Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH:28]=O)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:1]([O:4][C@@H:5]([CH2:28][NH:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:6]([CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([N:21]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]2[CH3:27])[N:15]=1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8])[CH:2]=[CH2:3]
Reactant: NCc1ccccc1
Reactant: C=CCO[C@@H](C=O)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Solvent: C1CCOC1
Product: C=CCO[C@@H](CNCc1ccccc1)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 16 (240 mg, 0.6 mmol) in THF (5 mL) was added benzylamine (100 μL, 0.9 mmol) followed by NaHB(OAc)3 (153 mg, 0.72 mmol). The reaction was allowed to stir for an additional 3 h then partitioned between EtOAc (100 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc:hexanes, 1:2-1:1) to give 19 (270 mg, 0.55 mmol, 92%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 0.99-1.01 (d, J=6.5 Hz, 3H), 1.09-1.11 (d, J=6.5 Hz, 3H), 2.13 (s, 6H), 2.37 (s, 3H), 2.76-2.85 (ddd, J=4.5, 5.0, 12.5, Hz, 1H), 2.98-3.08 (ddd, J=5.5, 14.0, 15.5, Hz, 1H), 3.49-3.52 (m, 1H), 3.81 (s, 2H), 3.82-3.89 (m, 1H), 4.04-4.08 (dd, J=6.0, 12.5, Hz, 1H), 4.09-4.12 ((dd, J=5.5, 13.0, Hz, 1H), 4.86-4.89 (m, 1H), 5.13-5.15 (dd, J=1.0, 10.0, Hz, 1H), 5.23-5.28 (dd, J=1.5, 17.0, Hz, 1H), 5.86-5.91 (m, 3H), 6.85 (s, 1H), 7.00 (s, 1H), 7.20-7.27 (m, 2H), 7.27-7.35 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 13.6, 21.2, 21.8, 21.9, 35.1, 47.6, 49.9, 54.0, 68.0, 71.4, 79.4, 106.8, 117.2, 120.3, 123.4, 127.2, 128.4, 128.6, 128.8, 134.9, 140.4, 149.5, 151.7, 159.4, 173.0; LCQ-MS (M+H+) calcd for C30H40N3O3 490. found 490; LC-TOF-MS (M+H+) calcd for C30H40N3O3 490.30697. found 490.30644.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:7]([CH3:14])[CH:6]=[C:5]([CH3:15])[C:3]=1[NH2:4].C[Al](C)C.[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](OC)=[O:27].Cl>ClCCCl>[NH2:20][C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26]([NH:4][C:3]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]=1[CH3:1])=[O:27]
Reactant: COC(=O)c1sccc1N
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NC(=O)c1sccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
To a solution of 2,4,6-trimethyl-3-pyrrolidin-1-yl-aniline, (1.5 g, 7.6 mmol) in anhydrous 1,2 dichloroethane (20 mL), chilled to 0° C. under N2, was added a solution of trimethylaluminum (2M in hexanes) (7.6 mL, 15.2 mmol). Upon completion of the addition, the ice bath was removed and the reaction was stirred for 30 min. at room temperature. Methyl 3-amino-2-thiophenecarboxylate (0.95 g, 0.8 equivalents.) was added in one portion to the flask, and the reaction mixture was refluxed for 18 hours. The reaction mixture was acidified with hydrochloric acid (2N) (2×50 mL) and washed with dichloromethane (2×50 mL). The combined aqueous layers were then adjusted basic using a saturated, aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic ethyl acetate extracts were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to yield a brown oil. The material was further purified by silica gel chromatography using 5% ethyl acetate in hexanes as the mobile phase (gradient) to yield 3-amino-N-(2,4,6-trimethyl-3-pyrrolidin-1-ylphenyl)thiophene-2-carboxamide as a yellow foam (640 mg).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:21]([CH3:22])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[C:18]([C:17]1[CH:20]=[C:21]([CH3:22])[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[CH3:25])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)#[N:19]
