Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]([O:29][CH2:30][C@H:31]1[O:36][C@H:35](Br)[C@H:34]([O:38][C:39]([CH3:41])=[O:40])[C@@H:33]([O:42][C:43]([CH3:45])=[O:44])[C@H:32]1[O:46][C:47]([CH3:49])=[O:48])=[O:28].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:39]([O:38][C@@H:34]1[C@@H:33]([O:42][C:43](=[O:44])[CH3:45])[C@@H:32]([O:46][C:47](=[O:48])[CH3:49])[C@@H:31]([CH2:30][O:29][C:27](=[O:28])[CH3:26])[O:36][C@H:35]1[O:24][C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:25])=[C:20]([CH:21]([CH3:22])[CH3:23])[NH:19][N:18]=1)(=[O:40])[CH3:41]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:20]4[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 66% overall yield. FDMS m/e=380 (M+ of free base). α[D]589 =-11.77 (c=0.61, methanol).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](B2OCCN(C3C=CC=CC=3)CCO2)[N:17]=1)([CH3:15])[C:13]#[N:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([CH:4]=[O:5])=[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:12]([CH3:15])([CH3:11])[C:13]#[N:14])[N:17]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C#N)c1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(-c2ccnc(Cl)c2C=O)n1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A suspension of 2-chloro-4-iodonicotinaldehyde (90.3 mg, 0.338 mmol)(prepared via J. Org. Chem., 1993, 58, 7832), 2-methyl-2-(6-(6-phenyl-1,3,6,2-dioxazaborocan-2-yl)pyridin-2-yl)propanenitrile (226 mg, 0.675 mmol), tri-o-tolylphosphine (21 mg, 0.068 mmol), palladium acetate (5 mol %, 3.8 mg, 0.017 mmol), potassium carbonate (93 mg, 0.675 mmol) and copper(I) iodide (26 mg, 0.135 mmol) in tetrahydrofuran (5 ml) was heated at reflux under nitrogen for 75 minutes. The mixture was cooled down to room temperature, filtered through a path of celite and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as an off-white solid (71 mg, 74% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([CH3:17])[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][C:3]1=O.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([CH3:17])[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: Cc1c(N2CCOCC2)ccc2c1NC(=O)C2(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)ccc2c1NCC2(C)C
Temperature: 25 °C
Yield: 76.3 %

Procedure:
To a solution of 3,3,7-trimethyl-6-morpholinoindolin-2-one (45.7 mg, 0.176 mmol) in toluene (10 mL) at 80° C. under N2, Red-Al (0.18 mL, 3M, 0.53 mmol) was added dropwise. The resultant mixture was stirred at 80° C. for 2 h. The mixture was cooled to rt and quenched with NaOH (2 mL, 3N). The mixture was diluted with EtOAc and washed with water and brine, dried and concentrated. Purification of the residue by flash chromatography over silica gel, using 40% EtOAc in hexane, gave 4-(3,3,7-trimethylindolin-6-yl)morpholine (33.1 mg, 76%): 1H-NMR (DMSO-d6) δ 6.74 (1H, d, J=8.0 Hz), 6.29 (1H, d, J=8.0 Hz), 5.11 (1H, s), 3.69 (4H, s), 3.16 (2H, s), 2.72 (4H, s), 1.96 (3H, s), 1.18 (6H, s). Mass Spectrum (ESI) m/e=247.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@H:8]([CH3:24])[C@H:9]([C@@H:20]([CH3:23])[CH2:21][OH:22])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([CH3:4])[CH3:3].CCN(CC)CC.C(Cl)Cl>CS(C)=O.CCOCC>[CH3:1][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C@@H:20]([CH3:23])[CH:21]=[O:22])([CH3:3])[CH3:4]
Reactant: COc1ccc(CO[C@@H]([C@@H](C)CO)[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(CO[C@@H]([C@@H](C)C=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A solution of 2,4-dideoxy-1-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-arabinitol (10.77 g, 28.19 mmol), DMSO (30 mL), NEt3 (11.39 g, 112.76 mmol) and methylene chloride is cooled to −10° C., and treated with SO3-Pyr (13.45 9, 84.58 mmol)in DMSO (60 mL) over 40 min. After additional 2 h at 0° C., the mixture is diluted with ether (300 mL), washed with 1 M aqueous NaHSO4 (100 mL), brine (100 mL), and concentrated. Flash chromatography (5% ethyl acetate in hexane) gives the desired compound (9 g, 84%) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[NH:11])[NH2:14])=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2ccccc2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with benzoic acid and subsequently hydrogenated according to the the procedure described in Example 58, to give Example 62. ESI-MS m/e 327.5 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][S:3]1.[F:16][C:17]([F:38])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=O)[CH2:23][CH2:22]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:38][C:17]([F:16])([F:37])[C:18]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24](/[CH:27]=[C:4]2/[C:5]([NH:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:6][C:2](=[O:1])[S:3]/2)[CH2:23][CH2:22]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl N-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinate (4.41 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (5.00 g) in 2-propanol (50 mL) was added piperidinium acetate (2.14 g). The reaction mixture was stirred at 70° C. for 3 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (5.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].C(O)(=O)C>[Fe].C(O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c2ccccc2c1Oc1ccccc1N
Reaction time: 3 h

