Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5]OS(C2C=CC=C([N+]([O-])=O)C=2)(=O)=O)[CH2:4][O:3]1.[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:26][C:25]=2[OH:40])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:19]1([NH:22][C:23](=[O:41])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:26][C:25]=2[O:40][CH2:1][C@:2]2([CH3:5])[CH2:4][O:3]2)[CH2:21][CH2:20]1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: COc1ccc(COc2ccc(C(=O)NC3CC3)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(=O)NC3CC3)c(OC[C@]3(C)CO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of [(2S)-2-methyloxiran-2-yl]methyl3-nitrobenzenesulfonate (218 mg, 0.797 mmol), N-cyclopropyl-2-hydroxy-4-[(4-methoxybenzyl)oxy]benzamide (250 mg, 0.797 mmol) and cesium carbonate, Cs2CO3, (311 mg, 0.956 mmol) in dimethylformamide (5 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (260 mg).
Reaction SMILES: [C:1]([S:20][CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:29](=O)([O:35]C(C)(C)C)[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:29]([NH:23][C@H:22]([C:24]([OH:26])=[O:25])[CH2:21][S:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of S-trityl cysteine (see Hiskey and Adams, J. Org. Chem., 30:1340, (1965)) (36.3 g, 0.10 mol) in dioxane (200 ml) and 1M aqueous NaOH (100 ml, 0.10 mol) was added di-t-butyl carbonate (25.36 g, 0.12 mol). The resulting opaque solution became warm and effervesced and the pH fell from 12 to 8 over one hour. After stirring for 90 min, 50% aqueous citric acid (40 ml) was added and the resulting mixture (pH 4) was extracted with ether. The ether was washed with water, then saturated brine, dried (MgSO4), filtered and evaporated to give N-BOC-S-(triphenylmethyl)-cysteine as an oil. Half of this material was dissolved in ether (200 ml) and treated with dicyclohexylamine (10 ml, 50 mmol) to give compound (XX) as a white precipitate which was filtered off, washed with ether and dried (25.1 g, 78%), mp 205°-207°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Reactant: NC(=O)CBr
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(CC(N)=O)C3)ccc1OCC2

Procedure:
Following the procedure for 143, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with bromo acetamide and the crude product subjected flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 155 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1 H); 7.83 (d, J=2.18 Hz, 1 H); 7.24 (d, J=2.21 Hz, 1 H); 7.18 (d, J=8.31 Hz, 1 H); 6.86 (s, 1 H); 5.71-5.63 (m, 1 H); 5.45 (s, 1 H); 4.54 (t, J=5.98 Hz, 2 H); 3.87 (t, J=7.28 Hz, 2 H); 3.81-3.72 (m, 1 H); 3.38 (t, J=6.84 Hz, 2 H); 3.22 (s, 2 H); 3.16 (t, J=5.99 Hz, 2 H); 1.59 (d, J=6.62 Hz, 6 H). 1 Exchangeable proton not observed. LCMS: RT=5.84 min, M+H+=408
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[SH-:17].[Na+]>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:17][C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]3[C:4]([N:3]=1)=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=3)=[N:3]2
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nc2cc(Cl)c(Cl)cc2nc1C(C)C
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (105 mg, 0.38 mmol) in DMF (3 ml) was added sodium hydrosulfide (21 mg, 0.23 mmol). The reaction mixture was stirred at 55-60° C. in an oil bath overnight. The product was purified by a plug filtration through silica gel using ethyl acetate:hexanes 1:20 followed by preparative thin layer chromatography using ethyl acetate:hexanes 1:60. Extraction of the product band using chloroform afforded the title compound as a white solid in 20% yield.