Reactant: O=C1NCCO1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Product: Cc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Yield: 23.4 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using 6-[4-(4-bromo-2-methylbenzoyl)piperazin-1-yl]-5-methylnicotinonitrile (210 mg) described in Preparation Example 133 and oxazolidin-2-one (69 mg), the title compound (50 mg) was obtained.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[N:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[CH:23][C:22]=3[CH3:35])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].Cl>O>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[N:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][C:22]=3[CH3:35])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Agent: Cl
Solvent: O
Product: Cc1cc(CC(=O)O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1

Procedure:
tert-Butyl [6-(2-{(1S,2R)-2-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]cyclopropyl}ethoxy)-5-methylpyridin-3-yl]acetate (380 mg, 0.89 mmol) was treated with 3 mL of HCl (4M in dioxane) and 2 mL of water for 2 hrs at 40° C., then overnight at room temperature. The removal of the volatiles in vacuo gave the crude product which was then used for next step. LCMS (ESI) m/z 429 [M+H]+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:27](OC(OCC)CBr)[CH3:28]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]5[S:26][CH:27]=[CH:28][N:25]=5)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: CCOC(CBr)OCC
Product: c1csc(C2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)n1
Yield: 39 %

Procedure:
The title compound (92 mg, 39%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and bromoacetaldehyde diethylacetal similarly to the procedure used for example 137. 1H NMR (400 MHz, CDCl3) δ 1.66-1.72 (m, 2H), 1.77-1.89 (m, 5H), 1.95-2.04 (m, 4H), 2.11 (m, 1H), 2.36-2.43 (m, 2H), 2.58-2.72 (m, 5H), 3.71 (t, 2H), 3.84-3.88 (m, 2H), 4.27 (m, 1H), 6.84 (d, 2H), 7.23-7.26 (m, 3H), 7.70 (s, 1H). LRMS APCI+ m/z 399 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([C:16](=O)[CH3:17])[C:14]#[N:15].O.[NH2:20][NH2:21]>C(O)C>[CH3:17][C:16]1[C:13]([CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]=2[CH3:1])=[C:14]([NH2:15])[NH:21][N:20]=1
Reactant: NN
Reactant: CC(=O)C(C#N)Cc1cccc(C(F)(F)F)c1C
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (3.5 g, 33.2 mmol) in N,N-Dimethylformamide (25 mL) stirred under nitrogen at 0° C. was added a solution of 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.0 g, 27.7 mmol) in 10 ml of DMF dropwise during 30 min. The reaction mixture was stirred at 40° C. for 2 hours. Then this solution was diluted with saturated ammonium chloride solution. This solution was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried, concentrated to dryness in vacuo. The crude product was purified with on a silica gel column to give 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-3-oxobutanenitrile. (5.2 g, 74%). To a solution of 2-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}3-oxobutanenitrile (5.2 g, 20.4 mmol) in ethanol (400 mL) stirred under nitrogen at 20° C. was added neat hydrazine monohydrate (2.25 g, 30.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 100° C. for overnight. After cooled to room temperature, the reaction mixture was evaporated to dryness in vacuo. The residue was purified on a silica gel column (methanol/DCM gradient solvent system) to provide titled product. (2.16 g, 39%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (s, 3H) 2.39 (s, 3H) 3.63 (s, 2H) 4.30 (br. s., 2H) 7.19 (d, J=7.58 Hz, 1H) 7.27 (t, J=7.71 Hz, 1H) 7.49 (s, 1H) 11.09 (br. s., 1H)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:34]=[CH:33][C:13]([C:14]([NH:16][CH2:17][C@H:18]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[C:19]([O:21][CH3:22])=[O:20])=[O:15])=[CH:12][CH:11]=1>C(C(C)=O)C>[CH3:32][S:29]([N:26]1[CH2:25][CH2:24][N:23]([C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]2[CH:33]=[CH:34][C:10]([O:9][CH3:1])=[CH:11][CH:12]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:28][CH2:27]1)(=[O:31])=[O:30]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1ccc(OC)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 80 °C
Yield: 93 %

Procedure:
