Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:1][C:2]2[C:3]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: COC(=O)COc1nc(OC)ccc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-hydroxy-6-methoxy-2-(methoxycarbonyl)methoxypyridine, 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and N,N-dimethylformamide is added potassium carbonate, and the mixture is stirred for 2 hours at 70° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[CH3:17][NH:18][CH3:19]>C(N(CC)CC)C>[CH3:17][N:18]([CH3:19])[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:11][CH3:12])[CH3:10])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:16])[N:3]=1
Reactant: CCC(C)Nc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: CNC
Solvent: CCN(CC)CC
Product: CCC(C)Nc1nc(N(C)C)nc(C)c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 98.4 %

Procedure:
10 ml of triethylamine are added to a solution of 15.9 g of 2-chloro-4-sec. butylamino-5-nitro-6-methylpyrimidine (0.065 mole) in 250 ml of alcohol. Then 4.5 g (0.1 mole) of dimethylamine are passed in and the mixture is boiled for 4 hours at 100° C. After it has cooled, the mixture is evaporated and the residue is suspended in water. The resultant precipitate is filtered off with suction and washed with water until no more chlorine ions are dissolved out. The product is dried in a water jet vacuum at 50° C to yield 16.2 g of 2-dimethylamino-4-sec. butylamino-5-nitro-6-methylpyrimidine (=98.5% yield) of m.p. 98°-100° C. On recrystallisation from petroleum ether, the melting point of the product rises to 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[N:21]=[CH:22][N:23]=[CH:24][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[CH:24]=[N:23][CH:22]=[N:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cncnc21
Product: CC1c2ncncc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: O=C(Cl)c1cccs1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3cccs3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-thiophene carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.28-1.37 (m, 2H) 2.26 (t, J=7.20 Hz, 2H) 6.80 (s, 1H) 7.27 (t, J=4.29 Hz, 1H) 7.63 (t, J=7.58 Hz, 1H) 7.75 (d, J=8.34 Hz, 2H) 7.86 (t, J=7.58 Hz, 1H) 7.92 (d, J=5.05 Hz, 2H) 8.05 (d, J=8.59 Hz, 2H) 8.08 (d, J=3.79 Hz, 1H) 8.15 (d, J=8.08 Hz, 1H) 10.56 (s, 1H); ESI-MS: m/z calc'd for C26H22N4O2S2 486.61. found 487.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[S:20][CH2:19][CH2:18][CH2:17][CH2:16][S:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:15]1[CH2:16][CH2:17][CH2:18][CH2:19][S:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1SCCCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1SCCCCS1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl1,3-dithiepane (36.5 grams), potassium carbonate (34 grams) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dithiepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([S:21][CH:22]([C:26](O)=[O:27])[C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([S:21][C:22]2[C:23](=[O:24])[O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:26]=2[OH:27])[CH:18]=[CH:19][CH:20]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(O)C(Sc1cccc(Cl)c1)C(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1cccc(Cl)c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(3-chlorophenyl)thio]propanedioic acid (1.53 g, 5.07 mmol). m.p.181-182° C.; 1H NMR (400 MHz, DMSO-d6) δ6.88 (s, 1H), 7.13 (dt, 2H), 7.19 (dt, 1H), 7.29 (t, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[CH:20][S:19][C:18]=12.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24].[Cl-].[NH4+]>C1COCC1>[CH3:12][S:13][C:14]1[N:15]=[CH:16][N:17]2[CH:21]=[C:20]([Si:23]([CH3:25])([CH3:24])[CH3:22])[S:19][C:18]=12
Reactant: C[Si](C)(C)Cl
Reactant: CSc1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ncn2cc([Si](C)(C)C)sc12
Temperature: -30 °C
Reaction time: 0.42 h