Reaction SMILES: [CH2:1]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+].Cl>O1CCCC1.CO.CCOCC>[CH2:1]([CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCCC(C=O)CCCCCCCC/C=C\CCCCCCCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCCC(CO)CCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Crude 2,3-di(9-(Z)-octadecenyl)propanal of formula (10) from Preparation 7 (10.0 g, 16.9 mmol) was dissolved in tetrahydrofuran/methanol (1:1, 200 ml) and cooled to 0° C. Sodium borohydride (3.13 g, 85.0 mmol) was added and the mixture was stirred overnight. The solution was acidified with 1N HCl to pH<2, diluted with ether, washed with water, concentrated and column chromatographed (chloroform) to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:5][N:4]([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(C1C=CC(C2CCN2C(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)(C)(C)C>>[F:28][C:25]([F:26])([F:27])[C:21]1[CH:20]=[C:19]([CH:2]2[CH2:3][N:4]([CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:5]2)[CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1cccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: CC(C)(C)c1ccc(C2CCN2C(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cccc(C2CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
This compound was prepared compound (37) using the procedure described for compound (11).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH:29]2[CH2:31][CH2:30]2)=[N:27][N:28]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[N:27][N:28]=3)[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: ClCc1nnc(C2CC2)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1nnc(C2CC2)o1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 75 mg, 0.331 mmol) in DMSO (2 mL) followed by sodium tert-butoxide (35.0 mg, 0.364 mmol) and 2-(chloromethyl)-5-cyclopropyl-1,3,4-oxadiazole (68.2 mg, 0.430 mmol). 1H NMR (400 MHz, DMSO-d6) δ 0.92-1.00 (m, 2 H), 1.07-1.16 (m, 2 H), 2.14-2.25 (m, 1 H), 2.92-3.03 (m, 1 H), 3.03-3.11 (m, 1 H), 3.11-3.20 (m, 1 H), 3.34-3.51 (m, 1 H), 3.53-3.58 (m, 1 H), 3.59-3.72 (m, 1 H), 3.85-4.00 (m, 2 H), 4.20-4.29 (m, 1 H), 4.53-4.63 (m, 1 H), 4.79-4.88 (m, 1 H), 7.56 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C15H17ClN6O2, 348.11; found 348.2.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:3]=1[O:4][C@@H:5]([CH3:27])[C:6]([NH:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[CH:18][NH:17][C:16]2=[O:24])[C@@H:12]([F:25])[C@@H:11]1[OH:26])=[O:7].[C:35]([NH:42][C@@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[C:38]([O:37][C:35]([NH:42][C@@H:43]([C:47]([O:26][C@@H:11]1[C@@H:10]([CH2:9][NH:8][C:6](=[O:7])[C@@H:5]([O:4][C:3]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([Cl:32])=[CH:31][C:2]=2[Cl:1])[CH3:27])[O:14][C@@H:13]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[CH:18][NH:17][C:16]2=[O:24])[C@H:12]1[F:25])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: CCc1c[nH]c(=O)n([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](O)[C@@H]2F)c1=O
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCc1c[nH]c(=O)n([C@@H]2O[C@H](CNC(=O)[C@H](C)Oc3cc(OC)c(Cl)cc3Cl)[C@@H](OC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H]2F)c1=O

Procedure:
Coupling of 1-[5-[2(S)-(2,4-dichloro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl-5-ethyluracil with N-Boc-D-valine in a manner analogous to that described in Example 1(A) gave 1-[3-O-[N-(tert-butoxycarbonyl)-D-valyl]-5-[2(S)-(2,4-dichioro-5-methoxyphenoxy)-propionamido]-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl-5-ethyluracil as a white solid, m.p. 101° C. (dec.).
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[N:12]([C:5]=2[CH2:4][CH2:3][NH:2]1)[C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[N:9]=3.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:23]([N:2]1[CH2:3][CH2:4][C:5]2[N:12]3[C:11]4[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=4[N:9]=[C:8]3[S:7][C:6]=2[CH2:1]1)(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)Cl
Reactant: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCC(=O)N1CCc2c(sc3nc4ccccc4n23)C1
Reaction time: 24 h

Procedure:
1,2,3,4-Tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (2.29 g., 0.01 mole) in 100 ml. of pyridine at 0° is treated with 1.06 g. (0.01 mole) butyryl chloride. After 24 hours at 5°, the mixture is stripped to a slurry, shaken with sodium bicarbonate and chloroform. Drying and evaporation of the organic solvents gives a solid which is recrystallized from methanol to give pure 2-butyryl-1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([C@@:18]1([CH2:33][CH2:34]Br)[CH:22]([F:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([O:15][C:16]([C@@:18]12[CH2:33][CH2:34][C@:22]1([F:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[CH2:19]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCBr)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC[C@]2(F)C1=O
