)CC)CC2
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)CC(C)(CO)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of N-[2-(5-bromo-6-hydroxy-7-(2-methyl-2-propenyl)indan-1-yl)ethyl]propionamide (550 mg, 1.5 mmol.) in dichloromethane (5 mL) was cooled with ice. To the solution were added triethylamine (0.2 mL, 1.5 mmol.) and methachloroperbenzoic acid (1.0 g, 4.1 mmol.). The mixture was stirred for two hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium thiosulfate. The organic matter was extracted with ethyl acetate. The extract solution was washed with 1N HCl and a saturated aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was dissolved in dichloromethane, to which was added triethylamine (1 mL). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford the title compound (yield 420 mg, 73%) as an oily product.