Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([NH:36]C=O)[CH:6]=[C:7]([CH2:25][P:26]([O:32]C(C)C)([O:28]C(C)C)=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)[CH3:2].C[Si](C)(C)Br.C1OC1C>ClCCl.C(O)C>[CH2:1]([O:3][C:4](=[O:39])[CH:5]([NH2:36])[CH:6]=[C:7]([CH2:25][P:26]([OH:28])([OH:32])=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH3:2]
Reactant: CCOC(=O)C(C=C(CCCCCCNC(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CCCCCCN)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 58.4 %

Procedure:
8.63 g (15.2 mmol) of 10-(N-benzyloxycarbonylamino)-4-diisopropylphosphonomethyl-2-formylamino-dec-3-enoic acid ethyl ester are dissolved in 22 ml of dichloromethane, and 9.82 ml (75.9 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is stirred at room temperature for 22 hours, 22 ml of absolute ethanol are then added dropwise, and the mixture is stirred for a further 22 hours and concentrated by evaporation in a rotary evaporator. 20 ml of toluene are poured over the residue, and the mixture is concentrated by evaporation in vacuo. This operation is repeated a further three times. The resulting pale yellow foam is dissolved in 150 ml of absolute ethanol, and a solution of 7.5 ml of propylene oxide in 7.5 ml of ethanol is added dropwise within a period of 90 minutes. A crystalline suspension forms, which is stirred overnight at room temperature. The product is filtered off and washed with ethanol and ether. Drying under a high vacuum at room temperature yields 4.70 g of crude product in the form of pale yellow crystals. For further purification, the product is stirred with 46 ml of water. After a small amount (0.33 g) of undissolved material has been filtered off, the clear pale yellow filtrate is completely concentrated by evaporation in vacuo. 20 ml of ethanol and 20 ml of toluene are added to the residue, and the mixture is again concentrated to dryness by evaporation. This operation is repeated twice more using toluene. After drying under a high vacuum, the residue is suspended in 150 ml of absolute ethanol, and a 5-normal solution of hydrogen chloride gas in ethanol is added dropwise, with stirring, until the mixture gives an acid reaction to Congo red. A mixture of 7.4 ml of propylene oxide in 7.4 ml of ethanol is added dropwise to the resulting clear solution within a period of one hour. A crystalline suspension forms, which is stirred for a further 15 hours and then filtered with suction. After washing with ethanol and ether, the product is dried under a high vacuum at 50° for 48 hours, yielding 2.86 g of 2,10-diamino-4-phosphonomethyl-dec-3-enoic acid ethyl ester, which begins to sinter at 157° and melts at 194° with decomposition.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[C:9]([O:31][CH3:32])=[C:10]([NH2:30])[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:30][C:10]1[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=[C:8]([Br:7])[C:9]=1[O:31][CH3:32]
Reactant: COC(=O)CBr
Reactant: COc1c(N)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(Br)c1OC
Reaction time: 48 h
Yield: 71.1 %

Procedure:
Methyl bromoacetate (0.285 mL, 3.01 mmol) was added to a stirred, room temperature suspension of 3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) in DMF (1.7 mL). After two days, more methyl bromoacetate (0.135 mL, 1.5 mmol) and the reaction mixture was stirred for a day longer. The reaction mixture was added to water and the solid was filtered and washed with water. The solid was triturated with pet. ether and dried at 60° C. under vacumm to provide the title compound as a white solid (0.212 g, 71%): mp 194-198° C.: NMR (DMSO-d6); 8.17 (dd, J=8, 1 Hz, 1H), 7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.53-7.45 (m, 2H), 6.77 (d, J=2 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.10 (t, J=7 Hz, 1H), 3.97 (dd, J=7, 4 Hz, 2H), 3.83 (s, 3H), 3.52 (s, 3H),2.43 (s, 3H), 1.69 (s, 3H); MS (FAB+): 2 bromine isotope pattern 561, 563, 565; Anal. Calc. for C24H21Br2NO3S: C, 51.17; H, 3.76; N, 2.49. Found: C, 50.43; H, 3.63; N, 2.53.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])[CH:5](O)[C:6](=[CH2:10])[CH2:7][CH:8]=[CH2:9].C=CCCC=C.S(Br)([Br:24])=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:12][CH:13]=[O:14])/[CH:5]=[C:6](/[CH2:10][Br:24])\[CH2:7][CH:8]=[CH2:9]
Reactant: C=CCC(=C)C(O)C(NC=O)C(=O)OC
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC/C(=C\C(NC=O)C(=O)OC)CBr
Reaction time: 3 h

