Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[CH:8][C:9]([C:11](Cl)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.N1C=CC=CC=1.[CH3:21][C:22]1[CH:37]=[C:25]2[N:26]=[C:27]([NH2:36])[CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:24]2[N:23]=1>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:36][C:27]3[CH:28]=[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:24]4[N:23]=[C:22]([CH3:21])[CH:37]=[C:25]4[N:26]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: CC1(C)COc2cc(C(=O)Cl)ccc21
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc2nc(NC(=O)c3ccc4c(c3)OCC4(C)C)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.7 %

Procedure:
In a 25 ml pear flask containing crude 3,3-dimethyl-2,3-dihydrobenzofuran-6-carbonyl chloride (25 mg, 0.12 mmol) was added pyridine (1 mL), immediately followed by 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 26.9 mg, 0.120 mmol). The mixture was stirred at room temperature for ˜16 h. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were washed once more with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by SiO2 (20% EtOAc, second spot from the top) to give an off-white solid. To facilitate transfer of the small amount of product, the solid was dissolved in 0.5 mL of acetonitrile, and then suspended in 15 mL of water. Lyophilization of the mixture gave the titled product (5.1 mg, 11% yield). 1H NMR (CHLOROFORM-d) δ: 8.58 (s, 1H), 8.08-8.15 (m, 3H), 7.53-7.59 (m, 3H), 7.46 (dd, J=7.7, 1.6 Hz, 1H), 7.34 (d, J=1.3 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.28 (s, 1H), 4.31-4.34 (m, 2H), 2.50 (s, 3H), 1.36-1.42 (m, 6H); ESI-MS: m/z 399.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6](=[O:28])/[CH:7]=[CH:8]/[C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:2].C(O)=O.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C.CC(OC)(C)C.CCCCCC.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@H:6]([OH:28])/[CH:7]=[CH:8]/[C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C

Procedure:
A solution of (E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoic acid ethyl ester (2.0 g, 5.08 mmol), Ru[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH2]Cl(η6-p-cymene) (12.8 mg, 0.025 mmol) and a mixture of HCOOH (1.40 g, 30.5 mmol)/NEt3 (1.23 g, 12.2 mmol) is heated in DMF (8.0 ml) at 50° C. for 21 h. After that the solution is diluted with MTBE (5 ml) and neutralised with NaHCO3 (4 ml). Standard aquous work-up with NaCl solution and extraction with MTBE and removel of the solvent give the crude product. Chromatography on silica gel using a 4:1 hexane-MTBE mixture as eluent to afford of (E)-(S)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-pent-4-enoic acid ethyl ester. MS: 395.48
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH:14]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2ccn(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of commercially available 1H-indole-6-carboxylic acid methyl ester (0.35 g, 2.0 mmol) and cyclohexylmethyl bromide (0.31 mL, 2.2 mmol) in DMF (2 mL) was added sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 3 hr, the solution was diluted with water (25 mL) and ethyl acetate (75 mL), the organic layer was washed again with dilute NaHCO3 (25 mL) and then brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The remaining residue was subjected to flash chromatography (ethyl acetate/hexane, 1:24) to provide 1-cyclohexylmethyl-1H-indole-6-carboxylic acid methyl ester as a white solid (0.40 g, 74% yield). 1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.62 (m, 2W), 7.58 (d, 1H, J=3.1 Hz), 6.52 (d, 1H, J=3.1 Hz), 4.10 (d, 2H, J=7.4 Hz), 3.85 (s, 3H), 1.77 (m, 1H), 1.65-1.57 (m 3H), 1.46 (m, 2H), 1.19 (m, 3H), 0.98 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:39](N1C=CN=C1)([N:41]1C=CN=C1)=O.C(N(CC)CC)C.Cl.CN>CN(C=O)C.O>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:41][CH3:39])=[O:34])(=[O:29])=[O:28])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A mixture of 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid. (159 mg, 0.30 mmol) and 1,1′-carbonyldiimidazole (73 mg, 0.45 mmol) in DMF (2 ml) was stirred at 50° C.(bath) for 10 min. Triethylamine (0.21 ml, 1.50 mmol) and methylamine hydrochloride (61 mg, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 24 h. Water (15 ml) was added and stirred at 0° C. for 30 min. The precipitate was filtered, washed with water, and dried to give a crude product which was recrystalized from ethyl acetate-MeOH to afford the required compound as a light brown solid, 85 mg, 52% yield; mp 249-251° C. NMR was consistent with the structure. Calcd. For C30H29N3O5S:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[F:9][C:10](I)([F:12])[F:11].C(S(CCCC)=O)CCC.S(=O)(=O)(O)O.OO>S([O-])([O-])(=O)=O.[Fe+2]>[F:9][C:10]([F:12])([F:11])[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: CCCCS(=O)CCCC
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 0.2 %