Procedure:
A 1.59 N n-butyllithium/n-hexane solution (9.91 ml) was added dropwise in an argon atmosphere at −50° C. to a solution of 2.55 g of 7-methylthioimidazo[5,1-b]thiazole in 100 ml of THF. The mixture was stirred at the same temperature for 25 min. Trimethylsilyl chloride (2.08 ml) was added thereto, and the mixture was stirred for 30 min. The temperature of the system was raised to −30° C. A 1.59 N n-butyllithium/n-hexane solution (5.72 ml) was added dropwise thereto, and the mixture was stirred at the same temperature for 30 min. An aqueous ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.58 g of 7-methylthio-2-trimethylsilylimidazo[5,1-b]-thiazole.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][SH:9].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[C:21]([CH3:28])[N:20]=1)=[O:18].C(O)(=O)C>CN(C)C=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([C:4]([F:13])([F:14])[F:3])[CH:6]=2)=[C:21]([CH3:28])[N:20]=1)=[O:18]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)n1
Reactant: FC(F)(F)c1cccc(CS)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SCc2cccc(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To the stirred suspension of 1.08 g of sodium hydride in 25 ml of dimethylformamide the solution of 9.0 g of m-trifluoromethylbenzylmercaptan in 50 ml of dimethylformamide is added during 3 minutes and the mixture stirred for 10 minutes. It is combined with 7.75 g of 6-methyl-5-nitropyridine-2-carboxylic acid methyl ester and the whole stirred on the steam bath for 30 minutes and allowed to stand overnight at room temperature. 2 ml of acetic acid are added and the solution is mixed with ice water to produce a dense, grainy precipitate. It is filtered off and recrystallized from isopropanol-diethyl ether, to yield the 6-methyl-5-(m-trifluoromethylbenzylmercapto)-pyridine-2-carboxylic acid methyl ester melting at 91°-93°.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:18][N:13]3[CH2:14][CH2:15][NH:16][CH2:17][C@@H:12]3[CH2:11]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:28]([CH:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29]>ClCCl>[CH2:28]([CH:30]([CH2:34][CH3:35])[C:31]([N:16]1[CH2:15][CH2:14][N:13]2[CH2:18][C@@H:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][N:7]=3)[CH2:11][C@H:12]2[CH2:17]1)=[O:32])[CH3:29]
Reactant: FC(F)(F)c1ccc(N[C@H]2C[C@H]3CNCCN3C2)nc1
Reactant: CCC(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)C(=O)N1CCN2C[C@@H](Nc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 20 (286 mg, 1 mmol) and triethylamine (202 mg, 2 mmol) in dichloromethane (5 mL) was added 2-ethylbutanoyl chloride (141 mg, 1.05 mmol) in dichloromethane (1 mL). The mixture was stirred room temperature for 2 hours, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR(400 MHz, DMSO-d6) δ ppm 0.80 (m, 6H), 1.35 (m, 3H), 1.50 (m, 3H), 1.80-2.00 (m, 2H), 2.35 (m, 3H), 2.60-3.07 (m, 3H), 4.02-4.10 (m, 1H), 4.33 (m, 1H), 4.48-4.60 (m, 1H), 6.60 (d, 1H, J=7 Hz), 7.56 (m, 1H), 7.60 (d, 1H, J=7 Hz), 8.28 (s, 1H); MS (ESI) m/z 385 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH:25][C:26]1[C:27]([N+:37]([O-:39])=[O:38])=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].ClCCl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([OH:25])[C:27]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 73.7 %

Procedure:
6.5 g of L-proline methyl ester and 10.5 g of N,N'-dicyclohexylcarbodiimide were successively added to an ice-cooled and constantly stirred solution of 10.7 g of 3-hydroxy-4-methoxy-2-nitrobenzoic acid dissolved in a mixture consisting of 180 ml of dichloromethane and 15 ml of N,N'-dimethylformamide, and then the same treatment as in Example 1 was carried out. Thus, there was obtained 12 g of 1-(3-hydroxy-4-methoxy-2-nitrobenzoyl)-L-proline methyl ester as a yellow-colored prismatic crystal having melting point of 108° to 110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)c1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a solution of (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g, 5.0 mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid (0.75 g, 5.5 mmol), Pd(PPh3)4 (45 mg, 0.15 mmol), potassium carbonate (0.75 g, 5.5 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (25 mL×3). The combined organics were concentrated under reduced pressure to give the crude product, which was washed with EtOAc to give pure (R)-(1-(3′-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2) (810 mg, 49%). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz, 1H), 3.66-3.77 (m, 3H), 3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H), 1.68-1.88 (m, 3H), 1.45-1.55 (m, 1H). MS (ESI) m/e (M+H+) 333.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+].CC(C)=O>O>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCCCCCCCCCI

Procedure:
11-Iodo undecanoic acid was synthesized according to Bergbreiter, J. Org. Chem., 40 (6), (1975) 779-782. Briefly, 250 g 11-Bromo undecanoic acid, 325 g Sodium iodide and 2 liter acetone were refluxed under N2 atmosphere for 24 hours. The mixture was divided and added to 4 liter H2O each. The mixtures were fritted and the crude product recrystallized from methanol and finally characterized by the melting point.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH:18]([NH2:20])=O>CN(C)C=O.C(O)=O>[NH2:8][C:7]1[C:6]2[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:2]=2[N:1]=[CH:18][N:20]=1
Reactant: Cc1c(C#N)c(N)n(-c2ccc(Cl)cc2)c1C
Reactant: NC=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1c(C)n(-c2ccc(Cl)cc2)c2ncnc(N)c12

Procedure:
15 g (0.06 mol) of 2-amino-1-(4-chlorophenyl)-3-cyano-4,5-dimethylpyrrole in 100 ml of formamide, 30 ml of dimethylformamide and 15 ml of concentrated formic acid are heated under reflux for 7 hours. The crystals which precipitate on cooling are washed with water and recrystallised from ethanolic potassium hydroxide solution. Melting point: 250° C., yield: 13 g (79% of theory).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]3[N:24]=[C:23]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:21][N:20]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[CH2:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH3:34]>C(O)C>[CH2:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:3][C:4]2[CH:32]=[CH:31][C:7]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:22]=[CH:21][N:20]=4)[CH:12]=3)=[O:9])=[CH:6][CH:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCN1CCNCC1
Agent: Cl
Solvent: CCO
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 466 mg (1 mmol) of 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide hydrochloride in 25 ml of dry ethanol is treated with 381 μl (3 mmol) N-ethylpiperazine and then heated under reflux for 16 hours. The yellow solution is cooled to room temperature and decanted from a small amount of a brown insoluble residue which forms on the wall of the flask. The solvent is evaporated and the residue taken up in citric acid solution (10% w/w) and washed with dichloromethane. The aqueous layer is made basic by addition of sodium bicarbonate and sodium carbonate solution and extracted three times with 150 ml of dichloromethane containing 2 ml of ethanol. The combined organic extracts are washed with conc. sodium chloride solution, dried over sodium sulfate, and evaporated. The residue was stirred with 3 ml of ethyl acetate and the crystalline product filtered and washed with a small amount of ethyl acetate to obtain 4-(4-ethyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; m.p. 209.5-210.5° C.; tR(HPLC)1) 6.62 min.
Reaction SMILES: [BH4-].[Na+].[I-:3].[CH3:4][NH+:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:6]1[CH3:23].I>C(O)(C)C.O>[IH:3].[CH3:4][N:5]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:6]1[CH3:23]
Reactant: [I-]
Reactant: CN1C(c2cccc(F)c2)=CC(c2ccccc2)[NH+]1C
Agent: I
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN1C(c2ccccc2)CC(c2cccc(F)c2)N1C
Reaction time: 24 h

