Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47].Cl>ClCCl.CO>[ClH:30].[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCN(C)CC2)cc1
Yield: 121.2 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)quinolin-3-yl)ethanone (6.0 g, 13.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.2 g, 15.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 200 mL) after which HCl (36 mL, 1.25 M in methanol) was added to form a solution. The solution was concentrated to dryness and the resultant solid was triturated with dichloromethane. The mixture was filtered, washed with dichloromethane, and dried to obtain desired product (5.2 g, 66% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.30 (s, 1H), 8.15 (dd, J=8.8, 1.9 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.10 (s, 2H), 3.81 (s, 2H), 3.55-3.31 (m, 2H), 3.29-2.89 (m, 4H), 2.89 (s, 3H), 2.82 (s, 3H), 2.80-2.35 (m, 2H); APCI MS m/z 535 [C29H28Cl2N4O2+H]+; HPLC>99% (AUC), tR=7.89 min.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:10]
Reactant: O=C(O)c1ccccc1O
Reactant: Nc1nnn[nH]1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1ccccc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 1.4 g (0.01 mole) of salicylic acid and 1.03 g (0.01 mole) of 5-aminotetrazole monohydrate in 40 ml. of pyridine was added dropwise 1.0 g (0.008 mole) of thionyl chloride. The mixture was stirred for one hour at 50° C. The stirred mixture was poured into water, acidified, and cooled. The resulting precipitate was collected by filtration and recrystallized from ethanol to provide 1.2 g 2-hydroxy-N-(tetrazol-5-yl)benzamide, in the form of a white solid, m.p. 264°-266° C.
Reaction SMILES: [ClH:1].CO.[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][C:7]=1[CH2:8][NH:9][C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1.[H][H]>[Pt]>[ClH:1].[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][C:7]=1[CH2:8][NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][C@H:11]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CNc1cccnc1-c1ccccc1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COc1ccc(OC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Yield: 25.2 %

Procedure:
To a 250 mL Parr bottle were charged 5.1 gms 5% Pt/C, 85 mL 1.0M HCl/CH3OH, and 1.7 grams of 3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenylpyridine. The reaction mixture was hydrogenated at 46-50 psi hydrogen at ambient temperature for 9.5 hours. After filtering the reaction mixture over Celite® and washing the cake with methanol, the filtrate was concentrated to a white solid. This material was repulped in acetonitrile at ambient temperature, filtered, and dried to yield 0.52 grams (25.2%) of a white material. The identity of this material was establishd by high resolution NMR.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:32]([O:42][CH3:43])[CH:31]=3)=[N:25][C:24]=2[C:44]([OH:46])=[O:45])=[CH:19][CH:18]=1.[Br:47][CH2:48][CH2:49]O.O.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:27][C:26](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][C:33]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:32]([O:42][CH3:43])[CH:31]=3)=[N:25][C:24]=2[C:44]([O:46][CH2:49][CH2:48][Br:47])=[O:45])=[CH:21][CH:22]=1
Reactant: COc1cc(/C=C/c2nc(C(=O)O)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: OCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/c2nc(C(=O)OCCBr)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
DCC (47 mg) was added to a solution of 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylic acid (80 mg) and 2-bromoethanol (0.27 mL), DMAP (5 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for 15 hours. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 27 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([F:19])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:19])[C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1cc(F)c(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2cc(O)cc(F)c2Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
Under nitrogen atmosphere, 3-chloro-5-(2-chloro-3-fluoro-5-methoxyphenoxy)-benzonitrile (50-4) (9.6 g, 30.8 mmol) was diluted in CH2Cl2 (60 mL, 0.5M) and then cooled to 0° C. To this solution BBr3 (61.5 mL, 61.5 mmol, 1M in CH2Cl2) was slowly added to the reaction. The reaction mixture was allowed to slowly warm to room temperature and stir for 12 hours. It was then cooled to 0° C. and slowly quenched with water (60 mL). The aqueous layer was then extracted with methylene chloride (3×30 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (1%-20% EtOAc/Hexanes) gave 3-chloro-5-(2-chloro-3-fluoro-5-hydroxyphenoxy)benzonitrile (50-5) (3.2 g, 35%). LCMS (ES) m/z 298.2 (M)+.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C1(CCCCCC(O)=O)C=CC=CC=1.[CH:40]1([N:46]=[C:47]=[N:48][CH:49]2[CH2:54][CH2:53][CH2:52]CC2)CCCCC1>O1CCCC1>[CH3:1][N:46]([C:47]1[CH:52]=[CH:53][CH:54]=[CH:49][N:48]=1)[CH3:40]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)CCCCCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 659 mg of 6-phenylhexanoic acid, 15 ml of dry tetrahydrofuran, 707 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 704 mg of the title compound were obtained.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])C>C(O)C.O>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:8]3([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[CH2:9]3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1)#[N:37]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(OCC3(C(=O)O)CCN(C(=O)c4ccc(F)cc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
