Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]O)=[CH:4][CH:3]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:47]([O:46][C:44]([C@@H:40]1[CH2:41][CH2:42][CH2:43][N:38]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:39]1)=[O:45])[CH3:48]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: OCCOCCC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCOCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
A solution of 2-(3,3-bis(4-chlorophenyl)-1-propyloxy) ethanol (3.5 g, 10.8 mmol) in dry THF (25 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (4.3 ml, 2.5 M) was added dropwise. When addition was complete the reaction mixture was stirred for 1 h at room temperature. p-Toluenesulphonyl chloride (2.1 g, 10.8 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The solvent was evaporated in vacuo and acetone (30 ml) was added to the residue. The mixture was filtered and to the filtrate was added ethyl (R)-3-piperidinecarboxylate (1.8 g, 11.5 mmol) and potassium carbonate (1.5 g, 10.8 mmol). The mixture was heated at reflux temperature for 3 h and then stirred for 2 days at room temperature. The reaction mixture was filtered and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel (200 g) using a mixture of n-heptane and ethyl acetate (6:4) as eluent provided 2.0 g (40%) of the title compound as an oil. TLC: rf=0.17 (SiO2 ; n-heptane/ethyl acetate=7.3). 1H NMR (CDCl3)δ 4.13 (t, 1H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(OC)=O>C1COCC1>[OH:4][CH:2]=[C:18]([CH2:17][C:9]1[N:8]([CH3:7])[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCc1cc2ccccc2n1C
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC=O
Product: COC(=O)C(=CO)Cc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a suspension of potassium tert-butoxide (300 mg, 2.67 mmol) in dry THF (5 mL) were added dropwise a solution of methyl 3-(1-methyl-1H-indol-2-yl)propanoate (322 mg, 1.482 mmol) and methyl formate (0.30 mL, 4.87 mmol) in dry THF (5 mL) over 15 min. The mixture was stirred at room temperature for 1 h. Concentration in vacuo then afforded the title compound (400 mg, 0.522 mmol, 35.2% yield). LCMS: rt=2.82 min, [M+H+]=246
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:23](O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([F:14])[C:7]2[N:13]=[CH:23][NH:10][C:8]=2[CH:9]=1)=[O:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1
Reactant: O=CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 712.2 %

Procedure:
4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mmol) and 20% Pd(OH)2/C (9.00 g, 16.91 mmol) in ethanol (250 mL) are stirred at 40° C. for two hours under N2 and then at 95° C. for 16 hours. The reaction mixture is cooled to room temperature and filtered through Celite rinsing with ethyl acetate. The filtrate is concentrated under reduced pressure to give a yellow solid. The solid is triturated with diethyl ether to give 13.47 g (86%) of the desired product as a tan solid. MS APCI (+) m/z 286 (M+1) detected; MS APCI (−) m/z 284 (M−1) detected.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCOCC1.O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Glycine ethyl ester hydrochloride (31.39 g, 225.0 mmol) is dissolved in dioxane (150 mL) and water (150 mL), triethylamine (69.0 mL, 495.0 mmol) is added, and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (51.15 g, 248.0 mmol) over 10 minutes. The reaction is warmed to room temperature and stirred overnight. The next day the mixture is reduced to one-half volume by evaporating solvent, diluted with 1N sodium hydroxide, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/ethyl acetate/hexanes to give ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:31]([C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]([CH3:43])[CH3:42])[C:35]=1[NH2:36])([CH3:33])[CH3:32].OS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:36]/[C:35]2[C:37]([CH:41]([CH3:42])[CH3:43])=[CH:38][CH:39]=[CH:40][C:34]=2[CH:31]([CH3:33])[CH3:32])/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[OH:17]
Reactant: Cc1cc(Br)c(O)c(C(=O)c2ccccc2)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)c(O)c(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1
Temperature: 170 °C
Reaction time: 35 h
Yield: 69.1 %

Procedure:
In 50 mL Claisen's flask in argon atmosphere, a mixture of 13.5 g (46.3 mmol) of 26, 20.2 g (97.2 mmol) of Si(OEt)4, and 9.03 g (50.9 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.37 mL of 96% H2SO4 was added. This mixture was stirred at this temperature for 35 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 100:1, vol.). This procedure gave 14.4 g (69%) of the title product.
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:8][C:12]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of phenylmethanol (10.7 g, 98.95 mmol, 1.05 equiv) in N,N-dimethylformamide (100 mL). This was followed by the addition of sodium hydride (3.9 g, 162.50 mmol, 1.20 equiv, 70%) in several batches at 0° C. The mixture was stirred for 25 min at 0° C. To this was added a solution of methyl 2-fluoro-3-nitrobenzoate (18.8 g, 94.41 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The mixture was diluted with 700 mL of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 20 g (74%) of methyl 2-(benzyloxy)-3-nitrobenzoate as yellow oil. MS (ESI) m/z 288 ([M+H]+).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[Br:28]C1C=C(C=CC=1)C=O>>[Br:28][C:16]1[CH:15]=[C:14]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][I:1])[N:4]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccc(Br)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-bromobenzaldehyde gave 2-(3-bromophenyl)-4-iodomethyl-5-methyloxazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (3.2 g, 11.31 mmol) in anhydrous THF (100 mL) and IMS (70 mL) was added sodium borohydride (0.47 g, 12.42 mmol) and the resulting mixture stirred at RT for 2 h. The reaction mixture was partitioned between DCM and a sat. aqueous solution of NaHCO3. The organic layer was isolated, dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with water gave the title compound as a white solid (2.9 g, 91%).
