Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[CH3:6])=[O:4].[CH2:22]([NH2:25])[CH2:23][NH2:24].C(N(CC)CC)C>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:7]2[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][N:24]3[CH2:23][CH2:22][NH:25][C:9]3([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH:17]=1
Reactant: NCCN
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1C(=O)CN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 6.4 g. (20 mmole) of 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone, 12.0 g. (0.2 mole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to a residue which was partitioned between ether and water. The ether layer was washed with water, dried and concentrated to a small amount of liquid which was treated with a small amount of ethanol to give upon standing the above-titled product as colorless crystals, m.p. 164°-167°.
Reaction SMILES: BrC[CH2:3][O:4][CH3:5].[CH:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH3:3][O:4][CH2:5][C:6]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C1CCCCC1
Reactant: COCCBr
Product: COCC1(C(=O)OC)CCCCC1

Procedure:
The title compound was prepared by substituting bromomethylmethyl ether for 1-bromo-2-methoxyethane and methyl cyclohexanecarboxylate for EXAMPLE 134A in EXAMPLE 134B.
Reaction SMILES: N[C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8]C2C=C(C3SC=CC=3)C=CC=2N(CC(NC)=O)C(=O)OC(C)(C)C)=[O:7])=[CH:4][CH:3]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O.CCOC(C)=O>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:33]=[CH:34][CH:2]=[CH:3][CH:4]=1
Reactant: CNC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccccc1

Procedure:
tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl][2-(methylamino)-2-oxoethyl]carbamate was dissolved in 1:1 TFA:CH2Cl2 and stirred at room temperature for 1 hour. The crude reaction was diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired 4-amino-N-[2-{[2-methylamino)-2-oxoethyl]amino}-5-(2-thienyl)phenyl]benzamide: 1H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.27 (d, J=4.5 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H), 7.83 (d, J=8.6 Hz, 2H), 7.54 (d, J=3.4 Hz, 1H), 7.37 (dd, J=8.2, 2.1 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.12 (dd, J=5.0, 3.7 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 5.73 (s, 2H), 4.62 (d, J=16.8 Hz, 1H), 3.80 (d, J=16.9 Hz, 1H), 2.64 (d, J=4.5 Hz, 3H), 1.05 (s, 9H); MS: cal'd 381.1 (MH+), exp 381.1 (MH+).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].[F-].[K+].[OH-].[Na+]>CN(C=O)C>[Br:14][C:15]1[CH:22]=[C:21]([CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])[O:23][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: O=Cc1ccc(O)cc1Br
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(C=O)c(Br)c1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
2-Fluoro-4-trifluoromethyl-benzonitrile (3.1 g, 20 mmol), 2-bromo-4-hydroxybenzaldehyde (4 g, 20 mmol) and potassium fluoride-(3.47 g, 60 mmol) were heated with stirring in dry DMF (20 mL) at 120° C. for 4 h, 80° C. for 16 h, 120° C. for 4 h, 130° C. for 1 h, and then at 140° C. for 16 h. The reaction mixture was cooled, poured onto 1N sodium hydroxide, extracted with ethyl acetate, and then dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-bromo-4-formyl-phenoxy)-4-trifluoromethyl-benzonitrile (6.38 g, 96%) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]#[N:10])[CH:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][S:19]([NH2:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[C:9]([C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19]([NH2:22])(=[O:20])=[O:21])=[CH:14][CH:13]=2)[CH:3]=1)#[N:10]
Reactant: Cc1nc(Cl)cc(C#N)n1
Reactant: NS(=O)(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C#N)cc(Oc2ccc(CS(N)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.2 %