Lithium hydroxide (16 mg, 0.67 mmol) was added to a stirred solution of 3-(4′-cyano-biphenyl-4-yloxymethyl)-1-(4-fluoro-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 29) (105 mg, 0.22 mmol) in ethanol (1 mL) and water (1 mL). The resulting mixture was stirred at RT for 5 hours. The mixture was concentrated under reduced pressure to remove ethanol and the residue was partitioned between ethyl acetate (5 mL) and 2M HCl aqueous solution (5 mL). The organic layer was washed with brine (5 mL), dried over magnesium sulphate and concentrated under reduced pressure to afford a white solid. This was recrystallised from isopropyl alcohol (2.5 mL) to afford the title compound as a white solid (76 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>CN(C=O)C.CCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)[C:8](=[O:11])[CH2:7]2
Reactant: O=C1Nc2c(Br)cccc2C1=O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1Cc2cccc(Br)c2N1Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
A mixture of 7-bromo-1H-indole-2,3-dione (4.5 g), Cs2CO3 (10 g) and 1-bromomethyl-4-trifluoromethylbenzene (5 g) in 50 ml of DMF was stirred at 55° C. for 6 h. The reaction mixture was cooled to r.t., diluted with 100 ml of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated under vacuum and the crude product was dissolved in 100 ml of ethanol and 10 ml of 50% aqueous solution of hydrazine. The resulting mixture was heated to reflux for 10 h and diluted with 50 ml of water. After cooling to r.t., solid was collected by filtration and air-dried to give the title compound as a white solid (5.2 g).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1)[CH3:23]
Reactant: CCS
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Yield: 90.4 %

Procedure:
A mixture of 0.25 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 0.11 g of ethyl mercaptan sodium salt and 3.5 ml of DMF was stirred under ice-cooling for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.26 g of 3-ethylthio-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 12”).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:23]1([N:33]=[C:34]=[O:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:34]([NH:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:35])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4cccc5ccccc45)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 54.8 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 1-naphthyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.40 g of the product in 60% yield: mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.51-2.65 (m, 2H), 2.85-2.97 (m, 1H), 4.78 (d, J=6.0 Hz, 2H), 5.18 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 7.23 (t, J=6.0, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.49-7.58 (m, 3H), 7.80-7.91 (m, 4H), 7.98 (d, J=7.3, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.81 (s, 1H), 11.20 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.9, 48.9, 116.8, 121.4, 121.9, 122.3, 125.4, 125.7, 125.8, 125.9, 127.3, 128.3, 131.7, 133.7, 133.8, 134.8, 134.9, 140.2, 155.7, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C25H20N4O5.0.25H2O: C, 65.14; H, 4.48; N, 12.15. Found: C, 65.08; H, 4.48; N, 11.96.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([O:13][CH3:12])=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1cccc(C(=O)OC)c1

Procedure:
A solution of 1-bromodecane (11.05 g, 0.050 mol) in butanone (50 ml) was added dropwise to a stirred, refluxing mixture of methyl-3-hydroxybenzoate (5.0 g, 0.033 mol) and anhydrous potassium carbonate (K2CO3) (30.0 g, 0.20 mol) in butanone (200 ml). The stirred mixture was heated under reflux for 24 h. The K2CO3 was filtered off and the solvent removed. The residue was purified by gravity column chromatography (silica gel/dichloromethane) to yield a colourless oil.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].Cl.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C>C1COCC1.CCOCC>[CH2:22]([O:21][C:17]([CH:18]1[C:6](=[O:16])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:19]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: C=CC(=O)OCC
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a refluxing suspension of 1.58 g (66 mmol) sodium hydride in 100 ml THF was added dropwise a solution of 12.79 g (60 mmol) N-tert-butyloxycarbonyl-glycine ethyl ester and 7.15 g (66 mmol) ethyl acrylate in 100 ml THF. After the addition was complete the mixture was heated to reflux for additional 2 h. The clear solution was cooled to room temperature, poured on 100 ml ether/100 ml water and acidified under vigorous stirring with 1N hydrochloric acid against methyl orange. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with sat. sodium bicarbonate and brine, dried over MgSO4 and evaporated. Short-path distillation of the residue gave 10.92 g (71%) 4-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert. butylester 3-ethylester as a colorless oil, b.p. 119°-122° C. (0.2 mbar), which solidified on prolonged standing in the freezer.
