Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:34])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:14])[CH:11]=2)[O:6][CH2:5][CH2:4]1.[CH:35]([C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=1)=O>O1C(CC)C1>[CH3:34][C:3]1([CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10](/[C:13](/[CH3:14])=[CH:35]/[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=3)[CH:11]=2)[O:6][CH2:5][CH2:4]1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCO2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CCC1CO1
Agent: [Br-]
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1
Yield: 27 %

Procedure:
A solution of 2.0 g (3.8 mmol) of 1-(4,4-dimethyl-6-chromanyl)ethyltriphenylphosphonium bromide and 630 mg (3.8 mmol) of methyl 4-formylbenzoate in 100 ml of 1,2-epoxybutane was heated under reflux for 72 hours. The reaction mixture was then concentrated in vacuo to an oil. The oil was purified by column chromatography on silicic acid, eluting with ether-hexane (1:9). This afforded mg (27% yield) of the title compound as a solid, mp 92°-95° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>C(OCC)(=O)C.CO>[CH3:26][N:27]([CH3:33])[CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:29]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: CN(C)C1CCNC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(N3CCC(N(C)C)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 44 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-(dimethylamino)pyrrolidine according to the procedure of example 25, except that the reaction time was of 16 h and that ethyl acetate/methanol (9:1) was used. Yield: 44%; MS: m/z=446 (M+H).
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([C:18]1[CH:26]=[C:22]([C:23]([OH:25])=[O:24])[C:21]([OH:27])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:7]([O:27][C:21]1[CH:20]=[CH:19][C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])(=[O:9])[CH3:8]
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridine (0.034 mL) and acetic anhydride (0.034 mL) were sequentially added to a methylene chloride (0.54 mL) solution of 5-tert-butylsalicylic acid (0.054 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.049 g of 2-acetoxy-5-tert-butylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1.Cl.[NH2:33][OH:34].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:34][NH:33][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:13]1[N:21]([S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1)=[NH:12]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C#N)cc34)cc3cccnc32)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C(=N)NO)cc34)cc3cccnc32)cc1
Yield: 123.2 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carbonitrile [2.11 g, Reference Example 13(c)] in ethanol (150 mL) at ambient temperature was treated with hydroxylamine hydrochloride (1.72 g) and potassium carbonate (3.43 g). The reaction mixture was heated at reflux under nitrogen for 15 hours then filtered. The filtrate was evaporated to give the title compound (2.8 g) as a dark green solid. MS: 460(MH+). HPLC (METHOD A): RT=6.19 minutes.
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]([C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:1][CH:2]1[CH2:5][N:4]([C:6]([C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9][CH2:10][CH3:11])=[O:7])[CH2:3]1
Reactant: CCC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(=O)N1CC(F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.9 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide (126 mg, 0.21 mmol) was dissolved in dichloromethane (1.1 ml) and trifluoroacetic acid (0.65 ml, 8.4 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in dichloromethane (1.1 ml) and ethylenediamine (0.85 ml, 12.7 mmol) was added. The reaction was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 49 mg (50%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(3-fluoro-azetidine-1-carbonyl)-butyl]-amide as an off-white powder. MS: (M+H)+=468; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.84 (br. s, 1H), 9.15 (s, 1H), 8.74 (dt, J=9.3, 4.6 Hz, 1H), 8.41-8.52 (m, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.02-7.17 (m, 1H), 5.29-5.61 (m, 1H), 4.18-4.84 (m, 4H), 4.16 (s, 3H), 3.87-4.09 (m, 1H), 1.62-1.91 (m, 2H), 1.41 (d, J=7.2 Hz, 2H), 0.82-0.97 (m, 3H).
Reaction SMILES: C([O:8][C:9](=[O:29])[C@H:10]([CH:26]([CH3:28])[CH3:27])[NH:11][CH2:12][CH:13]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:24]([O:23][C:21]([CH:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:12][NH:11][C@H:10]([C:9]([OH:29])=[O:8])[CH:26]([CH3:28])[CH3:27])=[O:22])[CH3:25]
Reactant: CCOC(=O)C(CN[C@H](C(=O)OCc1ccccc1)C(C)C)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CN[C@H](C(=O)O)C(C)C)Cc1ccccc1
Reaction time: 3 h

