Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27]/[CH:28]=[C:29]1/[C:30]2[CH:43]=[C:42]([C:44]([OH:47])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:31]=2[O:32][CH2:33][C:34]2[N:39]=[CH:38][CH:37]=[CH:36][C:35]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:13]2)[CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(N(CC(N)=O)Cc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-acetamide (0.21 g, 0.8 mmol) in acetonitrile:water (4:1) was added potassium carbonate (0.6 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) and the resulting mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by HPLC. 1H-NMR (CDCl3) δ: 1.35 (6H, s), 1.55-1.75 (1H, m), 1.80-2.00 (1H, m), 2.20-2.85 (8H, m), 2.90-3.10 (2H, d), 3.30-3.50 (1H, m), 3.60 (1H, d), 4.80-5.30 (2H, br, s), 6.10 (1H, t), 6.70 (1H, dd), 7.00-7.45 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 562 (M+1), UV retention time: 1.31 min.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]1([C:13]([NH:15][S:16]([CH:19]2[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[O:14])[CH2:10][C@H:9]1[CH2:11][CH3:12])(C)(C)C.C(Cl)[Cl:24]>>[ClH:24].[NH2:7][C@:8]1([C:13]([NH:15][S:16]([CH:19]2[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[O:14])[CH2:10][C@H:9]1[CH2:11][CH3:12]
Reactant: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reactant: ClCCl
Product: CC[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Product: Cl
Reaction time: 0.17 h

Procedure:
A solution of the product from step 1 above (92 g, 0.28 mol) in DCM (1200 mL) was cooled to 0° C., and HCl was bubbled through the solution. After 10 min, the cooling bath was removed, and the reaction mixture was stirred for 2 h. Nitrogen was bubbled through the reaction mixture for 5 min, and the volatiles evaporated. The residue was azeotroped with DCM (×3) to give an off white powder (75 g). LRMS (M+H)+ Calcd.=233; found 233.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:19])=[N:13][C:14]([C:15]([O:17]C)=O)=[C:10]3[CH2:9][C:8](=[O:20])[N:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:27]=1.[Cl-].[Li+].[CH3:30][N:31]([CH3:40])P(=O)(N(C)C)N(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:19])=[N:13][C:14]([C:15]([N:31]([CH3:40])[CH3:30])=[O:17])=[C:10]3[CH2:9][C:8](=[O:20])[N:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:27]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)c1nc(C)n2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2
Agent: [Cl-]
Agent: [Li+]
Product: Cc1nc(C(=O)N(C)C)c2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2

Procedure:
A mixture of 1.2 g of methyl 8-chloro-4,6-dihydro-1-methyl-6-phenyl-5-oxo-5H-imidazo[1,5-a][1,5]benzodiazepin-3-carboxylate, 2 g of lithium chloride and 12 ml of hexamethyl phosphoric triamide was stirred and heated up to 230°. As soon as this temperature was reached, the reaction mixture was cooled and partitioned between methylene chloride and water. The organic phase was washed with water, dried over sodium sulfate and evaporated. Crystallization of the residue from ether yielded the end product which was recrystallized from ethyl acetate/hexane for analysis, mp 213°-215°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:10][C:11]1[CH:12]=[C:13]([C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:7])[CH:8]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Cc1ccc(Br)cc1N
Product: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Yield: 94 %

Procedure:
Using the same method as in Example 5-(i), 5-bromo-2-methylaniline was reacted with 3,5-dimethylphenyl boronic acid to give 3′,4,5′-trimethylbiphenyl-3-amine (yield: 94%).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][OH:15])[NH:9]2.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([CH2:14][O:15][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:9]2
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCc1cc2c(OCC3CO3)cccc2[nH]1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCc1cc2c(OCC3CO3)cccc2[nH]1