Procedure:
5.0 g of 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in 200 ml of dry tetrahydrofuran are cooled to -78°, and 20 ml of 1,5-hexadiene are added thereto. 9 ml of thionyl bromide are added slowly dropwise in such a manner that the reaction temperature does not exceed -50°. When the addition is complete, the reaction solution is heated to 0° within a period of approximately 3 hours and is stirred at that temperature for 3 hours. The solution is then poured onto 300 ml of a cold (5°-10°) saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane 1:1) yields E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester in the form of a colourless oil, 1H-NMR (CDCl3): 3.20 (d, 2H, C(5 )-H); 4.00 (s, 2H, CH2Br).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[N:35][CH:36]=1>CN(C=O)C>[OH:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: Oc1ccc(Br)cn1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(O)nc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 179.2 %

Procedure:
To a solution of N-(4-(4-hydroxy-2,6-dimethylphenyl)-thiazol-2-yl)isonicotinamide (5-3, 325 mg, 1.0 mmol) in DMF (15 mL) were added cesium carbonate (650 mg, 2.0 mmol, 2.0 equiv) and Cu (19.5 mg, 0.30 mmol, 0.30 equiv). The mixture was stirred at 80-90° C. for 60 min. 5-Bromo-2-hydroxypyridine (261 mg, 1.5 mmol) was added to the solution and the reaction mixture was stirred at 100° C. for additional 24 hr. The solution was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 5 (0.75 g) in 18% yield: 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J=5.0 Hz, 2 H), 8.29 (d, J=5.0 Hz, 2 H), 7.23 (d, J=9.5 Hz, 1 H), 6.81 (s, 1 H), 6.60 (d, J=4.76 Hz, 1 H), 6.49 (s, 2 H), 5.42 (s, 1 H), 2.04 (s, 6 H), ESI-MS=m/z 417.2 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:15][S:16]([OH:19])(=[O:18])=[O:17].[BH4-].[Na+].C([SiH](CC)CC)C>O.O1CCCC1.O1CCOCC1.ClCCl>[NH:1]1[CH:6]=[CH:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:15][S:16]([OH:19])(=[O:18])=[O:17]
Reactant: O=C1CNCCN1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC=CN1

Procedure:
In step c, scheme 5, cleavage of the acetal and reductive cyclization of 26 leads to piperazinone 22 (L=a bond, p=0, R8 and R10═H), described as intermediate in scheme 4. This conversion is performed either in one step using an acid, e.g., trifluoroacetic acid or methanesulfonic acid, and a reducing agent such as sodium borohydride or triethylsilane, in solvents such as dichloromethane, 1,4-dioxane, tetrahydrofuran, water, or mixtures thereof. Alternatively, the reaction may be performed in two steps, by first forming a 3,4-dihydro-1H-pyrazin-2-one intermediate in the presence of an acid, e.g., trifluoroacetic acid or methanesulfonic acid, in a solvent such as water or dichloromethane, and subsequent catalytic hydrogenation at pressures between 1 bar and 10 bar, using a suitable catalyst, e.g., palladium on activated charcoal, in solvents such as methanol, ethanol, ethyl acetate, or mixtures thereof, at temperatures between 0° C. and 50° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[C:10]2[CH:19]=[N:18][N:17]([CH2:20][CH3:21])[C:11]2=[N:12][C:13]=1[O:14][CH2:15][CH3:16])=[O:7])C>C(O)C>[CH2:15]([O:14][C:13]1[N:12]=[C:11]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:10]2=[N:9][C:8]=1[C:6]([OH:7])=[O:5])[CH3:16]
Reactant: CCOC(=O)c1nc2cnn(CC)c2nc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2c(cnn2CC)nc1C(=O)O
Yield: 94 %