Procedure:
0.11 g (1.0 mmol) of uracil was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with trifluoromethyl iodide. The following materials were added thereinto: 5.0 ml of dibutyl sulfoxide, 0.053 ml of concentrated sulfuric acid, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyluracil (19F-NMR yield: 0.2%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@@H:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH2:13][Cl:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([NH:10][C@@H:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:12]([OH:15])[CH2:13][Cl:14])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)CCl)cc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)[C@@H](O)CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(3S)-3-(p-Toluenesulfonyl)amino-1-chloro-4-phenyl-2-butanone (175.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=500) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R, 3S)-3-(p-toluenesulfonyl)amino-1-chloro-2-hydroxy-4-phenylbutane (173.5 mg; yield: 98.3%). HPLC analysis revealed that the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 10.9:1. The results of elementary analysis were as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>C(Cl)Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of N-[(4-fluorophenyl)-sulfonyl]-D-valine from Example 1a (8.00 g, 29.1 mmol) in CH2Cl2 /dioxane was treated with isobutylene in the presence of H2SO4 at room temperature at a pressure of 18 psi. The reaction was quenched by adding the solution to a mixture of NaHCO3 (20 g) in water (300 mL) cooled in an ice bath. The mixture was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with H2O and brine, dried over MgSO4, and concentrated to a solid. Recrystallization from diethyl ether/hexane afforded N-[(4-fluorophenyl)-sulfonyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (6.99 g, 73%): MS MH+ calc'd for Cl5H22NO4SF: 332, found: 332. Anal. calc'd for Cl5H22NO4SF: C, 54.36; H, 6.69; N, 4.23. Found: C, 54.21; H, 6.86; N, 4.14.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].CN(C=O)C.[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[CH2:13]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 50.0 g (0.657 mol) of 1,3-propandiol 11 in 500 mL of cosolvent (DMF : THF=3:1) in an ice bath was carefully added 26.3 g (0.657 mol) of 60% sodium hydride and stirred for 1 hour, followed by slow addition of 80.5 g (0.636 mol) of benzyl chloride at 0° C. and stirring at room temperature overnight. After adding 50 mL of water to quench the reaction, the mixture was extracted with ether (2×600 mL). The organic layer was washed with water (50 mL) and Brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Distillation at 118-120° C./5 mmHg gave 54.8 g of a liquid in 50.2% yield. 1H NMR (CDCl3): δ 7.35-7.28 (m, 5H, ArH), 4.51 (s, 2H, ArCH2O), 3.76 (m, 2H, CH2O), 3.65 (t, J=6.0 Hz, 2H, CH2O), 2.58 (m, 1H, OH), 1.85 (p, J=6.0 Hz, 2H, CH2). 13C NMR (CDCl3): δ 137.93, 128.34, 127.60, 127.54, 73.15, 69.15, 61.58, 32.04.
Reaction SMILES: Cl.Cl.[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([NH:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:25]([O-])=[O:26].[Na+]>O>[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:22][C:23]#[N:24])[N:25]=[O:26])[CH2:17][CH2:16]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCNN1CCN(CCCCC(=O)c2ccccc2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCN(N=O)N1CCN(CCCCC(=O)c2ccccc2)CC1
Reaction time: 2 h

