Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3](=[O:35])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:33]=[CH2:34])[CH:6]=1.C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:36][N:2]([CH3:1])[C:3](=[O:35])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([Br:38])([OH:32])[CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH:33]=[CH2:34])[CH:6]=1
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 4-[3-(t-butyl-diphenyl-silanyloxy)-1-hydroxy-propyl]-3-vinyl-phenyl dimethylcarbamate (3.00 g, 5.95 mmol) synthesized in step (f) of Example 192 and carbon tetrabromide (3.98 g, 12.0 mmol) in dichloromethane (20 ml) was added triphenyl phosphine (3.14 g, 12.0 mmol) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-2:1) as the eluent to afford the title compound (2.62 g, yield: 78%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])=[C:4]([CH3:16])[CH:3]=1.[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])=[C:4]([CH3:16])[CH:3]=1
Reactant: CCI
Reactant: Cc1cc(Cl)ccc1NC(=S)NCC(N)=O
Agent: Cl
Product: CCSC1=NCC(=O)N1c1ccc(Cl)cc1C

Procedure:
The title compound was prepared by the procedure described in Example 6 using 18.0 g of 2-[3-(4-chloro-2-methylphenyl)-thioureido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as an off-white solid, mono-hydrochloride (17.6 g), m.p. 166°-168° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S. HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.24; H, 4.45; N, 9.05. Mass spectrum (+FAB, [M+H]+) m/z 269/271 1H-NMR (DMSO-d6 ; 400 MHz) δ9.05-9.78 (broad s, 2H), 7.53 (m, 1H), 7.44 (d, 1H), 7.41 (d, 1H), 7.33 (d, 1H), 4.48 (q, 2H), 3.20 (m, 2H), 2.13 (s, 3H), and 1.29 ppm (t, 3H).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[C:20]3[N:27]([CH2:28][CH3:29])[C:26]([C:30]4[C:34]([NH2:35])=[N:33][O:32][N:31]=4)=[N:25][C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)(C)(C)C>CO>[ClH:1].[ClH:1].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[C:20]3[N:27]([CH2:28][CH3:29])[C:26]([C:30]4[C:34]([NH2:35])=[N:33][O:32][N:31]=4)=[N:25][C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCN(CCNC(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCN(CCN)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Ethereal hydrogen chloride (1.0M; 1 ml) was added to a solution of the product from example 251 (0.042 g, 0.086 mmol) in methanol (2 ml) and the solution stirred at room temperature for 16 h. The solvent was evaporated and the residual solid triturated under ether (10 ml) and filtered to give the title compound as a colourless solid (0.039 g, 99%); MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[ClH:9].N1C=CC=CC=1>C(#N)C>[Cl:9][CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:8])[CH2:1]1
Reactant: Cl
Reactant: CCCCCC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1CCCC(CCl)C1
Temperature: 82 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The title compound was prepared following the procedure described in (N. Di Bello et al., Synthesis, 1978, 227. To a solution of bicycle[4.1.0]heptan-2-one (13.8 g, 125 mmol) in acetonitrile (300 mL) was added pyridine hydrochloride (43.3 g, 375 mmol) which had been triturated with Et2O and dried under high vacuum. The solution was stirred under N2 at 82° C., overnight. The reaction mixture was partially concentrated, poured into brine (200 mL) and extracted with Et2O (4×100 mL). The ether extracts were combined, washed with brine (100 mL), dried and concentrated. The residual oil was purified on a Biotage flash chromatography system (15% ethyl acetate in hexanes) to yield the title compound (13.4 g, 91 mmol, 73.1% yield) as an oil. LCMS: 147.09 (M+H), 149.10 (M+3, 30% rel. intensity). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.51-1.60 (m, 1 H) 1.62-1.74 (m, 1 H) 1.95-2.02 (m, 1 H) 2.06-2.13 (m, J=13.47, 9.80, 3.62, 3.62 Hz, 1 H) 2.13-2.20 (m, 1 H) 2.20-2.31 (m, 2 H) 2.35-2.43 (m, 1 H) 2.45-2.51 (m, 1 H) 3.45-3.55 (m, 2 H). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 24.63, 28.75, 40.85, 41.15, 45.39, 210.25.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[N:20]1[NH:21][N:22]=[N:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:20]=[N:21][NH:22][N:23]=2)=[CH:30][CH:29]=1)=[O:9]
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Reactant: NCc1ccc(-c2nn[nH]n2)cc1
