Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](O)(=[O:26])/[CH:21]=[CH:22]\[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]3=[O:26])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)C=CC1=O)OC2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.53 g, 1.86 mmol, prepared as described in Example 17) in tetrahydrofuran (10 ml) was added, maleic acid (0.24 g, 2.05 mmol) and diisopropylcarbodiimide (0.58 ml, 3.72 mmol). The reaction mixture was heated to reflux for 3 hours and then allowed to cool to room temperature over an 18 hour period. The solvent was stripped off in vacuo and the residue diluted into ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (2×50 ml), 1% hydrochloric acid (2×20 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo affording an oil which was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (6:4) as eluant. Pure fractions (Rf=0.25) were collected and the solvent evaporated in vacuo to give 0.60 g (90%) of 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [OH-].[Na+].CO.C1(C)C=CC=CC=1.C([S:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]([CH3:25])[CH2:21][N+:22]([O-])=[O:23])=[O:18])(=O)C>O>[N:22](=[C:21]1[CH:20]([CH3:25])[N:19]([CH3:26])[C:17](=[O:18])[CH2:16][S:15]1)[OH:23]
Reactant: CC(=O)SCC(=O)N(C)C(C)C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1C(=NO)SCC(=O)N1C
Reaction time: 0.08 h
Yield: 29.2 %

Procedure:
A solution of 5.6 g of sodium hydroxide, 100 ml of methanol and 100 ml of toluene was charged into a flask and stirred vigorously while adding 23 g of 2-(acetylthio)-N-methyl-N-(1-nitro-2-propyl)acetamide, over a 5 minute period at 30°-40° C. The reaction mixture was stirred at 40° C for 8 hours, then stirred overnight at room temperature. The mixture was stripped of solvents under reduced pressure. The solid residue was dissolved in 200 ml of water. The mixture was filtered and the filtrate was acidified with hydrochloric acid. The solid which precipitated was filtered, washed with water and dried at room temperature. The solid product was recrystallized from isopropanol to yield 5.0 g of 2-oximino-3,4-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.436 mmol) produced in Example 16(vi) in pyridine (4 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (120 μL, 0.871 mmol), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate (15 mL)/tetrahydrofuran (5 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was washed with acetone (15 mL) to give the title compound (69 mg, 37%) as a white solid.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+].BrC[CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>CN(C=O)C>[O:21]1[CH2:22][CH2:23][CH:18]([O:13][CH2:10][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: BrCC1CCOCC1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(COC2CCOCC2)cc1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a mixture of 4-hydroxybenzonitrile (665 mg, 5.59 mmol) and caesium carbonate (2.00 g, 6.14 mmol) in DMF (5 mL) was added 4-(bromomethyl)tetrahydro-2H-pyran (1.00 g, 5.59 mmol), and the reaction mixture was stirred at 80° C. over night. After cooling to rt, the reaction mixture was poured into water. After stirring for a few minutes, the precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (785 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 2H), 7.92 (d, 2H), 4.05-4.00 (dd, 2H), 3.82 (d, 2H), 3.48-3.41 (m, 2H), 2.15-2.02 (m, 1H), 1.78-1.72 (dd, 2H), 1.52-1.41 (m, 2H); ES-MS m/z 218, HPLC RT (Method D) 2.09 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:3]=[C:2]([NH:1][S:42]([CH3:41])(=[O:44])=[O:43])[CH:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cc(N)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc(NS(C)(=O)=O)c2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a 0° C. solution of 51.1D (512 mg, 1.16 mmol) and triethylamine (478 μl, 3.44 mmol) in CH2Cl2 (10 mL) under N2 was added methanesulfonyl chloride (available from Aldrich) (84.3 μl, 1.08 mmol) drop wise over 10 min. After stirring at 0° C. for 30 min, the reaction mixture was treated with saturated aqueous NaHCO3 (1 mL), diluted with water (10 mL), and extracted with CH2Cl2 (3×10 mL). Organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-70% EtOAc/CH2Cl2 provided title product 51.1E as white solid (268 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13](O)[CH2:14][C@H:15]([CH2:19][O:20]CC2C=CC=CC=2)[CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][OH:47]>[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C@@H:13]([CH2:46][OH:47])[CH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:17])[CH3:18])[CH2:11][C@@H:10]([CH:29]([CH3:31])[CH3:30])[C@@H:9]1[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CO
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](O)C[C@H](COCc3ccccc3)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC
Agent: [Pd]
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H]([C@@H](CO)C[C@H](CO)C(C)C)N2C(=O)OC(C)(C)C)ccc1OC