Procedure:
Dissolve 6-chloro-2-methylpyrimidine-4-carbonitrile (628 mg, 4.1 mmol) in DMF (15 mL) at RT under a nitrogen atmosphere. Add (4-hydroxyphenyl)methanesulfonamide (859 mg, 4.1 mmol) and potassium carbonate (1.13 g, 8.2 mmol) to the solution. Stir at ambient temperature for 3 hours. Pour the mixture into a brine solution, and extract with EtOAc. Combine the extracts; dry over magnesium sulfate; filter; and concentrate the filtrate under reduced pressure to provide the title compound (80% pure, 1.5 g, 96.4%). MS (m/z): 305 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:5][CH3:6])[CH2:3][CH3:4].CN(C)C1C=CC=CC=1.[Br:17][CH2:18][C:19](Br)=[O:20].O>ClCCl>[Br:17][CH2:18][C:19]([O:7][C:2]([CH2:5][CH3:6])([CH3:1])[CH2:3][CH3:4])=[O:20]
Reactant: O=C(Br)CBr
Reactant: CCC(C)(O)CC
Solvent: ClCCl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: CCC(C)(CC)OC(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 3-methyl-3-pentanol (10.6 g, 103 mmol) in dichloromethane (49 ml), N,N-dimethylaniline (15.0 g, 124 mmol) and bromoacetyl bromide (25.0 g, 124 mmol) were added and stirred at room temperature for 2 hours under a nitrogen stream. The reaction mixture was poured into water, extracted with tert-butyl methyl ether, washed sequentially with saturated aqueous potassium bisulfate and saturated aqueous sodium bicarbonate, and then dried over sodium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by vacuum distillation (5 mmHg, 71° C. to 72° C.) to give the titled compound (20.4 g, 89%) as a colorless oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH:13]1[CH:14]=[CH:15][N:16]=[C:17]([NH:19][S:20]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:18]=1>>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([NH:19][C:17]3[CH:18]=[CH:13][CH:14]=[CH:15][N:16]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2/C1=C/Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one and sulfapyridine. Electrospray MS 393 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CNCc1ccccc1
Reactant: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Solvent: CN(C)C=O
Product: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CN(C)Cc3ccccc3)c2c1=O
Reaction time: 1 h
Yield: 92 %

Procedure:
The compound (1.04 g, 1.8 mmol) obtained in Example 18 was dissolved in dimethylformamide (70 ml). To the solution was added diisopropylaminoethyl(1.15 g, 8.9 mmol) and N-methylbenzylamine (0.54 g, 4.5 mmol) at room temperature, and the mixture was further stirred for one hour. The reaction mixture was concentrated to dryness, and the residue was partitioned between ethyl acetate (300 ml) and water. The aqueous layer was extracted with ethyl acetate (100 ml), the extracts were combined, washed with an aqueous sodium chloride solution, dried with Na2 SO4, and the solvent was distilled off. Thus obtained residue was purified by silica gel column chromatography to give a solid form (1.09 g), and recrystallization from dichloromethane-ether-n-hexane gave pale yellow crystals (1.03 g, 93%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(=O)c2ccccc2C(=O)O)c1

Procedure:
Monomers. The spirobislactone endcapping group, 4-carboxy-7,7'-dioxa-2,2'-spirobi (benzo[c]tetrahydrofuran) 5,was synthesized using a three-step procedure. Phthalic anhydride (PA) 1 was reacted with p-xylene 2 in the presence of AlCl3 to produce ##STR6## 2,5-dimethyl-2'-carboxybenzophenone 3. Oxidation by potassium permanganate yielded the triacid 4 which was cyclized to 5 by refluxing with Dowex 50X8-100 resin (H+) in 2-methoxyethyl ether and removing the water of reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:26]OC(OC)N(C)C.CO.Cl>C1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:25])=[C:22]([OH:24])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(O)c(F)cc2c1=O
Yield: 38.9 %

Procedure:
In 2 ml of benzene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and 87 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 10 hours. Thereafter the crystals thus deposited were collected by filtration. To the crystals thus obtained were added 0.5 ml of methanol and 1 ml of water, and the pH thereof was adjusted to 1.0 with 2N hydrochloric acid, after which the crystals thus deposited were collected by filtration to obtain 80 mg (yield 38.9%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 243°-248° C.
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCCC2)c2cccc(O)c2)cc1
Yield: 90.8 %