Procedure:
A mixture of 3.12g of methyl-3-[o-nitrophenoxy]-indole-2-carboxylate, 10g of 40 mesh iron filings, 5ml of 5% aqueous acetic acid and 300ml of ethanol was refluxed with stirring for 3 hours. The mixture was filtered and concentrated to a solid. Recrystallization from ethanol gave analytical material, mp. 183°-4°.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.CC(C)=O>[C:1]1([C:7]2[N:11]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 5-phenyl-1H-tetrazole (21.9 g) and chlorotriphenylmethane (46 g) in methylene chloride (500 ml) was added triethylamine (16.7 g). The resulting mixture was stirred at room temperature for one hour. The reaction mixture was washed successively with water, 10% aqueous citric acid solution and water and was then dried over anhydrous magnesium sulfate, followed by removal through distillation. The residue so obtained was dispersed in acetone, collected by filtration and then dried, whereby 51.8 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH:31]=C)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OCC)(=[O:35])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:3][C:4]([C:6]1([CH2:30][CH:31]=[O:35])[CH2:7][CH2:8][CH:9]([O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OCC)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1-Allyl-4-(tert-butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (5 g, 11.1 mmol) was dissolved in 2-propanol (100 mL) and water (50 mL). To this was added an aqueous solution of NaIO4 (5.94 g, 27.8 mmol) in water (50 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours at rt. The reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, and concentrated to dryness. The resulting product was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 4.45 g (87%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH2:23](I)[CH2:24][CH3:25]>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(C#N)cc2)sc2ncccc2c1=O
Yield: 70.9 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 42 mg of lithium hydride and 655 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 734 mg of 2-[(4-cyanophenyl)imino]-2,3-dihydro-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (71%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 100 mg of 2-[N- (4-cyanophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH:15]1([NH2:19])[CH2:18][CH2:17][CH2:16]1>ClCCl.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: NC1CCC1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC2CCC2)c([N+](=O)[O-])c1
Yield: 148.8 %

