Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:20]=[CH:19][S:18][C:4]=2[N:5]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[N:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]2[CH:20]=[CH:19][S:18][C:4]=2[N:5]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:6](=[O:13])[C:7]=1[C:8]([NH:30][CH2:29][CH2:28][CH2:27][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:10]
Reactant: CCOC(=O)c1c(O)c2ccsc2n(CC(C)C)c1=O
Reactant: NCCCN1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=O)c(C(=O)NCCCN2CCCCC2)c(O)c2ccsc21
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A mixture of ethyl 6,7-dihydro-4-hydroxy-7-isobutyl-6-oxothieno[2,3-b]pyridine-5-carboxylate (0.1 g, 0.34 mmol), 3-(piperidin-1-yl)propan-1-amine (96 mg, 0.68 mmol) and toluene (15 mL) was heated at 100° C. for 2 h and cooled to room temperature. Solvent was removed under reduced pressure; the residue was purified on a silica gel flash chromatography column eluted with 3% methanol-dichloromethane to afford the title compound as a colorless oil (0.11 g, 83% yield). 1H NMR (400 MHz, CDCl3): δ 10.20 (br s, 1H), 7.38 (d, 1H), 6.95 (d, 1H), 3.92 (d, 2H), 3.49-3.44 (m, 2H), 2.90-2.78 (m, 6H), 2.40 (m, 1H), 2.20-1.38 (m, 8H), 1.00 (d, 6H); MS: m/e 392 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cc(F)ccc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (1.28 g, 7.08 mmol) in acetonitrile (17.7 mL) was treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (1.15 mL, 6.95 mmol) and acetonitrile (17.7 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,5-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.56 g, 6.44 mmol) in acetonitrile (16.1 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 17%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+H]+ 340.1355, observed 340.1355; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.35-1.53 (m, 1H), 1.53-1.69 (m, 1H), 1.72-1.89 (m, 1H), 3.66 (s, 3H), 4.13-4.33 (m, 2H), 4.73 (dd, J=11.5, 4.5 Hz, 1H), 5.07 (s, 1H), 7.13-7.35 (m, 1H), 7.42-7.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[C:9]([Cl:15])=[N:10][C:11](Cl)=[N:12][CH:13]=1.C(N(CC)CC)C.[Cl-:23].[NH4+]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[N:12]=[C:13]([Cl:23])[CH:8]=[C:9]([Cl:15])[N:10]=2)[NH:5][CH:6]=1
Reactant: [Cl-]
Reactant: Cc1c[nH]cn1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c[nH]c(-c2nc(Cl)cc(Cl)n2)n1
Reaction time: 16 h

Procedure:
4-Methylimidazole (11.45 g, 140 mmol) was added in one portion to a solution of trichloropyrimidine in (2.47 g, 135 mmol) and triethylamine (30 mL, 216 mmol) in THF (500 mL). After 16 hrs, the reaction mixture was poured into saturated, aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The reaction mixture was filtered and all volatiles were removed under reduced pressure. 2-(4-methylimidazolyl)-4,6-dichloropyrimidine was isolated by flash chromatography (15% ethyl acetate in hexane) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:17])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 56 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.50 mmol) in DMF (20 mL) cooled on an ice-bath was added sodium hydride (120 mg, 3.00 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 10 min. Methyl iodide (233 μL, 532 mg, 3.75 mmol) was added and the resulting mixture stirred at room temperature for 18 h. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated in vacuo affording 4-Methyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester as a yellow oil (300 mg, 56%). 1H NMR (CDCl3, 300 MHz): δ 4.08 (s, 2 H); 3.65 (t, J=5.4 Hz, 2 H); 3.35 (t, J=5.4 Hz, 2 H); 3.00 (s, 3 H); 1.47 (s, 9 H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:19])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C([O-])([O-])=O.[Na+].[Na+].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:19][C:3]1[C:2]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[C:21](=[O:20])[NH:22][CH2:23][CH2:24]3)=[CH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:4]=1
Reactant: CCS(=O)(=O)c1ccc(-c2cnc(N)c(Br)c2)cc1
Reactant: O=C1NCCc2cc(B(O)O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
