Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[BH4-].[Na+]>CO.CCOCC>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCC=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1

Procedure:
A solution of 12 g of trans-4′-[4-(3-oxo-propyl)-cyclohexyl]-biphenyl-4-carbonitrile (preparation: Mol. Cryst. Liq. Cryst. 1985, Vol. 131, 327) in 100 ml methanol/ether (9:1) was added dropwise at 0° C. within 5 minutes to a suspension of 1.39 g of sodium borohydride in 30 ml of methanol/ether (9:1). After 45 minutes a further 1 g of sodium borohydride was added. After a further hour the reaction was interrupted and the mixture was partitioned between methylene chloride and 1N hydrochloric acid. Thereupon, the organic phase was washed several times with water, dried over magnesium sulphate, filtered and evaporated. Crystallization from ethyl acetate/methylene chloride gave 11.5 g of trans-4′-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carbonitrile as yellowish crystals.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[CH3:21][C:22]([CH3:24])=[O:23]>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[C:22]([OH:23])([CH3:24])[CH3:21]
Reactant: CC(C)=O
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)cncc1Br
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 48.2 %

Procedure:
n-BuLi 1.6M in hexanes (11.25 ml, 18.00 mmol) was added dropwise to a solution of diisopropylamine (2.78 ml, 19.50 mmol) in THF (50.0 ml) at −78° C. under N2. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recooled to −78° C. 3-bromo-5-fluoropyridine (2.64 g, 15 mmol) in 5 mL THF was added dropwise at this temperature. After 30 min, acetone (3.30 ml, 45.0 mmol) was added dropwise and the resulting mixture was stirred for 30 min at −78° C., and then for another 30 min at 0° C. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (0-30% AcOEt/heptane, SNAP50) giving 10a (1.691 g, 48%) as a yellow oil. LC-MS (M+1) 235.9, t=1.18 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:19]=[C:20]([NH2:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=2)[CH:17]=1.C(N(CC)C(C)C)(C)C>O=S(Cl)Cl.CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:28][C:20]1[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:18]([N:16]2[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]2)[CH:19]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Iodo-4-methylbenzoic acid (2.62 g, 10 mmol) was refluxed in SOCl2 (10 mL) for 1 h. The volatile components were removed on a rotavap and the residue was dissolved in benzene (10 mL), concentrated to dryness on a rotavap and further dried under vacuum. The resulting acyl chloride was added to a solution 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzenamine (2.46 g, 10.2 mmol), N,N-diisopropylethylamine (1.56 g, 12 mmol), and a catalytic amount of DMAP in THF (20 mL). After stirring at rt for 2 h, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to dryness and used without purification in next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)=O.CC(C)=O.[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](Cl)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.O=[Si]=O.C(NCC)C.C>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C:32]([C:27]2[C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=3)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ccc(C=O)c(N)c1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: C
Agent: O=C=O
Agent: O=[Si]=O
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: CC(C)=O
Product: Nc1cc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
To a nitrogen purged 12 liter 3-neck flask fitted with a mechanical stirrer and temperature probe was added THF (4.3 L) and 2,4-diaminobenzaldehyde (50 g, 0.37 mol, 1 equiv). After cooling the solution to −70° C. (dry ice/acetone bath), poly(4-vinylpyridine), which can be obtained from Aldrich, Milwaukee, Wis., 25% cross-linked, (210 g) was added. A solution of 4′-trifluoromethyl-biphenyl-2-carbonyl chloride (105 g, 0.37 mol, 1 equiv) in THF (1 L) was added at such a rate as to maintain the temperature below −60° C. The light orange reaction mixture was allowed to warm to room temperature over 4 hours to give a dark red reaction mixture. (HPLC analysis showed an 18:1 mixture of mono- (retention time (rt)=4.8 min) to di- (rt=3.1 min) acylated products along with 5% residual starting material (rt=18.8 min), (Zorbax SIL (150 mm) from Agilent Technologies, Palo Alto, Calif. 2 mL/min 90:10 hexanes/isopropanol, 0.1% diethylamine, 250 nm, 40° C.). The reaction was quenched with 1 N NaOH (450 mL) and allowed to stir overnight at 25° C. The reaction mixture was filtered and the solids were washed with ethyl acetate (5×200 mL) and the combined organic layers were concentrated in vacuo to give a brown oil. The oil was dissolved in CH2Cl2 (1.5 L) and silica gel (EM Science, Gibbstown, N.J., 230-400 mesh or 0.04-0.06 mm particle size) (410 g) and Darco G-60® (10 g, BNL Fine Chemicals and Reagents) were added. The slurry was stirred for 15 minutes and filtered. The silica was washed with CH2Cl2 (5×200 mL). The combined organic layers were concentrated in vacuo and the methylene chloride was displaced with 1:1 hexanes/diisopropylether. The precipitated product was collected by suction filtration and dried in air to give 4′-trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-4-formyl-phenyl)-amide (40 g, 30%, 43:1 mono:bis acylated by HPLC) as a light yellow solid.
Reaction SMILES: [Br:1]Br.[C:3]([Si:7]([CH3:24])([CH3:23])[N:8]1[C:12]2=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=[C:11]2[CH:10]=[CH:9]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:16]=2)[N:8]([Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:24])[CH3:23])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccnc3)cnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccnc3)cnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of bromine (0.166 mL, 0.0032 mol) in 1 mL of CCl4 was added dropwise to a stirred solution of 20 (1.0 g, 0.0032 mol) and pyridine (0.314 mL, 0.0039 mol) in dry CHCl3 (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then neutralized with 10 mL of a mixture of sodium bicarbonate-sodium thiosulfate (1:1). The organic layer was separated and further extracted with dichloromethane (3×10 mL) and the combined organics dried and concentrated in vacuo. The residue was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 0.97 g (78%) of the desired material 21. 1H NMR CDCl3 8.9 (s, 1H), 8.55 (d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.4 (dd, 1H), 7.2 (s, 1H), 0.9 (s, 9H), 0.5 (s, 6H).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1>C(Cl)(Cl)Cl>[NH2:3][C:4]1[C:9]([Br:1])=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Cc1cnc(N)cn1
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N)c(Br)n1
Reaction time: 1.5 h

