Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](OC)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C1COCC1.CCCCCC>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(F)c1
Reactant: COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)C(=O)Cc1ccnc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of diisopropylamine (12.6 mL, 89.9 mmol) in anhydrous THF (50 mL) is added n-butyllithum (42.2 mL of an 1.6M in hexane) dropwise at 0° C. After 30 min at 0° C., 2-fluoro-4-methylpyridine (5 g, 45 mmol) is added. The resulting mixture is stirred at 0° C. for 30 min. After the addition of methyl isobutyrate (5.4 mL, 47.3 mmol) at 0° C., the reaction mixture is stirred overnight. The reaction mixture is quenched with acetic acid at 0° C., diluted with water, and extracted with ethyl ether. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/heptane 7:93 to 60:40) to give 4.8 g of 1-(2-fluoro-pyridin-4-yl)-3-methyl-butan-2-one as a light yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23]C(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][CH3:23])=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NC

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, a methylamine 30% ethanol solution was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29].Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=3)[CH2:35][CH2:34]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3,4-dichlorophenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS, m/z=438 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([OH:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([O:19][CH3:20])[CH:8]=2)=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:21])[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:9]([O:19][CH3:20])[CH:8]=2)=[CH:22][CH:23]=1
Reactant: COc1cc(C(O)c2ccc(Br)cc2)ccc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccc(Br)cc2)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 4370.3 %

Procedure:
To a solution of 4′-bromo-4-cyclopentoxy-3-methoxybenzhydrol (10 g 0.5 mmol) in dichloromethane(50 ml), was added manganese (IV) oxide (24.0 g, 267 mmol). The mixture was stirred at the room temperature for two days then filtered through celite and the residue washed with dichloromethane. The filtrate was evaporated and the residue crystallized from ethanol to afford the title compound as a white solid (8.2 g, 83%). MS (m/e): 375 [(M+1)+].
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:16][C:15]([CH2:25]O)=[N:14]2)=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl>[Br:2][CH2:25][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=2)[N:14]=1
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(C)cc2)cc1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(-n2nc(CBr)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of phosphorus tribromide (9.31 g, 34.5 mmol) in CH2Cl2 (186 mL) was added drop-wise to a stirred solution of [1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazol-3-yl]-methanol (7.80 g, 26.5 mmol; prepared analogously to the procedure described in Step C of Example 1) in 50 mL CH2Cl2 at 0° C. The reaction mixture was stirred for an additional 18 h at rt, and then the mixture was neutralized by addition of 40% NaOH with cooling in an ice bath. The organic layer was separated and dried over Na2SO4, and solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (CH2Cl2) yielding 8.09 g (86%) of 3-bromomethyl-1-(4-methoxy-phenyl)-5-p-tolyl-1H-pyrazole. HPLC: Rt=10.38. (Method A). MS (ES+): mass calculated for C18H17BrN2O, 356.05; m/z found 357.5 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.42 (s, 4H), 7.39-7.34 (m, 2H), 7.02-6.98 (m, 2H), 6.69 (s, 2H), 4.73 (s, 2H), 3.97 (s, 1H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([C:11]([NH2:15])=[O:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c[nH]c2ncnc(Cl)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1c[nH]c2ncnc(Cl)c12
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (H-1) (3.11 g, 15.7 mmol, 1.0 eq) and a catalytic amount of DMF in a mixture of DCM (40 mL) and THF (40 mL) at RT, oxalyl chloride (2.0 mL, 23.5 mmol, 1.5 eq) is added dropwise. The resulting mixture is stirred for 2 h and then concentrated in vacuo. The residue is dissolved in DCM (50 mL) and the resulting solution is added dropwise to saturated aqueous ammonium hydroxide (200 mL) at RT. The resulting mixture is stirred for 30 min and then filtered. The filter cake is rinsed with H2O (30 mL×2). The filtrate is acidified with conc. HCl to adjust the pH to 4-5. The solid is collected by filtration, rinsed with water and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (H-2).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>CCO>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][N:22]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2[C:14]([N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]2=[O:20])=[CH:15]1)[CH3:30]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (996 mg, 2.95 mmol), ethyl 4-aminobutanoate hydrochloride (489 mg, 2.95 mmol) and triethylamine (0.823 ml, 5.91 mmol) were combined in EtOH (15 ml) and heated at reflux for 2.5 hours. The reaction mixture was cooled to RT and evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water (1×) and brine (1×). The organic phase was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound as an off-white solid;
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][CH:7]=1>N1C=CC=CC=1.C1COCC1>[CH2:1]([NH:4][C:11]([C:9]1[S:10][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An ice-cooled solution of 2.63 ml (35 mmol) of allylamine in 14.2 ml of absolute pyridine and 14.2 ml of absolute THF is admixed dropwise with 5-chloro-thiophene-2-carbonyl chloride (7.61 g, 42 mmol). Ice-cooling is removed and the mixture is stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue is admixed with water and the solid is filtered off. The crude product is purified by flash chromatography over silica gel (dichloromethane).
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7](=[C:31]([F:33])[F:32])[CH2:8][CH2:9][CH:10]([C:21]([O:23]CC1C=CC=CC=1)=[O:22])[C:11]([O:13]CC1C=CC=CC=1)=[O:12]>O>[F:6][C:7](=[C:31]([F:32])[F:33])[CH2:8][CH2:9][CH:10]([C:21]([OH:23])=[O:22])[C:11]([OH:13])=[O:12]
Reactant: O=C(OCc1ccccc1)C(CCC(F)=C(F)F)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCC(F)=C(F)F)C(=O)O

