Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]1([CH2:25][N:26]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[N:27]2)[CH2:24][CH2:23]1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:25][CH:22]3[CH2:24][CH2:23]3)[N:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1ccn(CC2CC2)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(NCc1ccn(CC2CC2)n1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and C-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-methylamine (51 mg, 0.33 mmol) as starting materials; off white solid (48 mg, 33.3%). MS (ESI): 437 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:21]1([C:27](=[O:31])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:28](=[O:29])[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31])[CH3:2]
Reactant: CCN(C=Cc1ccccc1)CC
Reactant: O=C(Cl)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reaction time: 1.25 h

Procedure:
Seven grams of N,N-diethylstyrylamine was dissolved in 100 ml. of diethyl ether and the solution was cooled to 0° C. Four grams of anhydrous triethylamine was added. A 7 g. portion of phenylglyoxyloyl chloride was dissolved in 50 ml. of diethyl ether and the solution was added dropwise, with stirring, to the first solution over about 75 minutes. As soon as the addition was complete, the reaction mixture was filtered, and the precipitated amine hydrochloride was washed with an additional 50 ml. of diethyl ether. The filtrate contained 1-diethylamino-2,4-diphenyl-1-buten-3,4-dione, in dissolved form, and was used in the next step of the synthesis without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[C:7]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:8]=1)#[N:11]
Reactant: CC(C)N=C=O
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
To a solution of compound 24 (0.100 g, 0.27 mmol) in CH2Cl2 (3 mL) was added isopropyl isocyanate (0.032 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). Reaction was stirred for 20 hrs at room temperature, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/hexanes and vacuum filtered to yield a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with hexanes and vacuum filtered to afford compound 58 as a white powder (0.014 g, 11.3% yield, 99.1% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H) 6.93 (s, 1H), 6.89 (s, J=9 Hz, 1H), 6.69 (s, 2H), 4.17 (m, 1H), 3.95 (m, 1H), 3.44 (m, 4H), 3.35 (m, 4H), 2.34 (s, 6H), 1.14 (d, J=7 Hz, 6H); MS (ESI, EI+): m/z=457 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:11]2[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-bromophenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].N1CCC1=O>CO.O>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)N1C(=O)OC[C@@H]1c1ccccc1
Agent: O=C1CCN1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate (1 g, 4.01 mmol) in 35 mL of MeOH was added, at 0° C., 14.3 mL (12.04 mmol) of a 0.84 M solution of LiOH in water. The reaction mixture was then stirred for 3 h. at ambient temperature. Upon complete hydrolysis of the azetidinone, the MeOH was removed by evaporation, the crude residue dissolved in CH2Cl2 and treated with saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afford the title compound (racemic mixture) as a white solid (0.906 g, 96%); 1H NMR (CDCl3) δ 1.13/1.57 (d/d, J=7.5 Hz, 3H), 3.75/4.50 (q/q, J=7.5 Hz, 1H), 4.10-4.16 (m, 1H), 4.62-4.72 (m, 1H), 4.92-5.03 (m, 1H), 7.32-7.43 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.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>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]([CH3:14])[C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Br
Reactant: CB1OB(C)OB(C)O1
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: Cc1cc(C(F)(F)F)cc(Cl)c1N
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline (1.00 g, 3.64 mmol), trimethylboroxine (0.66 ml, 0.59 g, 4.47 mmol), potassium carbonate (1.00 g, 7.30 mmol) and catalytic amount (10%) Pd(PPh3)4 in DMF (5 ml) was heated to 90° C. for 14 h. Water (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a colorless oil after a flash column using EtOAc:hexane (1:9) as the elute. 1H NMR (CDCl3, 500 MHz): δ 7.43 (s, 1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:21])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0° C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (10.0 g, 53 mmol), 3,4-dihydro-2H-pyran (9.5 mL, 93 mmol) and p-toluenesulfonic acid monohydrate (1.0 g, 5.0 mmol) in THF (100 mL) was heated at 100° C. for 18 h, then cooled to RT and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10% ethyl acetate in cyclohexane) affording 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine as a cream solid (10.9 g, 75%). 1H NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 5.77 (1H, dd, J=10.4, 2.4 Hz), 4.19 (1H, m), 3.78 (1H, dt, J=11.6, 2.9 Hz), 2.17 (1H, m), 2.09 (1H, m), 1.98 (1H, m), 1.87-1.69 (3H, m).