Procedure:
A solution of bromine (0.11 ml) in chloroform (20 ml) was added dropwise over 20 minutes to a solution of 2-amino-5-methylpyrazine (0.218 g) in chloroform (30 ml) which was protected from light. The reaction mixture was stirred for 90 minutes after addition was complete and was then washed with water (50 ml). The organic phase was dried (MgSO4) and volatile material was removed by evaporation to give a yellow oil. The oil was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 2-amino-3-bromo-5-methylpyrazine (0.286 g) as white solid, m.p. 51°-52° C.; mass spectrum (positive chemical ionisation (+ve CI)): 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N1C(Cl)=NC(Cl)=NC=1Cl.ClC1C=C(C=CC=1OC)N.[CH:38]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[OH-].[Na+]>CC(C)=O>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:45][CH:38]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[N:14]=1
Reactant: NC1CCCCCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: COc1ccc(N)cc1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl

Procedure:
Among the bases and solvents screened, sodium acetate (NaOAc) and 1,4-dioxane showed consistently good results for a 1 kg preparation. This scheme involves the preparation of compound 101 by reaction of cyanuric chloride with 3-chloro-4-methoxyaniline in acetone at 0–5° C. in the absence of base, which is then made to react with cycloheptylamine in presence of NaOH under reflux to give compound 133. This compound 133 was reacted with 1-methyl-(4-methylamino)piperidine using NaOAc in 1,4-dioxane solvent to yield the crude compound 137 which is purified by making hydrochloride salt, N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-N″-methyl-N″-(1-methyl piperidin-4-yl)[1,3,5]triazine-2,4,6-triamine, HCl salt, compound E31 and by recrystallisation in isopropanol. The hydrochloride salt was then released to give the free base, compound 137. Compound obtained in this manner exhibited the same high quality of appearance, purity, low residual solvents, assay and impurity profile, and the like.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]
Reactant: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Yield: 86 %