Agent: Cl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(F)cnc1Cc1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 75 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3 of Example 58) and 1-[4-(2H-tetrazol-5-yl)phenyl]methanamine hydrochloride: 1H-NMR (DMSO-d6) δ 9.20 (1H, t, J=5.7 Hz), 8.59 (1H, d, J=2.8 Hz), 7.98 (2H, d, J=8.1 Hz), 7.83 (1H, dd, J=8.8, 2.9 Hz), 7.44 (2H, d, J=8.1 Hz), 7.20–7.16 (2H, m), 7.03 (2H, t, J=8.9 Hz), 4.50 (2H, d, J=5.7 Hz), 4.21 (2H, s); MS (ESI) m/z 407 (M+H)+, 405 (M−H)−.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]O)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:45][CH:46]([CH2:49][OH:50])[CH2:47][OH:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(CO)CO
Agent: CC(C)(N)CO
Product: Cc1cc(OCCNC(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][C:14](O)=[O:15])=[CH:11][C:5]=2[NH:4][C:3]1=[O:17]>C1COCC1>[OH:15][CH2:14][CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][CH:2]([CH3:1])[C:3](=[O:17])[NH:4][C:5]=2[CH:11]=1
Reactant: CC1Oc2ccc(CCC(=O)O)cc2NC1=O
Solvent: C1CCOC1
Product: CC1Oc2ccc(CCCO)cc2NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a 50 mL round bottom flask under nitrogen was added 185 (161 mg, 0.68 mmol) and THF (1 mL). The mixture was stirred magnetically at 0° C. and then BH3 in THF (1 M, 2.25 mL, 2.25 mmol) was added slowly dropwise. After 1 h, the reaction was quenched with HCl in MeOH (2 M, 1.4 mL). The reaction was concentrated in vacuo and the residue was purified by preparative HPLC-MS using a 15-40% MeCN in water gradient. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a white solid (39 mg, 26% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=6.82 Hz, 3H) 1.61-1.69 (m, 2H) 3.37-3.42 (m, 2H) 4.47 (br. s., 1H) 4.56-4.63 (m, 1H) 6.70 (d, J=2.02 Hz, 1H) 6.71-6.76 (m, 1H) 6.84 (d, J=8.08 Hz, 1H) 10.58 (s, 1H). ESI-MS: m/z 222.2 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][O:11]/[N:12]=[C:13](/[C:17]2[N:18]=[C:19]([NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)\[C:14]([OH:16])=O)[CH2:9][CH2:8]1.[NH2:42][C@@H:43]1[C:71](=[O:72])[N:45]2[C:46]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:47]([CH2:50][O:51][C:52](=[O:54])[NH2:53])[CH2:48][S:49][C@H:44]12.CN(C)C1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[C:52]([O:51][CH2:50][C:47]1[CH2:48][S:49][C@@H:44]2[C@H:43]([NH:42][C:14](=[O:16])/[C:13](=[N:12]\[O:11][CH2:10][CH:7]3[CH2:8][CH2:9]3)/[C:17]3[N:18]=[C:19]([NH:22][C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:20][CH:21]=3)[C:71](=[O:72])[N:45]2[C:46]=1[C:55]([O:57][CH:58]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:56])(=[O:54])[NH2:53]
Reactant: O=C(O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
Oxalyl chloride (0.37 ml) was added to a solution of N,N-dimethylformamide (0.38 ml) in methylene chloride (10 ml) at -20° with stirring. After five minutes at 0°, the mixture was recooled to -20° and (Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.94 g) was added. The solution was stirred at 0° for ten minutes before recooling to -20°. A slurry of diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate (1.76 g) in methylene chloride (10 ml) containing N,N-dimethylaniline (1.26 ml) was added. The solution was allowed to warm to 21° and was stirred for 1.5 hours. After dilution with methylene chloride, the solution was washed with dilute hydrochloric acid and water, each time back-extracting with methylene chloride. The combined organic layers were dried (magnesium sulphate) and concentrated. The solution was loaded into a column of Sorbsil U30 (70 g) which was eluted with a gradient of ethyl acetate (10 to 100%) in petroleum ether (b.p. 40°-60°). Evaporation of the appropriate eluate gave the title compound (3.03 g) as a foam, [α]D21 +10.7° (c 1.03, CHCl3); νinfl 238.5 nm (E1 cm1% 2.78), 258.5 (E1 cm1% 227), 264.5 (E1 cm1% 212), 271.5 (E1 cm1% 186) and 296.5 (E1 cm1% 88)
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:3][C:4]1[N:5]=[N:6][C:7]([NH:1][NH2:2])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: NN
Reactant: Clc1ccc(-c2cc(Cl)nnc2Cl)cc1
Solvent: c1ccncc1