Procedure:
To a cold (5° C.) solution of 1,1-dimethylethyl (2E)-3-{4-[cycloheptylidene(3-hydroxyphenyl)methyl]phenyl}-2-propenoate (194) (0.200 g, 0.49 mmol) in CH2Cl2 (8 mL) was added TFA (2 mL). The resultant mixture was stirred for 3 h at RT. The reaction mixture was concentrated under reduced pressure and the crude product. purified by silica gel chromatography using n-hexanes:EtOAc (4:1 to 3:2) as an eluent to afford 0.155 g (90%) of compound 195 as an off-white foam. 1H NMR (300 MHz, CD3OD): δ 7.65 (d, J=15.9 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.21 (d, J=7.8 Hz, 2H), 7.10 (app t, J=7.5 Hz, 1H), 6.32 (br d, J=8.7 Hz, 3H), 6.45 (d, J=15.9 Hz, 1H), 2.33 (br s, 4H), 1.61 (br s, 8H). LCMS (ESI): m/z 347 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([Cl:19])=[N:14][C:15]([Br:18])=[CH:16][CH:17]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([Cl:19])=[N:14][C:15]([Br:18])=[CH:16][CH:17]=1)[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(COCc1ccccc1)c1ccc(Br)nc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(COCc1ccccc1)c1ccc(Br)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a solution of 2-(benzyloxy)-1-(6-bromo-2-chloropyridin-3-yl)ethanol (1.54 g, 4.49 mmol) in DCM (10 mL) at 0° C. was added diethylaminosulfur trifluoride (0.594 ml, 4.49 mmol). The resulting mixture was stirred at 0° C. for 30 min, then warmed to RT and stirred for 1 h. The mixture was concentrated in vacuo and the resulting residue purified using column chromatography (eluted with 0-20% ethyl acetate/hexane) to provide 3-(2-(benzyloxy)-1-fluoroethyl)-6-bromo-2-chloropyridine (490 mg, yield: 32%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][C@@H:8]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:9][C@H](C1C=CC=CC=1)C)C.C([O-])=O.[NH4+]>CO.[Pd]>[CH:18]1([C@H:8]2[NH:9][C:4](=[O:3])[CH2:5][CH2:6][CH2:7]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)CCC[C@H](N[C@@H](C)c1ccccc1)C1CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CCC[C@@H](C2CCCCC2)N1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of (S)-5-Cyclohexyl-5-((S)-1-phenyl-ethylamino)-pentanoic acid ethyl ester (2.0 g, 6.0 mmol, 1.0 equiv) in MeOH (60 mL) was added Pd (1.6 g, 10% on carbon, 1.51 mmol, 0.25 equiv) and ammonium formate (3.8 g, 60.3 mmol, 10.0 equiv). The mixture was heated to reflux for 2 hours. The solution was then cooled at room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography, acetone/heptane 50% to give product 1.05 g (96% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([CH2:7][C:8]([O-:10])=[O:9])[C:4](=[O:11])[NH:3]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18]N1C(=O)C(=O)N(CC(O)=O)C1=S)([O-:14])=[O:13].Cl>C(O)(=O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:3]1[C:2](=[O:1])[CH2:6][N:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]1=[O:11])([O-:14])=[O:13]
Reactant: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Reactant: O=C([O-])CN1CC(=O)NC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1CC(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=O

Procedure:
The above-prepared dioxoimidazolidine-1-acetate product of paragraph (2) from several production runs (1.7 g) was heated to reflux in a mixed solvent of 12 mL of acetic acid and 4 mL of concentrated hydrochloric acid for one hour. After evaporating the solvent therefrom, 12 mL of acetic acid and 4 mL of concentrated hydrochloric acid were added to the residue and the mixture was heated to reflux for one hour more. The refluxed mixture was poured over a mixed solution of ethyl acetate and 10% sodium hydroxide, the mixture was extracted with 10% sodium hydroxide several times and the resulting aqueous extract was subjected to a reverse extraction several times. The extracts were combined, dried over sodium sulfate, concentrated and recrystallized from ethanol to give 350 mg of 3-(3-nitrobenzyl)-2,4-dioxoimidazolidine-1-acetic acid [Compound 6]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5](F)[CH:4]=1.[Cl:14]C1C=C(C=CC=1F)C=O>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:5]([Cl:14])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1F
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: CS(=O)(=O)c1ccc(CBr)cc1Cl

