Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][N:20]=1)[C:14](OC)=[O:15]>C1COCC1>[C:1]([CH2:2][C:14]([C:13]1[CH:18]=[CH:19][N:20]=[C:11]([O:10][CH3:9])[CH:12]=1)=[O:15])#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1ccnc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)CC#N)ccn1
Temperature: -78 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
To a 100 ml flask was added 30 ml of THF and acetonitrile (1.41 ml, 26.9 mmole). The mixture was cooled to −78° C. and then n-butyllithium (16.8 ml, 26.9 mmole, 1.6M solution in hexane) was added. The reaction was stirred for 30 minutes at which time 5 ml of a THF solution of methyl 2-methoxyisonicotinate 105.1.A (1.50 g, 9.0 mmole) was added. After 3 hours at −78° C., the reaction mixture was quenched by 1.7 ml of acetic acid, and was warmed to room temperature. The solvent was removed by rotary evaporation and the crude was purified on a silica gel column to give 105.1.B (676 mg, 43% yield) as orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:24]>>[ClH:24].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:20][C:4]=2[CH:3]=1
Reactant: CC(C)c1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Reactant: Cl[Sn]Cl
Product: CC(C)c1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Product: Cl
Yield: 74 %

Procedure:
By using a method similar to the method of Example 532, using 2-(4-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.559 g, (1.87 mmol), tin (II) chloride(1.06 g, 5.60 mmol) to obtain (0.422 g, 1.38 mmol, 74% yield) of the title compound as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CS(O[CH2:12][CH2:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=O)=O.[CH:24]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]2[CH2:31][NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[SH:40].CCCCCC.CC(=O)OCC>CN(C=O)C>[CH:27]12[CH2:30][CH:24]([CH:25]([CH2:31][NH:32][C:33]([C:34]3[C:35]([S:40][CH2:12][CH2:13][C:14]([F:22])([F:23])[C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:41])[CH2:26]1)[CH2:29][CH2:28]2
Reactant: CS(=O)(=O)OCCC(F)(F)c1ccc(F)cc1
Reactant: O=C(NCC1CC2CCC1C2)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCC1CC2CCC1C2)c1cccnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 60 °C
Yield: 50 %

Procedure:
553 mg (4 mmol) of K2CO3 and 268 mg (1.0 mmol) of 3,3-difluoro-3-(4-fluorophenyl)-propyl methanesulfonate were added in succession to a solution of 262 mg (1.0 mmol) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide in DMF (3 ml), and the mixture was heated for 3 h at 60° C. Dilution with water and extraction with EA were then carried out. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 229 mg (0.5 mmol, 53%) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[[3,3-difluoro-3-(4-fluoro-phenyl)-propyl]sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 435.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[C@H:34]([C:35]([CH3:43])([CH3:42])[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH2:32][C:31]2=[O:44])[CH:26]=[N:27][CH:28]=1>>[C:38]([SiH2:37][O:36][C:35]([CH3:43])([CH3:42])[C@@H:34]1[CH2:33][CH2:32][C:31](=[O:44])[N:30]1[CH2:29][C:25]1[CH:24]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:28]=[N:27][CH:26]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(CN4C(=O)CC[C@H]4C(C)(C)O[SiH2]C(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to (S)-1-(5-bromo-pyridin-3-ylmethyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one to give the title compound as a brown foam. MS: 480.3 (M+H+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH:22]([NH2:40])[CH2:23][O:24][CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].C(N(CC)CC)C>C1COCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:43]([CH2:42][NH:40][CH:22]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=1)([O:45][CH3:46])=[O:44]
Reactant: NC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21
Reactant: COC(=O)CBr
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CNC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1c2ccccc2CCc2ccccc21

Procedure:
A mixture of the title product of Example 6, methyl bromoacetate (one equivalent) and triethylamine (one equivalent) were refluxed in THF for 22h. The reaction was partitioned between diethyl ether-water and the organic phase separated and dried (MgSO4). Solvent was removed in vacuo and the residue redissolved in ethanol. Oxalic acid was added, solvent removed in vacuo, and the residue recrystallised to give the title compound. mp 160°-165° C. (ethyl acetate-petroleum ether). 1H NMR (360MHz, DMSO-d6) 2.8-3.0 (2H, m), 3.2 (2H, s), 3.4-3.5 (6H, m), 3.6-3.65 (1H, m), 3.9-3.95 (1H, m), 4.5 (3H, s), 7.00-7.2 (8H, m), 7.9 (3H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[CH3:9][O-:10].[Na+]>N1C=CC=CC=1>[O:10]([C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)[C:9]1[CH:7]=[CH:8][CH:1]=[CH:3][CH:4]=1
Reactant: Oc1cccc(O)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Oc1cccc(Oc2ccccc2)c1

