Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.C([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)(OC(C)(C)C)=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:30]3[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]3)[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cc(F)cc2cc(-c3ccccc3)[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Product: Fc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
5-Fluoro-7-nitro-2-phenyl-1H-indole prepared in Preparation 25 and 1-BOC-piperidinone were reacted according to the same procedure as Example 90 to give the title compound.
Reaction SMILES: [OH-].[Na+].O.[C:4]1([CH3:14])[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[Cl-].[CH2:16]([N+:34]([CH3:43])([CH3:42])[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O>[S:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:14])=[CH:5][CH:6]=1)([O-:13])(=[O:12])=[O:11].[CH2:16]([N+:34]([CH3:43])([CH3:42])[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CN1CCCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask equipped with stirrer and thermometer was added at ambient temperature 50.0 g. distilled water 7.2 g. sodium hydroxide solution (50%) and 13.3 g. (0.069 m) p-toluenesulfonic acid monohydrate, [C6H4 (CH3)-SO3H]. The mixture was stirred at ambient temperature for about 0.5 hour, after which 30.0 g. (0.069 m) octadecyldimethyl N-[(2-pyrrolidonyl) methyl]ammonium chloride was added. The reaction mixture was heated to 40°-45° to ensure complete solution and stirring continued for an additional 2 hours. The reaction was then cooled to 10°-15° C. to precipitate the crude tosylate salt product. The crude product was filtered to recover 19.8 g. of white solid product, which product was found to have 98.2% quaternized product, 0.4% amine, and 0.04% chloride. The above solid was heated in a 50° oven for 30 days and showed no loss of activity.
Reaction SMILES: C[C@@H]([NH3+])C1C=CC=CC=1.[CH2:10]([C@H:14]([CH2:18][OH:19])[C:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH3:13].C(OC(C)C)(=O)C>Cl>[CH2:10]([C@H:14]([CH2:18][OH:19])[C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[C@H](CO)C(=O)[O-]
Agent: C[C@@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: CCCC[C@H](CO)C(=O)O
Yield: 98.8 %

Procedure:
(R)-2-Butyl-3-hydroxypropionic acid (R)-α-methylbenzylammonium salt (5, 10.0 g) is dissolved in 2 N HCl (40.0 mL) and isopropyl acetate (50.0 mL) is added to the mixture. After mixing for 5 min, the organic layer is separated and the aqueous layer is extracted with isopropyl acetate (3×50.0 mL). The combined organic layers are washed with water (20.0 mL) and concentrated under vacuum (20 mbar) until no further solvent distills to afford (R)-2-butyl-3-hydroxypropionic acid (1, 5.4 g, 98%); oil; [α]D+6.5 (c=1.0, CH3OH), (R):(S)=99.3:0.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:15])[CH2:14][O:13]1.CC(C)([O-])C.[K+]>CN(C=O)C.[Cl-].[NH4+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[N:9][N:10]([CH2:11][C:12]([CH3:15])([OH:13])[CH3:14])[C:5]2=[CH:4][CH:3]=1
Reactant: CC1(C)CO1
Reactant: Clc1ccc2[nH]nnc2n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1nnc2nc(Cl)ccc21
Temperature: 60 °C
Reaction time: 36 h

Procedure:
5-Chloro-1H-[1,2,3]triazolo[4,5-b]pyridine (Example 27, Step 1) (285 mg, 1.85 mmol) and 2,2-dimethyloxirane (0.18 mL, 1.94 mmol) were taken-up in DMF (7.4 mL) and potassium tert-butoxide (310 mg, 2.77 mmol) was added. The mixture was heated to 60° C. overnight and then to 85° C. for an additional 36 hours. The mixture was then cooled to room temperature, diluted with saturated aqueous ammonium chloride, and extracted with ethyl acetate (3×). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo and purified via reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier). Desired fractions were lyophilized to afford the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC([C:49]3N(CCNC(C)C)[CH:51]=[C:52]([C:54]4C=CC(F)=C(C(F)(F)F)C=4)[N:53]=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:49][NH:53][CH:52]([CH3:54])[CH3:51])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CC(C)NCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-isopropylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=535, obsd.=535).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(N)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 88.9 %