Procedure:
2.0 g of 4-(4-benzoylbutyl)-1-(cyanomethylamino)-piperazine dihydrochloride was dissolved in 22 ml of water, and while the solution was cooled to below 5° C., an aqueous solution containing 1.0 g of sodium nitrite was added over the course of 10 minutes. The reaction was carried out at this temperature for 2 hours. The reaction mixture was extracted with chloroform. The extract was washed with water and dried, and the chloroform was distilled off to give 4-(4-benzoylbutyl)-1-(N-nitrosocyanomethylamino)-piperazine.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[N:8]=[C:7]2[C:12](=[N:13][CH:26]=[N:6]2)[C:11](=[O:14])[N:10]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)COc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: CC(C)COc1ccccc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
In a similar manner to Example 1 reaction of 4,5-diamino-2-(2-isobutoxyphenyl)pyrimidin-6-one sulphate (1.4 g) with formamide (5 ml) afforded the title compound, 0.24 g, m.p. 272°-273° C., (recrystallised from ethanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20]1.[CH:35]([Sn](CCCC)(CCCC)CCCC)=[CH2:36]>C1(C)C=CC=CC=1>[C:12]1([C:7]2[CH:6]=[C:5]([O:18][C@H:19]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31]([O:33][CH3:34])=[O:32])[CH2:20]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:35]=[CH2:36])[CH:3]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3ccc(Br)cc23)CN1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 110 °C
Yield: 56.7 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-[(6-bromo-2-phenylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 24 (1.45 g, 2.75 mmol) in toluene (20 mL) was added vinyltributyltin (0.96 mL, 3.3 mmol) and tetrakis-triphenylphosphine palladium (318 mg, 0.27 mmol). The mixture was then heated to 110° C. for 3 h, at which time, LC-MS revealed the disappearance of starting material. The reaction mixture was concentrated and purified on silica gel (gradient elution 15% to 50% EtOAc in hexanes) to give 1-tert-butyl 2-methyl (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 25 (0.74 g, 56% yield) as a yellow solid. LRMS (M+H)+ Calcd.: 475. found 475.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:29]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[OH:29][CH2:3][CH2:2][CH2:1][C:4]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5]1
Reactant: C=CCC1(c2ccccc2)CCN(CCc2ccccc2)C(=O)O1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: O=C1OC(CCCO)(c2ccccc2)CCN1CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-3-phenethyl-6-phenyl-[1,3]oxazinan-2-one (100 mg, 0.31 mmol) in dry THF (4 mL) was added dropwise BH3.THF (0.6 mL, 0.62 mmol, 1 M) at 0° C. After 2 h at rt, the reaction mixture was cooled to 0° C., and water (1 mL), aqueous NaOH (1 mL, 3 M) and H2O2 (0.5 mL, 30%) were successively added. The mixture was stirred for 2-3 h at rt, and then diluted with water (8 mL). The pH of the mixture was adjusted to 6-7 with 0.5 N HCl. The layers were separated, and the aqueous phase was extracted with EtOAc (3×6 mL). The combined organic layers were washed with a saturated aqueous NaHCO3 solution (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by preparative TLC to afford two isomers of 6-(3-hydroxypropyl)-3-phenethyl-6-phenyl-1,3-oxazinan-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH3:10]>COCCOC>[CH3:16][C:14]1[N:1]=[C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]2[C:13]=1[C:12]([O:11][CH2:9][CH3:10])=[O:18]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Cc1ccnc(N)c1
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2cc(C)ccn12
Yield: 78 %

Procedure:
In this specific example of synthesis of ND-8454, a solution of 2-amino-4-picoline (10.0 g, 91.5 mmol) and ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 mL of 1,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered and solids (2-amino-4-picoline hydrochloride salt) was collected and washed with hexanes. The filtrate liquor was concentrated in vacuo and residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2×) and brine. The organic phase was collected, dried over sodium sulfate (Na2SO4), filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 20% ethyl acetate:CH2Cl2 solvent system to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate as a tan solid. mp 59-61° C.; 1H NMR (300 MHz, CDCl3) 9.14 δ(d, J=7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J=7.1, 1.7 Hz, 1H), 4.40 (q, J=7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1.42 (t, J=7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calcd. for C12H15N2O2, 219.1155; found 219.1128. Retention time=1.4 minutes (mobile phase: 60% water:acetonitrile).
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH2:3]1.[ClH:15].[NH2:16]O.CCOCC>C(#N)CC>[ClH:15].[NH2:16][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH:3]=1
Reactant: COC(=O)C1SCC(=O)C1C(=O)OC
Reactant: NO
Agent: Cl
Solvent: CCC#N
Solvent: CCOCC
Product: COC(=O)c1scc(N)c1C(=O)OC

