Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19](OCC)=[O:20])=[CH:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[Br:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[C:10]2[CH2:18][CH2:19][OH:20]
Reactant: CCOC(=O)Cc1cn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 6 g of N-tert-butoxycarbonyl-5-bromo-3-ethoxycarbonylmethylindole in 50 ml of tetrahydrofuran is added dropwise to a suspension, cooled to 0° C., of 0.9 g of LiAlH4 in 35 ml of tetrahydrofuran. After stirring for 20 hours at ambient temperature, the mixture is cooled to 0° C. and then treated in succession with 0.9 ml of water, 3,2 ml of an aqueous 20% sodium hydroxide solution and 3.6 ml of water. After filtration and concentration of the filtrate in vacuo, the residue is chromatographed on silica gel (dichloromethane/ethyl acetate: 90/10), enabling the expected product to be isolated.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH3:15][S:16][C:17]1[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:23]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH3:15])[N:22]=2)[OH:24])=[CH:7][N:6]=1
Reactant: CSc1nccc(C=O)n1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(O)c2cnc(Cl)nc2Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (14.83 g, 65 mmol) in THF (200 mL) was added isopropylmagnesium chloride (78 mL, 1M, 78 mmol) dropwise at −30° C. After 30 minutes, 2-(methylthio)pyrimidine-4-carbaldehyde (10 g, 65 mmol) was added to the mixture. The mixture was warmed to 0° C. and stirred for 1 hour. Then the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL). The filtrate was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica, 20 g, 200-300 mesh, eluting with methanol:dichloromethane, 1:50) to afford (2,4-dichloro-pyrimidin-5-yl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanol. (Yield 13.85 g, 71%).
Reaction SMILES: [OH-].[Li+].C(O/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)/[C:7]([O:9]CC)=[O:8])C.[C:35](O)(=[O:37])[CH3:36].O>O1CCCC1.C(OCC)(=O)C>[CH3:36][CH2:35][O:37]/[C:12](/[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[N:20]=2)=[CH:15][CH:14]=1)=[CH:6]\[C:7]([OH:9])=[O:8]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Reactant: CC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C(=C/C(=O)O)OCC)cc2)n1
Temperature: 68 °C
Reaction time: 18 h

Procedure:
0.68 mL (0.68 mmol) of aqueous 1 M lithium hydroxide solution is added to a solution of 0.20 g (0.45 mmol) of ethyl (Z)-2-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate in 6 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 18 hours. After cooling, the reaction is worked up by addition of 0.68 mL (0.68 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvents are evaporated off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.S(O)(O)(=O)=O.[CH3:24][N:25]([CH3:29])[C:26]([NH2:28])=[NH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:27]=[C:26]([N:25]([CH3:29])[CH3:24])[N:28]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: CN(C)C(=N)N
Agent: O=S(=O)(O)O
Product: CN(C)c1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1,1-dimethylguanidine sulfate were converted to I-22 (42%): HRMS Calcd. for C14H13ClN4O: 289.0856, Found 289.0843.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:23])=[C:6]([N:11]2[C:15](=[O:16])[NH:14][C:13]([C:17]3[S:18][C:19](Br)=[CH:20][CH:21]=3)=[N:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:2]=[CH2:3]>C(O)C.[Pt]>[Cl:10][C:8]1[CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]([OH:23])=[C:6]([N:11]2[C:15](=[O:16])[NH:14][C:13]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[N:12]2)[CH:7]=1
Reactant: C=CCc1cc(Cl)cc(-n2nc(-c3ccc(Br)s3)[nH]c2=O)c1O
Agent: [Pt]
Solvent: CCO
Product: CCCc1cc(Cl)cc(-n2nc(-c3cccs3)[nH]c2=O)c1O
Reaction time: 3 h
Yield: 29.8 %

Procedure:
A suspension of 2-(3-Allyl-5-chloro-2-hydroxyphenyl)-5-(5-bromothiophen-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one (Compound of Example 20) (206 mg) and 10%Pt(S)/C (206 mg) in ethanol (8 ml) was hydrogenated at 50 psi for 3 hours. After filtration and concentration, the residue was purified to give 50 mg (30%) of 2-(5-chloro-2-hydroxy-3-propylphenyl)-5-(thiophen-2-yl)-2,4-dihydro-[1,2,4]triazol-3-one. 1H NMR (300 MHz, DMSO-d6) δ12.9 (s, 1 H), 9.56 (s, 1 H), 7.79 (dd, J=4.89, 0.9 Hz, 1 H), 7.31 (d, J=2.6 Hz, 1 H), 7.23-7.21 (m, 2 H), 2.61 (t, J=7.4 Hz, 2 H), 1.64 (m, 2 H), 0.94 (t, J=7.2 Hz, 2 H); 13C NMR (75 MHz, DMSO-d6) δ153.9, 147.9, 142.8, 133.7, 129.4, 129.0, 128.5, 128.3, 125.6, 123.0, 122.6, 31.8, 22.4,13.9; IR (KBr, cm−1) 1701; MS(ESI) 334 (M−1)−.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C[O:10][CH2:9][CH2:8]1>>[CH3:3][C:2]([C:1]([O:6][CH2:8][CH2:9][OH:10])=[O:5])=[CH2:4]
Reactant: C=C(C)C(=O)[O-]
Reactant: C1CCOC1
Product: C=C(C)C(=O)OCCO