Procedure:
11.5 g. 4-(2,3-epoxypropoxy)-2-hydroxymethyl-indole (see U.S. Pat. No. 3,705,907) were dissolved in 100 ml. pyridine. To this solution were added dropwise, while cooling to 0° - 5° C., 6.5 g. (6.7 ml.) pivaloyl chloride. After an hour, the reaction mixture was poured on to ice and extracted with diethyl ether. The ethereal solution was successively washed with dilute sulfuric acid, aqueous sodium bicarbonate solution and water. After drying and treating with active charcoal, the solution was filtered and evaporated. The residue (13 g.; 82% of theory) crystallized upon triturating with diethyl ether/ligroin to give 4-(2,3-epoxypropoxy)-2-pivaloyloxymethyl-indole; m.p. 129° - 131° C.
Reaction SMILES: C(OO)(=[O:3])C.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13]#[N:14])[CH:7]=1.O>C(O)(=O)C>[CH:10]1[CH:11]=[N+:6]([O-:3])[CH:7]=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=1
Reactant: CC(=O)OO
Reactant: N#CCc1cccnc1
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
The title compound is prepared in accordance with the procedures as outlined in S. Okuda et al., J. Am. Chem. Soc., 81, 740, (1959). Peracetic acid (38%, 40 mL, 0.2 mol) is added to a stirred solution of 3-pyridylacetonitrile (15.0 g, 127 mmol) in acetic acid (75 mL) and the reaction is heated at 95° C. for 24 hr, then stirred at room temperature for 24 hr. Water is added and the solvents are removed. More water (100 mL) is added and again removed. This process is repeated with toluene and with ether to give (1-oxypyridin-3-yl)acetonitrile as a cream solid.
Reaction SMILES: [NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67]2[C:62]1=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C>O>[NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[C:73]1=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCN)NC(=O)[C@@H](CCCCN)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude crystals (100 mg) of Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) were added to a solution (2 ml) of trifluoroacetic acid:triisopropylsilane:water=95:2.5:2.5 under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and methyl tert-butyl ether (MTBE)/cyclohexane was added to the residue. The precipitate was washed at 40° C. and collected by filtration to give Fmoc-D-Lys-D-Lys-Leu-Leu-OH (29 mg).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=O.[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1.[Cl-].[Na+]>ClCCl>[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:20][C:21]([N:30]1[CH2:31][CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29]1)=[O:23])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H](CC(=O)O)CC(C)C
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(CC(=O)N1CCc2ccccc2C1)CC(C)C
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
iso-Butyl chloroformate (33.64 mg, 0.2463 mmol) in dichloromethane (2 ml) and N-methyl morpholine (49.83 mg, 0.4927 mmol) in dichloromethane (2 ml) were simultaneously added to a stirred solution of (R)-2-isobutyl succinic acid 1-methyl ester (42.15 mg, 0.2239 mmol) in dichloromethane (2 ml) at −15° C. under argon over 5 minutes. The mixture was stirred at −15° C. for 15 minutes. A freshly prepared solution of 1,2,3,4-tetrahydro-isoquinoline (29.83 mg, 0.2239 mmol) in dichloromethane (2 ml) and N-methylmorpholine (24.92 mg, 0.2463 mmol) was then added dropwise. The mixture was then stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated aqueous sodium chloride solution (1 ml). The aqueous layer was extracted with diethyl ether (2×5 ml) which was discarded. The aqueous layer was acidified with 1M hydrochloric acid to pH (12), then the product was extracted into dichloromethane (3×5 ml). The combined dichloromethane layers were washed with water (2×5 ml), saturated aqueous sodium chloride solution (2×5 ml) then dried (Na2SO4). The solvent was removed in vacuo to give a residue which was purified over silica gel eluting with a gradient of n-heptane:ethyl acetate 4:1. Desired fractions were combined and reduced in vacuo to leave 2-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-4-methyl-pentanoic acid methyl ester as a colourless oil (35 mg, 51.5% from starting acid). TLC (single UV spot, Rf=0.6, n-heptane:ethyl acetate 1:1), HPLC-MS (single UV peak with Rt=9.544 mins, 304.2 [M+H]+, 305.2 [M+2]+, 306.2 [M+3]+, 629.3 [2M+Na]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)=[O:7].[CH2:13]1[O:22][C:16]2(CCNC[CH2:17]2)[O:15][CH2:14]1>C1COCC1>[CH2:13]1[O:22][C:16]2([CH2:17][CH2:9][N:8]([C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: O=C(c1ccc[nH]1)n1ccnc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCOC1
Product: O=C(c1ccc[nH]1)N1CCC2(CC1)OCCO2
Yield: 70.7 %