Reaction SMILES: [C:1]([Si:5]([CH3:37])([CH3:36])[O:6][C:7]1([C:11]2[S:12][C:13]([C:16]3[CH:17]=[C:18]([NH:25][C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:19]=[C:20]([N+:22]([O-])=O)[CH:21]=3)=[CH:14][N:15]=2)[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:5]([O:6][C:7]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([NH:25][C:26]4[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][N:27]=4)[CH:17]=3)=[CH:14][N:15]=2)[CH2:10][CH2:9][CH2:8]1)([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:36])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OC1(c2ncc(-c3cc(Nc4nccc(C(F)(F)F)n4)cc([N+](=O)[O-])c3)s2)CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1(c2ncc(-c3cc(N)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a solution of the product of Step 1 (252 mg, 0.457 mmol) in ethyl acetate (5 mL) was added 10% Pd/C (97 mg, 0.091 mmol), then the vessel headspace was purged with H2(g) and the mixture was stirred under an atmosphere of H2 (g) (1 atm) for 2 hours. Due to incomplete reaction (as evidenced by LCMS analysis), the headspace was purged with N2, additional catalyst (˜100 mg) was added and the vessel was again purged with H2 and stirred under H2 balloon overnight. The catalyst was deactivated by addition of dichloromethane, then the mixture was filtered through Celite (ethyl acetate rinse) and concentrated in vacuo to provide 219 mg (0.420 mmol, 92%) of 5-[2-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclobutyl)-1,3-thiazol-5-yl]-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzene-1,3-diamine as a brown foam.
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]([CH3:13])[CH2:10][CH:11]=[CH2:12])[CH:3]=[CH:4][C:5](=[O:7])[CH3:6]>[Ru].CO>[CH3:1][CH:2]([CH2:8][CH:9]([CH3:13])[CH2:10][CH2:11][CH3:12])[CH2:3][CH2:4][CH:5]([OH:7])[CH3:6]
Reactant: C=CCC(C)C=C(C)C=CC(C)=O
Agent: [Ru]
Solvent: CO
Product: CCCC(C)CC(C)CCC(C)O
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a glass autoclave liner is added 249 g of 5,7-dimethyl-3,5,9-decatrien-2-one, 2.2 g of 5% rutheniumon carbon and 200 ml of methanol. The glass liner is sealed inside a 3 L, stainless steel, rocking autoclave and the autoclave purged once with 250 psig N2, once with 250 psig H2 and then charged with 500 psig H2. With mixing, the reaction mixture is heated. At about 75° C., the reaction initiates and begins consuming H2 and exotherms to 170° C. In 10 minutes, the temperature has dropped to 115-120° C. and the pressure dropped to 270 psig. The autoclave is boosted to 1000 psig with H2, mixed at 110-115° C. for an additional 7 hours and 15 minutes then cooled to 30° C. The reaction mixture is removed from autoclave, filtered to remove catalyst and concentrated by evaporation of methanol under vacuum to yield 225.8 g of 5,7-dimethyl-2-decanol.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]([CH2:17][N:18]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C@H:19]([C:24]([NH:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:8][C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]([OH:10])[CH2:17][N:18]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:19]([C:24]([NH:26][C@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)C)C(=O)OCc1ccccc1)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC(O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1)C(C)C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
