Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=2)[N:4]=1.CN(C)C(N(C)C)=N.Cl[CH:47]([O:49][C:50](=[O:52])[CH3:51])[CH3:48]>CN(C=O)C>[C:50]([O:49][CH:47]([O:36][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37])[CH3:48])(=[O:52])[CH3:51]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Reactant: CC(=O)OC(C)Cl
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)OC(C)OC(C)=O)c2)nc1OC
Temperature: 60 °C

Procedure:
To a solution of 0.52 g of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, in DMF (10 ml) were added at RT 0.23 g of 1,1,3,3-tetramethylguanidine followed by 0,245 g of acetic acid 1-chloroethyl ester (preparation described by M. Ertan et al., Arzneim. Forsch. 1992, Vol. 42, 70). The reaction mixture was then heated at 60° C. for 20 h, cooled to RT and partitioned between ice water and EtOAc. The organic layer was washed with water, dried over Na2SO4 and the organic layer was removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with tert-butyl methyl ether). Combinations of the purified fractions and evacuation in vacuo afforded 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid 1-acetoxy-ethyl ester as a white solid. ISN mass spectrum, m/e 608 (M−1 calculated for C28H27N5O9S: 608).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([CH3:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[C:39]([CH3:44])[N:40]=[C:41]([CH3:43])[CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (163 mg, 0.5 mmol) according to the general procedure M. Obtained as a white solid (185 mg, 67%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:21]2[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=2)=[N:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccc([N+](=O)[O-])cn2)cc(OC)c1OC
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
Under nitrogen, tetrakis(triphenylphosphine)palladium (504.6 mg, 0.437 mmol) and a 2.0 M aqueous sodium carbonate (25 mL, 50 mmol) were added to a solution of 2-bromo-5-nitropyridine (2.87 g, 14.1 mmol) and 3,4,5-trimethoxyphenylboronic acid (3.00 g, 14.2 mmol) in ethanol-toluene (1:5, 90 mL), and the resulting mixture was stirred at 70° C. for 12 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and crude crystals were obtained. The crude crystals were recrystallized from chloroform-hexane to provide 5-nitro-2-(3,4,5-trimethoxyphenyl)pyridine as yellow needles (melting point: 134.0-136.5° C. )(3.31 g, yield: 81%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[N:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][NH:33]3)=[C:29]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:41][CH:42]=3)[N:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:13][CH2:14][C:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[S:22][C:23]=3[C:24]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: O=C1c2sc3c(c2CCN1c1cc(F)cc(-c2nc(Nc4ccc(N5CCN(C6COC6)CC5)cc4)c4nc[nH]c4n2)c1CO)CCCC3
Temperature: 30 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A mixture of 119b (150 mg, 0.210 mmol) and lithium hydroxide (50 mg, 2.10 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 119 (85 mg, 58%) as a yellow solid. MS-ESI: [M+H]+ 681.3. 1H NMR (500 MHz, CDCl3) δ 12.72 (s, 1H), 8.45 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 4.74-4.67 (m, 6H), 4.09-4.04 (m, 1H), 3.78-3.73 (m, 1H), 3.57 (t, J=6.5 Hz, 1H), 3.24-3.22 (m, 4H), 2.99-2.93 (m, 1H), 2.88-2.83 (m, 3H), 2.53-2.51 (m, 6H), 1.93-1.81 (m, 5H).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][N:8]([CH3:10])[C:7](=[O:11])[N:6]([CH3:12])[CH2:5]1)=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH:4]1[CH2:9][N:8]([CH3:10])[C:7](=[O:11])[N:6]([CH3:12])[CH2:5]1
Reactant: CN1CC(N=[N+]=[N-])CN(C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CC(N)CN(C)C1=O
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
A mixture of 5-azido-1,3-dimethyl-tetrahydro-pyrimidin-2-one (Step P5) (2.5 g, 11.1 mmol) and Pd/C 10% (500 mg) in EtOH (70 mL) was stirred at rt under a hydrogen atmosphere for 13.5 h. The reaction mixture was filtered through a pad of celite, washed with THF and MeOH and concentrated. The residue was dissolved in EtOAc and extracted with cold 1N HCl. The aqueous phase was basified with a saturated aqueous NaHCO3 solution. The resulting aqueous phase was extracted with CH2Cl2/isopropanol 3:1 (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford the title compound. ESI-MS: [M+H]+ 144.1 (MS 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH:19]1([NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:19]1([NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([O:35][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]6)=[O:12])[S:10][C:3]=45)=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:21][CH2:20]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NC1CC1
Yield: 65.8 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a (113 mg, 0.40 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner as previously described for example 1 to give a yellow solid (130 mg, 66%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.46 Hz), 8.46 (1H, d, J=4.33 Hz), 8.06, 8.00 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 5.07 (1H, m), 4.38, 4.33 (1H, br s), 4.02-3.92 (2H, m), 3.67-3.44 (2H, m), 2.93-2.87 (1H, m), 2.57 (3H, s), 2.08-1.79 (2H, m), 0.76-0.70 (2H, m), 0.60-0.55 (2H, m).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH2:11])[CH:9]=C.C=O>>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:9]=[CH:8][NH:11]1
Reactant: C=CCN
Reactant: Oc1ccccc1
Agent: C=O
Product: C1=Cc2ccccc2ON1
Yield: 82.1 %