Procedure:
5.56 g (99 mmol) KOH flakes were dissolved in 6.82 ml water and 13.65 ml ethanol and then treated with 11.12 g (28.34 mmol) of dibenzyl 2-(3,4,4-trifluoro-3-butenyl)-malonate. After heating under reflux for 4 hours, the reaction mixture was poured into 30 ml water and washed with ether. The aqueous phase was acidified with dilute hydrochloric acid and extracted 4 times with ether. The organic phase was dried over sodium sulphate, filtered and then concentrated in a rotary evaporator.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>C(O)(C)(C)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
p-Cresol (190 g; 1.76 mol), potassium-tert-butoxide (220.2 g; 1.93 mol) and t-butanol (from calcium hydride; 1 l) were stirred at room temperature, under nitrogen, for 15 mins; followed by the dropwise addition of p-fluoronitrobenzene (272.7 g; 1.93 mol). After heating at reflux for 18 hours, followed by cooling, the resulting yellow precipitate was removed by filtration and washed with absolute ethanol. The combined filtrate and washings were evaporated on the Buchi and the residue taken up in benzene (4 l). The combined benzene layers were dried over magnesium sulphate and evaporated to yield a yellow residue which was recrystallised from hexane (2 l) to give 4-(4-nitrophenoxy)toluene as a yellow solid. m.p. 65°-66° C. NMR (CDCl3): 8.01 (d, 2H), 7.5 (q, 6H) and 2.31 (s, 3H). Analysis for C13H11NO3 : Calculated: C, 68.10, H, 4.84, N, 6.11; found: C, 68.13; H, 4.87; N, 6.14.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[CH:24]=[CH:23]1.C>CO>[C:8]([C:24]1[C:25]2[C:30](=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[NH:22][CH:23]=1)(=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CCCCCCCCCCCC(=O)N(C)C
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 90 °C
Yield: 39.2 %

