Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=O)[N:7]=1.CO.Cl.[NH2:17][OH:18]>C(N(CC)CC)C>[CH3:1][N:2]([CH2:10][C:11]#[C:12][I:13])[C:3]1[S:4][CH:5]=[C:6]([CH:8]=[N:17][OH:18])[N:7]=1
Reactant: NO
Reactant: CN(CC#CI)c1nc(C=O)cs1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CC#CI)c1nc(C=NO)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2-(N-methyl-3-iodo-2-propynylamino)-4-formylthiazole (No. 21) (72 mg) were added methanol (5 ml), triethylamine (0.2 ml) and hydroxylamine hydrochloride (24 mg) and the mixture was stirred at room temperature for 4 hours and evaporated to remove the solvent. After addition of a 5% aqueous solution of potassium carbonate, the residue was extracted with chloroform. The extract was washed with water, dried and evaporated to remove the solvent. The crystalline residue was treated with acetone to give 2-(N-methyl-3-iodo-2-propynylamino)-4-hydroxyiminomethylthiazole (No. 22) melting at 155°-156° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=1>C([O-])(O)=O.[Na+]>[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[C:42]([C:47]([F:48])([F:49])[F:50])[CH:41]=1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CC(=O)Nc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (300 mg, 1.54 mmol) were added HOBt (417 mg, 3.09 mmol), EDC (593 mg, 3.09 mmol) and DIEA (539 μL, 3.09 mmol). After 1.5 h, 4-methoxy-2-(trifluoromethyl)aniline (325 mg, 1.70 mmol) was added. After stirring for 14 h, the mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 114 mg (31%) of methyl 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoate INT-54. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; found 368 [M+H]+, tR=3.27 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.40 (t, J=14.6 Hz, 2H), 7.13 (s, 1H), 7.09-6.96 (m, 2H), 3.92 (d, J=10.8 Hz, 3H), 3.81 (m, 5H).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][Cl:25])=[CH:22][CH:21]=1>CCO>[ClH:25].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Product: Cl
Temperature: 25 °C
Yield: 64.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-methylbenzyl chloride (0.208 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 199 mg of the product 211. 1H NMR (DMSO-d6) δ 11.18 (s, 2H), 7.45 (d, 2H), 7.25 (d, 2H), 7.20-6.90 (m, 6H), 6.90-6.65 (m, 4H), 5.77 (s, 2H), 4.73 (s, 2H), 2.35 (s, 3H); MS: m/z 359 (M++1).
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].N1C=CN=C1.C(O)(=O)C.[C:52]([O:56][C:57]([N:59]([CH2:67][CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:60][C:61](OCC#N)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>O.[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1COCC1>[C:52]([O:56][C:57]([N:59]([CH2:67][CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:60][C:61]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)OCC#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 100 mg, 0.157 mmol) in water (1.0 ml) was added to a buffer (40 ml) in which imidazole (272.3 mg, 4.00 mmol) and N,N,N-trimethylhexadecan-1-aminium chloride (256.0 mg, 0.80 mmol) were dissolved and which was adjusted to pH 8 with acetic acid. A solution of cyanomethyl 2-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)acetate (Compound 6g-A, 198 mg, 0.546 mmol) in THF (1.2 ml) was then added and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly lyophilized, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=85:15).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[N:22]O)[C:16]=2[F:24])[N:12]([S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[C:16]=2[F:24])[N:12]([S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:11]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1cc(-c2cccc(C=NO)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccc(C#N)c2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution (5 mL) of tert-butyl{[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) in tetrahydrofuran were added triethylamine (93 mg) and methanesulfonyl chloride (84 mg) at room temperature. The reaction mixture was stirred at 70° C. for 8 hr, and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a pale-yellow oil (yield 106 mg, 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.O>COCCO>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: O
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 40 °C