Procedure:
2.4 g of N-(2-ethoxycarbonyl-3-phenylpropyl)-L-valine benzyl ester is dissolved in 50 mL of ethanol, to which is added 500 mg of 10% Pd-C, and the mixture is hydrogenated at 50 psi for 3 h. The resulting mixture is filtered and the solvent removed with a rotoevaporator to afford N-(2-ethoxycarbonyl-3-phenylpropyl)-L-valine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1.O.C(OCC)(=O)C>[C:10]([N:9]1[C:6]2[C:5](=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[C:14]([CH3:16])([CH3:15])[CH2:13]1)(=[O:12])[CH3:11]
Reactant: C=C(C)CN(C(C)=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CC(C)(C)c2cc(O)ccc21
Temperature: 0 °C
Yield: 33.1 %

Procedure:
A solution of N-(4-methoxyphenyl)-N-(2-methylallyl)acetamide (1.00 g, 4.56 mmol) and aluminium chloride (2.0 g, 15.0 mmol) in 1.0 mL of chlorobenzene was stirred at 110° C. for 3 h. After the reaction mixture was cooled to 0° C., the reaction mixture was diluted with water and ethyl acetate. The separated organic layer was washed with 1 M HCl, saturated NaHCO3 aqueous solution and brine, successively, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 20/80) to obtain the title compound (0.31 g, 33%), and followed by recrystallization (hexane/ethyl acetate) to obtain the title compound (0.17 g) as a white solid.
Reaction SMILES: [CH:1]1([C@H:5]([NH:7][C:8]2[C:13]3[N:14]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[C:15]([C:17]4[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[C:11](C)=[C:10](C#N)[N:9]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1.[OH-:40].[Na+].[CH2:42]([OH:44])[CH3:43]>>[CH:1]1([C@H:5]([NH:7][C:8]2[C:13]3[N:14]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[C:15]([C:17]4[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[C:11]([CH3:10])=[C:43]([C:42]([OH:40])=[O:44])[N:9]=2)[CH3:6])[CH2:4][CH2:3][CH2:2]1.[C:30]([OH:44])([C:33]([F:36])([F:35])[F:34])=[O:40]
Reactant: CCO
Reactant: Cc1c(C#N)nc(N[C@H](C)C2CCC2)c2c1nc(-c1cc(C(C)C)ccn1)n2Cc1ccc(C(F)(F)F)cc1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1c(C(=O)O)nc(N[C@H](C)C2CCC2)c2c1nc(-c1cc(C(C)C)ccn1)n2Cc1ccc(C(F)(F)F)cc1
Product: O=C(O)C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropylpyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (26 mg, 0.049 mmol) dissolved in ethanol (1 ml) was added sodium hydroxide (5.0 M in water, 1 mL, 5.0 mmol). The reaction was heated to 110° C. and stirred overnight. The solution was cooled to room temperature, concentrated, and then diluted with EtOAc. It was washed with 1N HCl, then dried over sodium sulfate, filtered and concentrated. The residue was purified by mass triggered, reverse phase (C-18) preparative HPLC (acetonitrile:water: 0.1% v/v trifluoroacetic acid modifier) to afford (R)-4-((1-cyclobutylethyl)amino)-2-(4-isopropyl pyridin-2-yl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (as a TFA salt). MS ESI calc'd for C30H32F3N5O2 [M+H]+ 552. found 552. 1H NMR (500 MHz, CDCl3): δ 0.99 (d, J=6.1 Hz, 3H); 1.32-1.25 (m, 1H); 1.35 (d, J=6.9 Hz, 6H); 1.50-1.42 (m, 1H); 1.63-1.54 (m, 2H); 1.78-1.67 (m, 1H); 1.92-1.85 (m, 1H); 2.06-1.99 (m, 1H); 2.89 (s, 3H); 3.08-3.02 (m, 1H); 3.81 (s, 1H); 5.30 (s, 1H); 6.36 (d, J=17.1 Hz, 1H); 6.59 (d, J=16.8 Hz, 1H); 7.29-7.27 (m, 1H); 7.33 (d, J=8.0 Hz, 2H); 7.68 (d, J=8.0 Hz, 2H); 8.33 (s, 1H); 8.45 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:32][O-:33].[Na+].