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (5.02 mL) was added dropwise to a solution of (3S)-3-(2-bromoethyl)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.04 g, 4.92 mmol) in tetrahydrofuran (40 mL) in a nitrogen atmosphere at −72° C. over 10 minutes. The mixture was stirred at the same temperature for 15 minutes and then at 0° C. for 30 minutes. The reaction was quenched with a 10% citric acid solution (2 mL) and then poured into a mixture of ethyl acetate (100 mL) and a 10% citric acid solution (20 mL). After extraction with ethyl acetate (150 mL), the organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.41 g (86%) of the title compound as a white solid.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[C:5]([SiH2:9][O:10][C:11]([CH3:22])([CH3:21])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH2:16])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:5]([SiH2:9][O:10][C:11]([CH3:22])([CH3:21])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][NH:16][C:1](=[O:2])[CH3:3])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
AcCl (0.547 mL, 7.70 mmol) was added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (2.00 g, 7.00 mmol) and DIPEA (4.80 mL, 28.0 mmol) in CH2Cl2 (70 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. CH2Cl2 (30 mL) was added, and the mixture was washed with aq. sat. NH4Cl (2×), aq. 1M NaOH (1×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 60:40) yielded the title compound (2.10 g, 91%). LC-MS: tR=1.07 min; ES+: 369.19.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:17]=2)=[N:13][CH:14]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[CH:30]=1.NC1C=NC=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:9]1[CH:10]=[N:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[CH:22]=[C:23]2[CH2:28][CH2:27][N:26]([C:36]([NH:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[O:37])[CH2:25][CH2:24]2)=[N:13][CH:14]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Brc1cnc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
5-Bromo-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyrimidine trifluoroacetate (0.315 mmol, from Step 5), in acetonitrile (1.5 mL) was treated with phenyl pyridin-3-ylcarbamate (75 mg, 0.35 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridine) and diisopropylethylamine (0.192 mL, 1.10 mmol) and stirred at room temperature. After 72 h, the reaction was concentrated and the residue was purified by flash chromatography on silica gel (0-10% ethanol (containing 11% aq NH4OH):dichloromethane) to afford the title compound (0.114 g, 78% yield) as a white foam. MS (APCI) M+1=466; 1H NMR (400 MHz, CDCl3) δ ppm 2.48 (t, J=5.36 Hz, 2H) 2.61 (t, J=5.36 Hz, 2H) 3.55-3.63 (m, 2H) 3.66-3.73 (m, 2H) 6.41 (s, 1H) 7.01-7.09 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.40 (t, J=7.80 Hz, 1H) 7.43-7.48 (m, 1H) 7.89 (br. s., 1H) 8.21 (d, J=4.29 Hz, 1H) 8.48 (d, J=8.97 Hz, 1H) 8.58 (s, 2H) 8.88 (br. s, 1H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[CH2:5])[CH3:2].[N+:8]([O-])([OH:10])=[O:9]>>[CH2:4]([C:3]([CH2:6][CH3:7])=[CH:1][CH2:2][N+:8]([O-:10])=[O:9])[CH3:5]
Reactant: O=[N+]([O-])O
Reactant: C=CC(CC)CC
Product: CCC(=CC[N+](=O)[O-])CC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
3-Ethyl-1-pentene (15 mL, 0.11 moles) and concentrated nitric acid (9.6 mL, 0.15 moles) were mixed together at room temperature then with rapid stirring, heated to 70° C. for 4 hours. Heat was removed and stirring continued an additional 30 min. The organic layer was separated and washed with a saturated sodium chloride solution (3×15 mL) then dried over magnesium sulfate. After filtering, vacuum distillation (20 Torr, 28° C.) removed unreacted 3-ethyl-1-pentene. The remaining yellow oil contains 3-ethyl-1-nitro-2-pentene (12% yield) and a small amount of 3-ethyl-2-pentylnitrate. This was confirmed by IR and GC analysis.
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH2:13])[CH3:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[CH2:8]([O:7][C:5](=[O:6])[C:4]([NH:13][CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCN
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: ClCCl
Product: CCNC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To 135.8 ml (1000 mM) of diethyloxalate and 1 g of aliquat 336 in 1000 ml of dichloromethane were added 64.4 ml (1000 mM) of ethylamine (70% in water). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was removed under vacuum, to give an oil, wick was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 59.9 g of ethyl(ethyl amino)(oxo)acetate as an oil. Yield: 41.3%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:9][CH2:10]O)=[N:5][N:6]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[F:19][C:14]1[CH:13]=[C:12]([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[N:6]=[C:2]([NH2:1])[N:3]=[C:4]23)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nnc(N(CCCO)c2ccc(F)c(F)c2)[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2n(n1)CCCN2c1ccc(F)c(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-((5-amino-4H-1,2,4-triazol-3-yl)(3,4-difluorophenyl)amino)propan-1-ol (31 mg, 115 μmol) in tetrahydrofurane (1.15 mL) was added at 0° C. under an atmosphere of nitrogen triphenylphosphine (45.3 mg, 173 μmol). The reaction was stirred for 15 minutes and then DEAD (31.0 mg, 28.2 μL, 173 μmol) was added. The reaction was stirred for 30 minutes at 0° C. and then at room temperature over night. The same procedure was repeated with additional triphenylphosphine (45.3 mg, 173 μmol) and DEAD (31.0 mg, 28.2 μL, 173 μmol). Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a colorless solid (14 mg, 48%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent. MS ISP (m/e): 252.3 (100) [(M+H)+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[C:15]([F:16])=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[CH:23]([C:11]1[C:10]2[C:14](=[C:15]([F:16])[C:7]([Cl:6])=[CH:8][CH:9]=2)[NH:13][CH:12]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: Fc1c(Cl)ccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(F)c(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add phosphorus oxychloride (0.94 g, 6.16 mmol) to DMF (12 mL, cooled in an ice bath) with vigorous stirring. After about 10 minutes, add 6-chloro-7-fluoro indole (0.93 g, 5.6 mmol) in anhydrous DMF (4 mL), stir at 0° C. for 1 hour, warm to room temperature and stir overnight at room temperature (−16 hrs). Treat with 14.0 mL of 2N NaOH (4 eq.) with vigorous stirring. Heat the reaction to 80° C. for half an hour then cool. Pour the reaction into cold water with vigorous stirring to give a solid. Collect the solid by filtration and dry overnight in a vacuum oven at room temperature, to give the title compound: 1H NMR (300 MHz, CD3COCD3/CDCl3) 7.09 (t, 1H, J=7.7 Hz), 7.83-7.86 (m, 2H), 9.89 (s, 1H). By the method of Example 316 the following compounds were prepared: a) 3-Formyl-5,7-difluoro-1H-indole: 1H NMR (300 MHz, CD3COCD3) 6.98-7.06 (m, 1H), 7.71-7.75 (m, 1H), 8.35 (s, 1H), 10.04 (s, 1H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:16]1([CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Yield: 156.5 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), 4-methylcyclohexanone (21.31 g, 0.187 mol) and pyrrolidine (12.63 g, 0.178 mol) in methanol (400 mL) was refluxed for overnight. The reaction mixture was concentrated in vacuo, diluted with an equal volume of H2O and then added HCl until pH=1. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-4′-methylspiro(chroman-2,1′-cyclohexan)-4-one (45 g, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][C:3](=O)[CH2:4][CH2:5][CH3:6].[CH2:13]([SH:16])[CH2:14][SH:15].CS(O)(=O)=O>C(Cl)Cl>[CH2:4]([C:3]1([CH2:2][CH2:1][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[S:16][CH2:13][CH2:14][S:15]1)[CH2:5][CH3:6]
Reactant: SCCS
Reactant: CCCC(=O)CCn1ccnc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC1(CCn2ccnc2)SCCS1
Reaction time: 0.25 h

Procedure:
A solution 1-(hexan-3-on-1-yl)imidazole (1.00 g) was stirred with ethane-1,2-dithiol (1 ml) at room temperature and then 1 ml of methanesulfonic acid was added in portions with cooling. After 15 minutes, 20 ml of methylene chloride was added and the mixture stirred for 4 hours. The reaction mixture was poured into 300 ml of methylene chloride which solution was washed with 3×100 ml 5% sodium hydroxide, 1×100 ml water and the organic layer dried over magnesium sulfate. Removal of the solvent afforded an oil which was chromatographed on silica gel, eluting with hexane, 50% hexane/ethyl acetate and ethyl acetate to yield 1.2 g of 1-[2-(2-propyl-1,3-dithiolan-2-yl)ethyl]imidazole. The residue was taken up in a small volume of ether and treated with ethereal hydrogen chloride until precipitation was complete. The resulting precipitate was filtered off and recrystallized from methanol/ethyl acetate, to give 1-[2-(propyl-1,3-dithiolan-2-yl)ethyl]imidazole hydrochloride, m.p. 118° -121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][CH2:15][CH2:16][C:17]#[N:18].CO.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[C:16]([CH2:15][O:14][CH3:13])[C:17]#[N:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COCCC#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCC(C#N)=Cc1ccc(OC)c(OC)c1
Temperature: 30 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 200 g (1.20 mole) of 3,4-dimethoxy-benzaldehyde, 150 g (1.75 mole) of β-methoxy-propinitrile, 260 ml of methanol and 10 g of a 55% methanolic potassium hydroxide solution is stirred at 60°-62° C. for 8 hours, whereupon the reaction mixture is cooled to 30° C., and 170 g of a 55% methanolic potassium hydroxide solution are added dropwise. The reaction mixture is stirred for 5 hours and diluted with 1000 ml of water. The precipitated crystalline product is filtered, washed with methanol and water. Thus 280 g of α-(3,4-dimethoxy-benzal)-β-methoxy-propionitrile are obtained, yield 85%, mp.: 82°-83° C.