100 mg (0.8 mmol) of potassium carbonate and 0.1 ml (2 mmol) of methyl iodide are added to a solution of 250 mg (0.7 mmol) of methyl (S)-3-(4-hydroxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 10 ml of methyl ethyl ketone. The reaction medium is heated at 80° C. for 4 h. After cooling, it is filtered then concentrated. 260 mg (100%) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-(4-methoxybenzoylamino)-propanoate are obtained in the form of a white solid.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:30])[CH:12]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:4]=1>CO>[C:3]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([OH:30])[CH:12]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 69.3 %

Procedure:
Sodium borohydride (1.05 g, 27.7 mmol) was added portion wise to a stirred solution of tert-butyl 5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoate (12.1 g, 25.2 mmol) in methanol (80 mL) at 0° C. under nitrogen. On completion of addition stirring was continued for 1.5 h then the reaction was quenched with saturated aqueous ammonium chloride solution (80 mL). The resulting mixture was extracted with diethyl ether (3×200 mL) then the organic layers were combined, washed with brine (100 mL), dried (magnesium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (10% to 50% diethyl ether: cyclohexane) to give the title compound (8.47 g, 69%) as a colourless oil which was a mixture of diastereomers. LC/MS: 4.49 min; z/e 485, calcd (M+1) 485. 1H NMR (400 MHz: CDCl3): 7.60 (2H), 7.50 (2H), 7.45 (2H), 3.90 (1H minor), 3.80 (1H minor), 3.70 (1H major), 3.65 (1H major), 3.25 (1H minor), 3.00 (1H major), 2.90 (1H), 2.75 (1H), 2.60 (1H major), 2.55 (1H minor), 1.90 (1H), 1.85 (2H), 1.45 (10H), 0.90 (9H), 0.5 (6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C.O.C(Cl)Cl>[CH3:11][N:5]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:3]=[N:4]1
Reactant: COC(=O)c1[nH]ncc1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
Methyl 4-methyl-1H-pyrazole-5-carboxylate (0.5 g) and cesium carbonate (1.16 g) were dissolved in acetonitrile (10 ml). Methyl iodide (0.25 ml) was added and the mixture stirred at RT for 16 h. The reaction mixture was diluted with water (20 ml) and DCM (20 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with DCM (2×20 ml) using a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give the title compound (0.172 g) as a colourless oil.
Reaction SMILES: [Br-].[CH2:2]([N:4]([CH2:24][CH3:25])[C:5]1[CH:23]=[CH:22][C:8]([C:9](=[O:21])[CH2:10][N+:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:3].BrCC(C1C=C[C:33]([N:36](CC)CC)=[CH:32][CH:31]=1)=O>>[C:33]([C:32]1[CH:31]=[C:10]([C:9](=[O:21])[C:8]2[CH:7]=[CH:6][C:5]([N:4]([CH2:2][CH3:3])[CH2:24][CH3:25])=[CH:23][CH:22]=2)[N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=12)#[N:36]
Reactant: CCN(CC)c1ccc(C(=O)CBr)cc1
Reactant: CCN(CC)c1ccc(C(=O)C[n+]2cccc3ccccc32)cc1
Agent: [Br-]
Product: CCN(CC)c1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
1-(4-Diethylamino-phenacyl)-quinolinium bromide: The title compound was prepared from 2-bromo-1-(4-diethylamino phenyl) ethanone (2.23 g, 13.6 mmol), by a method similar to that described for the preparation of Example 1a, and yielded 1.67 g (92%). 1H NMR (DMSO-d6): 9.60 (d, J=6.0 Hz, 1H), 9.52 (d, J=8.4 Hz, 1H), 8.64 (d, J=8.1 Hz, 1H), 8.41 (d, J=9.9 Hz, 1H), 8.39 (d, J=7.5 Hz, 1H), 8.31 (t, J=6.9 Hz, 1H), 8.14 (dd, J=7.8, 6.9 Hz, 1H), 8.04, (d, J=8.7 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.93 (s, 2H), 3.60 (q, J=8.4 Hz, 4H), 1.26 (t, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[N:36]=[C:37]([NH:39][C:40]3[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=[C:44](B4OC(C)(C)C(C)(C)O4)[CH:45]=3)[CH:38]=[C:32]2[CH2:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:44]3[CH:45]=[C:40]([NH:39][C:37]4[CH:38]=[C:32]5[CH2:31][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH2:35][CH2:34][N:33]5[N:36]=4)[C:41](=[O:56])[N:42]([CH3:55])[CH:43]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (100 mg, 0.28 mmol), 133d (144.4 mg, 0.42 mmol), Pd(dppf)Cl2 (11.3 mg, 0.0139 mmol), K3PO4 (117.8 mg, 0.556 mmol), sodium acetate (45.6 mg, 0.556 mmol), acetonitrile (10 mL), and water (3 drops). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h under N2 protection. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 133e as a yellow solid (140 mg, 80%). MS-ESI: [M+H]+ 627.3
