Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Cl:2][C:3]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([Cl:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:23](O)[CH2:24][OH:25].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:17][C:16]1[C:12]([C:8]2[CH:7]=[C:4]([CH:5]3[O:25][CH2:24][CH2:23][O:6]3)[C:3]([Cl:2])=[CH:10][C:9]=2[F:11])=[N:13][N:14]([CH3:22])[C:15]=1[C:18]([F:21])([F:20])[F:19]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-c2cc(C3OCCO3)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Yield: 61.2 %

Procedure:
In an apparatus equipped with a Dean-Stark trap for azeotropic removal of water, 2.4 g (7.0 mmoles) 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzaldehyde, 0.4 mL (7.7 mmoles) ethylene glycol and a catalytic amount of P-toluenesulfonic acid in 50 mL toluene was heated to reflux for 24 hours. The resultant mixture was concentrated and the residue purified by chromatography to give 1.65 g (61%) of 4-chloro-3-(4-chloro-5-(1,3-dioxolan-2-yl)-2-fluorophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole as a clear colorless oil; nD25 1.5348.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=O)[CH2:10][C:11]([O:13]C)=[O:12].[N:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])=[N+:17]=[N-:18]>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[N:17]=[N:18][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1N=[N+]=[N-]
Reactant: COCCCCC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A solution of sodium hydride (60% in oil, 280 mg) in DMF (10 ml) was cooled to 0° C.-5° C., methyl 7-methoxy-3-oxoheptanoate (1.32 g) was added, and the mixture was stirred at 0° C.-5° C. for 30 min. Then, 1-azido-2-methylbenzene (932 mg) was added, and the mixture was stirred at room temperature for 15 hr. The solvent was concentrated under reduced pressure, methanol (10 ml) was added to the residue, and 4N aqueous sodium hydroxide solution (5 ml) was added and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue. 6N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (20 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (930 mg) as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: CCCCCCCCO
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOC(=O)CBr
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Bromoacetyl bromide (20 g, 99.1 mmol) was added to a solution of 1-octanol (12.9 g, 99.1 mmol) and 10 ml of pyridine in 100 ml of methylene chloride at 0° C. After 10 minutes, the mixture was quenched with 100 ml of ice/water, and the aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with 1N HCl (3×100ml) and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the product was distilled under high vacuum to afford 6 g of 1-octyl bromoacetate as an oil, b.p. 93° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>O=S(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc—hexanes) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.Cl[CH2:16][C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[O:19][N:18]=1>>[CH3:1][C:2]1[N:3]([CH2:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)[O:19][N:18]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Product: Cc1cc2c(C(F)(F)F)cccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.64 (m, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 6.52 (s, 1H), 5.45 (s, 2H), 2.66 (s, 3H); MS (ES) m/z 426 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][NH:29][CH3:30].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl.O>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][N:29]([CH3:30])[C:11](=[O:13])[C:10]1[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Yield: 84 %

Procedure:
A mixture of 46 mg (0.15 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acid, 43 mg (0.17 mmol) (3,5-bis-trifluoromethyl-benzyl)-methylamine, 32 mg (0.17 mmol) 1-(3-diaminopropyl)-3-ethyl-carbodiimide hydrochloride and a catalytic amount of 4-(N,N-dimethylamino)-pyridine in 3 ml dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with water, adjusted to pH 6 with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. Flash column chromatography afforded 68 mg (83%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH:13][CH3:14]>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CNC
Product: Cc1c(O)cccc1C(=O)N(C)C
Yield: 42 %

Procedure:
The title compound was prepared from 3-hydroxy-2-methylbenzoic acid and dimethylamine, using the same method as that described for preparation 75, as a solid in 42% yield. 1H NMR(400 MHz, CDCl3) δ: 1.95(s, 3H), 2.70(s, 3H), 2.95(s, 3H), 6.55(d, 1H), 6.80 (d, 1H), 7.00(m, 1H), 9.50(s, 1H); LRMS APCI m/z 180 [M+H]+
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: N#CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 67.5 %