Product: NNc1cc(-c2ccc(Cl)cc2)c(Cl)nn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Anhydrous hydrazine (8 mL) was added to a solution of 3,6-dichloro-4-(4-chlorophenyl)pyridazine (7.1 g, 27.4 mmol) in pyridine (30 mL) at 100° C. The resulting mixture was stirred at 100° C. for 30 min. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the pyridine. To the residue was added isopropanol (200 mL), the resulting suspension was refluxed for 20 min. After cooling to room temperature, the suspension was filtered. The collected solid was washed with isopropanol, dried in a 50° C. vacuum oven overnight to afford 4.0 g (57%) of the title compound as an off-white solid. LC/MS (method A): retention time=2.24 min, (M+H)+=255.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=O>CO.O>[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=[N:2][OH:3]
Reactant: CC(C)(C=O)SC(F)(F)F
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C=NO)SC(F)(F)F

Procedure:
A mixture of hydroxylamine hydrochloride (0.09 mole) in methanol (230 ml), sodium carbonate (4.8 g, 0.045 mole) in 50 ml of water and 2-trifluoromethylthio-2-methylpropionaldehyde (14.85 g, 0.086 mole) from Step 1 was stirred at room temperature overnight. The reaction mixture was poured into water, the oxime was extracted into diethyl ether, the combined ether extracts were washed with water and then dried. The drying agent was removed by filtration and the filtrate was distilled to provide 2-trifluoromethylthio-2-methylpropionaldehyde oxime, b.p. 80°C/18 mm. The structure of this product was confirmed by elemental and spectroscopic analyses.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.Cl.[CH3:23][O:24][C:25]([CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][CH:27]([C:25]([O:24][CH3:23])=[O:26])[CH2:28]3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)C1CCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)C1
Temperature: 95 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
To a solution of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (140 mg, 0.433 mmol), methylpyrrolidine-3-carboxylate hydrochloride (107.7 mg, 0.65 mmol), X-Phos (115 mg, 0.24 mmol) and Cs2CO3 (580 mg, 1.78 mmol) in 60 mL of dry dioxane was added Pd2(dba)3 (60 mg, 0.065 mmol) in one portion at room temperature under nitrogen. Then the reaction mixture was degassed by nitrogen for 15 minutes. The mixture was then stirred at 95° C. under nitrogen for 24 hours. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting a mixture of ethyl acetate and petroleum ether (2:1)) to give methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylate (160 mg, 88.7%) as a yellow solid. LC-MS: 416.1 [M+H]+, tR=1.60 min.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
NaH (0.19 g, 4.80 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (5 mL), the suspension cooled to 0° C. and 3-pyridylcarbinol (0.40 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (1.33 g, 4.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 3-pyridylcarbinol in THF were added after 7 and 25 h, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid) and Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 40% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-3-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (46.3 mg, 3.8%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][OH:17]>>[CH3:16][O:17][C:11](=[O:12])[C:6]1[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=1[F:13])[C:8]([OH:10])=[O:9]
Reactant: CO
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Product: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Reaction time: 2 h
Yield: 98 %

Procedure:
Into a 100 ml glass reactor equipped with a reflux condenser and a stirrer, 20 g (0.091 mol) of the tetrafluorophthalic anhydride prepared in Example 3 and 40 ml of methanol were charged, and the mixture was stirred for 2 hours under reflux. After completion of the reaction, methanol was distilled off to obtain 22.5 g of 3,4,5,6-tetrafluorophthalic acid-monomethyl ester. The yield was 98.0%.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:37]=[CH:36][C:23]([C:24]([O:26][CH2:27][C@@H:28]([F:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[CH:22][CH:21]=3)=[N:18][CH:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][C@@H:28]([F:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[CH:36][CH:37]=3)=[N:18][CH:19]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC[C@H](F)COC(=O)c1ccc(-c2ncc(C#Cc3ccc(CCCCC)cc3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCC[C@H](F)COC(=O)c1ccc(-c2ncc(CCc3ccc(CCCCC)cc3)cn2)cc1

Procedure:
Hydrogenation of the compound obtained in Example 4 using hydrogen under atmospheric pressure at room temperature and using palladium/charcoal as catalyst gives (S)-2-fluorooctyl 4-{5-[2-(4-pentylphenyl)ethyl]-pyrimidin-2-yl}benzoate.