Procedure:
A solution of ethyl N-(3,4-dichlorobenzyl)-4-nitroindole-2-carboxylate (2.41 g) in tetrahydrofuran (100 ml) was stirred in the presence of titanium trichloride (15% aqueous solution, 50 ml) at room temperature overnight. The reaction was treated with 40% sodium hydroxide solution and extracted with 5% methanol in dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the product as a brown solid (1.98 g, 89%); NMR d (CD3SOCD3) 1.3 (t, 3H), 4.2 (q, 2H), 5.7 (s, 4H), 6.2 (d, 1H), 6.6 (d, 1H), 7.0 (m, 2H), 7.25 (m, 1H), 7.5 (d, 1H), 7.6 (m, 1H); M/z (+) 363.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7](=[O:28])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:27])[C:16]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[N:20][C:19]=2Cl)=[O:17])[N:13]=1.[CH3:32][NH:33][CH3:34]>O1CCOCC1>[CH3:32][N:33]([CH3:34])[C:19]1[N:20]=[N:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:16]([N:15]([CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:7]([NH:6][CH2:5][C:4]2[CH:29]=[CH:30][CH:31]=[C:2]([F:1])[CH:3]=2)=[O:28])[S:10][CH:11]=1)[CH3:27])=[O:17]
Reactant: CNC
Reactant: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(Cl)nn1
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(N(C)C)nn1

Procedure:
3-Chloro-6-methoxypyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide was treated with dimethylamine in 1,4-dioxane to afford the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.O>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Yield: 90 %

Procedure:
As described in Example VI, a mixture of 5.6 g. of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydropyrido(2,3-d)pyrimidine, 7.04 g. of N-benzylpiperazine and 80 cm3 of toluene is heated under reflux for 2 hours. After cooling, the mass is diluted with 100 cm3 of chloroform and is taken up in 200 cm3 of water. After washing the organic phase with water, the reaction product is isolated as described in the Example mentioned. It is recrystallised from isopropanol. 7.6 g. (90%) of 2-(4'-benzyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine are obtained; melting point 152° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCl)Oc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a solution of chloromethyl chloroformate (1 g, 7.8 mmol) in DCM (40 mL) was added a mixture of phenol (0.73 g, 7.8 mmol) and pyridine (750 μL, 9.3 mmol) in DCM (10 mL) at −20° C. over 20 min. The reaction was stirred at 0° C. for 4 h, then at rt for another 1 h. The mixture was washed with 1N HCl solution (50 mL), followed by brine (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=100/1) to give the title compound as colorless oil (847 mg, 58.2%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=O)[CH2:2][CH2:3][CH3:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)(=[O:22])[CH3:21]>>[CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:15])[F:17])=[CH:13][C:8]=2[S:7][C:6]=1[CH:18]=[CH:21][C:20]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([CH3:35])[CH:24]=1)=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Product: CCCCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from the above-mentioned 3-butyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (88 mg, 0.31 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (67 mg, 0.31 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (77 mg, yield 51%).
Reaction SMILES: [CH3:1][N:2](C)[C:3](C1C=CC(Br)=CN=1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=1>>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:2]([CH3:3])[CH3:1])=[O:19])=[CH:16][N:15]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Product: CN(C)C(=O)c1ccc(Br)nc1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 6-bromo-nicotinic acid (1.00 g, 4.95 mmol) to give a colorless oil (780 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=2.53 Hz, 1 H) 7.61-7.71 (m, 1 H) 7.56 (d, J=8.08 Hz, 1 H) 3.08 (d, J=41.68 Hz, 6 H); LCMS for C8H9BrN2O m/z 229.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2([CH3:14])[O:12][C:6]([CH3:13])([C:7](Cl)(Cl)[C:8]=1[Cl:9])[CH:5]=[CH:4]2.CCCCCC.C(OCC)(=[O:23])C.C(=O)([O-])O.[Na+].[N+]([O-])(O)=O>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:9][C:8]1[C:7](=[O:23])[C:6]2([CH3:13])[O:12][C:3]([CH3:14])([C:2]=1[Cl:1])[CH:4]=[CH:5]2
Reactant: CC12C=CC(C)(O1)C(Cl)(Cl)C(Cl)=C2Cl
Reactant: CCOC(C)=O
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: CCCCCC
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Product: CC12C=CC(C)(O1)C(Cl)=C(Cl)C2=O
Temperature: 67.5 °C
Yield: 54 %