Reaction SMILES: Cl.Cl.Cl[CH2:4][C:5]1[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([OH:35])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:4][C:5]4[N:6]=[C:7]([CH2:10][N:11]([CH3:13])[CH3:12])[S:8][CH:9]=4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: CN(C)Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 50 h
Yield: 15 %

Procedure:
N-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.050 g, 0.220 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methoxy)quinazolin-7-ol (0.074 g, 0.220 mmol) were suspended in DMF (4 mL) and potassium carbonate (0.152 g, 1.10 mmol) was added. The mixture was stirred at room temperature for 50 h and then at 70° C. for 3.5 h. An additional portion of N-{[4-(chloromethyl)-1,3-thiazol-2-yl]methyl}-N,N-dimethylamine hydrochloride hydrochloride (0.019 g, 0.084 mmol) was added and the mixture was stirred at 70° C. for a further 25 h. The reaction mixture was concentrated in vacuo. and the residue was partitioned between ethyl acetate and brine. The organic portion was washed with 1 N aqueous sodium hydroxide, brine, dried over sodium sulfate, filtered and concentrated in vacuo. to afford a brown solid. Recrystallization from ethyl acetate/diethyl ether afforded the title compound as a pale brown solid (0.016 g, 0.033 mmol, 15% yield). 1H NMR (400 MHz; CDCl3): 2.37 (s, 6H); 3.79 (s, 2H); 4.00 (s, 3H); 5.34 (s, 2H); 7.00 (s, 1H); 7.15 (br s, 1H); 7.34-7.37 (m, 2H); 7.55 (d, 1H); 7.57 (d, 1H); 7.96 (d, 1H); 8.66 (s, 1H); MS (EI) for C22H21Cl2N5O2S: 490 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:30][CH2:31][CH2:32][OH:33])[N:13]=1
Reactant: NCCO
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NCCO)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.17 (m, 2H), 3.48 (m, 2H), 6.08 (br s, 1H), 6.45 (d, 1H, J=9.6 Hz), 7.26-7.67 (m, 9H). LC MS (m/e)=427 (MH+).
Reaction SMILES: [OH2:1].O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[CH2:29])[CH2:24][CH2:23][CH2:22]2.C(Cl)(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C:29](=[O:1])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=1
Reactant: O
Reactant: C=C1CCCc2cc(OC)ccc21
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CCCC(=O)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1977, 21, 1827. To a suspension of methyltriphenylphosphonium bromide (11.5 g) in tetrahydrofuran (50 ml) was added dropwise potassium tert-butoxide (1.0 M solution in tetrahydrofuran) (40 ml) on an ice bath under a nitrogen atmosphere, the solution was stirred for 1 hour, then a solution of 6-methoxy-1-tetralone (4.74 g) in tetrahydrofuran (26 ml) was added dropwise thereto followed by stirring for 2.5 hours at room temperature. Water was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (4.4 g). To a solution of thallium(III) nitrate trihydrate (4.5 g) in methanol (40 ml) was added dropwise a solution of 6-methoxy-1-methylene-1,2,3,4-tetrahydronaphthalene (1.7 g) in methanol (13 ml) on an ice bath, and the solution was stirred for 10 minutes at room temperature. Chloroform was added thereto, the solution was stirred, then filtered through celite pad, extracted with diethyl ether, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[I:17]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([I:17])=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2ccn3ccnc3c2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccn3c(I)cnc3c2)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of 7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (13.0 g, 61.3 mmol) in N,N-dimethylformamide (100 mL) stirring under a nitrogen atmosphere at ambient was added N-iodosuccinimide (14.5 g, 64.4 mmol). The reaction mixture was stirred for 2 h and then poured into water (1 L) and stirred for a further 30 min. The solid obtained was collected by filtration, washed with water and air dried on the filter. The solid was triturated with ether, collected by filtration and dried under vacuum at 50° C. The solid obtained was partitioned between water and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The solid thus obtained was partitioned between aqueous sodium thiosulphate solution and EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The product was triturated with EtOAc, collected by filtration and air-dried to afford 6.0 g (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d), 7.91 (1H, s), 7.78 (1H, s), 7.67 (2H, dd), 7.28 (1H, d), 7.22 (2H, t). A further crop of product (11.0 g) containing minor impurities was obtained by evaporating the filtrates under reduced pressure, triturating with petrol/EtOAc and collection by filtration.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH2:12][NH:13][CH3:14])[NH:10][CH:11]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[CH2:27]([N:13]([CH3:14])[CH2:12][C:9]1[NH:10][CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:2][CH:3]=2)[N:8]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CNCc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccccc1)Cc1nc(-c2ccc(-c3ccccc3)cc2)c[nH]1