Procedure:
The 1H NMR spectrum of the PIB before, as seen in FIG. 7a, and after, as seen in FIG. 7b, methacrylation are provided. The resonance at δ3.6 ppm, corresponding to the —CH2— protons next to the hydroxyl group, as seen in FIG. 7a, disappeared and new resonances attributed to the vinylidene [δ5.6 (e2), δ6.1 (e1)], methyl [δ2.0 (f)] and methylene protons adjacent to the methacrylate end group [δ4.2 (g)] appeared at the expected positions. The integration ratios of (e2):(e1):(g):(f) were 1:1:2:3 which demonstrated quantitative functionalization. The use of THF solvent gave incomplete conversion after 24 hours, although PEG-MA was obtained in quantitative yield under similar conditions. At this point we do not understand the reason for this discrepancy. We hope to get a better understanding of the mechanism of enzymatic polymerizations, which we are actively investigating.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[CH:9][CH:10]=[C:11]3[C:20]([N:19]=[C:18]4[C:13]([CH:14]=[CH:15][CH:16]=[C:17]4[C:21]([OH:23])=O)=[N:12]3)=[C:7]2[CH:6]=[CH:5][N:4]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:21]([C:17]1[C:18]2[C:13](=[N:12][C:11]3[C:20]([N:19]=2)=[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]2=[CH:9][CH:10]=3)[CH:14]=[CH:15][CH:16]=1)=[O:23]
Reactant: CN(C)CCN
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)O)c3nc12
Product: COc1nccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
4-Methoxypyrido [4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 4-methoxypyrido[4,3-α]phenazine-11-carboxylic acid (II.4) and N,N-dimethylethylenediamine
Reaction SMILES: C([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1([NH2:20])[C:17](O)=O)(OC(C)(C)C)=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:36]([C:41]1[CH:42]=[C:43]([NH2:48])[C:44]([NH2:47])=[CH:45][CH:46]=1)[C:37]([CH3:40])([CH3:39])[CH3:38].C(O)(=O)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:38][C:37]([CH3:40])([CH3:39])[CH2:36][C:41]1[CH:46]=[CH:45][C:44]2[N:47]=[C:17]([C:9]3([NH2:20])[CH2:8][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)[NH:48][C:43]=2[CH:42]=1
Reactant: CC(C)(C)Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)C1c2ccccc2CC1(N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)Cc1ccc2nc(C3(N)Cc4ccccc4C3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a solution of Boc-2-aminoindane-2-carboxylic acid (107 mg, 0.386 mmol) in acetonitrile (2.0 mL) and 4-methylmorpholine (0.11 mL, 1.0 mmol) cooled in an ice/brine bath was added isobutylchloroformate (0.050 mL, 0.38 mmol). The mixture was stirred for 30 minutes and then 4-neopentylbenzene-1,2-diamine (Preparation 83, 82 mg, 0.46 mmol) was added. The reaction mixture was allowed to warm to room temperature and stir for 4 hours. The solvent was evaporated and the resulting oil was dissolved in acetic acid (3.0 mL, 50 mmol) and heated at 65° C. for 16 hours. After cooling, the solvent was removed in vacuo and the residue purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient. The resulting oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (0.5 mL, 6 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with a 0-100% CMA80/methylene chloride gradient. This provided the title compound (63.7 mg, 52%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:11]=[CH:10][C:9]#[N:12])=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Product: N#CC=Cc1ccc(Br)cc1
Yield: 76 %

Procedure:
The procedure described in Example 47 is repeated, but using 7.07 g (25 mmols) of 4-bromoiodobenzene and 1.83 g (27.5 mmols) of acrylonitrile. After a reaction time of 8 hours at 130° C., 3.95 g (19.0 mmols) of 4-bromocinnamonitrile are obtained, corresponding to a yield of 76% of theory (conversion figure 7600; Pd content 0.01 mol %).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2ccncc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.81 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) followed by HPLC to provide pure product. 1HNMR (DMSO, Oxalate Salt) δ (ppm): 8.60 (d, 2H), 7.62 (m, 3H), 7.40 (s, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 4.40 (m, 2H), 3.10 (m, 4H), 2.99 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][C@H:41]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C(Cl)Cl.CCOC(C)=O>[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][C@H:41]1[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:27])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 56.9 %