Procedure:
360 ml. of aqueous sodium hydroxide (2.5 N) are added to a solution of 47.5 g. of 6-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid ethyl ester (0.18 mol.) in 360 ml. of ethanol and stirred at room temperature for 15 hours. After removing the alcohol under vacuum, the aqueous solution is acidified with concentrated hydrochloric acid to give 6-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid in a yield of 94%, m.p. 128°-130°. A sample recrystallized from acetonitrile melts at 130°-132°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([OH:30])=O)[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:30])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4nncn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and N-methylpiperazine were reacted in the general amide coupling procedure to give 374. NMR: (CDCl3): 2.37 (3 H, s, Me), 2.37-2.51 (4 H, m), 3.13-3.17 (2 H, m), 3.51-3.78 (4 H, m), 4.32-4.35 (2 H, m), 6.98 (1 H, s, Ar), 7.05 (1 H, d, J 8.3, Ar), 7.12-7.17 (2 H, m, Ar), 7.24-7.27 (1 H, m, Ar), 7.42-7.48 (1 H, m, Ar), 7.61-7.62 (1 H, m, Ar) and 8.24 (1 H, s, Ar). MS: (ESI+) MH+=508.22
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11])[C:5]#[N:6]
Reactant: N#Cc1cc(F)c(C=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(F)c(CO)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-difluoro-4-formylbenzonitrile (1.0 g, 6.0 mmol) in EtOH (15 mL) at 0° C. was added NaBH4 (113 mg, 0.5 equiv). After stirring 2 h at 0° C., the reaction mixture was quenched with water and concentrated under reduced pressure. The crude residue was dissolved in DCM, washed with brine, dried over Na2SO4 and concentrated to give 3,5-difluoro-4-(hydroxymethyl)benzonitrile as a solid. All material was used in the next step. 1H NMR (400 MHz, CDCl3) δ 7.29-7.15 (m, 2H), 4.82 (d, J=6.2, 2H), 2.02 (dd, J=12.0, 5.6, 1H); GC-MS (ES) m/z 169 (M).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:18]([O:22][C:23]([N:25]([CH3:49])[C@@H:26]([CH3:48])[C:27]([NH:29][C@@H:30]([CH:45]([CH3:47])[CH3:46])[C:31]([N:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH2:35][C@H:34]1[C:42]([OH:44])=O)=[O:32])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[C:52]=1[NH2:53].CN1CCOCC1>C(Cl)Cl>[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([F:61])([F:60])[F:59])[C:52]=1[NH:53][C:42]([C@H:34]1[N:33]([C:31](=[O:32])[C@@H:30]([NH:29][C:27](=[O:28])[C@@H:26]([N:25]([CH3:49])[C:23](=[O:24])[O:22][C:18]([CH3:19])([CH3:20])[CH3:21])[CH3:48])[CH:45]([CH3:46])[CH3:47])[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[CH2:35]1)=[O:44]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
In a 50 mL round-bottomed flask, DMF (12.2 mg, 12.9 μL, 167 μmol Eq: 1.5) was combined with DCM (1 mL) to give a colorless solution. The reaction mixture was cooled in an ice bath and oxalyl chloride (21.2 mg, 14.6 μL, 167 μmol, Eq: 1.5) was added. Pyridine (13.2 mg, 13.5 μL, 167 μmol, Eq: 1.5) was then added followed by (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol Eq: 1.00) and the reaction was stirred at rt for 1 h. 2-Fluoro-6-(trifluoromethyl)aniline (30.0 mg, 167 μmol, Eq: 1.5) and N-methylmorpholine (18 μL, 167 μmol, Eq: 1.5) were added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (20 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[N:16]O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na]>C(O)CCCC>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH2:16])[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ON=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Na]
Solvent: CCCCCO
Product: NC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To 3.9 g (16.9 mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime was added 3.5 g of sodium in 200 ml of pentanol by portion over 1 hr. The mixture was refluxed for 3 hrs and cooled to ambient temperature. The reaction mixture was quenched with water and extracted with 6 N HCl. The aqueous layer was basified using NaOH pellets and extracted with EtOAc. The organic layer was dried over magnesium sulfate and the solvent was removed to afford 2.9 g (80%) of crude product as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=O)/[CH:16]=[C:17](/[C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=2)\[C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[NH2:32][OH:33].O.[OH-].[Cs+]>C(Cl)(Cl)Cl.O.ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([C:15]2[CH2:16][C@:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:33][N:32]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cc(C(=O)/C=C(/c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: NO
Agent: [Cs+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
A 1500 mL reaction-vessel was charged at RT with 1-Anthracen-9-ylmethyl quininium chloride 13.77 mmol, 7.59 g) and tert-butyl 2-methyl-4-[(Z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl]benzoate (68.87 mmol, 34 g) and dissolved in chloroform (700 mL). The mixture cooled down to −30° C. Then, a solution of hydroxylamine (50 mass % in H2O, 9.1 g) in water (50.9 mL) and cesium hydroxide hydrate (185.9 mmol, 32.88 g) in water (60 mL) were added simultaneously dropwise to the reaction mixture over 30 min. After the addition the reaction was kept 16 h at −30° C. after which time the conversion was complete. The reaction was brought to room temperature diluted with dichloromethane and washed three times with water. The organic phase was dried over MgSO4 and evaporated to yield crude title product. The product was purified over a silica gel column (eluent: EtOAc/Heptane) to obtain 39.0 g of the title product. LCMS (Method GR): RT 1.44 min, no ionisation: 1H NMR (400 MHz, CDCl3) 16.0 (s, 9H), 2.60 (s, 3H), 3.70 (d, 1H), 4.10-4.20 (m, 2H), 7.25-7.90 (m, 5H), 19F-NMR (CDCl3, 376 MHz): −79.40.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12>O1CCCC1>[CH2:1]([O:5][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]2[N:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:20]=[C:21]([CH3:22])[C:10]=12)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1c2ccccc2nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To an ice-cold solution of 1-butanol (5.0 g, 68 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (oiliness, content 60%, 0.41 g, 17 mmol), and the mixture was stirred at room temperature for 15 minutes. After 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.0 g, 3.39 mmol) was added thereto at 0° C., the mixture was heated under reflux further for 1 hour. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated and concentrated under reduced pressure. Iced water was added to the residue and the mixture was neutralized with dilute hydrochloric acid, and organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.29 g, 26% yield).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][CH3:15])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:15][O:14][CH2:13][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(COC)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCc1ncc2cn[nH]c(=O)n12