Procedure:
Potassium cyanide (2.6 g) was added to a stirred, two-phase mixture of 4-(chloromethyl)biphenyl (2.02 g) and tetrabutyl ammonium hydrogen sulphate (200 mg) in dichloromethane (50 ml). The reaction mixture was stirred at ambient temperature for 36 hours. The organic layer was separated and washed with water (10 ml), dried (MgSO4) and evaporated to give a solid residue which was crystallised from n-hexane to give 4-(cyanomethyl)biphenyl (1.3 g) as a solid, m.p. 95° C.; microanalysis, found: C, 86.3; H, 5.7; N, 7.2%; C14H11N .0.1H2O requires C, 86.2; H, 5.7; N, 7.18%.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([CH3:10])[C:7](O)=[O:8])(=[O:4])=[O:3].[CH3:11][N:12]1[CH2:16][C@@H:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:14][C:13]1=[O:24]>>[CH3:11][N:12]1[CH2:16][C@@H:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[N:14]([C:7](=[O:8])[C@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:10])[C:13]1=[O:24]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Reactant: C[C@@H](OS(C)(=O)=O)C(=O)O
Product: C[C@@H](OS(C)(=O)=O)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
D-lactic acid O-mesylate, namely (2R)-2-(methanesulfonyloxy)propionic acid (2.5 g) and t-butyl (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate (3.42 g) were treated similarly as in Example 1 - (1), and the crude product was purified by silica gel chromatography (chloroform:ethyl acetate=1:2) and crystallized from n-hexane to give t-butyl (4S)-1-methyl-3-[(2R)-2-(methanesulfonyloxy)-propionyl]-2-oxoimidazolidine-4carboxylate (3.95 g). Yield: 75.8%., m.p.: 97°-100° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH:18]([CH3:20])[CH3:19])[CH:6]=[O:7])[CH3:2]
Reactant: CC(C)I
Reactant: CCc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the 3-ethyl-4-hydroxy-benzaldehyde (7.8 g, 51.9 mmol) obtained in Example 179.1, K2CO3 (10.8 g, 78 mmol) and isopropyl iodide (7.86 ml, 78 mmol) was heated in DMF (65 ml) for 3 h. to 80° C. and subsequently stirred for 12 h. at room temperature. The mixture was poured into ice-cold 0.5M HCl and extracted with diethyl ether. The organic phase was washed with NaCl solution, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 4:1). 3-Ethyl-4-isopropoxy-benzaldehyde was obtained as an orange oil (6.12 g, 61%); MS: 192 ([M]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[NH2:16][CH2:17][CH2:18][CH:19]1[CH2:23][C:22]2[C:24]([CH3:38])=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]=2[O:20]1.Cl>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:31]([O:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:21]2[O:20][CH:19]([CH2:18][CH2:17][NH:16][C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=3)[CH2:23][C:22]=2[C:24]=1[CH3:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN)O2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)NCCC2Cc3c(C)c(OCc4ccccc4)c(C)c(C)c3O2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.86 g of 3,4,5-trimethoxybenzoyl chloride in 35 ml of chloroform is slowly added to a 3.85 g solution of 2-(RS)-(2-aminoethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-benzofurane in 35 ml of chloroform and 2.0 ml of triethylamine. After stirring for one hour at room temperature, 1 M hydrochloric acid is added and the organic phase is separated and washed in a sodium bicarbonate solution, dried and evaporated. 4.42 g of--a white solid are obtained that is purified by crystallization from ethanol/ethyl acetate. m.p. 171°-173° C. IR(KBr): 3271 (νN--H), 1684, 1545 cm-1 (νCONH); 1H-NMR (CDCl3): δ7.4-7.2 (5H,m), 7.0 (2H,s), 6.8 (1H,t), 5.1-4.7 (1H,m), 4.7 (2H,s), 3.8 (9H,s), 3.8-3.4 (2H,m), 3.2-2.7 (2H,m), 2.2 (6H,s), 2.1 (3H,s), 2.1-1.8 (2H,m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)CC)C.[N:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[CH2:61][NH2:62]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([NH:62][CH2:61][C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][N:55]=4)=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NCc1ccccn1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reaction time: 0.25 h
Yield: 49.3 %