Procedure:
At room temperature, phenol, allyl amine and paraformaldehyde were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated to a molten state, reacted for 4 h and placed in a cooling unit to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 82.1%.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=O)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[OH-].[Na+]>C1COCC1>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:12][CH2:13][N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(-n3cnnn3)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCc2cccc(-n3cnnn3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-{[3-(1H-tetrazol-1yl)phenyl]acetyl}piperazine-1-carboxylate (0.80 g, 2.148 mmol) was dissolved in THF (20 ml) and added the borane-tetrahydrofuran complex (4.30 ml, 4.30 mmol) then stirred at RT overnight. TLC showed a less polar spot but still has SM. Added another 2 equiv of borane-THF complex and followed the reaction with TLC. The reaction was first shaken with 1N HCl then basified with 1N NaOH and extracted with ETOAc. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed by MPLC-using 40 g ISCO Redi-sep column and eluted with 50% ethyl acetate/50% hexane to yield t-butyl 4-{2-[3-(1H-tetrazol-1yl)phenyl]ethyl}piperazine-1-carboxylate. LC-MS (IE, m/z): 359 [M+1]+; 1H-NMR (500 MHz, CDCl3) δ ppm 9.04 (s, 1H), 7.64 (s, 1H), 7.60 (t, J=8.2 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 3.87 (b, 4H), 3.32-3.36 (m, 2H), 3.12 (d, J=11.9 Hz, 2H), 3.024-3.06 (m, 2H), 2.70-2.75 (m, 2H), 1.49 (s, 9H);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:16])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: O=C(Cl)CCCCl
Product: O=C1CCCN1CCc1ccc(Br)cc1

Procedure:
The title compound was prepared from 4-bromophenethylamine and 4-chlorobutyryl chloride using a similar procedure to that described for Description 28.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:62])[C@H:6]([C:10]([NH:12][C@H:13]([C:17]([N:19]([C@@H:21]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:22]([O:56][CH3:57])[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C@H:31]([O:54][CH3:55])[C@@H:32]([CH3:53])[C:33]([NH:35][C@@:36]1([C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:46])[CH2:38][C@@H:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])=[O:25])[CH3:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:7]([CH3:9])[CH3:8].C(=O)([O-])O.[Na+].[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])N1C(OC)=O>O1CCOCC1>[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:1]1[CH2:2][CH2:3][CH2:4][N:5]([CH3:62])[C@H:6]([C:10]([NH:12][C@H:13]([C:17]([N:19]([C@@H:21]([C@@H:58]([CH3:61])[CH2:59][CH3:60])[C@H:22]([O:56][CH3:57])[CH2:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[C@H:31]([O:54][CH3:55])[C@@H:32]([CH3:53])[C:33]([NH:35][C@@:36]1([C:45]([N:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)=[O:46])[CH2:38][C@@H:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:34])=[O:25])[CH3:20])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCN)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@]1(C(=O)N2CCCCO2)C[C@@H]1c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 mg (14 μmol) of N-(3-aminopropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(1S,2R)-1-(1,2-oxazinan-2-ylcarbonyl)-2-phenylcyclopropyl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 66) were taken up in 750 μl of dioxane and admixed with 1.5 ml of saturated sodium hydrogencarbonate solution and then with 3.2 mg (21 μmol) of methyl 2,5-dioxo-2,5-dihydro-1H-pyrrole-1-carboxylate. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The remaining residue was purified by means of preparative HPLC. After lyophilization, 4.2 mg (32% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2ccccc2c(=O)[nH]1
Product: COc1cc2ccccc2c(Cl)n1
Yield: 44 %