Reaction SMILES: [CH:1]([N:4]([CH:32]([CH3:34])[CH3:33])[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][O:23]CC3C=CC=CC=3)=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[CH:32]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][OH:23])=[O:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:34])[CH3:33]
Reactant: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)N(C(=O)COc1ccc(-c2ccc(C(=O)NO)cc2)cc1)C(C)C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
80 mg of the benzyl hydroxamate of Stage A were mixed with 50 mg of palladium on charcoal, 5 ml of ethanol and 40 ml of ethyl acetate, and the mixture was stirred for 8 hours under a hydrogen atmosphere. The reaction medium was filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica, eluting with a mixture of cyclohexane/ethyl acetate (50/50) then ethyl acetate and finally ethyl acetate/acetic acid 99/1. The product was finally crystallized from ethyl acetate to obtain 5.2 mg of the expected product.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]=2)[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]1=[O:30])(C)(C)C.C(N1C2C(=CC(Br)=CC=2)CC(N[S:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)(=[O:53])=[O:52])C1=O)C1C=CC=CC=1>>[CH2:23]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][S:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)(=[O:53])=[O:52])[C:9]1=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccsc3)ccc2N(Cc2ccccc2)C1=O
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(Br)ccc2N1Cc1ccccc1
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccsc3)ccc2N1Cc1ccccc1

Procedure:
The title compound (6 mg) was prepared from 12A (14.5 mg, somewhat impure) according to the procedures described in 3D and 3E. HPLC/MS retention time=3.9 min (Phenomenex Luna 5 micron C18 4.6 mm×50 mm column eluted with a 0% to 100% B solvent gradient over 4 min; solvent A=90% H2O, 10% MeOH, 10 mM NH4OAc and solvent B=10% H2O, 90% MeOH, 10 mM NH4OAc; flow rate=4.0 mL/min; UV detection at 220 nm); m/z=475 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]([N:39]1[CH:43]=[C:42]([CH:44]=[O:45])[N:41]=[CH:40]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[F:13][C:14]1[C:19]([CH:44]([C:42]2[N:41]=[CH:40][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:43]=2)[OH:45])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Fc1ccccn1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccnc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A 2.5M n-butyl lithium in hexanes solution (6 ml, 15 mmol) was added dropwise to a solution of diisopropylamine (2.12 ml, 15 mmol) in tetrahydrofuran (30 ml), cooled to −78° C. The reaction mixture was allowed to warm up to 0° C. for 30 minutes before being cooled down to −78° C. 2-Fluoropyridine (1.36 g, 14 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 1 hour. A solution of 1-trityl-1H-imidazole-4-carbaldehyde (4.5 g, 13.3 mmol) in tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate and extracted into ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (1.3 g, 22% yield).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[C:3]=1[C:4]#[N:5].[C:42](Cl)(=[O:44])[CH3:43].N1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:42](=[O:44])[CH3:43])=[C:28]([O:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:27]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(NC(C)=O)c(OCCN4CCCCC4)c3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-4-{4-amino-3-[2-(1-piperidinyl)ethoxy]phenyl}-6-{2-[(4-methoxybenzyl)oxy]-phenyl}nicotinonitrile, acetyl chloride, pyridine and CH2Cl2 was stirred at 0° C. for 1 hr. and at room temperature for 2 hrs. The usual work-up and column chromatography gave N-{4-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-[2-(1-piperidinyl)ethoxy]-phenyl}acetamide.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]1>C1COCC1>[C:12]([CH:11]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]1)#[N:13]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=CC#N)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 0.75 g (0.019 mol, 60% by weight in oil) of sodium hydride (washed three times with hexanes) in 40 ml of THF was added 3.34 g (0.019 mol) of diethylcyanomethylphosphonate. After stirring the reaction mixture for thirty minutes at room temperature, a solution of 4.26 g (0.016 mol) of ethyl 4-oxo-N-t-butoxycarbonyl-2-piperidinecarboxylate in 10 ml of THF was added. The mixture was stirred for 30 minutes at room temperature and 90 minutes at the reflux temperature of the reaction mixture, then cooled to room temperature and quenched with water. The organic layer was separated and the aqueous layer extracted twice with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. High pressure liquid chromatography of the residue afforded 3.58 g of ethyl 4-cyanomethylidene-N-t-butoxycarbonyl-2-piperidinecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[O:27]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:6][C:5]=1[OH:27]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(C(=O)O)cc2)cc1O