Procedure:
To a solution of 4-fluoro-3-nitro-benzoic acid methyl ester (14.51 g, 50.9 mmol) in dichloromethane (150 ml) was added cyclobutylamine (14 ml, 164 mmol) slowly with cooling on an ice bath. After 2 hours at 23° C. the reaction was diluted with water and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 18.95 g of 4-cyclobutylamino-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[CH:16][C:3]=12.[Br:17]Br>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sccc2c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 65) (1 g, 4.23 mmol) in acetic acid (3 mL) was added bromine (0.65 mL, 12.70 mmol) and the resulting mixture stirred at RT overnight (ca. 18 h). The reaction was quenched by pouring the reaction mixture into water and the aqueous solution was basified with NaOH (5M) and diluted with ethyl acetate (30 mL). The organic layer was separated and the aqueous layer was re-extracted with ethyl acetate (20 mL×3). The combined organics were washed with saturated sodium thiosulphate solution, dried and concentrated. Purification by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in DCM afforded the title compound (1.16 g). LCMS (A) m/z: 315/317 [M+1]+, Rt 0.95 min (acidic).
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])C=CN=C1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19]C(O)=O>ClCCl>[N:8]1([C:6](=[O:7])[CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][O:13]2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(O)CCC1CCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(CCC1CCCO1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Di(1H-imidazol-1-yl)methanone (1.196 g, 7.38 mmol) was added in small portions to a stirred solution of 3-(tetrahydrofuran-2-yl)propanoic acid (1.013 g, 7.03 mmol) in dichloromethane (3 mL) at room temperature under argon. The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed twice with water, dried over MgSO4 and concentrated giving 1-(1H-imidazol-1-yl)-3-(tetrahydrofuran-2-yl)propan-1-one (1.099 g, 81%) as the product. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.34-8.51 (m, 1 H), 7.64-7.79 (m, 1 H), 6.98-7.17 (m, 1 H), 3.76-3.85 (m, 1 H), 3.66-3.76 (m, 1 H), 3.55-3.60 (m, 1 H), 3.03-3.10 (m, 2 H), 1.90-2.00 (m, 1 H), 1.73-1.90 (m, 4 H), 1.39-1.53 (m, 1 H); MS (ES−) m/z 194 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:23])[CH:9]([NH:21][CH3:22])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:24]1([C:34](Cl)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:23])[CH:9]([N:21]([CH3:22])[C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:35])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CNC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cccc2ccccc12)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (150 mg, 0.46 mmol) in ethyl acetate (5 ml) were added 1-naphthoyl chloride (76 ml, 0.50 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 6 hrs. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (166 mg, 75%).
Reaction SMILES: [OH-:1].[Na+].BrBr.[CH:5]1[C:16]2=[C:17]3[CH:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11][CH2:10][CH2:9][C:8]3=[CH:7][C:6]=1[C:18](=[O:20])C.S([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH:5]1[C:16]2=[C:17]3[CH:12]([CH2:13][CH2:14][CH2:15]2)[CH2:11][CH2:10][CH2:9][C:8]3=[CH:7][C:6]=1[C:18]([OH:20])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1cc2c3c(c1)CCCC3CCC2
Agent: BrBr
Agent: Cl
Agent: O=S([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2c3c(c1)CCCC3CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
2.5 N Aqueous sodium hydroxide (9.2 ml) was cooled to 0° C., and slowly added with bromine (0.30 ml), and then the mixture was diluted with 1,4-dioxane (1.5 ml) to obtain a yellow solution. A solution of 1-(5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)ethanone (0.380 g) in water (5 ml) and 1,4-dioxane (10 ml) was cooled to 0° C., and slowly added with the yellow solution prepared above, and the mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and added with 10% aqueous sodium sulfite, then the mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.338 g, yield: 88%) as colorless needles (melting point: 208-209° C.).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]([C:21]#[N:22])=[CH:18][NH:19][CH:20]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]3[C:17](=[CH:18][NH:19][CH:20]=3)[CH2:21][N:22]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:14]=1
Reactant: N#Cc1c[nH]cc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Ni]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1c[nH]cc1-2
Reaction time: 4 h

Procedure:
A mixture of 4.0 g (13 mmole) of 4-[2-benzoyl-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, 4 g of Raney nickel, and 300 ml of acetic acid were hydrogenated on a Parr apparatus for 4 hr. The Raney nickel was removed by filtration, and the filtrate was diluted with 400 ml of ice water. The acetic acid was neutralized with sodium bicarbonate, and the resulting solution extracted with methylene chloride. The methylene chloride solution was washed with water, and was dried with sodium sulfate. Concentration of the methylene chloride solution gave a yellow solid. Recrystallization from methylene chloride/ether gave a white solid, mp 203°14 206°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26](CCC#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=[C:48](C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)[C:49](C3C=CC=CC=3)=[CH:50][C:43]=2[NH:42]1.BrCCCC#N>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:48][CH2:49][CH2:50][C:43]#[N:42])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Agent: N#CCCCBr
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCC#N)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 4-bromobutanenitrile (94 mg, 0.636 mmol) to afford the title compound (68 mg. 1H NMR (500 MHz, CDCl3): 7.20-7.32 (10H, m), 5.1 (1H, br), 4.90 (2H, s), 4.11 (2H, m), 2.44-2.50 (6H, m), 2.05-2.13 (3H, m), 1.79-1.84 (1H, m), 1.27-1.36 (9H, br).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[O:42]C=3CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:14]=[CH:13][O:42][C:18]=3[CH2:17][CH2:16][CH2:15]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3occc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3occc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.29, 6.03, 5.18, 4.49, 2.81, 2.65, 2.55, 2.03, 1.89, 1.23; (FAB) calcd for C16H20BrN3O+H 351.0, found 351.0.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(=[O:15])[CH2:14][CH2:13][CH:12]=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>O>[C:1]1([CH:12]2[CH2:13][CH2:14][C:10](=[O:15])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCC(c2ccccc2)C1
Temperature: 80 °C

Procedure:
A mixture of phenylboronic acid (1.63 g, 13.4 mmol), cyclopent-2-enone (1.0 g, 10.4 mmol), and Na2CO3 (2.2 g, 20.8 mmol) was purged with nitrogen for 15 min followed by the addition of [Rh(cod)Cl]2 (100 mg, 0.21 mmol) and water (30 mL). The resulting suspension was heated to 80° C. for 20 min. The mixture was extracted with CH2Cl2, washed with brine, dried over MgSO4 and chromatographed on silica gel using 3:1 hexanes:ethylacetate to afford the title compound as a colorless oil. MS m/z: 161 (M+1).