Procedure:
Sodium borohydride (76 g, 0.02 mole) is added to a slurry of 1,2-dimethyl-3-(m-fluorophenyl)-5-phenylpyrazolinium iodide (4 g, 0.01 mole) in isopropanol (125 ml). After becoming homogeneous, the reaction mixture is stirred for 24 hours. Water (10 ml) is then slowly added. Isopropanol is removed on a rotary evaporator and resultant residue is slurried in water (50 ml) and extracted with chloroform. Evaporation of the organic layer yields an oil, which is slurried in water. Aqueous hydriodic acid (5 ml, 46-50%) is next added. After stirring for one hour, resulting solid is filtered and dried to give 3,3 g, 83%; melting point 187°-189° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]2=[O:18])=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>CN(C=O)C>[CH3:19][N:20]([CH3:29])[C:21]([CH:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])=[CH:5][CH:4]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: O=c1cc(O)ccn1CCc1ccc(CBr)cc1
Reactant: CN(C)C(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(Cc2ccc(CCn3ccc(O)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (1.62 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-hydroxy-1H-pyridin-2-one (preparation 4) in 2.5 mL DMF is added at RT 482 mg (1.79) piperidine-4-carboxylic acid dimethylamide and 0.46 mL (3.25 mmol) triethylamine. The mixture is stirred overnight at RT and after filtration is purified via HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH:13](N1CCOCC1)=[O:14]>C1COCC1>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([CH:13]=[O:14])[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: O=CN1CCOCC1
Reactant: CC(=O)Nc1ncc(Cl)cc1F
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Cl)c(C=O)c1F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 2-acetylamino-5-chloro-3-fluoropyridine (20 mg, 0.11 mmol) and 4-formylmorpholine (64 μL, 0.64 mmol) were dissolved in THF (0.2 mL) at room temperature. The solution was cooled to −20° C., a 1.0 M lithium hexamethyldisilazide THF solution (244 μL, 0.24 mmol) was added dropwise, and the mixture was stirred for 2 hours at that temperature. The reaction mixture was subjected to HPLC analysis under the following conditions, and the purity and conversion rate were calculated from the area ratio of the title compound and the starting compound (2-acetylamino-5-chloro-3-fluoropyridine). The formula used was: Conversion rate (%)=100−(area ratio of starting compound).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[C:12]([F:14])[F:13])[CH:6]=1.[CH:15](N1CCCCC1)=[O:16].Cl>O1CCCC1>[F:13][C:12]([F:14])=[CH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH:15]=[O:16]
Reactant: O=CN1CCCCC1
Reactant: FC(F)=Cc1cccc(Br)c1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1cccc(C=C(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
To a mixture of 0.67 g of magnesium and 10 ml of tetrahydrofuran was added a catalytic amount of iodine, and added dropwise a solution of 6.0 g of 1-bromo-3-(2,2-difluoroethenyl)benzene in 20 ml of tetrahydrofuran at 55° C. After stirred at room temperature for 15 minutes, a solution of 3.98 g of 1-formylpiperidine in 5 ml of tetrahydrofuran was added dropwise. This was heated under reflux for 15 minutes, and ice water and 10% hydrochloric acid were added, followed by extraction with t-butyl methyl ether. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography to obtained 1.13 g of oily 3-(2,2-difluoroethenyl)benzaldehyde [Compound No. (1)].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=3)[NH:8][C:5]2=[CH:6][N:7]=1
Reactant: COC(=O)CCC#Cc1ccc(Cl)cc1
Reactant: Nc1cnc(Cl)cc1I
Product: COC(=O)CCc1c(-c2ccc(Cl)cc2)[nH]c2cnc(Cl)cc12

Procedure:
Prepared from 6-chloro-4-iodo-3-pyridinamine (Description 8) and methyl 5-(4-chlorophenyl)-4-pentynoate (Description 2) according to the method of Description 4. 1H NMR (360 MHz, CDCl3) δ 8.56 (1H, br s), 8.50 (1H, s), 7.50 (5H, m), 3.63 (3H, s), 3.15 (2H, t, J 7.9 Hz), and 2.62 (2H, t, J 7.9 Hz). m/z (ES+) 349, 351 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH:16]1[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1)=O)C.C1(C)C=CC=CC=1>>[O:20]1[C:19]2([CH2:24][CH2:25][CH:16]([CH:14]=[O:13])[CH2:17][CH2:18]2)[O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
Diisobutylaluminium hydride (1.5 M solution in toluene, 102 ml, 153 mmol) was added dropwise to a solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester 2 (32.13 g, 150 mmol) in absol. toluene (160 mol) at −70 to −65° C. under argon and the mixture was stirred for 30 min. The mixture was then quenched at −70 to −60° C. by addition of methanol (80 ml). The reaction solution was warmed to RT, saturated sodium chloride solution (100 ml) was added, and the reaction solution was filtered with suction over kieselguhr. The kieselguhr was washed twice with ethyl acetate, and the aqueous solution was separated and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.