Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:30])[C@@H:17]3[C@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:14]=2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:8][CH:9]=[C:10]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:30])[C@@H:17]3[C@H:20]([OH:22])[CH3:21])[C:14]=2[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:11][CH2:12]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(C2=CCN(C(=O)OCC=C)CC2)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(C2=CCN(C(=O)OCC=C)CC2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.94 g) in tetrahydrofuran (38 ml) were added dropwise acetic acid (1.65 ml) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 9.6 ml) at 0° C. After standing at ambient temperature for 8 hours, the reaction mixture was taken up into a mixture of ethyl acetate (300 ml) and water (300 ml). After adjusting pH to around 7 with aqueous sodium hydrogen carbonate the organic layer was separated washed in turn with water and brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (25 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-3:7, V/V) to give allyl (5R,6S)-3-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (281 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1c(F)ccc(F)c1F
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3cccnc3)no2)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,6-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.26-7.35 (m, J=9.4, 9.4, 3.8, 2.0 Hz, 1H), 7.62-7.77 (m, 2H), 8.57 (dt, J=8.0, 1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 9.30 (dd, J=2.4, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: [Cl:1][N:2]1[C:6]([Cl:7])=[CH:5][N:4]=[CH:3]1.[H-].[Na+].[CH3:10][O:11][CH2:12][CH2:13]Cl.O>CN(C=O)C.C(OCC)(=O)C>[CH3:10][O:11][CH:12]([C:3]1[N:2]([Cl:1])[C:6]([Cl:7])=[CH:5][N:4]=1)[CH3:13]
Reactant: COCCCl
Reactant: Clc1cncn1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(C)c1ncc(Cl)n1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 mmol of 3,4-dichloroimidazole in anhydrous DMF (5 mL) is treated with sodium hydride (1.05 mmol) at 0° C. under nitrogen with magnetic stirring. After 30 min., 2-chloroethyl methyl ether (1 mmol) is added and the reaction mixture is warmed to 60° C. for 2 h. The reaction mixture is cooled, portioned between water and ethyl acetate. The organic layer is separated, washed with water, brine and dried over sodium sulfate. The reaction mixture is filtered, evaporated and purified by chromatography on silica gel to obtain 1-methoxyethyl-3,4-dichloroimidazole.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:19]1[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22](=O)[O:21]C1=O)[CH:17]=[CH2:18].Cl>CN(C=O)C>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:19]([CH2:16][CH:17]=[CH2:18])[C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[CH:28][C:23]=2[C:22]=1[OH:21])=[O:8])[CH3:11]
Reactant: C=CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
To a 50 ml. solution of NaOEt (0.3 g. Na-0.013 mole) was added 2.08 g. (0.013 mole) of diethyl malonate and this was stirred 10 minutes, then stripped to dryness. DMF was added to form a solution and then 1.85 g. (0.0065 mole) of 1-(2-propenyl)7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and heated at reflux for 1.5 hours. When cool, the reaction was poured into dilute HCl and the resulting precipitate collected on a filter and rinsed with water. Recrystallization from ethyl acetate gave 1.0 g. of product--m.p. 177°-180° C.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:14][C:13]([CH:26]([F:28])[F:27])=[CH:12][C:11]=1[N:29](CC1C=CC(OC)=CC=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:9][C:10]1[C:15]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:14][C:13]([CH:26]([F:28])[F:27])=[CH:12][C:11]=1[NH2:29]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(F)F)cc(N3CCN(C4COC4)CC3)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: Nc1cc(C(F)F)cc(N2CCN(C3COC3)CC2)c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
Anisole (633 μl, 5.80 mmol) was added to a solution of tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (312 mg, 0.58 mmol) in DCE (3 mL), followed by the addition 2.8 mL of TFA. The reaction was stirred at 60° C. for 3 h. The residue was partitioned between CH2Cl2 and sat. NaHCO3, and extracted into CH2Cl2 (3×). The solution was dried over Na2SO4 and concentrated. The residue was dissolved in MeOH and loaded onto a 5 g Strata SCX ion exchange cartridge, washing with MeOH. The desired product was eluted with 7 N NH3—CH3OH. After concentration, 163.4 mg of 2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26][N:27]3[CH2:32][C@H:31]([CH3:33])[O:30][C@H:29]([CH3:34])[CH2:28]3)=[N:24][N:25]=2)[CH:3]=1.[CH3:35][O:36][C:37]1[C:42]([NH2:43])=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][N:38]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:34][C@H:29]1[O:30][C@@H:31]([CH3:33])[CH2:32][N:27]([CH2:26][C:23]2[O:22][C:21]([C:4]3[CH:3]=[C:2]([C:40]4[CH:41]=[C:42]([NH2:43])[C:37]([O:36][CH3:35])=[N:38][CH:39]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:25][N:24]=2)[CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5C[C@@H](C)O[C@@H](C)C5)o4)cc(Br)cc32)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Temperature: 80 °C
Yield: 43.6 %