Procedure:
Lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (0.060 g, 0.17 mmol) was dissolved in dry DMF (1.7 mL), and then TSTU (0.064 g, 0.21 mmol) was added followed by triethylamine (0.059 mL, 0.43 mmol). The reaction was stirred for 15 min then 2-picolylamine (0.019 mL, 0.19 mmol) was added. The reaction was stirred at room temperature under argon over night. The crude product was purified by preparative LC. The fractions were combined and the acetonitrile was evaporated. DCM was added and the layers separated. The aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated to give 37 mg (49%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[C:5]([Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cncc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)c1ncc(Br)cc1CO
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-3-ylmethanol (Chem. Pharm. Bull. 1990, 38, 2446) (29 g, 154 mmoL) and tert-butylchlorodiphenylsilane (47.5 g, 173 mmoL) in CH2Cl2 (500 mL) at r.t., there was added imidazole (15.8 g, 232 mmoL). The mixture was stirred for 1 hr. and filtered. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with a 1:7 mixture of EtOAc and hexane, to afford the product as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[N+](=C)=[N-]>C1COCC1.CCOCC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][C:14]=1[C:6]([O:5][CH3:1])=[O:7])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: C=[N+]=[N-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 3 h
Yield: 159.4 %

Procedure:
4-t-butoxycarbonylaminobenzotrifluoride (3.90 g) was dissolved in THF. At −50° C., t-butyl lithium (30 ml) was added dropwise thereto. The mixture was stirred for 3 hours with keeping at −50° C. Carbon dioxide gas was bubbled into this mixture under stirring (the temperature increased to about −30° C.). The solvent was distilled out. The back-extractraction of the residue with 2N NaOH-ether mixture solution was carried out. The aqueous layer was acidified by adding 2N HCl, extracted with ether, washed and dried over. In addition, the layer containing ether was washed, dried over, filtered and concentrated after combining the said layer containing ether to give the crude compound. Such crude compound was dissolved in ether. A solution of diazomethane in ether was added thereto until the reaction solution became yellow. The reaction solution was concentrated and purified on silica gel column chromatography (hexane:AcOEt=20:1→10:1) to give the title compound (3.80 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:29]([NH:33][CH3:34])[CH:30]([CH3:32])[CH3:31]>C1COCC1>[CH2:29]([N:33]([CH3:34])[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: O=C(O)c1cccc(-c2cc(-c3ccc(Cl)nc3)on2)c1
Reactant: CNCC(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CN(C)c1ccc(-c2cc(-c3cccc(C(=O)O)c3)no2)cn1
Temperature: 120 °C
Reaction time: 60 h

Procedure:
In a pressure tube, 200 mg (0.64 mmol) of 3-[5-(6-chloro-pyridin-3-yl)-isoxazol-3-yl]-benzoic acid, 97 mg (0.96 mmol, 1.5 eq.) of triethyl amine and 166 mg (1.9 mmol, 3.0 eq.) of isobutyl-methyl-amine are dissolved in 3 ml of THF. The reaction mixture is heated to 120° C. and after 6 h to 150° C. After 60 h, the mixture is cooled to room temperature and the solvent is removed. After addition of 10 ml of water, the pH is adjusted to 2 and the precipitate filtered off. The solid is then dissolved in 10 ml of methanol and 5 ml of dichloroethane, precipitated through addition of 10 ml of hexane and filtered. Recrystallisation from 15 ml of dichloromethane and 1 ml of methanol yields the title compound as a white solid. Mass spectrum: m/z (M+H)+: 352.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16]S(C)(=O)=O)[CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:10][CH:11]=[C:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Yield: 69.6 %