Procedure:
A solution of 1-(1H-pyrrole-2-carbonyl)imidazole (0.54 g, 3.4 mnmol) and 4-piperidone ethylene ketal (0.43 ml, 3.4 mmol) in THF (10 ml) was heated at reflux for 1 h. The mixture was cooled and evaporated, diluted with ethyl acetate, washed with dilute HCl, dried over sodium sulphate and evaporated to afford a beige solid (0.56 g), MS (+CI) 237 ([M+H]+), 1H NMR (CDCl3) 9.47 (1H, br. s), 6.92 (1H, m), 6.53 (1H, m), 6.25 (1H, m), 4.00 (4H, s), 3.91 (4H, t, J 5.4 Hz), 1.78 (4H, t, J 5.8 Hz).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([S:12](=[O:22])(=[O:21])[N:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH3:14])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[CH:15]1([N:13]([CH3:14])[S:12]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:23])=[O:2])(=[O:22])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)N(C)C2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 3-(Cyclohexyl-methyl-sulfamoyl)-4-methoxy-benzoic acid methyl ester (1.50 g, 4.39 mmol) in 1,4 dioxane (40 ml) is treated with 2 N NaOH (10 ml) and the resulting solution is stirred at room temperature for 21 hours. The solvent is removed in vacuo and ice cold 2 N HCl (25 ml) is added and the white solid which forms is extracted into DCM (150 ml). The organic layer is washed with water, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid; [M−1]+ 326.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:11]([NH:12][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cccc(C(=O)OC)c1N

Procedure:
To a solution of methyl 2,3-diaminobenzoate (3.0 g) in THF (50 mL) was added N,N-diisopropylethylamine (4.0 mL). The solution was stirred under ice-cooling, methoxyacetyl chloride (1.81 mL) in THF (10 mL) was added dropwise slowly, and it was stirred for 3 hours at the same temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and THF was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (3.60 g) as pale yellow powder.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=[O:14]>>[OH:13][OH:14].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH:11]=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O
Product: OO

Procedure:
Galactose oxidase catalyzes the interaction of D-galactose and oxygen to produce hydrogen peroxide and D-galacto-hexodialdose;
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18](O)=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]1([S:7]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[S:15][CH:16]=[C:17]([C:18]([Cl:25])=[O:19])[C:13]=3[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1csc2ccc(OS(=O)(=O)c3ccccc3)cc12
Yield: 100 %

Procedure:
5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (5.582 g, 16.7 mmol) prepared in Examples above was refluxed for 1.5 hours with dimethylformamide (1 drop), thionyl chloride (3.57 ml, 50 mmol) and toluene (22 ml), and the solvent was removed under reduced pressure to provide 5.89 g of the title compound (10).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@:10]1([O:24][CH3:25])[CH2:21][CH:22]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:26]=[O+][O-]>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:11][C@@:10]1([CH2:21][CH2:22][OH:26])[O:24][CH3:25])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=[O+][O-]
Reactant: C=CC[C@@]1(OC)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CO[C@]1(CCO)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-methoxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate (230 mg) in CH2Cl2 (10 mL) was cooled to −78° C. and treated with a stream of ozone until a blue color persisted. A stream of nitrogen was passed through the solution for 15 minutes to remove excess ozone from solution. The solution was then treated with dimethylsulfide (0.2 mL) and allowed to warm to 23° C. over 30 min. Volatile components of the reaction mixture were removed in vacuo. The residue was dissolved in methanol (10 mL). To the solution was added NaBH4 (50 mg) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The mixture was poured into saturated aqueous solution of NH4Cl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=99/1˜1/99) to give tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-(2-hydroxyethyl)-3-methoxypyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O>[CH2:33]([C:13]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:34]
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC1CCOCC1

Procedure:
A solution of tert-butyl [4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in trifluoroacetic acid was stirred at 40° C. for 4 hrs. Reaction mixture was then poured on ice-water mixture and extracted with chloroform. Organic layer was dried over sodium sulphate and concentrated under deduced pressure to afford the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][N:14]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=[C:15]32)=[CH:10][CH:9]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)c1cnc2n(c1=O)CCc1ccc(O)cc1-2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)Oc1ccc2c(c1)-c1ncc(C(=O)O)c(=O)n1CC2
Temperature: 0 °C
Yield: 63.7 %