Procedure:
6-Bromo-4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-[(4-methylphenyl)sulfonyl]-1H-indazole (680 mg, 1.244 mmol) was dissolved in 1,4-dioxane (15 ml) and water (1.5 ml). 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (311 mg, 1.244 mmol), bis(diphenylphosphino)ferrocene palladium dichloride (182 mg, 0.249 mmol) and tripotassium phosphate monohydrate (860 mg, 3.73 mmol) were added and the reaction mixture heated at 80° C. for 2 h. 2-(methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.1 eq, 31 mg) was added and the reaction mixture heated at 80° C. for a further 18 h. The solvent was removed in vacuo and the residue partitioned between DCM (50 ml) and water (50 ml). The layers were separated (hydrophobic frit), the organic concentrated in vacuo and the residue purified by column chromatography, loading in dichloromethane and purified on a silica cartridge (100 g), using a 0-30% methanol(+1% triethylamine)-dichloromethane over 40 mins. The appropriate fractions were combined and concentrated in vacuo to a brown gum. This was purified again by column chromatography, loading in dichloromethane and purified on a silica cartridge (50 g) using a 0-100% ethyl acetate-cyclohexane+0-20% methanol over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (320 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][NH:31][C:25]=2[CH:24]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][N:31]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[C:25]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 100 °C
Yield: 57.3 %

Procedure:
To a mixture of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (2.55 g, 7.16 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.51 mmol) in 1,4-dioxane (20 mL) was added CuI (494 mg, 2.6 mmol), K2CO3 (3.6 g, 26 mmol), and N1,N2-dimethylethane-1,2-diamine (460 mg, 5.2 mmol). The mixture was heated at 100° C. for 3 hours, which was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The crude was purified by silica gel chromatography using petroleum ether/EtOAc (2/1) as eluting solvents to afford tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate as a yellow solid (1.6 g, 57%). MS (ESI) m/z: 429[M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].C1(P(=[CH:31][CH:32]=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[CH:31][CH:32]=[O:33])#[N:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(O)c(C=O)c1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(O)c(C=CC=O)c1
Yield: 45.4 %

Procedure:
A solution of 5-cyano-2-hydroxybenzaldehyde (4.3 g) and (triphenylphosphoranylidene)acetaldehyde (9.4 g) in toluene (150 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=3/1 as an eluant to give the desired compound (2.3 g, yield 44%) as a colorless solid.
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10].C(N)=O>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [O-2]
Solvent: NC=O
Solvent: O
Product: O=C([O-])C(=O)[O-]

Procedure:
(STEP 2): To 40 ml of water is added 1.47 grams of vanadium pentoxide, 3.24 grams of oxalic acid and 7.37 grams of formamide at room temperature with stirring to form vanadium oxalate, and this solution was then mixed with 26.0 grams of the 1.9 wt. % V2O5 on titanium dioxide anatase (powder prepared as described above in Step 1) and 1.37 grams of Sb2O3 (which were first dispersed in 20 ml of water). The resulting mixture was heated with stirring at 65° C. to evaporate the majority of the water, followed by drying in an oven (101 kPa) at 110° C. for 16 hours. The resulting solid was then calcined in a flowing oxygen gas stream at 450° C. for 2 hours, followed by crushing and screening to form -20 +40 mesh particle size. The catalyst formed by the above impregnation procedure was determined by calculation (based on the vanadium salt, antimcny salt, and the weight of th titanium dioxide particles) to contain a total of 4.8 wt. % Sb2O3 and 6.8 wt. % V2O5 on the TiO2. Catalyst D; Sequential Impregnation
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)CCCBr)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Bromobutyryl chloride (29.4 mg, 0.158 mmol) was added to a solution of 8-(aminomethyl)-10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (61 mg, 0.132 mmol) and triethylamine (0.022 mL, 0.158 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 3.5 hours, then diluted with DCM (30 ml) and washed with saturated NaHCO3(aq) (30 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly
Reaction SMILES: C([Si]([S:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2)(C(C)C)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].[F-].[Cs+].F[C:31]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:32]=1[C:33]#[N:34]>CN(C=O)C>[CH3:21][N:17]1[C:18]2[C:14](=[CH:13][C:12]([S:11][C:31]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:32]=3[C:33]#[N:34])=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: N#Cc1cc(F)ccc1F
Reactant: CC(C)[Si](Sc1ccc2c(cnn2C)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Sc3ccc(F)cc3C#N)ccc21
Temperature: 100 °C
Yield: 75.9 %