A solution of 177 mg (nom. 0.27 mmol) of N-[N-[[(4S)-3-[(t-butyloxy)carbonyl]-2,2-dimethyl-4-(2-methylpropyl)-5-oxazolidinyl]methyl]-N-[(phenylmethoxy)carbonyl]-L-leucyl]-L-valine, methyl ester (Isomer A) in 1.7 ml of dry dichloromethane was cooled in an ice bath under nitrogen, then treated with 0.85 ml of distilled trifluoroacetic acid. After 11/2 hours, the reaction was concentrated in vacuo to an oil, dissolved in 1 ml of distilled tetrahydrofuran, and treated with 0.6 ml (0.6 mmol) of 1N hydrochloric acid. After four hours, the reaction was worked up by treating with 6 ml of saturated sodium bicarbonate (aqueous), then extracting with 2×6 ml of chloroform, washing the organic extracts with brine, drying (magnesium sulfate), and concentrating to afford 127 mg of the title compound as a crude oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([NH2:12])=[CH:7]2.ClC1C=CN=C2C=1N=CC(N=C(C1C=CC=CC=1)C1C=CC=CC=1)=C2.Cl.C(=O)(O)[O-:40].[Na+]>O1CCCC1>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:40])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: Nc1cnc2c(Cl)ccnc2c1
Reactant: O=C([O-])O
Agent: Cl
Agent: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
8-chloro-1,5-naphthyridin-3-amine. A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C8H6ClN3=179.6. 2) 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine. A round bottom flask under nitrogen atmosphere was charged with 8-chloro-1,5-naphthyridin-3-amine (160 mg, 0.89 mmol), DMF (2.2 mL, 0.89 mmol). This was cooled to 0° C. and SODIUM HYDRIDE (60% dispersion in oil) (107 mg, 4.45 mmol) added portionwise. This was quickly followed by addition of 1-bromo-2-methoxyethane (0.12 mL, 1.25 mmol) dropwise via syringe. Ice bath removed and reaction mixture heated to 85° C. and stirred at this temperature for 16 hours. Reaction diluted with 5 mL of 5% MeOH/Dichloromethane, loaded onto silica gel column and eluted with 2% MeOH/DCM to afford 8-chloro-N-(2-methoxyethyl)-1,5-naphthyridin-3-amine (70 mg, 33% yield) as a light yellow solid. MS[M+H]=238.2. Calc'd for C11H12ClN3O=237.7.
Reaction SMILES: [NH2:1][C:2]1([C:9]([OH:11])=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN(C=O)C.C1CCN2C(=NCCC2)CC1.[Cl:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[N:38]=[C:39]=[O:40]>ClCCCl.C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:30]=1[N:38]1[C:9](=[O:11])[C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:1][C:39]1=[O:40]
Reactant: NC1(C(=O)O)CCCCCC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1NC2(CCCCCC2)C(=O)N1c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 18.9 %

Procedure:
A mixture of 1-aminocycloheptanecarboxylic acid (125 mg, 0.8 mmol) and DMF (0.8 mL) was treated with DBU (0.119 mL, 0.8 mmol) and allowed to stir for 5 min. The solution was then treated with 2-chloro-4-nitrophenylisocyanate (237 mg, 1.2 mmol) in DCE (2 ml) and the resulting mixture was allowed to stir for 30 min at ambient temperature and then reacted in a microwave vessel at 160° C. for 10 min. The reaction mixture was then cooled to rt, diluted with CH2Cl2 and then extracted with water, 1N HCl, sat. aq. NaHCO3, and the solvent removed under reduced pressure. The crude residue was re-crystallized from hot MeOH to afford 51 mg of 3-(2-chloro-4-nitrophenyl)-1,3-diazaspiro[4.6]undecane-2,4-dione, 1.1.15, (18%).