Reaction SMILES: C(OC([NH:8][C:9]1([C:22](=[O:36])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH:25]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.Cl.O1CCOCC1>CO>[CH3:33][N:32]([CH3:34])[C:31](=[O:35])[O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][C:22]([C:9]2([NH2:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:36])[CH:25]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(N)CCNCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-4-(3-(dimethylcarbamoyloxy)phenylcarbamoyl)piperidine-1-carboxylate from step A (0.141 g, 0.28 mmol) in MeOH (2 mL) was added HCl (4 N in dioxane, 0.21 mL, 0.84 mmol). The mixture was stirred at room temperature for 14 hours. Further eqivalents of HCl/dioxane were added at this time, and the mixture stirred for a further 24 hours at room temperature. The solvent was removed under vacuum to afford the title compound (0.084 g, 98%), which was carried on crude. MS (ES+) [M+H]+=307.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].BrCCC.OC1C=CC(C=O)=CC=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=[O:12]
Reactant: CCCCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=Cc1ccc(O)cc1
Solvent: CCCBr
Product: CCCCCOc1ccc(C=O)cc1Cl
Yield: 96 %

Procedure:
When the 1-bromopentane and 3-chloro-4-hydroxybenzaldehyde was substituted for 1-bromopropane and 4-hydroxybenzaldehyde in Example 50 Step A the identical process afforded the title compound in 96% yield, as light yellow oil. 1H-NMR (CDCl3) 0.9 (tr, 3H, J=7.05 Hz); 1.34-1.39 (m, 4H); 1.41-1.45 (m, 2H); 4.07 (tr, 2H, J=3.66 Hz); 6.97 (d, 1H, J=8.49 Hz); 7.7 (dd, 1H, J=2.01, 8.46 Hz); 7.85 (d, 1H, J=2.04 Hz); 9.81 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:25]=[CH:24][C:18]([CH2:19][C:20]4([NH2:23])[CH2:22][CH2:21]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:23][C:20]1([CH2:19][C:18]2[CH:24]=[CH:25][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[CH2:21][CH2:22]1)=[O:44])([CH3:55])[CH3:54]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: NC1(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2(Cc3ccc(-c4ncn(-c5ccc(OC(F)(F)F)cc5)n4)cc3)CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanamine (CB30) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red oil (0.104 g, 37%).
Reaction SMILES: CO[C:3]([C:5]1[C:10]([C:11]([O:13]C)=O)=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18]>CCO>[OH:18][CH2:17][CH:16]([NH:15][C:3]([C:5]1[C:10]([C:11]([NH:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18])=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4])[CH2:19][OH:20]
Reactant: COC(=O)c1cccnc1C(=O)OC
Reactant: NC(CO)CO
Solvent: CCO
Product: O=C(NC(CO)CO)c1cccnc1C(=O)NC(CO)CO
Yield: 124.6 %

Procedure:
Pyridine-2,3-dicarboxylic acid dimethyl ester (2 g, 10.25 mmol) was dissolved in EtOH (5 mL). 2-Amino-1,3-propanediol (1.87 g, 20.5 mmol) was added and the mixture was heated under reflux for 6 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 7:4) to afford the title compound (4 g, 75%).