Procedure:
The titled compound is prepared analogously to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 3-chloro-4-fluorobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[F:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=[O:47])=[CH:44][C:43]=1Br>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:43]5[CH:44]=[C:45]([CH:48]=[CH:49][C:42]=5[F:41])[CH:46]=[O:47])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cc(C=O)ccc3F)cn2)cc1

Procedure:
In the same manner as Step A in Example 1-D-26, using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg) and 4-fluoro-3-bromo-benzaldehyde (113 mg) instead of 2-(4-bromo-phenyl)-[1,3]dioxolane, a crude product of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde was obtained as a colorless solid (260 mg). Using a crude product (130 mg) of 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-4-fluoro-benzaldehyde, in the same manner as Step B in Example 1-D-26, using 1-ethylpiperazine (0.05 ml) instead of 1-methylpiperazine, a crude product of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained as a colorless solid (57 mg). Using a crude product (57 mg) of 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-{7-[5-(4-ethyl-piperazin-1-ylmethyl)-2-fluoro-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-ylamine was obtained as a colorless powder (26 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:24])[S:12][C:13]=2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([NH:24][C:11]1[S:12][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1)=[O:31]
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 60.8 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 6 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 60.8%, mp: 106-108└. 1H-NMR (CDCl3, 400 MHz) δ: 3.83 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.97 (3H, s, OCH3), 4.33 (2H, s, CH2), 6.85˜6.89 (3H, m, ArH), 7.37˜7.45 (6H, m, ArH), 8.18 (2H, t, J=8.68 Hz, ArH), 10.48 (1H, br, CONH, exchangable); EI-MS m/e (%): 505.0 (M+, 54), 165.0 (100); HREI-MS Calcd. for C26H23N3O6S: 505.1308. found: 505.1315. Anal. Calcd. for C26H23N3O6S: C, 61.77; H, 4.59; N, 8.31. found: C, 61.90; H, 4.70; N, 8.05.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH:3]([OH:22])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.[S:25](Cl)([CH3:28])(=[O:27])=[O:26].C(N(CC)CC)C.C1COCC1>O>[F:24][C:2]([F:1])([F:23])[CH:3]([O:22][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:4][O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(OCC(O)C(F)(F)F)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OC(COC1CCN(C(=O)OCc2ccccc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of benzyl 4-(3,3,3-trifluoro-2-hydroxypropoxy)piperidine-1-carboxylate (983 mg), mesyl chloride (0.438 mL), triethylamine (0.789 mL) and THF (10 mL) was stirred at 0° C. for 1 hr, and then at room temperature overnight. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.12 g).
Reaction SMILES: [CH:1]([C:3]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C1(=O)CCCCCCCCCCC1>>[C:3]1(=[O:15])[CH2:1][CH2:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: C=CC1(O)CCCCCCCCCCC1
Agent: O=C1CCCCCCCCCCC1
Product: O=C1CCCCCCCCCCCCC1
Yield: 71.9 %

Procedure:
5 g (23.8 mmol) of 1-vinylcyclododecanol, quartz reactor 25/400 mm, temperature 660° C.±10, vaporization at 125-135° C. (airbath temperature) in about 30 min. Nitrogen stream about 1-2 l/h, vacuum 4-6 mbar. The oily condensate began to crystallize in the cool trap already. 4.4 g (88% crude yield) of a wax-like solid were obtained which, according to GC and GC/MS analyses, comprises as well as 80-85% of the main component also up to about 5% cyclododecanone and about 5-10% other components which, according to the molecular masses found, are dehydrogenation products. Recrystallization twice from hexane at 0° and −20° C., gave 3.6 g (72%) of cyclotetradecanone (GC purity>98%) as colorless needles with a melting point of 56° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][N:4]=1)#[N:2].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][N:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C(=O)O)cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
6-Cyano-nicotinic acid (120 mg, 810 μmol) was suspended in toluene (1 mL) and thionyl chloride (119 μL, 1.62 mmol) was added dropwise followed by one drop of DMF. The reaction mixture was refluxed for 2.5 hours and then allowed to cool to room temperature for 18 hours. The solvents were removed in vacuo and the residue was azeotroped with toluene to furnish the title compound as a brown oil (134 mg) which was used in further experiments without purification.