[CH3:35][OH:36]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:33][CH3:32])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([N:15]=[C:16]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([O:36][CH3:35])[N:26]=4)[CH2:21][CH2:20]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)n5)CC4)nc23)c(Cl)c1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(OC)n5)CC4)nc23)c(Cl)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(2-chloro-4-fluorophenyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 190b) (71 mg, 0.155 mmol) in MeOH (1.5 mL) was added sodium methoxide solution (30% in MeOH, 35 L, 0.186 mmol) and the reaction mixture was stirred in a sealed tube under Argon at 60° C. for 18 hours and then heated in the microwave to 150° C. for 30 minutes. The mixture was then evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:15])[C:11](=[O:14])[O:12][CH3:13])=[CH:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].[C:26](OCC)(OCC)(OCC)[CH3:27]>>[CH3:15][N:10]([CH2:9][CH2:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:26]([CH3:27])=[C:16]2[S:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])[C:11](=[O:14])[O:12][CH3:13]
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)N(C)CCc1ccc(N)c(CS(=O)(=O)c2ccccc2)c1
Product: COC(=O)N(C)CCc1ccc2[nH]c(C)c(S(=O)(=O)c3ccccc3)c2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step 3 starting from methyl (2-{4-amino-3-[(phenylsulfonyl)methyl]phenyl}ethyl)methylcarbamate (160 mg, 0.44 mmol), and triethyl ortho acetate, and was obtained as a white solid. Mp: 188-191° C., MS (+) 387 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][C:14](=C)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:18]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][C:14](=[O:18])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=C1CC(NC(=O)OCc2ccccc2)C1
Solvent: ClCCl
Product: O=C1CC(NC(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N-(Benzyloxycarbonyl)-3-methylenecyclobutanamine (4 g, 18.4 mmol) from Step A of Example 5, 34 mL of methanol and 136 mL of methylene chloride were mixed together and cooled to -78° C. under a nitrogen atmosphere. Ozone was bubbled through the mixture for approximately 20 minutes and then the reaction mixture was flushed with nitrogen for approximately 10 minutes. Dimethyl sulfide (17 mL) was added to the reaction mixture and the reaction mixture was then stirred for 0.5 h at -78° C. and 0.5 h at ambient temperature. The reaction mixture was concentrated under reduced pressure to a syrup. The syrup (6.2 g) was purified on a 1.5×40 cm silica gel column, rinsed with hexane and eluted @ 5 psi with 400 mL of 25% acetone in hexane to give 3.74 g (93% yield) of the title compound; MS DCI-NH3M/Z: 237 (M+NH4)+ ; 1H NMR (CDCl 3) δ 3.10 (m, 2H), 3.43 (m, 2H), 4.31 (m, 1H), 5.13 (s, 2H), 7.45 (s, 5H).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]([C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O>C(O)C>[OH:3][N:2]=[CH:4][C:6]1[N:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=[CH:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C=O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
Hydroxylamine hydrochloride (4.3 grams, 0.062 mole) was added to a cold solution of 5-formyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (7 grams, 0.031 mole) in absolute ethanol (40 ml.). The reaction mixture was stirred in the cold for thirty minutes, then at room temperature for 16 hours. The reaction mixture was then poured over ice-water, and the precipitated product was separated, dried, and recrystallized from toluene, yielding 3 grams of 5-(hydroxyiminomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester, m.p., 105°-107° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]([CH2:15][OH:16])[CH2:13][OH:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]([O:24][CH2:25][CH:26]=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:24][CH2:25][C@H:26]1[O:14][CH2:13][C@H:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH2:15][O:16]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CCOCc1ccccc1
Reactant: CCCCC[C@H]1CC[C@H](C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC([C@H]2CO[C@H](COCc3ccccc3)OC2)CC1