Procedure:
Mixtures of each 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 30 parts of water, 70 parts of methylcellosolve and reducing agents and basic compounds, of kinds and in amounts as indicated in the following Table 4, were stirred at 90°-100°C for times, as indicated in the Table 4, then cooled to 40°C and filtered to recover crystals. The crystals were washed with water and dried under reduced pressure. In all of these Examples, the products were confirmed by infrared absorption spectrum to be 1-aminoanthraquinone. The yields of 1-aminoanthraquinone obtained in the form of crystals were as shown in the Table 4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)=[N:2]1.N1C=NN=N1.C(N(C(C)C)[P:30]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(C)C.OO.S([O-])([O-])(=[O:48])=S.[Na+].[Na+]>C1COCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([CH2:11][O:12][P:30](=[O:48])([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[N:10]=2)=[N:2]1
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=S([O-])([O-])=S
Reactant: C[Si](C)(C)CCOCn1cc(CO)nc1-c1ccon1
Agent: OO
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCc1cn(COCC[Si](C)(C)C)c(-c2ccon2)n1)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The compound obtained in step (3) (1.61 g) and 1H-tetrazole (760 mg) were dissolved in THF (20 ml), di-tert-butyl N,N-diisopropylphosphoramidite (2.45 ml) was added at room temperature under stirring, and stirring was conducted for 2 hours. This reaction solution was cooled to 0° C., 30% aqueous hydrogen peroxide (0.250 ml) was added, and stirring was conducted for 14 hours while the temperature was gradually returned to room temperature. A saturated aqueous sodium thiosulfate solution was added to the reaction solution to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract liquid was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→50%) using a silica gel column (trade name: SNAP Cartridge KP-Sil 100 g, manufactured by Biotage Ltd.) to give the title compound (2.21 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][C:12]([C:18]([OH:20])=O)=[CH:11]3)=[CH:5][CH:4]=1.Cl.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH:45][C:18]([C:12]1[N:13]=[CH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:22][CH:21]=1)=[CH:17][CH:16]=2)=[O:20])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1
Reactant: O=C(O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Yield: 26.9 %

Procedure:
A solution of 6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid (0.050 g, 0.149 mmol) in DMF (2.0 mL) was treated with 2(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.051 g, 0.164 mmol), HBTU (0.062 g, 0.164 mmol), and DIEA (0.112 mL) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using Hexanes:EtOAc 88:12 to give 0.025 g of 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-{[6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [I:1]I.C(Cl)(Cl)Cl.[F:7][C:8]1[CH:9]=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]>FC(F)(F)C([O-])=O.[Ag+]>[F:7][C:8]1[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][C:11]([I:1])=[C:10]([OH:18])[CH:9]=1
Reactant: Oc1ccc(C(F)(F)F)c(F)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(C(F)(F)F)cc1I
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of iodine (0.874 g, 3.44 mmol) in chloroform (17.1 mL, 214 mmol) was added over a period of 1.5 hours dropwise via addition funnel to a mixture of 3-fluoro-4-(trifluoromethyl)phenol (Preparation 886, 620 mg, 3.4 mmol) and silver trifluoroacetate (0.760 g, 3.44 mmol) in chloroform (3.4 mL, 43 mmol). After addition was complete, the reaction mixture was stirred an additional 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was washed successively with 10% aqueous sodium thiosulfate (w/v), half-saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated onto diatomaceous earth. The residue was purified by automated flash chromatography (24 g SiO2, hexanes to 1:1 methylene chloride-hexanes gradient elution). The initial product-containing fraction contained predominantly diiodinated material (by mass) with some monoiododinated material. The remaining fractions were concentrated in vacuo to afford the product as a light yellow oil (579 mg, 54%). The product was not dried under vacuum due to volatility.
Reaction SMILES: C(Cl)(Cl)Cl.[OH:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[CH3:18][C:19](OC(C)=O)=[O:20].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[C:19]([O:5][CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2ccc(CO)cc2N1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CHCl3 (30.0 mL) solution, the compound (670 mg) obtained in Step 52-1, Ac2O (536 μL), DMAP (20.0 mg) and Et3N (1.05 mL) were added under ice cooling and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60 N, mobile phase: MeOH/CHCl3=0/100 to 10/90; v/v) to obtain (2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl acetate (767 mg, a light yellow solid).
Reaction SMILES: ClC1C=CC(CC2N(C)C(C(C)C(O)=O)=CC=2)=CC=1.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([C:27]2[N:31]([CH3:32])[C:30]([CH:33]([CH3:39])[C:34]([O:36]CC)=[O:35])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1.[OH-].[Na+].C(O)C>O>[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([C:25]([C:27]2[N:31]([CH3:32])[C:30]([CH:33]([CH3:39])[C:34]([OH:36])=[O:35])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: CC(C(=O)O)c1ccc(Cc2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
5-(p-Chlorobenzyl)-α-methyl-1-methylpyrrole-2-acetic acid: A solution of 4.05 g. (0.0126 mole) of ethyl 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole- 2-acetate, 15 ml. of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed for 30 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitated solid is collected and recrystallized from methanol-water to give a white crystalline solid, 5-(p-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid, m.p. 135°-136°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C[O-].[Na+]>CC(N(C)C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][CH:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN1CCC(N)C1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CN1CCC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1=O
Temperature: 140 °C