Procedure:
3-Methoxyisoquinolin-1(2H)-one (2.8 g, 16.0 mmol) in POCl3 (10 mL) was heated to reflux for 3 h then evaporated in vacuo. The residue was poured into iced NaHCO3 solution (50 mL). The product was extracted with EtOAc (2×). The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by flash chromatography with 20% then 40% of EtOAc/hexane to afford 1.36 g (44%) of the desired product 1-chloro-3-methoxyisoquinoline as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29-8.16 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.63 (ddd, J=8.3, 6.8, 1.1 Hz, 1H), 7.47 (ddd, J=8.5, 7.0, 1.1 Hz, 1H), 6.98 (s, 1H), 4.05 (s, 3H). MS: MS m/z 194.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1.C([O-])(=O)C.[Na+].CC(O)=O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (D11) (44 mg) and ethyl 4-piperidinecarboxylate (89 mg) in methanol (10.00 mL) stirred at room temperature was added sodium acetate (55 mg) and AcOH (0.033 mL). The reaction mixture was stirred at room temperature for 10 min. And the solvent was removed by evaporation. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (72.3 mg) was added. Stirring continued for 2 h. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford ethyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-4-piperidinecarboxylate (D12) (60.1 mg). MS (ES): C28H34ClN3O3S requires 527. found 528.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22]([NH:25]C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:34]=[CH:33][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH2:20][NH:21][S:22](=[O:23])(=[O:24])[NH2:25])=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCc1nnc(Cc2nc3ccc(-c4ccccc4)cc3s2)o1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a solution of Compound 24a (1.16 g, 2.30 mmol) in DCM (10 mL) was added TFA (5 mL) and the reaction mixture stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure then azeotroped from toluene (2×). The crude residue was diluted with 1.5M K3PO4 then the aqueous layer extracted with DCM (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified on silica gel eluting with 0-15% MeOH/DCM to give Compound 24b (68 mg, 74% yield) as a pale brown solid. LCMS=1.71 min using analytical method (B), 402.0 (M+H). 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.5, 1.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.47 (t, J=7.7 Hz, 2H), 7.41-7.32 (m, 1H), 4.47 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[CH3:20][O:21][NH2:22]>CO>[CH3:20][O:21][N:22]=[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CON
Reactant: O=C1CCCc2ccc(Cl)cc21
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCCc2ccc(Cl)cc21
Temperature: 24 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred solution of 7-chloro-1-tetralone CAS: 26673-32-5 (5.0 g; 27.68 mmol) in methanol (55 ml) was added pyridine (2.87 ml; 34.05 mmol) followed by a portion wise addition of methoxyamine hydrochloride (2.84 g; 34.05 mmol). The reaction mixture was stirred at 24° C. for 16 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 6.22 g (100% of theory) of crude 7-chloro-3,4-dihydro-2H-naphthalen-1-one-O-methyl-oxime as a brown oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH:26]([CH3:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:24]2)=[O:22])=[CH:16][CH:15]=1.[CH3:36][O:37][C:38](=O)[O:39]C>O1CCCC1.CCCCCC.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]2[CH2:27][C:26]([C:38]([O:37][CH3:36])=[O:39])([CH3:28])[C:25]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[N:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: CC1CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(C(=O)Nc2ccc(Cl)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
To 2.1 ml of diisopropylamine dissolved in 15 ml of tetrahydrofuran and cooled in an ice salt bath was added 8.0 ml of a 2.7 molar solution of n-butyllithium in hexane. After stirring for 5 minutes a solution of 3.4 g of N,3-bis-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 7 ml of tetrahydrofuran was added and the resulting solution stirred for 15 minutes. To this solution was added 1.5 ml of dimethylcarbonate and, after 15 minutes 1.5 ml of acetic acid was added. The reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo to give 3.0 g of N,3-bis(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide, mp 122° C. NMR and IR data were consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:22][Si:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]O>CC#N.CN(C1C=CN=CC=1)C>[CH3:22][Si:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: C[Si](C)(C)CCO
Reactant: Cc1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(C(=O)OCC[Si](C)(C)C)s1
Reaction time: 0.08 h

Procedure:
A solution of 5-Methyl-thiophene-2-carboxylic acid (23.58 g, 166 mmol) in MeCN (300 mL) is treated with EDCl (33.41 g, 174 mmol) and DMAP (2.03 g, 16 mmol). The mixture is stirred for 5 min and 2-(trimethylsilyl)ethanol (19.61 g, 166 mmol) is added. The mixture is stirred at RT for 16 h and the solvent is evaporated. The residue is partitioned between EtOAc and water. The organic layer is diluted with an equal portion of hexane and dried over anhydrous MgSO4. The solution is passed through a plug of silica gel and the solvents are evaporated to dryness to give 5-methyl-thiophene-2-carboxylic acid 2-trimethylsilanyl-ethyl ester as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][CH:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC1CCC(C(=O)O)O1
Yield: 97.3 %

Procedure:
A solution of 5-methyl-2-furoic acid (3.65 g, 28.97 mmol) in ethyl acetate (60 ml) was hydrogenated over 5% rhodium on carbon (250 mg) until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo to yield the title compound as a pale yellow oil (3.67 g, 97%); νmax (CH2Cl2) 3384, 3359, 1775, 1724 and 1355 cm-1 ; δH (CDCl3, 250 MHz) 1.35 (3H, d, J 6.1 Hz), 1.53 (1H, m), 2.09 (1H, m), 2.17-2.40 (2H, m), 4.21 (1H, m) and 4.46 (1H, dd, J 8.9, 4.7 Hz). [Mass spectrum: +ve ion (ammonia) MNH4+ (148)].