Procedure:
A solution of 0.48 g of 8 in 1.5 mL of methanol is treated with 0.1 g of 10% palladium on charcoal. The suspension is stirred under an atmosphere of hydrogen until the uptake is stable. The suspension is filtered and the solid washed with 5 mL of methanol in two portions. Removal of the solvent in vacuum provides alcohol 9 as an oil. A negative [a]d (e.g. −34.1, −34.6) is found at c=1, CHCl3.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:30]([C:31](Cl)=O)=[CH:29][C:28]([Cl:34])=[CH:27][N:26]=1.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[C:30]([C:31]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)=[CH:29][C:28]([Cl:34])=[CH:27][N:26]=1
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)cnc2Cl)n1
Temperature: 150 °C
Yield: 14.2 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2,5-dichloro-3-pyridinecarbonyl chloride (0.223 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (14% yield) of pure product: MS (ES) m/z 480 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:4][CH:3]=1.CO>CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH2:14][CH2:13][NH:12][C:11](=[O:15])[C:10]=3[C:4]=2[CH:3]=1
Reactant: O=C1C=C(Nc2ccc(F)cc2)CCN1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NCCc2[nH]c3ccc(F)cc3c21
Temperature: 130 °C
Yield: 44.4 %

Procedure:
Cu(OAc)2 (9.69 g, 53.39 mmol) was added to a stirred solution of 4-(4-fluorophenylamino)-5,6-dihydropyridin-2(1H)-one (I-59e: 5 g, 24.27 mmol) and Pd(OAc)2 (490 mg, 2.18 mmol) in DMF (96 mL) under argon atmosphere and the resulting reaction mass was heated at 130° C. for 2 hours. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was cooled to room temperature and filtered through a celite bed. The filtrate was partitioned between water and ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM) afforded 2.2 g of the product (44.7% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C1C=NC=CC=1)([O-])=O.[CH3:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1.[CH3:39][N:40]([CH:42](OC)OC)[CH3:41]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CO.N1C=CC=CC=1>[CH3:39][N:40]([CH3:42])[CH:41]=[CH:29][C:30]1[C:35]([N+:36]([O-:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Pd]
Agent: O=[N+]([O-])c1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CN(C)C=Cc1ncccc1[N+](=O)[O-]
Yield: 84 %

Procedure:
Particularly key to an efficient synthesis of 3-AP or 3-AMP is the high-yield introduction of a methyl or vinyl group, preferably vinyl, at the 2 position of the pyridine moiety utilizing a Heck or Stille vinylation reaction or a methylation reaction under Suzuki conditions. These reactions proceed at the 2-position of a pyridine moiety in high yield (generally, greater than 50% and in most instances, greater than 70%). The advantage of the vinylation reaction is that the 2-vinyl group may be readily converted to a 2-carboxaldehyde group for further conversion to the 2-thiosemicarbazone using a high yield ozonolysis reaction conducted in a polar solvent, such as methanol. The preferred vinylation reaction is a Heck or Stille vinylation reaction performed utilizing a reagent selected from among the following: Bu3SnCH=CHR3, (OH)2B--CH=CHR3, ClZnCH=CHR3 and XMgCH=CHR3. The vinylation reaction takes place in the presence of triphenylphosphine (PPh3) and/or tetrakis(triphenylphosphine) palladium [Pd(PPh3)4 ] usually in a solvent such as toluene in the presence of heat. The advantages of the methylation reaction under Suzuki conditions over the two step methylation of the prior art include a greatly improved yield, reduction in the number of steps and therefore handling required and ease in scaling the synthesis up for commercial production. Alternatively, to introduce a vinyl group at the 2-position of 3-nitropyridine, one may advantageously react 2-methyl-3-nitropyridine with dimethylforamamidedimethylacetal (DMFDMA) to produce 2-dimethylamino vinyl-3-nitropyridine compound 3a, followed by oxidation with sodium periodate (NaIO4) to produce carboxaldehyde 4 in an unexpectedly high 84% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8].[Cl:18][C:19]1[CH:20]=[C:21]([C@H:26]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[NH:58]S(C)(=O)=O)[CH2:48][CH2:47]2)[CH2:27][N:28]([CH3:43])[C:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([C:41]#[N:42])[CH:32]=2)=[O:30])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[C:5]([OH:17])(=[O:16])[CH2:6][C:7]([CH2:12][C:13]([OH:15])=[O:14])([C:9]([OH:11])=[O:10])[OH:8].[Cl:18][C:19]1[CH:20]=[C:21]([C@H:26]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[NH:58][C:1](=[O:3])[CH3:2])[CH2:48][CH2:47]2)[CH2:27][N:28]([CH3:43])[C:29]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[C:33]([C:41]#[N:42])[CH:32]=2)=[O:30])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CN(C[C@@H](CCN1CCC(c2ccccc2NS(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reactant: CC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1ccccc1C1CCN(CC[C@H](CN(C)C(=O)c2cc(C#N)cc3ccccc23)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 8 h
Yield: 104.4 %