Procedure:
To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDC (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>O>[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Solvent: O
Product: O=C(O)CC1CCNCC1
Reaction time: 16 h
Yield: 119.6 %

Procedure:
Pyridin-4-yl-acetic acid hydrochloride (20.0 g, 115 mmol) was added to water/25% ammonia (125 mL:10 mL). The mixture was degassed and flushed with nitrogen before addition of rhodium on activated alumina (0.45 g). The mixture was again degassed, then stirred in a hydrogen atmosphere at 50 bar for 16 h. Filtration of the reaction mixture through filter paper afforded the bulk of the catalyst which was recycled after washing with methanol. The filtrate was then filtered through Celite and concentrated to afford a white solid (19.7 g, 96% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH:11]=[CH2:12]>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:12][CH:11]=[CH2:10])=[CH:4][CH:3]=1
Reactant: C=CC[Mg]Cl
Reactant: BrCc1ccc(Br)cc1
Solvent: CCOCC
Product: C=CCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A 250 ml two-necked round-bottom flask, equipped with an additional funnel and condenser, was charged with 4-bromo-benzyl bromide (20.0 g, 80 mmol) in 50 ml dry ether at 0° C. ice bath for 10 min. The allylmagnesium chloride (48.0 ml of a 2.0 M solution in ether, 96 mmol) was added dropwisely via an additional funnel over a period of 30 min at 0° C. Subsequently, the mixture was stirred at room temperature for 2 h and refluxed for another 3 h. The reaction was monitored by TLC analysis. After the starting material disappeared, the reaction was quenched by water and transferred to a separation funnel. The organic layer was washed with brine, dried over anhydrous MgSO4, and then concentrated under vacuum to yield a yellow crude liquid. The product was purified by Kugelrhor distillation to obtain the final product as a transparent liquid (14.10 g, 83%), whose 1H and 13C NMR spectra matched with the earlier reported literature data [7].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To a vigorously stirred suspension of ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (4.2 g, 15 mmol) in methanol (11 mL) was added 2 M aqueous solution of NaOH (22 mL, 44.0 mmol). The suspension was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove methanol. The residual aqueous suspension was acidified with 6 N aqueous solution of HCl to pH ˜1-2. The mixture was stirred and occasionally sonicated for 1 hr. The solid was filtered, washed with water, and dried to give 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (3.7 g, 100% yield) as a white solid. MS found: (M+H-Boc)+=145.
Reaction SMILES: C1C2NC3C(=CC=CC=3)C=2C=CC=1.N[C@H](C(O)=O)CS.[OH:21][CH2:22][C:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])=[O:24]>>[O:21]=[CH:22][C@@H:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: N[C@@H](CS)C(=O)O
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A mixture of 0.2 ml of a 1M aqueous D-glucose solution, 0.2 ml of a 0.05M aqueous MgSO4.7H2O solution, 0.2 ml of a 0.5M aqueous phosphate buffer solution (pH = 7.2) and a given amount of aqueous glucose isomerase extract is diluted with water to make 2 ml. The resulting mixture is maintained at a temperature of 70° C. for 60 minutes to effect the glucose isomerization which is terminated by the addition of 2 ml of 0.5M perchloric acid. The amount of fructose produced is determined by cystein carbazole method. The value obtained by dividing the amount of fructose produced by the amount of aqueous glucose isomerase extract is the activity, the unit of which is expressed by the abbreviation "U".
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][C:16]#[CH:17]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][CH2:13][OH:18])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1 a], 1-iodo-3-trifluoromethoxy-benzene was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to give the title compound as red oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]1([C:7]2([CH2:12][O:13][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCC1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (1-phenyl-cyclopentyl)-methanol (11.5 g, 64.34 mmol) in DCM (100 ml) was added TEA (17.5 ml, 130.68 mmol) and followed by methanesulfonyl chloride (MsCl) (8.9 g, 78.4 mmol) was added drop wise at 0° C. and the reaction mixture was stirred at RT for 16 h. After completion of the reaction, it was quenched with water and concentrated. Then the crude product was dissolved in DCM, extracted with DCM and the organic layer was washed with water, and brine and then dried over Na2SO4. The combined organic layer was concentrated to get crude methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (10 g, crude) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Commercially available p-hydroxybenzaldehyde (50 g) was dissolved in pyridine (400 ml), followed by dropwise adding octanoyl chloride (80 g) under ice cooling, allowing the mixture to stand overnight, adding toluene (300 ml) and 6N hydrochloric acid, separating the solution, further washing with an aqueous solution of 2N NaOH, washing with water, drying and distilling off toluene to obtain a raw product, which was then distilled under reduced pressure to obtain p-octanoyloxybenzaldehyde (b.p. 174°~7° C./7 mmHg) (58.2 g). This product was dissolved in acetic acid (80 ml), followed by dropwise adding to the solution, a mixed solution of chromium trioxide (23.4 g), water (25 ml) and acetic acid (48 ml), stirring at room temperature for 4 hours, pouring on ice, separating solids by filtering, dissolving them in ethanol (300 ml), adding active carbon, shaking, filtering on heating, ice cooling, filtering crystals and recrystallizing from ethanol (300 ml) to obtain p-octanoyloxybenzoic acid (35 g). M.P.: 151° C. This product (5 g) and oxalic acid chloride (7.2 g) were heated on a water bath at 60° C., followed by allowing the reaction mixture to stand overnight, and distilling off excess oxalic acid chloride in vacuo to obtain p-octanoyloxybenzoyl chloride (5 g). This product was used in the following step without purification.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:18]([CH:20]([OH:34])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>N1C=CC=CC=1>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:34][CH:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1