Procedure:
5-(4-fluorophenyl)-4-benzyloxy-2-mesyloxyethylbenzene (2.5 g, 6.24 mmol) was dissolved in methanol (80 mL). To this was added sodium hydroxide (300 mg, 7.5 mmol) dissolved in water (20 mL). The solution was heated to reflux and heating maintained for 24 hours, when an additional equivalent of sodium hydroxide was added, and reflux maintained for an additional 16 hours. The mixture was cooled, acidified with 1N HCl, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford an orange solid which was triturated with hexane to yield 5-(4-fluorophenyl)-4-benzyloxy-2-hydroxyethylbenzene (1.4 g) as an off-white powder. NMR (DMSO-d6): 1.11, t, (3H); 2.50, q (2H); 3.34, s (3H); 5.02, s (2H); 6.60, d (1H); 6.98, s (1H); 7.16, t (2H); 7.35, m (5H); 7.50, dd (2H); 9.44, s (1H). Mass Spec 5 (GCMS) 322 (M).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 116.1 %

Procedure:
A solution of THF (3 mL) containing 5-fluoro-6-methoxypyridin-3-amine (87 mg, 0.613 mmol) (Anichem) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 52; 182 mg, 0.409 mmol) was cooled to 0° C. in an ice bath and treated dropwise with 1 M LiHMDS (1.226 mL, 1.226 mmol). The solution was stirred at this temperature for 1.5 h and quenched with a saturated solution of NH4Cl. The product was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give crude 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (269.7 mg, 0.475 mmol) as a bright yellow amorphous solid which was used in the next step without further purification. m/z (ESI, +ve ion) 568.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.94 (1H, s); 8.82 (1H, dd, J=7.8, 2.0 Hz); 8.29 (1H, dd, J=4.8, 2.1 Hz); 8.05 (1H, dd, J=12.3, 2.2 Hz); 7.97 (1H, d, J=2.3 Hz); 7.20 (4H, dd, J=10.6, 8.6 Hz); 6.86 (4H, t, J=9.0 Hz); 6.78 (1H, dd, J=7.8, 4.7 Hz); 4.84 (2H, br. s.); 4.83 (2H, br. s.); 4.01 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.58 (3H, s).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17].[Na]>O>[C:1]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1ccccc1
Reaction time: 3.25 h
Yield: 61.6 %

Procedure:
A solution of 70.29 grams (0.50 mol) of benzoyl chloride in 500 milliters of methylene chloride was added to a solution of 44.57 grams (0.50 mol) of 2-dimethylaminoethanol, 20.0 grams (0.50 mol) of sodium hydroxideand 500 milliters of water over 15 minutes with rapid stirring. Stirring was continued for 3.25 hours after which the organic layer was separated, washed with water, dried over MgSO4 and concentrated. Distillation of the residue gave 59.5 grams of product; bp=102°-108° C./0.50 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:49])[CH2:8][CH2:9][CH2:10][C:11]1(O)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][O:14][C:13]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][C:12]1=2>N1C=CC=CC=1>[CH3:49][N:7]([CH3:6])[CH2:8][CH2:9][CH:10]=[C:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][O:14][C:13]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:25][C:12]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCC=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
In this process, 1.2 g of 11-(3-dimethylaminopropyl)-11-hydroxy-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is dropwise added 0.8 g of phosphorusoxychloride under a nitrogen atmosphere and ice-cooling. After stirring the mixture at room temperature for one hour, the solvent is distilled away under reduced pressure. The residue is extracted with 100 ml of methylene chloride, and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the mixture over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethylacetate:triethylamine=10:10:1 ) to obtain 0.82 g of the desired product as a colorless oily matter.