Procedure:
A solution of 100 mmol of trans-2-(4-pentylcyclohexyl)propane-1,3-diol, 100 mmol of benzyloxyacetaldehyde and 10 mmol of p-toluenesulfonic acid in 500 ml of toluene is heated at the boil on a water separator until the water separation is complete. Conventional work-up gives trans/trans-2-benzyloxymethyl-5- (4-pentylcyclohexyl)-1,3-dioxane.
Reaction SMILES: [NH2:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:30])[C:17]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]1([NH:1][CH:20]2[CH2:19][CH2:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([N:16]([CH3:30])[CH3:15])[CH2:22][CH2:21]2)[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: Nc1cccc2c1Cc1ccccc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(Nc2cccc3c2Cc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
1-Aminofluorene (181 mg, 1 mmol) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (1 mmol) and sodium triacetoxyborohydride (300 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 200 mg N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a colorless oil, which, for preparation of the hydrochloride, was dissolved in 2-butanone (5 ml), and 1.85 M ethanolic HCl (0.7 ml) was added. The N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (220 mg, m.p. 223-225° C.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[O:1]=[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(CN1C(=O)C2=C(CCCC2)C1=O)C(C)=O
Temperature: 80 °C

Procedure:
Ethyl 3-(1,3-dioxo-1,3,4,5,6,7-hexahydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (866 mg, 2.57 mmol) was dissolved in a a solvent mixture of acetone/water (v/v=5/1), and a catalytic amount of p-toluenesulfonic acid monohydrate (190 mg, 0.76 mmol) was then added to the obtained solution. The resulting mixture was then refluxed at 80° C. for 4 days. After the reaction was completed, the reaction mixture where white solid were formed was washed with water. Acetone was removed by a vacuum evaporation, and the residue was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and then distilled under a reduced pressure in order to remove dichloromethane. The desired product was obtained (421 mg, 56%) by performing column chromatography (eluent: n-hexane/ethyl acetate=3/1). Rf=0.54 (eluent: n-hexane/ethyl acetate=1/1)
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C:47]3[CH2:46][CH2:45][C@@:43]4([CH3:44])[C@@H:39]([CH2:40][CH2:41][C:42]4=O)[C:38]=3[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C:38]3[CH2:37][CH2:36][C:49]4[CH:50]=[C:33]([O:32][CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH:34]=[CH:35][C:48]=4[C:47]=3[CH2:46][CH2:45][C@:43]12[CH3:44]
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CCC3=C(CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 60.8 %

Procedure:
A solution of 2.7 g of difluoromethyldiphenylphosphine oxide in 85 ml of tetrahydrofuran is slowly mixed with 5.3 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1.5 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, washed with water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 1.0 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),8-tetraene is obtained as colorless crystals with a melting point of 124-125° C., [α]D22 =+2.0° (c=0.525% in pyridine).
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[C:1]([C:10]1[O:9][C:8]([CH3:7])=[CH:12][CH:11]=1)(=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: Cc1ccco1
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)C(C)C)o1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
In 50 ml of toluene were dissolved 4.41 g (0.05 mole) of isobutyric acid, 5.34 g (0.065 mole) of 2-methylfuran and 14.39 g (0.06 mole) of dichloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 6.74 g of 2-isobutyryl-5-methylfuran.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17])[CH:2]=[CH2:3].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O.C(N(C(C)C)C(C)C)C>C(O)CCC.C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1)[CH:2]=[CH2:3]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: C=CCOCc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: C=CCOCc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 120 °C

Procedure:
A stirred mixture of {2-[(2-propenyloxy)-methyl]-5-nitro-phenyl}-guanidine (3.75 g, 15 mmol), 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one (2.60 g, 15 mmol) and ethyl diisopropylamine (2.6 mL, 15 mmol) in 1-butanol (50 mL) is heated at 120° C. for 20 h. The solvent is then evaporated off under reduced pressure to give a residue which is dissolved in ethyl acetate (100 mL). The resulting mixture is filtered (celite), washed with saturated aqueous sodium chloride (50 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate, and recrystallised from ethyl acetate-hexane to give the title compound as a yellow crystalline solid, m.p. 213-2150C.