Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:20])[C@H:15]([CH:17]1[CH2:19][CH2:18]1)[O:16][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A cooled (0° C.) solution of (S)-4-benzyl-3-((S)-2-cyclopropyl-2-hydroxy-acetyl)-oxazolidin-2-one (4.137 g, 15.026 mmol) in dichloromethane (60 mL) was subsequently treated with 2,6-lutidine (3.5 mL, 30.052 mmol) and triisopropylsilyl trifluoromethanesulfonate (6.1 mL, 22.539 mmol). After stirring at room temperature for 1 h, the reaction was quenched with pH 4 buffer (phthalate). The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (5.28 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.40-0.49 (m, 2H), 0.53-0.62 (m, 1H), 0.63-0.71 (m, 1H), 1.02-1.18 (m, 21H), 1.20-1.34 (m, 1H), 2.66 (dd, J=13.1, 10.5 Hz, 1H), 3.49 (dd, J=13.1, 3.4 Hz, 1H), 4.17-4.27 (m, 2H), 4.63-4.73 (m, 1H), 5.58 (d, J=5.1 Hz, 1H), 7.24-7.40 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH2:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2N)c(OC)c1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 6.5 %

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-aminobenzonitrile (3.9 g) in acetonitrile (100 mL) was cooled to 0° C. and treated with potassium carbonate (6.3 g) followed by a solution containing 3 g of 2-chloro-5-nitro-4-thiocyanatopyrimidine (WO 2003/032994) in acetonitrile (50 mL). The mixture was stirred for 30 minutes at 0° C. and 30 minutes at room temperature resulting in the formation of a precipitate. The mixture was quenched at 0° C. by the addition of 4% acetic acid (150 mL) and filtered. The precipitate was swirled in 100 mL acetonitrile and filtered again. The precipitate was washed with acetonitrile, which resulted in the slow dissolution of product into the filtrate. After air-drying, 1.5 g of the title compound remained as the precipitate cake. The filtrate was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (0→20% EtOAc/DCM) and recrystallization from acetonitrile provided 0.415 g of additional title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[OH:16])=[O:8]>C(O)(C)C.CCCCCCC>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8]
Reactant: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
5-Bromo-N-((1RS,2SR)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide (103 g) was subjected to chiral chromatography on ChiralPak AD with 5% isopropanol/n-heptane as eluent. The product eluted as first peak to give after evaporation of the solvent the title compound (42.4 g) as a white solid, MS (ISP) 465.0, 467.0 (M+H)+; [α]D20=−19.8°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:31])[CH:7](P(OCC)(OCC)=O)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=1)[CH3:4].[CH:32](=O)[CH2:33][CH3:34]>C1COCC1>[CH2:3]([O:5][C:6](=[O:31])[C:7]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:13][CH:14]=1)=[CH:32][CH2:33][CH3:34])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)P(=O)(OCC)OCC
Reactant: CCC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of NaH (290.5 mg, 60% in mineral oil, 7.5 mmol) in THF (25 mL) at 0° C. was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-(diethoxy-phosphoryl)-propionic acid ethyl ester (2.5 g, 5.81 mmol) in THF (30 mL). The reaction mixture was allowed to stir at 0° C. for 1 h. To the reaction was added propionaldehyde (725 mg, 12.5 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at room temperature for 16 h. Propionaldehyde (2.5 g) was added and the mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with the slow addition of saturated aqueous NH4Cl (30 mL). The mixture was extracted with EtOAc, washed with brine and dried. The crude product was purified by column chromatography (EtOAc/hexane, 1:8) to give 2-(6tert-butoxycarbonylamino-pyridin-3-ylmethyl)-pent-2-enoic acid ethyl ester as a mixture of isomers (1.2 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:23]=[C:24](I)[CH:25]=[CH:26][CH:27]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[C:18][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:29])[F:30])[CH:23]=3)[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2cccc(OC(F)(F)F)c2)CC1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
A mixture of Compound 1c (60 mg, 0.25 mmol), 3-(trifluoromethoxy)iodobenzene (41.6 μL, 0.26 mmol), bis(triphenylphosphine)palladium(II)dichloride (8.65 mg, 0.01 mmol), CuI (4.69 mg, 0.1 mmol) in anhydrous and degassed triethylamine (3 mL) was heated at 80° C. under a nitrogen atmosphere for 2 h in a sealed vessel. The reaction mixture was cooled, filtered on Celite, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 5:95) affording the title product (57 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][C:13]([CH3:16])([O-:15])[CH3:14].[K+].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:15][C:13]([CH3:16])([CH3:14])[CH3:12])[CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25.2 g) in THF (250 mL) was added potassium tert-butoxide (25.3 g) portionwise at 0° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][N:5]=[N+:6]=[N-:7].[F:9][C:10]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C[O-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:8])[C:4]([N:5]=[N+:6]=[N-:7])=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]=1[F:9]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cccc(OCc2ccccc2)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1F)N=[N+]=[N-]
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A mixture of methylazidoacetate (36.64 g) and 2-Fluoro-3-benzyloxy benzaldehyde (18.32 g) in methanol (250 ml) was added dropwise, with stirring, over 1 hour to a mixture of sodium methoxide (17.20 g) in methanol (100 ml) at −25° C. under a stream of argon. Mixture was left to stir for 20 minutes, allowed to warm to 5° C. and stirred overnight.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[CH3:10]C1C2C(=CC=CC=2)NC=1>>[CH3:10][N:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1c[nH]c2ccccc12
Product: Cn1ccc2cccnc21
Yield: 58 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-azaindole (2.28 g, 1.83 mmole) for the 3-methylindole, the title compound (1.4 g, 58%) was prepared as a yellow oil: MS (ES) m/e 133 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=1>N1C=CC=CC=1>[N:1]1[NH:2][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[C:7]=1[C:6]1[C:15]([C:14]3=[O:18])=[CH:16][CH:17]=[CH:4][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Cl)ccc21
Reactant: NN
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2n[nH]c3cccc1c23
Temperature: 100 °C