Procedure:
To a stirred solution of 49.5 g (0.45 mol) of resorcinol in 75 ml dry pyridine under nitrogen atmosphere, 16.2 g (0.3 mol) of Sodium methoxide was added. Heating started and methanol fractionally distilled off over a period of 0.5 hr. Bromobenzene, 142 g (0.9 mole) was run in to the reaction mixture followed by 2.2 g, of Cuprous chloride. Reaction mixture heated under reflux for 3–4 hr, pyridine distilled off while the pot temperature rose to 150° C. The residue was poured into 50 ml conc. HCl in 120 ml water and stirred. Organic material extracted in 200 ml benzene followed by washing with 25 ml of 20% HCl. Organic layer extracted with 100 ml of 10% NaOH solution followed by a second extraction With 20 ml of 10% NaOH. The combined aqueous extracts were acidified with, HClconc, liberated m-phenoxy phenol was extracted into benzene (300 ml). From the organic layer benzene was removed by distillation. Crude product purified by filtration over a column of silica.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.Cl.[OH:35][NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:39]2[CH2:40][CH:37]([NH:36][OH:35])[CH2:38]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: ONC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(NO)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 45.6 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-hydroxyaminoazetidine hydrochloride, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 3 minutes. After adding 5 ml of diethylether, the mixture was allowed to stand for 1 hour and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 64 mg of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.C[Si]([N:35]=[C:36]=[O:37])(C)C>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([N:4]([CH2:14][C:15]([N:17]1[CH2:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH3:30])[CH2:18]1)=[O:16])[CH2:3][CH2:2][NH:1][C:36]([NH2:35])=[O:37])=[O:13]
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCN)C(=O)c2cccc(Cl)c2)CC1=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1N1CN(C(=O)CN(CCNC(N)=O)C(=O)c2cccc(Cl)c2)CC1=O

Procedure:
A mixture of N-(2-Amino-ethyl)-3-chloro-N-{2-[3-(3-chloro-2-methyl-phenyl)-4-oxo-imidazolidin-1-yl]-2-oxo-ethyl}-benzamide (80 mg, 0.16 mmol, 1 eq), Trimethylsilyl isocyanate (0.027 ml, 0.19 mmol, 1.2 eq), in THF (1 ml) was stirred at room temperature overnight. It was purified with HPLC to give the desired product. LCMS observed for (M+H)+: 492.1
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)=[O:4]
Reactant: Fc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-chloropropionyl chloride (49 ml) in dichloromethane (50 ml) was added to a mixture of anhydrous aluminium trichloride (55.5 g) in dichloromethane (120 ml). The mixture was stirred for 10 minutes at room temperature and then a solution of fluorobenzene (39.5 ml) in dichloromethane (30 ml) was added dropwise. The resulting mixture was stirred for one hour, allowed to stand for 16 hours and then poured on to an icehydrochloric acid mixture. The two phase mixture was vigorously stirred at room temperature for 11/2 hours, separated and the aqueous layer washed with dichloromethane (2×50 ml). The combined organic extracts were then washed with aqueous sodium hydroxide (3N, 2×100 ml), water (1×100 ml) and brine (1×100 ml), dried (MgSO4) and evaporated under reduced pressure to afford 2-chloro-1-(4-fluorophenyl)-1-propanone, 71.3 g.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: COC1(c2ccc(F)c(F)c2)CCNC1
Yield: 97.6 %