Reaction time: 48 h
Yield: 16 %

Procedure:
(4-(1,1′-biphenyl)-4-yl-1H-imidazol-2-yl)-N-methylmethanamine (1 g; 0.003 mol; prepared according to experimental conditions analogous to the preceding examples and using the appropriate starting compounds and reaction products) was diluted in 20 ml dimethylformamide. Potassium carbonate (1.23 g; 0.009 mol) was added at about 23° C. and then benzyl bromide (0.34 ml; 0.003 mol) was added quite slowly. The reaction mixture was agitated at this temperature for about 48 hours then poured in icy water. The mixture was extracted with ethyl acetate and the organic phase washed with water. After drying over magnesium sulfate, the solvents were concentrated using a rotative evaporator. After purification over a silica column (eluent: ethyl acetate-heptane/8-2), a white solid was obtained in the form of a glue (yield of 16%). Free base. Melting point: 106-108° C. MH+=354.2.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[C:21]([Cl:36])[CH:20]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=O)C.[OH-].[Na+].Cl.O>O1CCCC1>[Cl:36][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:17]3[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:10]=[CH:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butyl acetate (281 mg) in tetrahydrofuran (4.0 mL) was added 1N aqueous sodium hydroxide solution (2.8 mL), and the mixture was stirred at room temperature for 4.5 hrs. 1N Aqueous hydrochloric acid solution (2.8 mL) was added, and the mixture was stirred for 15 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (5/95) was added to the residue, and the mixture was stirred with heating to 80° C., allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate washed with diisopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([OH:13])[C:11]3[S:14][CH2:15][CH2:16][S:17][C:10]=3[C:9]2=[O:18])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23].C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([O:18][C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[C:10]3[S:17][CH2:16][CH2:15][S:14][C:11]=3[C:12]2=[O:13])=[N:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of 6-(5-chloropyrid-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.0 g.) in anhydrous tetrahydrofuran (150 cc.) is treated for 15 minutes at about 10°-15°C with sodium hydride (1.44 g.), and a solution of 1-chlorocarbonyl-4methylpiperazine (24.4 g.) in anhydrous tetrahydrofuran (200 cc.) is then added, at 5°C. The reaction mixture is stirred for 4 hours at 5°C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (450 cc.). The ether solution is rapidly extracted twice with an ice-cold normal aqueous solution of methanesulphonic acid (total 500 cc.). The combined aqueous extracts are rendered alkaline by adding 10N sodium hydroxide solution (100 cc.). The oil which separates out is extracted with methylene chloride (250 cc.) and then with diethyl ether (300 cc.). The combined organic extracts are washed five times with distilled water (total 250 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.1 g.) and evaporated. The crystals obtained (18.0 g.; m.p. 170°C.) are dissolved in boiling ethanol (225 cc.). After filtering the boiling solution and then cooling it for three hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold ethanol (total 45 cc.) and dried under reduced pressure (20 mm.Hg). 6-(5-Chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (15.6 g.), melting at 180°C., is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CS[C:32]1[N:33](C(OCC)=O)[CH2:34][CH2:35][N:36]=1.CC(O)=O.C([O-])(O)=O.[Na+]>CCO>[NH:36]1[CH2:35][CH2:34][N:33]=[C:32]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: CCOC(=O)N1CCN=C1SC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2ccc(NC3=NCCN3)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A mixture of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (150 mg), ethyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate (78.9 mg), AcOH (0.3 ml) and EtOH (3 ml) was refluxed for 7 hours under N2 atmosphere. After cooled to r.t., the reaction mixture was made basic with saturated NaHCO3. The mixture was extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (10:1) as an eluent. The amorphous substance was solidified with ethyl ether to give N-{4-{2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ethyl}-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (17.9 mg) as an off-white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(3-chloro-phenyl)-1-thiazolidin-3-yl-propan-1-one.