Procedure:
A method for the preparation of the compound (-)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluorophenylacetate comprising: reacting (+)-α-isopropyl-4-difluoromethoxyphenylacetyl chloride with α-cyano-m-phenoxybenzyl alcohol in the presence of pyridine and isolating from the thus-obtained mixture of (+)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluoromethoxyphenylacetate said (-)-α-cyano-m-phenoxybenzyl (+)-α-isopropyl-4-difluoromethoxyphenylacetate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([F:25])[C:18]([CH2:23]Br)=[C:19]([CH2:21]Br)[CH:20]=1>CN(C=O)C>[Br:14][C:15]1[CH:20]=[C:19]2[C:18]([CH2:23][N:13]([S:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=3)(=[O:12])=[O:11])[CH2:21]2)=[C:17]([F:25])[CH:16]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Fc1cc(Br)cc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)cc(F)c3C2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1.17 g of about 60% sodium hydride was suspended in 30 ml of DMF, to which was added 15 ml of DMF solution of 2.50 g of p-toluene sulfonamide, and the resulting mixture was stirred at 60° C. for 1 hour. 15 ml of DMF solution of 5.02 g of 5-bromo-1,2-bis(bromomethyl)-3-fluorobenzene (3-13) was dropped thereto and the resulting mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into ice water and the precipitated crystal was separated by filtering to obtain 5.10 g of 6-bromo-4-fluoro-2-(p-toluensulfonyl)isoindoline (3-14).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([N+:18]([O-])=O)[CH:5]=1.CN(C=O)C.[Cl-].[NH4+]>O1CCCC1.O.C(O)C.[Fe]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
A suspension of the product of Example 65A (as a mono DMF adduct) (7.25 g, 19.23 mmol) ammonium chloride (1.54 g, 28.8 mmol) and iron powder (5.37 g, 96.15 mmol) in tetrahydrofuran (75 mL), water (25 mL) and ethanol (75 mL) was heated at reflux for 3 hours. The reaction was cooled to room temperature, and the mixture was filtered through a pad of celite, which was then washed with methanol, and the filtrate concentrated to a solid under vacuum. The residue was then dissolved in water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as a white solid (4.2 g, 79%).