Procedure:
Preparation according to Example 1. (−)-1-benzyl-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.264 g, 0.87 mmol), 1,2-dichloroethane (20 ml), 1-chloroethyl chloroformate (0.49 g, 3.48 mmol) refluxed for 1 h, and methanol (20 ml) reflux 1 h Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 50:50) gave the title compound (0.181 g, 97%). [a]D=−6.1° (methanol). MS m/z (rel. intensity, 70 eV) 213 (M+, 1), 198 (51), 183 (88), 171 (bp), 141 (53).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]>O1CCCC1.[Pd]>[NH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Palladium-on-carbon (10% w/w; 0.25 g.) was added to a solution of (C) (1.5 g.) in tetrahydrofuran (50 ml. ) in a hydrogenation bottle. The mixture was hydrogenated at 3.45 bars for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was evaporated. The residual oil was purified by flash chromatography on silica gel (200 ml.) eluting with 1:1 v/v ethyl acetate:hexane, to give methyl 4-(5-aminoindol-3-ylmethyl)-3-methoxybenzoate (A) (1.12 g., 82%) as a viscous oil; NMR: 3.29(br,2H,NH2), 3.88(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 4.03(s,2H, CH2.Ar), 6.64(dd,1H), 6.78(m,2H), 7.10(m,2H), 7.44(m,2H), 7.68(br,1H, H1 -indole).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[C:10]1(=[O:36])[N:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]12.C(N(CC)CC)C>CN(C=O)C>[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]([CH2:16][CH2:15][N:14]1[C:13](=[O:31])[C:12]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:11]2[C:10]1=[O:36])[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])#[N:9]
Reactant: O=C1c2ccccc2C(=O)N1CCNCCN1C(=O)c2ccccc2C1=O
Reactant: N#CCCCCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCCCCN(CCN1C(=O)c2ccccc2C1=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture of 6-bromohexylcyanide (1) (13.88 g, 0.073 mol), bis(2-phthalimidoethyl)amine (2) (26.52 g, 0.073 mol), and triethylamine (7.37 g, 0.073 mol) in DMF (120 ml) was heated at 100° C. for 20 hours.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:5]=1[O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:13]2[CH2:16][CH3:17])=[CH:9][N:8]=1.Br[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>C1COCC1.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:18]([C:12]1[N:13]([CH2:16][CH3:17])[C:14]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([O:6][C:5]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:4]=1[F:3])[N:15]=2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34]
Reactant: CNC(=O)CBr
Reactant: CCn1c(Nc2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(N(CC(=O)NC)c2ccccc2Cl)nc2cnc(Oc3c(F)cccc3F)nc21
Reaction time: 1 h
Yield: 38 %

Procedure:
Sodium hydride (60% in oil, 0.010 g, 0.25 mmol) is added to a solution of [2-(2,6-difluorophenoxy)-9-ethyl-9H-purin-8-yl]-(2-chlorophenyl)-amine, 14, (0.1 g, 0.25 mmol) in THF (3 mL). After 5 minutes at room temperature 2-bromo-N-methyl-acetamide (0.06 mL, 0.37 mmol) is added and stirring is continued for 1 hour. The mixture is diluted with H2O (25 mL) and extracted three times with EtOAc (50 mL). The combined organic layers are washed with brine, dried over MgSO4, concentrated in vacuo and the residue purified by HPLC to afford 45 mg (38% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 7.54-7.59 (m, 2H), 7.15-7.36 (m, 4H), 7.04 (t, J=7.8 Hz, 2H), 4.53 (s, 2H), 3.61 (q, J=7.2 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H); ESI/MS: 473 (M+H).
Reaction SMILES: [OH-].[K+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[OH:14].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>O1CCCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:23])[CH:19]=[C:20]([O:14][C:8]2[C:7]([Cl:6])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:13])[N:21]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Oc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1cc(Oc2c(Cl)cccc2Cl)nc(Cl)n1
Yield: 55.1 %