A mixture of the 3-bromo-5-(4-(ethylsulfonyl)phenyl)pyridin-2-amine (100 mg, 0.29 mmol), 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (75 mg, 0.29 mmol), PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) and Na2CO3 in 3:1 MeCN:H2O was microwave heated at 150° C. for 3 min. At completion, the reaction mixture was filtered, then purified by preparatory HPLC to provide 6-(2-amino-5-(4-(ethylsulfonyl)phenyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one as a pale yellow solid (48 mg, 41% yield) after reverse phase preparatory HPLC purification. 1H NMR (400 MHz, MeOD) δ ppm 8.37 (d, J=2.5 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.5 Hz, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 3.56 (t, J=6.7 Hz, 2H), 3.19-3.27 (m, 2H), 3.07 (q, J=6.5 Hz, 2H), 1.25 (t, J=7.3 Hz, 3 H); MS (EI) m/z: 408 [M+H]+.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH3:4]>>[CH:1]([O-:3])=[O:2].[CH:1]([O-:3])=[O:2].[CH:1]([O-:3])=[O:2].[CH:1]([O-:3])=[O:2].[NH4+:4].[NH4+:4].[NH4+:4].[NH4+:4]
Reactant: N
Reactant: O=CO
Product: O=C[O-]
Product: [NH4+]

Procedure:
A 85% w/w solution of ammonium tetraformate was prepared by the reaction of 98-100% strength formic acid (1 mole, 46 g) with concentrated aqueous ammonia solution (12.9 g solution containing 33% w/w NH3 =0.25 mole, 4.25 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.CO.O.C([O-])(=O)C.[NH4+]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=[C:4]2[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1cc(Cl)ncn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: Clc1cc2nc(-c3ccccc3)cn2cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
A 100 mL round bottom flask was charged with commerically available 6-chloropyrimidin-4-amine (300 mg, 2.316 mmol) and 2-bromo-1-phenylethanone (922 mg, 4.63 mmol). The mixture was suspended in acetonitrile (23.2 mL) and the flask was fitted with a reflux condenser and heated to reflux via heating mantle. The reaction mixture was let stir overnight. After 17 hours, LCMS showed a major peak consistent with desired by mass (m/z=230 [M+H]+); (Methanol/Water/Ammonium Acetate/Phenomenex Luna C18, 30×2 mm, 3μ ES+/−). The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude solid was diluted with ethyl acetate and a saturated solution of sodium bicarbonate. The contents of the flask were transferred into a separatory funnel where the aqueous was extracted with ethyl acetate (×3), analyzed for product, and subsequently discarded. The combined organics were transferred into a 125 mL Erlenemyer flask and heated using a heat gun to dissolve the remaining crude. The solution was transferred back into a separatory funnel and the organic was washed with brine (×2), dried with magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography: (40 g SiO2, equilibrated with hexanes, loaded with dichloromethane, initial waste: 125 mL, fraction size: 12 mL 16×100 mm, and eluted with ethyl acetate in hexanes 0% [100 mL], 10% [250 mL], 20% [1000 mL]). Collected product containing fractions to give 7-chloro-2-phenylimidazo[1,2-c]pyrimidine (206 mg, 0.897 mmol, 38.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J=1.3 Hz, 1H), 8.54 (d, J=0.8 Hz, 1H), 8.06-7.99 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.54-7.45 (m, 2H), 7.44-7.37 (m, 1H). Mass found 230 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1[CH2:38][CH2:37][O:36]CC1.[CH3:39][N:40](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:33][CH2:38][C:37]([NH:40][CH3:39])=[O:36])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 20.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol) was dissolved in DMF (1 mL) and 4-methylmorpholine (0.038 mL, 0.348 mmol), 2-amino-N-methylacetamide, HCl (14.44 mg, 0.116 mmol), and HATU (39.7 mg, 0.104 mmol) were added. This solution was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.4 min) to give (R/S)-2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (6.2 mg, 0.012 mmol, 19.97% yield): LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.23 (2 H, m), 7.66-7.79 (4 H, m), 7.52-7.66 (3 H, m), 5.20 (1 H, s), 3.88-4.00 (2 H, m), 3.78-3.88 (2 H, m), 2.75 (3 H, s); HPLC Peak RT=8.1 min (Analytical Method C).