Procedure:
Acetyl chloride (0.060 g) was added to a solution of 4-(2-aminophenyl)-N-Boc-piperidine (0.070 g) (Example 21 sub-part (b)) and triethylamine (0.090 g) in DCM (2 mL) and stirred overnight. The reaction was diluted with Et2O and extracted sequentially with aqueous sodium bicarbonate and 1N HCl. The organic extract was dried and evaporated to give the title compound (0.070 g) as a colorless oil. MS m/z 341 (M+Na). 1H NMR (CDCl3) δ 7.26 (m, 4H), 7.69 (br, 1H), 4.15 (m, 2H), 2.67 (m, 3H), 2.23 (s, 3H), 1.75 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:23][CH:22]=1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: COc1ccc(OCCN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)cc1
Temperature: 100 °C
Reaction time: 27 h
Yield: 19.4 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(4-methoxyphenoxy)ethylamine hydrochloride (489 mg) and sodium hydrogencarbonate (1.37 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(4-methoxyphenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (98 mg).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][OH:20].CC(C)([O-])C.[K+]>C1COCC1>[CH3:23][O:22][C:18](=[O:21])[CH2:19][O:20][C:2]1[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Br)nc1
Reactant: COC(=O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 70 °C
Yield: 65.7 %

Procedure:
A suspension of 6-bromo-N-(4-fluoro-phenyl)nicotinamide (1.0 g, 3.4 mmol), methyl glycolate (1.6 mL, 19 mmol), and potassium tert-butoxide (1.5 g, 10 13.6 mmol) in THF (10 mL) was heated in a sealed tube at 70° C. After 3 h the reaction mixture was poured onto ice and the solids isolated by filtration. Purification on silica gel by column chromatography using 30% ethyl acetate in hexanes gave 0.68 g (65%) of the titled product as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-(trifluoromethyl)benzoic acid (224 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(O)CCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]3)=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3)CC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCCCO
Product: CC(=O)N1CCC(CCC(=O)c2ccc3c(c2)CCN3c2ccncc2)CC1
Reaction time: 3 h
Yield: 69.7 %

Procedure:
A mixed solution of 3-(1-acetyl-4-piperidinyl)-1-(2,3-dihydroindol-5-yl)-1-propanone (0.4 g, 1.33 mmol) and 4-chloropyridine hydrochloride (0.2 g, 1.33 mmol) in 1-butanol (4 ml) was heated and stirred for 3 hours. The solvent was then distilled off and the residue was dissolved in 5% sodium hydroxide/H2O-ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to provide the title compound (0.35 g) as colorless powders melting at 157-158° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[OH2:26]>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:2]2[CH2:7][CH2:6][C:5](=[O:26])[CH2:4][CH2:3]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O
Reactant: O=C1CCCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of a piperidone hydrochloride (1 eq) in dichloromethane was added pyridine (2.1 eq) at 0° C. and the reaction mixture was stirred for 15 min. To this, a solution p-toluene sulfonyl chloride (1.1 eq) in dichloromethane was added at 0° C. and the reaction was continued at room temperature for overnight. Water was added and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the 1-[(4-methylphenyl)sulfonyl]piperidin-4-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:15][S:16]([C:19]2[S:20][C:21]([C:24]#[C:25][Si](C)(C)C)=[CH:22][CH:23]=2)(=[O:18])=[O:17])[C:12]([OH:14])=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CO>[C:24]([C:21]1[S:20][C:19]([S:16]([NH:15][C@H:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:12]([OH:14])=[O:13])(=[O:18])=[O:17])=[CH:23][CH:22]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a solution of crude (R)-3-(1H-Indol-3-yl)-2-(5-trimethylsilanylethynyl-thiophene-2-sulfonylamino)-propionic acid 115 (0.126 g, 0.282 mmol) in dichloromethane/methanol mixture (1:1, 10 mL) was added K2CO3 (0.047 g, 0.34 mmol) and allowed to stir for 60 minutes. The reaction mixture was then filtered and retentate washed with dichloromethane-methanol mixture. The combined filtrate was concentrated under reduced pressure and then purified using a SAX column to obtain (R)-2-(5-Ethynyl-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid 116 (52 mg, 49%). LC-MS (ES+) 375; (ES−) 373.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O:17]1[C:21](=O)[CH2:20][NH:19][C:18]1=[O:23].N1CCCCC1.C(O)(=[O:32])C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[C:21]3/[C:20](=[O:32])[NH:19][C:18](=[O:23])[O:17]/3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)O1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)/C(=C/c2ccc(Oc3ccc(F)cc3)cc2)O1

Procedure:
The title compound was prepared by reacting 4-(4-fluorophenoxy)benzaldehyde (from Step A in Example 1) with oxazolidine-2,5-dione in toluene in the presence of piperidine and acetic acid with continuous removal of water, as described in Step B of Example 1. The crystalline product collected was washed with petroleum ether on the filter and dried in vacuo.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][CH:19]=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][C:19]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=CCCO3)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(S(=O)(=O)Cl)CCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, to dimethylformamide (0.2 ml) was added dropwise sulfuryl chloride (0.17 ml) and the mixture was stirred, under nitrogen atmosphere, at room temperature for 10 minutes. To the mixture was added 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine (0.3 g), and the mixture was stirred, under nitrogen atmosphere, at 90° C. for 3 hours. To the mixture was added ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The, solvent was evaporated to give 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-sulfonylchloride (0.36 g) as pale yellow crystals.