Procedure:
Isobutyryl chloride (455 mg., 4.26 mmoles) was added to a stirred, cooled (ice-water) mixture of 6,7-dihydro-10-hydroxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (1.03 g., 3.87 mmoles) and triethylamine (785 mg., 7.75 mmoles) in methylene chloride (20 ml.). The mixture was concentrated to dryness and the residue was triturated with cold 1N HCl, and then crystallized from benzene to give the title compound 0.81 g. (64% yield). The product was recrystallized successively from ethyl acetate and methanol to give the analytical sample, m.p. 183°-185°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14](OCC)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CO.[NH3:34]>>[NH2:34][C:14](=[O:15])[C:13]([NH:12][C:10]([C:7]1[CH:6]=[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:11])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[CH3:19]
Reactant: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1
Reactant: N
Solvent: CO
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(N)=O)no1
Yield: 69 %

Procedure:
A solution of ethyl 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147b, 0.05 g, 113 μmol) in ammonia 7N in MeOH (1.00 ml, 7.01 mmol) was stirred at room temperature overnight. Volatiles were removed in vacuo and the crude material was purified by preparative HPLC without any work-up protocol to yield the title compound (32 mg, 69%). MS (ESI, m/z): 414.5 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:28]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(c3cc(Cl)ncn3)CC1)O2

Procedure:
Compound 230 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4,6-dichloropyrimidine and conditions outlined in procedure AA. M.p.=172-174° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.25 (s, 1H), 7.91-7.86 (m, 2H), 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.08 (s, 1H), 3.42-3.33 (m, 4H), 3.10 (s, 2H), 2.09-2.04 (m, 2H), 1.85-1.76 (m, 2H); LCMS: 414 [M+H].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH3:15])[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([CH3:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)COCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](CO)COCc1ccccc1
Temperature: 27.5 °C
Yield: 88.5 %

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a reflux condenser and a 500 mL constant pressure addition funnel. The flask was charged with a solution of 62.252 g (0.299 mol) of methyl (S)-3-benzyloxy-2-methylpropanoate in 600 mL of anhydrous THF, and a 1.0 M solution of lithium aluminum hydride (300 mL; 0.3 mol) was transferred into the dropping funnel via a cannula. Stirring was started and the lithium aluminum hydride solution was added over 45 minutes to the reaction under an N2 atmosphere while the temperature of the reaction mixture was maintained between 25-30° C. using an external ice-water bath. After the addition was complete, the reaction was stirred an additional 6 h at room temperature at which point TLC analysis (20% EtOAc-hexane) indicated complete reaction. The reaction mixture was then cooled with an external ice-water bath and quenched by serial addition of 11.4 mL water, 11.4 mL of 15% aqueous NaOH, and 34.2 mL water. The reaction mixture was then filtered, the solids were washed with EtOAc, the filtrate and washings were combined and evaporated in vacuo. The residue was redissolved in EtOAc, washed with 10% aqueous NaHSO4, saturated NaCl, dried (MgSO4), filtered and evaporated. The residue was purified by Kugelrohr distillation to afford 47.67 g (89%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:21])=[C:6]([CH:19]=[O:20])[C:7]([C:10]2[C:11]([CH:17]=[O:18])=[C:12]([F:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:2].C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:11](=[C:12]([F:16])[CH:13]=[CH:14][CH:15]=3)[C:17](=[O:18])[C:19](=[O:20])[C:6]=2[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc(-c2cccc(F)c2C=O)c(C=O)c1F
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc2c(c1F)C(=O)C(=O)c1c(F)cccc1-2
Yield: 703.9 %

Procedure:
Under a nitrogen atmosphere, a DMF (50 mL) solution of compound (85) (10.0 g, 3.45 mmol), 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole-3-iumbromide (1.74 g, 6.89 mmol) and triethylamine (1.05 g, 10.34 mmol) was agitated at 60° C. for 6 hours. The reaction mixture was quenched with 150 mL of water, and extracted with 50 mL of dichloromethane three times. Combined organic layers were washed with a 1N hydrochloric acid aqueous solution, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was washed with toluene, and thus 2-ethoxy-1,8-difluorophenanthrene-9,10-dione (86) (7.0 g, yield 70.5%) was obtained.