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][C@@H:9]1[C:17](=[O:29])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)(Cl)Cl.C(OC(C)C)(C)C>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:17]([C@H:9]2[CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13][NH:8]2)=[O:29])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: CC(=O)N1CCN[C@@H](C(=O)NCc2ccc(C(C)C)cc2)C1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of the compound (4.72 g) obtained in Step 2 in chloroform (5 ml) was added, with stirring at room temperature, 4N hydrogen chloride/1,4-dioxane solution (20 ml). After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated again under reduced pressure. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.23 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([CH:31]([OH:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])=[CH:5]2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:44])[CH2:32][O:33][C:34]1[C:39]([F:40])=[C:38]([F:41])[CH:37]=[C:36]([F:42])[C:35]=1[F:43])[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])=[CH:5]2
Reactant: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)COc1c(F)c(F)cc(F)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-[(5-fluoro-1-methyl-indole-2-cabonyl)valinyl]-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluorophenyloxy)-pentanoic acid, tert-butyl ester (112.6 mg, 0.8 mmol) in CH2Cl2(5.0 ml) was added Dess-Martin periodinane (95 mg, 0.22 mmol) al d the solution stirred for 10 min. at room temperature. The reaction was quenched with Na2S2O4, diluted with EtOAc, washed with NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (1:1 EtOAc/hexane) to give the titled product as a white solid (which was directly taken to the next step in Example 115).
Reaction SMILES: [CH2:1]([Cl:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[S:21][S:20][C:19](=[S:22])[CH:18]=2)[CH2:13][CH2:12]1>C(O)C>[Cl-:10].[CH2:1]([S:22][C:19]1[S:20][S:21][C:17](=[N+:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[CH:18]=1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: S=c1cc(N2CCOCC2)ss1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCO
Product: O=C(CSc1cc(=[N+]2CCOCC2)ss1)c1ccccc1
Product: [Cl-]
Temperature: 10 °C
Yield: 85.2 %

Procedure:
Phenacyl chloride (10.5 g) is added to a suspension of 5-morpholino-1,2-dithiol-3-thione (9.85 g) in ethanol (200 cc), and the reaction mixture is kept under reflux for 3 hours. After cooling to a temperature of about 10° C., the insoluble product formed is filtered off and washed with ethanol (30 cc). After drying, N-(5-phenacylthio-1,2-dithiol-3-ylidene)-morpholinium chloride (14.3 g) is obtained, which melts at 138° C. and is solvated by 9% of ethanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[I:29]Cl>[Cu]I.O1CCCC1>[CH2:12]([N:19]1[C:2]([I:29])=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=2)[C:8]#[N:9])[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(F)c(C#N)c1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: ClI
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc(-c2nnn(Cc3ccccc3)c2I)ccc1F

Procedure:
A mixture of Example 62B (200 mg, 1.38 mmol), benzyl azide (0.176 mL, 1.38 mmol), tetrahydrofuran (12 mL), triethylamine (0.230, 1.56 mmol), CuI (263 mg, 1.38 mmol) and ICl (0.069 mL, 1.38 mmol) under argon was stirred at room temperature for 24 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane, loaded directly onto a silica gel column and eluted with ethyl acetate/hexanes (10-20%) to afford the title compound. MS (ESI+) m/z 404.9 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]2)=[CH:25][CH:24]=1.CON(C)[C:43]([CH:45]1[CH2:47][CH2:46]1)=[O:44]>C1COCC1.CCOC(C)=O>[CH:45]1([C:43]([C:30]2[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][N:28]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:39][CH:38]=3)[N:29]=2)=[O:44])[CH2:47][CH2:46]1
Reactant: CON(C)C(=O)C1CC1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 9.7 %

Procedure:
According to Scheme 16: Butyl lithium 2.5 M (9.9 mmol, 4 mL) was added to a solution of diisopropylamine (9.9 mmol, 1.4 mL) in THF (20 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 5 minutes and then at room temperature. To the resulting LDA solution was added at −78° C. a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (7.61 mmol, 1.98 g) in THF (30 mL) and the reaction mixture was stirred for 15 minutes at −78° C. Then N-methoxy-N-methylcyclopropanecarboxamide (9.14 mmol, 1.18 g) in THF (10 mL) was added and the reaction mixture was stirred at room temperature. The reaction mixture was diluted with AcOEt and washed with a saturated aqueous solution of NH4Cl. The combined organic phases were dried over MgSO4, were filtered and solvents were evaporated. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to yield ethyl 3-(cyclopropanecarbonyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (0.74 mmol, 244 mg, 9%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1>C(O)=O>[CH:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(N)n1
Solvent: O=CO
Product: COC(=O)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.) was stirred for 30 minutes at 40° to 50° C. and thereto was added methyl 6-amino-2-pyridinecarboxylate (616 g.) at 40° C., and then the mixture was stirred for 1 hour at 80° C. After the removal of the solvent from the reaction mixture, the residue was dissolved in a mixture of benzene and n-hexane and then filtered. Thus obtained precipitates were recrystallized from benzene (2 l.) to give methyl 6-formamido-2-pyridinecarboxylate (647.8 g.), mp 134° to 136° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][CH:3]=1.C([O-])C.[Na+].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([NH:19][C:20]([CH3:24])=[CH:21][C:22]#[N:23])[CH:16]=[CH:17][CH:18]=1.[CH:27]([C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)=O.N1CCCCC1>C(O)C>[C:2]([C:3]1[CH:27]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[C:21]([C:22]#[N:23])=[C:20]([CH3:24])[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:25])([F:26])[F:11])[CH:14]=2)[C:4]=1[NH2:5])(=[O:6])[CH3:1]
Reactant: CC(=CC#N)Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccno1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 100 mg (1.20 mmol) 5-methylisoxazole are dissolved in 2 ml ethanol and 81.90 mg (1.20 mmol) sodium ethanolate are added. The mixture is stirred at room temperature for one hour. Then 272.24 mg (1.20 mmol) of the compound of Example 2A, 157.82 mg (1.20 mmol) 4-formylbenzonitrile and 10.25 mg (11.90 μl, 0.12 mmol) piperidine are added to the mixture which is stirred at reflux overnight. After the reaction is finished, the mixture is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:18]([O-])=[O:19].[Na+]>Cl.C(O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:18]=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NCCc2ccc(Cl)nc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N(CCc2ccc(Cl)nc2)N=O)cc1
Temperature: 25 °C

Procedure:
A 250 mL reaction flask was charged with N-(2-(6-chloropyridin-3-yl)ethyl)-4-methylaniline (5 g, 20.3 mmol; Example 117B) in 1 N HCl (22 mL) and ethanol (20 mL). The mixture was stirred at room temperature until complete dissolution was obtained (˜2 hours). The reaction then was cooled in an ice bath and a solution of sodium nitrite (1.55 g, 22.47 mmol; Aldrich) in water (10 mL) was added dropwise with stirring. After the addition was complete, the reaction mixture was allowed to warm briefly to room temperature, then it was cooled again in an ice bath before filtering. The filter cake was washed with water several times and then dried to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.38 (s, 3H), 2.88 (t, J=7 Hz, 1H), 4.34 (t, J=7 Hz 2H), 7.25-7.39 (m, 5H), 7.63 (dd, J=8, 2 Hz, 1H), 8.11 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[O:24].C1(C)C=CC=CC=1>O1CCCC1>[OH:24][CH:23]([C:8]1[N:7]([CH3:6])[C:15]2[C:10]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:22]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cn1cc(-c2ccccc2)c2ccccc21
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(-c2ccccc2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A solution of butyllithium (1.6 M, 3.44 mL, 5.5 mmol) was added at −20° C. to a solution of 1-methyl-3-phenyl-1H-indole (1b) (1.08 g, 5.3 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.1 mL, 5.5 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (1c) as a white solid (360 mg, 1.16 mmol, 22%).