Reaction time: 8 h
Yield: 93 %

Procedure:
46.6 g of the benzyl 4-(4-nitro-3-benzyloxyphenoxy)benzoate (0.11 mol) prepared as described in Example 4 are dissolved in 500 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 5 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The pale violet solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then separated off and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C@:16]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:51])([F:50])[F:49])=[N:26][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:28]=1.C([SiH](CC)CC)C>ClCCl>[CH3:8][N:9]1[C:17]2[C@:16]3([CH3:21])[C:18]([CH3:19])([CH3:20])[C@@H:13]([CH2:14][CH2:15]3)[C:12]=2[C:11](=[O:22])[N:10]1[CH2:23][C:24]1[C:25]([C:48]([F:49])([F:50])[F:51])=[N:26][NH:27][CH:28]=1
Reactant: Cn1c2c(c(=O)n1Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c(=O)n1Cc1c[nH]nc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (410 mg, 0.69 mmol) in dichloromethane (4 mL) and the yellow solution was stirred at room temperature for 4 h. Triethylsilane (110 μL, 0.69 mmol) was added and the solution was stirred at room temperature for 10 min. The solvent was evaporated using a rotary evaporator and the residue was held under high vacuum overnight. The residue was taken up in dichloromethane (50 mL), the solution was transferred to a separatory funnel and water (50 mL) was added. Aqueous saturated sodium hydrogen carbonate (1 Pasteur pipette) was added and the layers were separated. The organic layer was washed with brine (50 mL), dried (magnesium sulfate), filtered, evaporated, and purified using a Biotage 40S system, eluting with 1-3% methanol/ethyl acetate, to give (4R,7S)-1,7,8,8-tetramethyl-2-(3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (118 mg, 48%) as an off-white solid. APCI(+)-MS (M+H) 355.
Reaction SMILES: [Li+].[BH4-].Cl[Si](C)(C)C.[CH3:8][N:9]([CH3:25])[C:10]1[C:15](/[CH:16]=[CH:17]/[N+:18]([O-])=O)=[CH:14][CH:13]=[C:12]([C:21]([F:24])([F:23])[F:22])[N:11]=1>C1COCC1>[NH2:18][CH2:17][CH2:16][C:15]1[C:10]([N:9]([CH3:8])[CH3:25])=[N:11][C:12]([C:21]([F:22])([F:23])[F:24])=[CH:13][CH:14]=1
Reactant: CN(C)c1nc(C(F)(F)F)ccc1/C=C/[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1CCN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
LiBH4 (13.3 mg, 0.613 mmol) was diluted with THF (1 mL) followed by the dropwise addition of chlorotrimethylsilane (155 μl, 1.23 mmol). After stirring for 15 minutes, argon was bubbled through the reaction mixture for 2 minutes to eliminate any trimethylsilane in the reaction. (E)-N,N-dimethyl-3-(2-nitrovinyl)-6-(trifluoromethyl)pyridin-2-amine (40 mg, 0.153 mmol) was added (in 500 μL of THF, gas evolution occurred). The reaction was heated to reflux for 2 hours, cooled to 0° C. and carefully quenched with methanol (300 μl). The reaction mixture was concentrated, diluted with DCM and 20% KOH. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield the desired compound (20 mg, 0.0858 mmol, 56.0% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:24][C:25]([F:28])([F:27])[F:26])[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a stirred solution of 4-hydroxy-3-methylbenzoic acid (10 g, 65.7 mmol) and cesium carbonate (64.2 g, 197 mmol) in DMF (150 mL) is added 2,2,2-trifluoroethyl trifluoromethanesulfonate (33.6 g, 145 mmol) at 0° C. The mixture is stirred at 0° C. for 10 minutes then at rt for 2 days. To the mixture, water (150 mL) and NaOH pellet (10 g) are added, and the mixture is stirred for 20 hours at rt. The mixture is diluted with water (100 mL). The aqueous phase is washed with ether (100 mL×2) and then acidified with conc. hydrochloric acid (pH 4) at 0° C. to give a white suspension. The precipitate is collected by filtration, washed with water and n-hexane, and dried in vacuo at 50° C. to give 14.8 g (96% yield) of the title compound as white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10]C)[CH:4]([CH3:9])[C:5](OC)=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[NH2:22].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[NH:22][CH:5]=[C:4]([CH3:9])[C:3]([O:2][CH3:1])=[O:10]
Reactant: COC(=O)C(C)C(OC)OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C(C)=CNc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A mixture of methyl 3,3-dimethoxy-2-methylpropionate (10 g, 46 mmol. Commercially available or can be prepared according to Org. Biomol. Chem. 2006, 4, 2945), 2-bromo-5-nitrophenylamine (12 g, 74 mmol) and p-TsOH (50 mg, 0.29 mmol) in benzene (200 mL) was stirred at reflux for 24 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from DCM to afford the desired product (9.8 g, yield: 67.5%) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.86 (s, 3H), 3.29 (s, 3H), 7.64 (dd, J=2.4, 8.4 Hz, 1H), 7.87 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H).