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24][CH3:25])[N:23]=2)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O.CO>[C:7]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:26])[NH:18][C:19]2[S:20][CH:21]=[C:22]([S:24]([CH3:25])=[O:1])[N:23]=2)=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CSc1csc(NC(=O)c2ccc(OC(C)=O)cc2)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Oc1ccc(C(=O)Nc2nc(S(C)=O)cs2)cc1

Procedure:
Using the Oxone® procedure as described in section 1.5.1.7 for the synthesis of compound (I), a solution of Oxone® (3.68 g, 6.00 mmol) is dissolved in a minimum amount of water (30.0 mL) and is added to a cold solution (0° C.) of 512 (0.63 g, 2.0 mmol) dissolved in a minimum amount of methanol (200 mL). Workup and purification by flash chromatography affords 3 as an off-white solid.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CC(C)=O>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:17])=[O:16]
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: O
Solvent: CC(C)=O
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 90 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 20 ml. of acetone and to the solution is added 20 ml. of N-hydrochloric acid. The mixture is refluxed for one hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed, dried, and evaporated to give a 90% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:14][O:13][C@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CO[C@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
3.5 g (11.4 mmol) of tert.-butyl N-(cis-1-benzyl-4-methoxypyrrolidin-3-yl)-carbamate are hydrogenated in 100 ml of methanol on 2 g of palladium-on-active charcoal (10% of Pd) at 100° C. under 100 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8](=O)[CH3:9])=[C:6]([I:11])[CH:5]=[C:4]([I:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1.Cl>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:11])[CH:5]=[C:4]([I:12])[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([N+:22]([O-:24])=[O:23])[CH:14]=1
Reactant: CC(=O)c1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: Cl
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12) is then reacted with a zinc mercury amalgam and hydrochloric acid and heated to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To as solution of Example 220B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound. MS (CI) m/z 532 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.C(NC1C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:14])[C:8](=[N+:35]=[N-:36])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)c1sccc1Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1sccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl 3-(3-chloro-2-thienyl)-3-oxopropanoate (1.26 g, 5.42 mmol) was dissolved in anhydrous acetonitrile (10 mL), treated with triethylamine (0.63 mL, 6.2 mmol, 1.15 equiv) and cooled to 0° C. To the mixture was added 4-acetamidobenzenesulfonyl azide (1.43 g, 6.0 mmol, 1.1 equiv) and after 10 minutes at 0° C., the mixture was warmed to ambient temperature. To the mixture, additional acetonitrile (20 mL) was added and the mixture was stirred at ambient temperature for an additional 45 minutes. The mixture was treated with sodium hydroxide (10 mL, 1 N aqueous), sodium carbonate (25 mL, aqueous saturated) and water (75 mL) and then extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NN
Solvent: CO
Solvent: O
Product: NN=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A solution of 4.0 g of D-arabinose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness in vacuo. The residue was triturated with 25 ml of methanol and the solid was collected, giving 3.5 g of D-arabinose hydrazone.