Procedure:
A mixture of 25.9 gm. of 3-[2-(methoxymethyl)-4-imidazolyl]methylene carbazic acid ethyl ester and 125 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 200°-205° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[F:8][C:7]1[C:2]([F:1])=[C:3]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:4]=[CH:5][C:6]=1[NH2:9]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(F)c1F
Reaction time: 5 h
Yield: 86.4 %

Procedure:
A mixture of 4-(2,3-difluoro-4-nitrophenyl)morpholine (11.5 g, 47 mmol) and 10% Pd—C (50% wet, 1.2 g) in EtOH (150 mL) was hydrogenated for 5 h at room temperature. The reaction mixture was filtered by celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (8.7 g, 86% yield) as a pale red powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.77-2.95 (4H, m), 3.60-3.79 (4H, m), 5.07 (2H, s), 6.49 (1H, td, J=9.0, 1.9 Hz), 6.62 (1H, td, J=8.9, 2.3 Hz). LC-MS (ESI) m/z 215 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:11]2[CH:19]=[CH:18][C:14](=[N+:15]([CH3:17])[CH3:16])[CH:13]=[CH:12]2)=[CH:6][CH:5]=1)[CH3:3].[Cl-].[C-:27]#[N:28].[Na+].O.C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:11]2[CH:12]=[CH:13][C:14]([N:15]([CH3:17])[CH3:16])=[CH:18][CH:19]=2)[C:27]#[N:28])=[CH:8][CH:9]=1
Reactant: [C-]#N
Reactant: CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CN(C)c1ccc(C(C#N)(c2ccccc2)c2ccc(N(C)C)cc2)cc1
Reaction time: 3 h

Procedure:
Commercially obtained Malachite Green, oxalate salt (4.644 g) and sodium cyanide (2.456 g) were combined, followed by addition of water (150 mL) and diethyl ether (150 mL). The mixture was rapidly stirred for three hours, at which point the green color had faded, and the mixture was a muddy brown. The mixture was transferred to a separatory funnel with the aid of ethyl acetate, partitioned, and the aqueous phase extracted with three portions of ethyl acetate (100 mL each). The combined organics were washed once with brine (50 mL), dried over sodium sulfate, filtered and concentrated by rotary evaporation to provide crude nitrile 3A contaminated by some of the triarylcarbinol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5](=[O:35])[CH2:6][CH:7]([OH:34])/[CH:8]=[CH:9]/[C:10]1[C:11]2([CH2:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:15][CH2:14][CH2:13][CH2:12]2.C(B(CC)CC)C.[BH4-].[Na+].OO>C1COCC1.O.C(OCC)(=O)C.CO>[CH3:1][O:2][C:3](=[O:36])[CH2:4][CH:5]([OH:35])[CH2:6][CH:7]([OH:34])/[CH:8]=[CH:9]/[C:10]1[C:11]2([CH2:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15]2
Reactant: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Agent: CCB(CC)CC
Agent: OO
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of methyl-(E)-7-[7,9-di-(4-fluorophenyl)spiro-[4.5]deca-6,8-dien-6-yl]-5-hydroxy-3-oxo-6-heptenoate (3.0 g, 6.09 mmoles) in 80 ml of anhydrous THF was added a 1M THF solution of triethylborane (9.07 ml, 9.07 mmoles). The solution was stirred for 5 minutes at room temperature and was then cooled to -78° C. in a dry ice-acetone bath. To this mixture was added sodium borohydride (0.27 g, 7.0 mmoles) followed by the dropwise addition over 30 minutes of a solution of 6.09 ml of methanol in 15 ml of THF. The reaction was stirred for 1 hour with the temperature slowly rising to -50° C. To this mixture was added a solution of 30% hydrogen peroxide (14.17 ml) in water (7 ml) dropwise over 5 minutes. The reaction was stirred at room temperature for 1 hour and was poured into 200 ml of ethyl acetate. The mixture was extracted with 1N HCl and then brine. The organic layer was evaporated in vacuo to give 2.8 g of material. The residue was dissolved in ethyl acetate and the solution was diluted with hexane to precipitate a solid product having an m.p. of 113°-15° C. (dec).