Procedure:
14 g (51.1 mmol) of unpurified 2,3,4,4-tetrachloro-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-2,6-diene and 17.36 g (102.2 mmol) of silver nitrate are dissolved in 500 ml of acetone/water 1:1 mixture and heated for 15 hours at a temperature of 65-70° C. until the reaction of the reactants is complete (thin-layer chromatography (TLC) monitoring (mobile phase hexane/ethyl acetate 4:1)). After the reaction mixture has cooled to ambient temperature, solid sodium hydrogen carbonate is then stirred into the mixture in portions in order to neutralise the nitric acid. The precipitated silver bromide is filtered off and most of the acetone is distilled off under reduced pressure. The aqueous phase that remains behind is extracted three times with ethyl acetate. The organic extract is washed with water, dried over sodium sulfate and concentrated by evaporation. The oily residue is purified by means of silica gel chromatography (eluant gradient: 3-50% ethyl acetate in hexane). 6.1 g (54%) of pure 3,4-dichloro-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one are obtained in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[CH2:32]([O:31][CH:27]([O:28][CH2:29][CH3:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:18]1[C:13]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:20])[CH3:33]
Reactant: CC(C)=NO
Reactant: CCOC(OCC)c1ccccc1C(=O)c1cccnc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(=O)c1cccnc1ON=C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 0.49 g of acetone oxime in 8 ml of dry tetrahydrofuran was added 0.75 g of potassium tert-butoxide. The solution was stirred for 15 min. then a solution of 1.86 g of (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenylmethanone in 8 ml of tetrahydrofuran was added. The solution was stirred at room temperature for 30 min. then quenched by the addition of 25 ml of a 1:1 water-saturated ammonium chloride solution. The solution was extracted with two 50 ml portions of ether and the combined ether extracts were washed with brine and dried over sodium sulfate. Evaporation afforded the intermediate 3-[2-(diethyloxymethyl)-benzoyl]-2-[[(isopropylidene)amino]oxy]-pyridine which was not characterised but dissolved in 30 ml of ethanol and 20 ml of 2 M hydrochloric acid added and the solution refluxed for 15 min. The solution was cooled to room temperature and the crystals of 2-(isoxazolo[5,4-b]pyridin-3-yl)-benzaldehyde were collected by filtration and dried in vacuo, 1H-NMR (200 MHz, CDCl3) d 10.26 (CHO).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)OC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Example 62 (100 mg) in CH2Cl2 (1.5 mL) at r.t., was added diisopropylethylamine (105 μL) and pivaloyl chloride (70 μL). The mixture was stirred at r.t. for 1.5 hr and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (80:20)) to give the title compound as a yellow solid, m.p. 66°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21](O)=[O:22].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: Nc1ccccc1
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Product: COc1cccc(-c2ccc3c(C(=O)Nc4ccccc4)c(OC)ccc3c2)c1
Yield: 85 %