Procedure:
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-1-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140° C. for 20 minutes. The reaction mixture was cooled to room temperature and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50° C. for 15 min. The mixture was then partitioned between aqueous saturated Na2CO3 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1coc(N)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1coc(NS(C)(=O)=O)n1
Reaction time: 14 h

Procedure:
To a 20 ml screw cap vial was added (1 g, 5.8069 mmoles) ethyl 2-amino-1,3-oxazole-4-carboxylate, (10 ml) dichloromethane and (1.39 ml, 7.9797 mmoles, 1.25 eq.) N,N-diisopropylethylamine. To the reaction was then added (0.545 ml, 7.0415 mmoles, 1.1 eq.) methanesulfonyl chloride, and the reaction was agitated for 14 hours. The reaction was then evaporated to dryness and purified using a Biotage silica gel column, resulting in (272 mg) of ethyl 2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate.
Reaction SMILES: [Mg].[CH:2]1([CH2:8][C:9]([CH3:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:12](Br)[C:13]#C.Cl.[CH3:17]COCC>C1C=CC=CC=1>[CH2:5]1[CH2:6][CH2:7][CH:2]([CH2:8][C:9]([CH3:17])([OH:10])[CH2:11][C:12]#[CH:13])[CH2:3][CH2:4]1
Reactant: C#CCBr
Reactant: CCOCC
Reactant: CC(=O)CC1CCCCC1
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Product: C#CCC(C)(O)CC1CCCCC1
Temperature: 25 °C

Procedure:
To a mixture of 43.5 parts of magnesium in 125 parts by volume of ether is added a portion of a solution containing 84 parts of methyl cyclohexylmethyl ketone and 71.4 parts of propargyl bromide in a solution consisting of 60 parts by volume of benzene and 180 parts by volume of ether. After the addition of 0.05 part of mercuric chloride to initiate the reaction, the remainder of the reactants is added dropwise. The reaction mixture is heated at the reflux temperature for about 15 minutes, allowed to cool to room temperature, then poured carefully into cold dilute hydrochloric acid. The aqueous phase is separated, extracted with ether and the combined ether extracts are washed successively with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness. Vacuum distillation of the residue affords 4(RS)-4-cyclohexylmethyl-4-methyl-1-butyn-4-ol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:18]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:4][CH:5]=4)[C:11]=3[CH2:19]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1
Temperature: 150 °C
Yield: 24.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (700 mg, 3.4 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (1.5 g, 10.2 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.1 mmol). The mixture was heated in a sealed tube at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (340 mg, 26%).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([O:22]CC)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.O>[C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9](=[O:18])[N:8]2[CH2:19][C:20]([OH:22])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
Ethyl (4,5-cis-diphenyl-2-oxo-3-oxazolidinyl)acetate (40.6 g, 125 mmol) was dissolved in tetrahydrofuran (100 ml) and a solution of sodium hydroxide (6 g, 150 mmol) in water (40 ml) was added thereto. The mixture was stirred at room temperature for 15 minutes. To the homogeneous solution was added water (150 ml) and the mixture was washed twice with diisopropyl ether (20 ml). The aqueous layer was adjusted to pH 2 with a 10-fold dilution of concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The filtrate was concentratred and the residue was recrystallized from methylenechloride-n-hexane mixture to give the title compound (29.1 g) as white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1.Cl.[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH2:29]Cl)=[CH:27][N:26]=[CH:25]2)=[CH:21][CH:20]=1)#[N:18].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[N:1]1([CH2:29][C:28]2[N:24]([CH2:23][C:22]3[CH:31]=[CH:32][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)[CH:25]=[N:26][CH:27]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CN2CCC3(CC2)C(=O)Nc2ccccc23)cc1
Reaction time: 15 h

Procedure:
A solution of spiro[3H-indole-3,4′-piperidin]-2(1H)-one, as described above in Step B, (110 mg, 0.54 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt, as described in Example 1, Alternate Step A, (134 mg, 0.50 mmol), and triethylamine (0.21 mL, 1.5 mmol) in anhydrous acetonitrile (1.5 mL) was stirred at room temp. for 15 hours. The resulting mixture was diluted with ethyl acetate and the solution washed with sat'd aqueous sodium carbonate, dried (anhyd. sodium sulfate), filtered and concentrated under vacuum. The resulting residue was triturated with ethyl acetate to give a white solid which was collected to afford the title compound as a crystalline freebase, mp: 245-247° C.