Procedure:
Potassium hydroxide/ethanol (10%; 0.035 mol) was added to a solution of 2,6-dichlorophenol (0.035 mol) in tetrahydrofuran (100 ml). The mixture was stirred and 2,4,6-trichloropyrimidine (0.044 mol) was added. The mixture was stirred overnight at 60° C. The reaction was quenched with NaOH 1N solution. The aqueous layers were extracted with EtOAc several times and then the organic layers were combined and washed with NaOH 3N and saturated NaCl, dried and concentrated. The residue was recrystallized from CH2Cl2/hexane. The precipitate was filtered off and dried, yielding 5.98 g 2,4-dichloro-6-(2,6-dichlorophenoxy)pyrimidine (55%) (interm. 12). b) Reaction under Argon atmosphere. 2,4,6-trimethylaniline (0.0678 mol) was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100 ml). N,N-di(1-methylethyl)-ethaneamine (0.0830 mol) was added. The reaction mixture was stirred and refluxed for 4 days and the solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution, then dried (Na2SO4), filtered and the solvent was evaporated to give 17.1 g solid residue. This solid was dissolved in CH2Cl2:hexane (1:1; 150 ml), and the resulting solution was concentrated to 100 ml, then filtered. The residue was purified by column chromatography on KP-Sil (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated. The less polar fraction was stirred in CH2Cl2 for 3 hours and filtered, yielding 0.44 g 4-chloro-N-(2,4,6-tri-methylphenyl)-2-pyrimidinamine (intermediate 48). A second fraction was recrystallized from acetonitrile, filtered off and dried, yielding 2-chloro-1V-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine (intermediate 49).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].Br[CH2:11][CH2:12][CH2:13]Cl.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[CH3:16]
Reactant: ClCCCBr
Reactant: CCNCC
Reactant: N#Cc1ccccc1O
Product: CCN(CC)CCCOc1ccccc1C#N
Yield: 95 %

Procedure:
According to a similar manner as that in Reference Example 36 except that 2-cyanophenol, 1-bromo-3-chloropropane, and diethylamine were used, 2-[3-(diethylamino)propoxy]benzonitrile (95%) was obtained as a crude product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[C:13]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:40]([CH3:39])(=[O:42])=[O:41])[C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2c(Cl)cc(Cl)cc2Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 4.0 g of 1-[(4-butylphenyl)methyl]-1-(6-hydroxyhexyl)-3-(2,4,6-trichlorophenyl)urea and 2.6 ml of triethylamine in 90 ml of dichloromethane was added dropwise a solution of 0.8 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was allowed to come to room temperature and was stirred for 16 hours. The procedure of Example 515 was continued and gave 4.5 g of the desired product as a light yellow oil in 97% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.I[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>>[Br:1][C:2]1[C:3]([O:16][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Product: COC(=O)c1ccc(Oc2cc3c(cc2Br)C(C)(C)CCC3(C)C)cc1

Procedure:
In the manner similar to Example 1(a), by the reaction of 1 g (3.5 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol with 770 mg (2.94 mmol) of methyl 4-iodobenzoate, 700 mg (58%) of the expected methyl ester of melting point 135-6° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=4[CH3:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: Cc1ccc(C)c(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,5-dimethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (56% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.16-7.11, 7.03-6.97, 4.12-3.67, 2.23, 2.22, 1.52, 0.82-0.69, 0.48-0.42, 0.11-0.05. MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[F:17])[CH:12]=O.[C:18]1(=O)[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1>C(O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]2[C:3]3[C:4](=[O:7])[NH:5][NH:6][C:2]=3[NH:1][C:18]3[CH2:22][CH2:21][C:20](=[O:23])[C:19]2=3)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Nc1cc(=O)[nH][nH]1
Solvent: CCO
Product: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)c1c([nH][nH]c1=O)N2
Yield: 22.9 %

Procedure:
5-Amino-1,2-dihydropyrazol-3-one (0.15 g, 1.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.31 g, 1.5 mmol), and 1,3-cyclopentanedione (0.15 g, 1.5 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate:formic acid:water (18:1:1) to provide 0.125 g of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.22 (t, 2H), 2.61 (m, 2H), 4.73 (s,1H), 7.15 (m, 1H), 7.2 (m, 1H), 7.4 (dd, 1H), 9.75 (s, 1H), 10.21 (s, 1H), 11.3 (bs, 1H); MS (ESI) m/z 362 (M−H)−; Anal. calcd for C15H, N3BrFO2.0.5H2O: C, 48.28; H, 3.24; N, 11.26Found: C, 48.88; H, 3.29; N, 10.83.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[C:14]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:23])=[CH:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OC(=O)Nc2cc(Cl)c(O)cc21
Reactant: O=S(CCCCBr)c1ccccc1
Product: CC1(C)OC(=O)Nc2cc(Cl)c(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinyl-butylbromide.