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (300 mg, 0.97 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired compound in a yield of 85%, 316 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][OH:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][O:17][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To alcohol 140 (6.14 mmol) in 30 mL CH2Cl2 at 0° C. was added DMAP (0.1 g), p-toluenesulfonyl chloride (1.37 g, 7.2 mmol), and then triethylamine (1.8 mL, 13 mmol) was added quickly dropwise. The mixture was warmed immediately to ambient temperature following addition and stirred overnight, and did not proceed to completion. The mixture was partitioned between Et2O and 1N HCl (aq), the phases were separated, and the organic phase washed with sat. NaHCO3 (aq), dried (MgSO4), and concentrated to provide tosylate 141. The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[CH3:12].C([Li])CCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>C1COCC1>[CH3:11][O:10][CH2:9][O:8][C:4]1[C:3]([CH3:12])=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOc1cccc(Br)c1C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(B(O)O)c1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
16.2 g (70 mmol) of 1-bromo-3-methoxymethoxy-2-methylbenzene are dissolved in 200 mL of anhydrous THF and the mixture is cooled to −78° C. 33.7 mL (84 mmol) of 2.5M butyllithium are added slowly and the mixture is then maintained at −78° C. for 1 hour. 19.4 mL (84 mmol) of triisopropyl borate are then added dropwise over a period of 15 minutes. The medium is stirred for 30 minutes at the same temperature and then poured into 300 mL of 1N hydrochloric acid. After the usual treatment, the whitish solid residue obtained is rinsed with heptane and then dried under reduced pressure. A flaky white solid is obtained (m=11.8 g; Y=86%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:29])/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:30]([O:32][CH3:33])=[O:31])[CH:8]=2)[NH:3]1.[H-].[Na+].[CH3:36]I>C1COCC1>[CH3:36][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:30]([O:32][CH3:33])=[O:31])=[CH:6][CH:5]=2)[C:10]2([CH2:15][CH2:14][N:13]([C:16](=[O:29])/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])[CH2:12][CH2:11]2)[C:2]1=[O:1]
Reactant: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A solution of (E)-methyl 2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (150 mg, 0.33 mmol) in THF (3 mL) was added to a suspension of NaH (27 mg, 0.66 mmol) in THF at 0° C. and stirred for 30 min at the same temperature. Methyl iodide (58 mg, 0.41 mmol) was added to the above mixture. The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic phases were dried over NaSO4, filtered and concentrated to give (E)-methyl 1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (90 mg, 58%). 1H NMR (CD3OD): 1.85-2.02 (m, 4H), 3.26 (s, 3H), 3.88 (s, 3H), 3.95 (m, 1H), 4.15 (m, 1H), 4.28 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.52 (m, 1H), 7.68 (m, 1H), 7.77 (m, 1H), 8.06 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([O:15][C:16](=O)C)(=O)[CH3:13].C(OC(OCC)OCC)C>>[CH2:12]([O:15]/[CH:16]=[C:4](/[C:3](=[O:10])[CH:2]([F:11])[F:1])\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: CCOC(OCC)OCC
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 110 °C

Procedure:
A mixture of ethyl 4,4-difluoro-3-oxobutanoate (4.65 g, 0.028 moles), acetic anhydride (8.0 g, 0.078 moles) and triethylorthoformate (7.3 g, 0.049 moles) is heated at 110° C. for 4 h. The mixture is concentrated under vacuum to afford (Z)-ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutanoate as yellow oil. The oil is dissolved in EtOH (25 mL) and cooled in an ice bath. To this cooled stirred mixture is added anhydrous hydrazine (0.7 mL, 0.022 mole) and the mixture is allowed to warm gradually to RT overnight. The mixture is concentrated under vacuum and the crude product is purified by silica gel column chromatography using 1-2% MeOH/CH2Cl2 to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=[O:11])[CH3:8])[CH3:3].FC(F)(F)C(O)=O.[H][H]>[Pd].S([O-])([O-])(=O)=O.[Ba+2].C(O)(C)(C)C>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCCC(C)CC=O

Procedure:
In a 3-L reaction flask were added 500.0 g (3.28 mol) of citral, 2.50 g (0.5 wt % based on the citral) of 5 wt. % Pd/barium sulfate, 10.0 g (22.9 mmol, 2.0 wt % based on the citral) of (2R,4R)-2-(bis-(4′-t-butylphenyl)methyl)-4-(ethylcarbamoyloxy)pyrrolidine, 2.6 g (22.9 mmol) of trifluoroacetic acid, and 500 mL of 10 wt % hydrous t-butanol in a nitrogen atmosphere. The resulting mixture was stirred and the atmosphere was exchanged with a hydrogen atmosphere (0.1 MPa (atmospheric pressure)). After stirring at 60° C. for 21 hours, the catalyst was filtered off and the residue was analyzed using gas chromatography. As a result, it was found that a conversion ratio from citral to citronellal was 99.4% and an optical purity was 90.9% e.e. The crude-citronellal thus obtained was distilled to obtain 398 g (2.58 mol, yield: 78.6%) of d-citronellal having a purity of 98%.