Procedure:
3-Oxo-4,5-bismethoxycarbonyltetrahydrothiophene (2.65 g) was dissolved in propionitrile (5 ml) and hydroxylamine hydrochloride (1 g) was added. The mixture was heated under reflux on the steam bath for 11/2 hours by which time it was almost solid. Ether was added to the cooled mixture and the title compound was filtered off. Yield 2.37 g (77.5%) M.P.166°-169° dec. 3-Amino-4,5-bismethoxycarbonylthiophene was liberated from the title compound by treatment with aqueous ammonia followed by bulk distillation (220° C., 0.1 mm Hg) and exhibited 'H n.m.r. δ (CDCl3) 6.40 (1H,s), 4.40 (2H, brs), 3.90, 3.94 (2×3H,s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]([O:37][CH3:38])[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][C:26]=1[CH3:39].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C@H:31]([O:37][CH3:38])[CH2:32][CH2:33][C:34]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:35])=[CH:27][C:26]=1[CH3:39]
Reactant: CO[C@H](CCC(=O)O)c1ccc(F)c(C)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CO[C@H](CCC(=O)NOC1CCCCO1)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (175 mg, 1.5 mmol), HOBt (810 mg, 6.0 mmol), NaHCO3 (1.0 g, 11.9 mmol) and the crude (R)-4-(4-fluoro-3-methylphenyl)-4-methoxybutanoic acid in 60 mL CH2Cl2 was added EDC.HCl (958 mg, 5.0 mmol). The mixture was stirred for 3 h at 25° C. The solvent was removed under reduced pressure and the product isolated by flash column chromatography, eluting with 10% to 60% Ethyl acetate/Hexane gradient solvent to give 208 mg of the title compound.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][C:2]21[CH2:16][C:15](=[O:17])[NH:14][C:13]2=[O:18].[H-].[Na+].I[CH3:22].Cl>CN(C=O)C.O>[CH3:22][N:14]1[C:15](=[O:17])[CH2:16][C:2]2([CH2:3][N:4]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[CH:6]=[C:5]3[CH2:1]2)[C:13]1=[O:18]
Reactant: CI
Reactant: O=C1CC2(Cc3cc4ccccc4n3C2)C(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CC2(Cc3cc4ccccc4n3C2)C1=O
Reaction time: 17 h

Procedure:
A solution of 1.96 g of 1',3'-dihydrospiro[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione [prepared as described in Example 11(iv)] in 10 ml of DMF was added dropwise to a stirred suspension of 330 mg of a 60% dispersion of sodium hydride in mineral oil in 10 ml of DMF. The mixture was treated with 1 ml of iodomethane and stirred for 17 hours. The mixture was diluted with water, neutralized with 1M aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with sodium chloride solution, dried and the solvent was removed by evaporation. Crystallization of the residue from ethyl acetate/n-hexane gave 1.81 g of 1',3'-dihydro-1-methylspiro-[pyrrolidine-3,2'-pyrrolo[1,2-a]indole]-2,5-dione of melting point 154°-156° C.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8]2([CH3:12])[C:9]([CH3:11])=[CH:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[N:4]1[CH2:18]C1C=CC=CC=1.C(N(CC)CC)C.C=O>[Pd].C(O)C>[CH3:18][N:4]1[CH:3]([CH3:2])[C:8]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:5]1[CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2
Reactant: CCOC(=O)C1CC2(C)C(C)=CC1N(Cc1ccccc1)C2C
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A mixture of ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]-oct-7-ene-6-carboxylate hydrochloride (17.4 g, 49.7 mol), 10% palladium on carbon (1.7 g) and ethanol (200 mL) was hydrogenated on a Parr hydrogenator at 50 psi for 6 hours. The mixture was removed from the Parr hydrogenator, cooled to 0° C. and triethylamine (7.0 mL, 50 mmol), followed by 37% formaldehyde (4.1 mL, 55 mmol) were added The mixture was then placed back on the Parr hydrogenator at 50 psi for 1 hour. The reaction mixture was removed from the Parr hydrogenator, the catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in water, basified with concentrated ammonium hydroxide (20 mL) and extracted with ether (3×300 mL). The combined organic layers were washed with brine (50 mL), dried over potassium carbonate and concentrated in vacuo to afford 11.5 g (96%) of ethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]-octane-6-carboxylate as a pale yellow oil.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[C:25]2([CH3:33])[CH3:32])[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:34].[ClH:42].[ClH:34].[ClH:34].[ClH:34].[Cl:34][C:19]1[N:20]=[C:21]([N:24]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:31])[CH3:30])[C:25]2([CH3:32])[CH3:33])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CN(C)C1CCN(c2nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)C1(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2nc(Cl)nc(NN)c2F)C1(C)C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of racemic tris(1,1-dimethylethyl)2-{2-chloro-6-[3-(dimethylamino)-2,2-dimethyl-1-pyrrolidinyl]-5-fluoro-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.4618 g, 0.766 mmol) in MeOH (5 mL) was added 4 N HCl in dioxane (5 mL). The solution was stirred for 3 days, and then concentrated in vacuo to afford racemic 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N,2,2-tetramethyl-3-pyrrolidinamine pentahydrochloride (0.3673 g, 99% yield) as an orange oil that crystallized under vacuum. LCMS: (M+H)+: 303.1.