Procedure:
Anhydrous hydrazine is added to a solution of 2-chloroanthraquinone (Aldrich) in 10 mL pyridine, and the mixture heated at 100° C. for 16 hours. The mixture is cooled and the solvent is evaporated in vacuo. The residue is taken in hot 6N HCl, and the solid is collected by filtration. Flash chromatography of the crude material on silica gel affords anthra[1,9cd]pyrazol-6(2H)-one (“Compound 1”) as yellow solids.
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][CH2:10][CH2:11]O>>[OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:11][CH2:10][Cl:9])=[O:4]
Reactant: OCCCl
Reactant: CC(C)C(O)C(=O)O
Product: CC(C)C(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-3-methylbutyrate was prepared from 2-hydroxy-3-methylbutyric acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 137° C./20 mm Hg; 1H NMR δ 0.90 (d, 3H, J=6.9 Hz), δ 1.04 (d, 3H, J=6.9 Hz), δ 2.12 (dqq, 1H, J=3.6, 6.9, 6.9 Hz), δ 2.76 (d, 1H, J=6.4 Hz), δ 3.72 (t, 2H, J=5.6 Hz), δ 4.10 (dd, 1H, J=3.6 Hz, 6.3 Hz), δ 4.36-4.53 (m, 2H); HRMS calcd for C6H9ClO3Tms (M--CH3) 237.0714, obsd 237.0677.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.06 g, 7.51 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.24 g, 11.26 mmol) in 20 mL 1,2-dichloroethane was treated with sodium triacetoxyborohydride (4.77 g, 22.53 mmol) then acetic acid (1.28 mL, 22.53 mmol). The suspension was stirred at room temperature overnight. At this time, a TLC analysis indicated that 1,2,3,4-tetrahydroquinoline is present along with a more polar spot. To the reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (1.12 g, 5.63 mmol) and sodium triacetoxyborohydride (2.39 g, 11.28 mmol). The suspension was stirred at room temperature for 4 days. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with 50 mL CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was purified by the Biotage purification system using a silica gel 40M column. A gradient of 5% ethyl acetate:hexanes to 30% ethyl acetate:hexanes over 10 column volumes was used to give the title compound (0.89 g, 37.4%). 1H-NMR (CDCl3) δ 7.09-7.03 (m, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.30-4.19 (m, 2H), 3.80-3.70 (m, 1H), 3.17 (t, J=5.7 Hz, 2H), 2.84-2.71 (m, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.93-1.85 (m, 2H), 1.78-1.63 (m, 4H), 1.48 (s, 9H). MS (ESI): 317.2 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@:7]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)([CH3:12])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].O>CC#N>[C:1]([CH:5]1[N:6]2[CH2:16][CH2:15][CH2:14][CH2:13][C:7]2([CH3:12])[C:8](=[O:11])[N:9]1[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1C(=O)[C@@](C)(CCCCCl)N[C@H]1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1C(=O)C2(C)CCCCN2C1C(C)(C)C
Temperature: 80 °C
Yield: 83.1 %

Procedure:
To a solution of (2R,5R)-2-(tert-butyl)-5-(4-chlorobutyl)-3,5-dimethylimidazolidin-4-one (D45) (310 mg, 1.18 mmol) in dry MeCN (4 ml), anhydrous Na2CO3 (63 mg, 0.6 mmol) and NaI (178 mg, 1.18 mmol) were added sequentially. The solution was heated at 80° C. for 12 hrs. The reaction was allowed to cool at RT, poured into water (10 ml) and extracted with Et2O (3×10 ml). The organic phases were collected, washed with NaCl sat sol, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D46) (220 mg)
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:20][O:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=NOC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -35 °C
Yield: 65 %