Procedure:
Phosphorus oxychloride (27.5 ml) was added dropwise during 20 minutes to stirred N,N-dimethyldodecanamide (84.9 g) at room temperature. The temperature of the mixture rose during the addition to 50° C. The mixture was stirred and heated at 90° C. for 15 minutes and then methyl indole-6-carboxylate (33.4 g) was added portionwise to the stirred mixture during 10 minutes, the temperature of the mixture being maintained at 90° C. during the addition. The mixture was then stirred for 2 hours at 90° C. and was then poured onto ice. The aqueous mixture was extracted with chloroform (3×300 ml) and the extract was dried over magnesium sulphate and was evaporated to give a red brown oil. The oil was dissolved in boiling methanol (100 ml), the solution was treated with charcoal and the solution was filtered and cooled (0° C.) to give methyl 3-(n-dodecanoyl)indole-6-carboxylate (26.7 g), in the form of a buff solid, m.p. 167°-169° C.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=1)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(=CCC1C=CC(OC(C)CC)=CC=1)CC(OCC)=O.[BH4-].[Na+]>O.[Ni](Cl)Cl.CO>[CH3:1][CH:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:21])[CH2:19][CH3:20])=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(C)CCc1ccc(OC(C)CC)cc1
Agent: Cl[Ni]Cl
Agent: CCOC(=O)CC(C)=CCc1ccc(OC(C)CC)cc1
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(C)CCc1ccc(OC(C)CC)cc1
Temperature: 25 °C

Procedure:
A mixture (2.90 g, 10.0 mmol) of ethyl 3-methyl-5-[4-(1-methylpropoxy)phenyl]-2-pentenoate and ethyl 3-methyl-5-[4-(1-methylpropoxy)phenyl]-3-pentenoate is combined with nickel chloride (129 mg, 1.0 mmol) and 80 ml of methanol and heated to 50°. Water (10 drops) is added to dissolve the nickel chloride. A second portion of nickel chloride (129 mg, 1.0 mmol) is heated with 10 drops of water, and the resulting solution is added, with 2 ml of methanol, to the mixture. The mixture is chilled to 15°, and sodium borohydride (757 mg, 20.0 mmol) is added in portions over 10 min. The mixture is allowed to warm to RT, and after 3.5 hours the nickel is removed by filtration. The filtrate is washed with methanol and concentrated in vacuo and water and ether are added. The aqueous phase is extracted with ether and the combined organic phases are washed with brine, dried, filtered and the filtrate concentrated to give ethyl 3-methyl-5-[4-(1-methylpropoxy)phenyl]pentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:27]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:27])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl
Product: N=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.06 g, 0.0049 mol), N-[3-(2-chlorobenzyloxy)pyrid2-yl]-N'-(4-chlorophenyl)thiourea (1.56 g, 0,004 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.72 g, (46%),m.p. 162°-163 ° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:7][CH2:6][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:12]([O-:14])=[O:13])(=[O:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A solution was prepared containing 2 grams of the 2,6-dinitrobenzyl alcohol and 2.37 grams of tosyl chloride in 15 ml of dry acetone (20 degrees Centigrade). A solution of dicyclohexyl amine (2.25 ml in 5 ml of dry acetone) was added dropwise to the 2,6-dinitrobenzyl alcohol mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then treated as described above for the preparation of 2,6-dinitrobenzyl alcohol. After recrystallization, 2.3 grams of 2,6-dinitrobenzyl tosylate was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].P(Br)(Br)[Br:12].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[F:10]
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1Br
Temperature: 20 °C
Yield: 61 %

Procedure:
To a solution of (4-bromo-3-fluorophenyl)methanol (5 g, 24.39 mmol) in DCM (100 mL) was added PBr3 (2.76 mL, 29.3 mmol) dropwise. The resulting mixture was stirred at 20° C. After LCMS analysis showed the starting material had disappeared, the mixture was adjusted to pH=8 by aq Na2CO3. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography (PE/EA=10/1) to yield a white solid of 1-bromo-4-(bromomethyl)-2-fluorobenzene (4.2 g, 14.89 mmol, 61.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 7.16 (d, J=6.4 Hz, 1H), 4.53 (s, 2H); ES-LCMS m/z 186.9 (M−79).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>ClCCl.C(#N)C>[Br:1][C:12]1[CH:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: BrBr
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: Oc1ccc(-c2ccc(F)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.9 %