Procedure:
N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (1.1 g, 4.18 mmol, Eq: 1.6) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (738 mg, 3.4 mmol, Eq: 1.3) and diisopropylethylamine (1.4 mL, 7.84 mmol, Eq: 3) in DCM (10 mL) and the resulting solution was stirred at rt for 1 h. (S)-Ethyl indoline-2-carboxylate (0.5 g, 2.61 mmol, Eq: 1.00) was added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was diluted with EtOAc (50 mL) and washed with 0.1 M aqueous HCl (50 mL), 0.1 M aqueous NaOH (50 mL) and brine (25 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 20% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylate (0.58 g), m/z=391 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[C:9]([CH3:11])[CH3:10])[CH2:5][C:6]([OH:8])=[O:7]>CO>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:9]([CH3:10])[CH3:11])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(CC(=O)O)=C(C)C
Solvent: CO
Product: COC(=O)[C@@H](CC(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of the tert-butylamnine salt of 2-isopropylidenesuccinic acid 1-methyl ester (162 g, 0.66 mol) in methanol (800 mL) was transferred to a 2 L high pressure hydrogenation vessel and degassed by pressurizing and venting four times with 10 bar of hydrogen. The vessel was then cooled to 0° C. and a solution of [Rh(COD)(S,S)-Me-BPE]OTf(0.80 g, 0.0013 mol) in methanol (10 mL) was added through the solvent port. The reaction was purged again with hydrogen and stirred at 0° C. under a pressure of hydrogen of 10-7 bar. After 22 hours, the temperature was allowed to raise to room temperature, the vessel was vented in a fume hood, the reaction mixture was transferred to a round-bottomed flask and the solvent was evaporated under reduced pressure. A sample (1 g) of the resulting solid residue was partitioned between HCl 2N (5 mL) and ethyl acetate (5 mL). The organic layer was dried over MgSO4 and evaporated to give 2-(S)-isopropylsuccinic acid 1-methyl ester, ee 96% by GC. The bulk residue was suspended in ethyl acetate (600 mL) and stirred at room temperature for 48 hours, then collected and dried under vacuum to give 154 g of the tert-butylamine salt of 2-(S)-isopropylsuccinic acid monomethyl ester (yield: 94%). A sample (1 g) of the salt was worked up and analyzed as above, indicating an enantiomeric excess of 99% for the free acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[CH:18][C:19]1[NH:20][C:21]([CH2:26][CH3:27])=[CH:22][C:23]=1[CH2:24][CH3:25])(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[CH:18][C:19]1[NH:20][C:21]([CH2:26][CH3:27])=[CH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1cc(CC)c(C=C2C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc32)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(CC)c(C=C2C(=O)Nc3ccc(N)cc32)[nH]1

Procedure:
[3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-carbamic acid tert-butyl ester in 50% trifluoroacetic acid in dichloromethane was stirred at room temperature for 2 hrs and concentrated. The red residue was suspended in saturated sodium bicarbonate solution. The precipitate was filtered, washed with water until pH 6 and dried overnight to give 5-amino-3-(3,5-diethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]#[C:20][CH3:21])[CH:15]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH3:21])[CH:15]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: CC#Cc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reaction time: 6 h
Yield: 95.9 %

Procedure:
7.4 g of 2-(3,4-difluorophenyl)-6-(1-propynyl)naphthalene was dissolved in 80 ml of ethyl acetate. To the solution was then added 1.5 g of 5% palladium carbon. Hydrogen was then introduced into the reaction mixture at ordinary temperature and pressure. The reaction mixture was then stirred for 6 hours. The catalyst was then removed by filtration. The solvent was then distilled off to obtain 7.2 g of 2-(3,4-difluorophenyl)-6-propylnaphthalene. The product was then recrystallized from methanol to obtain 4.2 g of a purified product. (Cr 62.5 I)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:16][OH:17]>C(O)C>[OH:17][NH:16][C:1](=[NH:2])[N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
To a solution of tert-butyl 4-cyanopiperazine-1-carboxylate (15 g, 76 mmol) in ethanol (150 mL) was added hydroxylamine (50% aqueous solution, 6.2 mL, 92 mmol) and the reaction mixture was stirred at RT for 6 hours. The solvent was evaporated under vacuum and the solid obtained was triturated with hexane (100 mL) and filtered to obtain 15 g (80%) of the title compound as a solid. TLC-Chloroform/methanol (9/1): Rf=0.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][C:3]=1[S:16](=[O:20])(=[O:19])[NH:17][CH3:18].[CH3:21][NH2:22]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:15])[N:22]([CH3:21])[C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:16](=[O:20])(=[O:19])[NH:17][CH3:18]
Reactant: CN
Reactant: CNS(=O)(=O)c1cc(C(=O)CCC(=O)OC)ccc1Cl
Solvent: CO
Product: CNS(=O)(=O)c1cc(C2(O)CCC(=O)N2C)ccc1Cl