Procedure:
2.9 ml of triethylamine were added at -10° C. to a mixture of 4.6 g of the product of Step A in 92 ml of methylene chloride and after cooling to -35° C., 6.1 g of trityl chloride were added thereto. The temperature was allowed to rise to room temperature in about 21/2 hours and the reaction mixture was washed with water and then with 0.5 N hydrochloric acid and finally with aqueous sodium acetate. The mixture was dried and evaporated to dryness. The residue was taken up in ether and the solution was concentrated to dryness again. The residue was dissolved in methanol and water and ether were added to cause crystallization. The mixture was vacuum filtered and the recovered precipitate was washed with ether to obtain 6.15 g of ethyl 2-(2-tritylamino-4-thiazolyl)-2-methoxyiminoacetate melting at 120° C. having the syn configuration.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=1)=[O:5].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:5]
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4Cl)cc23)CC1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 0.40 gm (1.04 mMol) 5-(2-chloro-4-fluorobenzoyl)amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 5.2 mL trifluoroacetic acid were added 0.208 mL (1.3 mMol) triethylsilane and the reaction mixture was stirred at ambient. After 2 hours, the reaction mixture was concentrated under reduced pressure. To the residue was added 2N sodium hydroxide and the aqueous was extracted with dichloromethane. The combined organic extracts were washed with 2N sodium hydroxide, dried over sodium sulfate and then concentrated under reduced pressure to give an orange foam. The foam was subjected to radial chromatography (2 mm silica), eluting with 100:10:1 dichloromethane:methanol: ammonium hydroxide. The residue was crystallized from ethyl acetate/hexanes to give 0.27 gm (67.3%) of the title compound as a burnt orange powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 3 h

Procedure:
In a 100-ml, three-necked, round-bottomed flask equipped with a magnetic stirrer, an oil bath, and a condenser topped with a drying tube were placed 1.69 g of 4-benzyloxy-4'-biphenylcarboxylic acid, 34 ml of thionyl chloride, and one drop of dimethylformamide. After stirring the solution for three hours under reflux, the thionyl chloride was distilled off, then 75 ml tetrachloromethane was added and distilled. The brown solid was dissolved in 500 ml hot dichloromethane, and the solution was treated with charcoal and filtered through Celite. The solids were washed with hot dichloromethane, and the filtrate was evaporated, to yield the following compound. ##STR26##
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:39]#[N:40].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:39]#[N:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: [C-]#N
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(C#N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium cyanide.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[CH:16]2)=[CH:11][CH:10]=1)#[N:4]>CCO.C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:33])[F:34])[O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]([OH:28])[C:25]([NH2:27])=[O:26])=[CH:16]2)=[CH:13][CH:14]=1)#[N:4]
Reactant: N#Cc1cc(Oc2ccc(-n3cc(C(=O)C(N)=O)c4ccccc43)cc2)ccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(Oc2ccc(-n3cc(C(O)C(N)=O)c4ccccc43)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
NaBH4 (40 mg) was added to a solution of compound 59 in EtOH/THF (2 mL/2 mL) at room temperature, and the mixture was shaken at room temperature for 3 hours. The reaction was quenched with water, extracted with EtOAc (30 mL), concentrated, and purified by column (CHCl3/MeOH 7/1) to give compound 60 as a white solid (70 mg, 70%): 1H-NMR (400 MHz, CD3OD): δ 7.92 (d, 1H, 8.8 Hz), 7.87 (d, 1H, 7.9 Hz), 7.66-7.69 (m, 3H), 7.53-7.56 (m, 2H), 7.45-7.48 (m, 1H), 7.35-7.38 (m, 1H), 7.15-7.25 (m, 2H), 5.41 (br, 1H); LC/MS: m/z=474.3 [M+Na]+ (Calc: 451.4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:45])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[C:38]([CH3:43])[C:37]=1[CH3:44])([CH3:34])[CH3:33])[CH3:29].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:28]([O:30][C:31](=[O:45])[C:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:38]([CH3:43])[C:37]=1[CH3:44])([CH3:33])[CH3:34])[CH3:29]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(C)c1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1C

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 2-(4-hydroxy-2,3-dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester (CAS RN: 851508-28-6), tri-n-butylphosphin and N,N,N′,N′-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless oil (11%). MS (Turbo Spray): m/z=625.5 [M+H].
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].N1C=CN=C1>C(Cl)(Cl)Cl>[Si:5]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
t-Butyldimethylchlorosilane (26.01 g; 172.56 mmol) was added to a solution of 3-hydroxybenzaldehyde (20.7 g; 164.35 mmol) and imidazole (27.97 g; 410.9 mmol) in chloroform (300 mL) under nitrogen at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give crude product (29.56 g), which was purified by column chromatography on silica gel eluting with (i) pentane and (ii) 3% ethyl acetate in pentane to give 3-(t-butyl-dimethylsilanyloxy)benzaldehyde (21.0 g; 54%). 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.45 (d, 1H, J=7.5 Hz), 7.38 (dd, 1H, J=7.5, 7.5 Hz), 7.31 (d, 1H, J=1.0 Hz), 7.09 (1H, dd, J=7.5, 1.0 Hz), 0.98 (s, 9H), 0.20 (s, 6H).