Procedure:
A solution of bromine (4.57 g, 28.59 mmol) in dichloromethane (20 mL) was added dropwise to a solution of 4-fluoro-4′-hydroxybiphenyl [purchased from TCI] (5.38 g, 28.59 mmol) in dichloromethane (100 mL) and acetonitrile (20 mL) and the reaction mixture stirred at room temperature under nitrogen for 18 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL) containing 10% aqueous sodium thiosulfate solution (20 mL), water (200 mL) and saturated brine (200 mL), dried (MgSO4), filtered and concentrated in vacuo to give crude 3-bromo-4′-fluoro-[1,1′-biphenyl]-4-ol (9.0 g) as a tan solid.
Reaction SMILES: [O:1]([C:8]1[N:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>N1C=CC=CC=1>[O:1]([C:8]1[C:9]([C:10]([NH:12][NH:13][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)=[O:11])=[CH:14][CH:15]=[CH:16][N:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccnc1Oc1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1cccnc1Oc1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
Alternatively, as shown in scheme 2, reaction of 2-phenoxy-nicotinic acid hydrazide with 3-trifluoromethyl-benzoyl chloride in the presence of a base such as pyridine produced N′-(2-phenoxypyridine-3-carbonyl)-3-(trifluoromethyl)benzhydrazide as the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-methoxybenzylamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.81 (d, 1H, J=2.7 Hz), 7.27 (m, 3H), 6.86 (m, 3H), 6.52 (s, 1H). 5.14 (s, 1H), 4.46 (d, 2H, J=5.4 Hz), 4.24 (s, 4H), 3.78 (s, 3H); LCMS: ret. time: 23.06 min.; purity: 94%; MS (m/e): 383 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH2:7])=[S:6].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>CC(C)=O>[Cl:12][CH2:13][C:14]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[S:6][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cl)c(Cl)c1
Solvent: CC(C)=O
Product: ClCc1csc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-dichlorothiobenzamide (8.24 g., 0.04 mol), 1,3-dichloroacetone (5.1 g., 0.04 mol) in acetone (150 ml) was stirred at room temperature overnight. After evaporation of the acetone under reduced pressure, the residue was dissolved in methanol (150 ml) and the solution refluxed 11/2 hours. After cooling and removal of the methanol, the residue was slurried with a small quantity of methanol. The solids which formed after filtration showed m.p. 93°-96° C. (6.05 g.).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Na+].[C:21](ON1C(=O)CCC1=O)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].C(=O)([O-])O.[Na+].Cl>CO.O1CCOCC1>[NH:1]([C:21]([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)ccc1O
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 2.0 g (8.0 mmol) of Tyr(3-tBu)-OMe in 40 ml of methanol, 8.8 ml (8.8 mmol) of 1 N aqueous sodium hydroxide was added dropwise under cooling with ice and the mixture was stirred for 2 hours, followed by stirring at room temperature for additional 4 hours. The reaction mixture was concentrated under reduced pressure and 1 N HCl was added under cooling with ice for pH adjustment to 9; to the reaction being maintained at pH 8-9, a solution of 3.0 g (8.8 mmol) of Fmoc-OSu in 1,4-dioxane (40 ml) and a saturated aqueous solution of sodium hydrogencarbonate were alternately added dropwise and the mixture was stirred at room temperature for 1 day. After being rendered acidic with hydrochloric acid, the reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (eluting solvents were ethyl acetate:n-hexane=1:1 and acetic acid supplemented ethyl acetate:n-hexane=1:1); to remove the acetic acid used in eluting, the fractions were washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give Fmoc-Tyr(3-tBu)-OH in the amount of 2.3 g (yield: 61%).