Procedure:
Compound (3r) (0.65 g, 2 mmol), potassium carbonate (0.34 g, 2.4 mmol), CsF (0.46 g, 3 mmol), 2,5-difluorobenzonitrile (0.56 g, 4.1 mmol) and DMF (5 mL) were placed in a 60 mL reaction vial and the vial was sealed. The mixture was heated to 100° C. for 16 hours. Excess DMF was removed under reduced pressure. This material was taken up in DCM (50 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine (2×) and dried over MgSO4, filtered through a plug of celite/silica gel and concentrated under reduced pressure. The residue was purified by silica gel chromatography with hexane/EtOAc (20%) to give the final product as a viscous liquid (4r) (0.43 g, 75% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.97 (s, 1H), 7.46 (dd, J=16.8, 8.8 Hz, 2H), 7.35-7.32 (m, 1H), 7.14-7.07 (m, 1H), 7.05-7.01 (m, 1H), 4.1 (s, 3H); MS (ESI) m/z 284.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-(trifluoromethyl)benzoic acid (224 mg, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 2-chloro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([C:20]1[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[C:18]([C:20]4[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.3 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclopentyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.592 mmol) described in Manufacturing Example 78-1-4 and 3-ethynyl-pyridin-2,6-diamine (50.3 mg, 0.378 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (206 μL, 1.48 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (64 mg, 31%).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:40][C:41]3[C:42]([C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:43][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:45][C:46]=3[C:47]([CH3:50])([CH3:49])[CH3:48])[O:21][C:22]3[C:23]([C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:24][C:25]([C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:40][C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][C:23]=1[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C(C)(C)C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 1.16 grams of 4,4'-isopropylidenebisphenol (0.005 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.24 gram (0.01 mol) of sodium hydride, as a 50 weight percent dispersion in mineral oil was added to the 4,4-iso-propylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,4,6-tri-t-butylphenyl) phosphorochloridite (6.0 grams, 0.01 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,4,6-tri-t-butylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 4.87 grams. The molecular weight, FD/MS was 1332.
Reaction SMILES: CN(C)C(=O)C.[C:7]([C:9]1[NH:10][N:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:31])[C:13]=1[N:14]=[N:15][C:16]1[CH:21]=[C:20]([S:22](O)(=[O:24])=[O:23])[C:19]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=1)#[N:8].P(Cl)(Cl)([Cl:40])=O>CC(C)=O>[C:7]([C:9]1[NH:10][N:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:31])[C:13]=1[N:14]=[N:15][C:16]1[CH:21]=[C:20]([S:22]([Cl:40])(=[O:24])=[O:23])[C:19]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=1)#[N:8]
Reactant: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 ml of N,N-dimethylacetamide was added dropwise at 50° C. or lower to a mixture of 51.0 g of 3-cyano-4-[4-(2-methoxyethoxy)-5-sulfophenylazo]-1-phenyl-5-pyrazolone prepared as described in Step (a) of Reference Synthesis Example 1 above, and then 250 ml of acetone and 50 ml of phosphorous oxychloride was added. After completion of the dropwise addition, the reaction mixture was stirred for about 1 hour, and was then gradually poured into 1.0 l of ice water. The crystals thus-precipitated were recovered by filtration, washed with 100 ml of acetonitrile and air-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](=O)[CH3:11].ClC1C=CC=CC=1C=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C@H:30]([NH2:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([NH:32][C@@H:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)[CH3:31])[CH3:11]
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: CC(=O)CCc1ccccc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=Cc1ccccc1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)N[C@H](C)CCc2ccccc2Cl)c1

Procedure:
In a similar fashion an equal molar amount of 4-(2-chlorophenyl)-2-butanone, prepared from o-chlorobezaldehyde, (R)-1(3-methoxyphenyl)ethylamine and 1.25 equivalents titanium(IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5% methanol in chloroform afforded (R,R)-N-[4-(2-chlorophenyl)-2-butyl]-1-(3-methoxyphenyl)ethylamine, 4T; m/z (rel. int.) 317 (M+, 3), 302 (16), 178 (62), 135 (100), 125 (15), 105 (10), 91 (6), 77 (8).