Procedure:
7.9 of methyl 4-(4-chloro-3-methylsulfamoylphenyl)-4-oxobutanoate are reacted with 6.9 g of methylamine in 100 ml of methanol and the mixture is worked up analogously to the instructions indicated in Example 2(b). 5-(4-Chloro-3-methylsulfamoylphenyl)-5-hydroxy-1-methyl-2-oxopyrrolidine of melting point 147°-150° C. is obtained.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[O:20])=[CH:9]2)=CC=1>Cl.O1CCOCC1>[F:30][C:27]([F:28])([F:29])[C:24]1[N:23]=[CH:22][C:21]([C:19]([C:10]2[C:11](=[O:18])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][CH:9]=2)=[O:20])=[CH:26][CH:25]=1
Reactant: COc1ccc(Cn2cc(C(=O)c3ccc(C(F)(F)F)nc3)c(=O)c3ccccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1c[nH]c2ccccc2c1=O
Yield: 58.4 %

Procedure:
800 mg (1.83 mmol) of 1-(4-methoxy-benzyl)-3-(6-trifluoromethyl-pyridine-3-carbonyl)-1H-quinolin-4-one was heated in a sealed tube to 120° C. in 15 mL of 4 M HCl in dioxane for 20 h. The solution was evaporated and the residue ultrasonicated in 20 mL saturated aqueous NaHCO3. Filtration of the solid followed by aqueous wash, DCM wash and drying gave 340 mg of a light-brown powder. LC-MSD, m/z for C16H9F3N2O2 [M+H]+=319.0; HPLC retention time: 1.8 min.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:10][C:9](=[O:11])[CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:13][CH3:14])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCCC(Oc1ccccc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 101.5 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.70 g of (2RS)-2-phenoxyvaleric acid and 1.0 g of (4S,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.34 g of the title compound as a colorless foam.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:21]([O-])=O)=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:24])[CH2:3][CH2:2]1.C(O)(=O)C>C1COCC1.[Fe]>[NH2:21][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:2][CH2:3]3)[C:11]2=[O:24])=[CH:16][C:15]=1[F:20]
Reactant: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C1CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc2c(cc1F)CCN(c1cnccc1C1CC1)C2=O
Yield: 96.6 %

Procedure:
2-(4-Cyclopropylpyridin-3-yl)-6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (I-82a: 400 mg, 1.219 mmol) was reduced with iron powder (340 mg, 6.09 mmol) and acetic acid (10 mL) in THF (10 mL) at 75° C. for 4 hours to afford 350 mg of the product (96.6% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]1[OH:33].N[C@H]1[C@H](OCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@H](COCC2C=CC=CC=2)C[C@H]1O>>[NH2:1][C@H:2]1[C@H:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@@H:6]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@@H:3]1[OH:33]
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Agent: N[C@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](COCc2ccccc2)C[C@H]1O
Product: N[C@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](COCc2ccccc2)C[C@@H]1O
Yield: 58 %

Procedure:
The product of step 1 was an enantiomeric isomer of (1R,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol described above in Intermediate Example 3, Step 3. It was prepared via a synthetic sequence substantially identical to that described above for Intermediate Example 3 Steps 1-3, starting from the enantiomeric (1R,2R,3S,4S,5S)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol. The purification conditions for each step reaction were also the same as described, (1S,2R,3S,4S,5S)-2-Amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol was obtained as a white solid with overall yield 58% employing procedures substantially as described for the Intermediate Example 3. 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 4.98 (d, J=11.3 Hz, 1H), 4.84 (d, J=10.8 Hz, 1H), 4.69 (d, J=11.3 Hz, 1H), 4.56 (d, J=10.8 Hz, 1H), 4.47 (s, 2H), 3.64 (dd, J=4.9, 8.9 Hz, 1H), 3.54-3.48 (m, 2H), 3.30-3.26 (m, 1H), 3.16 (t, J=9.4 Hz, 1H), 2.52-2.50 (m, 1H), 2.08-2.03 (m, 1H), 1.76-1.72 (m, 1H), 1.58-1.52 (m, 1H).