Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].N1C=CC=CC=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[CH2:1]([O:3][C:4](=[O:9])[CH:5]([C:6]#[N:7])[NH:8][C:19](=[O:20])[CH2:18][O:17][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(N)C#N
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC(=O)COC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
A solution of aminocyanacetic acid ethyl ester (1.00 g, 7.80 mmol) in dichloromethane (15.00 ml) was cooled to 0° C. and treated with pyridine (0.62 g, 7.80 mmol). Methoxy-acetyl chloride (0.85 g, 7.80 mmol) was added dropwise during 15 min. The mixture was stirred for 5 min at 0° C., then warmed to room temperature and stirred for 10 min. The volatiles were evaporated, and the residue was redissolved in dichloromethane and washed twice with water. The organic layer was dried with sodium sulphate and evaporated. The residue was triturated in diisopropyl ether to yield cyano-(2-methoxy-acetylamino)-acetic acid ethyl ester (1.04 g, 66%), MS (ISP): m/e=201.1 (M+H+).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][CH:20]=[O:21])[CH:6]=1)[OH:4].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O.C(OC(C)C)(=O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([O:4][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:2][Br:1])=[CH:6][C:7]=1[NH:19][CH:20]=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Reaction time: 72 h
Yield: 67.9 %

Procedure:
(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (9.9 g, 28 mmol) was dissolved in dimethylformamide (36 mL). Imidazole (2.3 g, 34 mmol) and tert-butyldimethylsilyl chloride (4.7 g, 31 mmol) were added. The solution was stirred under nitrogen atmosphere for 72 h. Additional imidazole (0.39 g, 5.7 mmol) and tert-butyldimethylsilyl chloride (0.64 g, 4.3 mmol) were added and the reaction was stirred for an additional 20 h. The reaction mixture was then diluted with a mixture of isopropyl acetate (53 mL) and hexanes (27 mL) and transferred to a separatory funnel. The organic layer was washed twice with a mixture of water (27 mL) and saturated aqueous sodium chloride (27 mL) followed by a final wash with saturated aqueous sodium chloride (27 mL). The organic layer was dried over sodium sulfate. Silica gel (23.6 g) and hexanes (27 mL) were added and the suspension was stirred for 10 min. The solids were removed by filtration and the filtrate concentrated under vacuum. The residue was crystallized from hexanes (45 mL) to afford 8.85 g (19 mmol, 68%) of the title compound as a solid. MS m/z: [M+H+] calcd for C22H30NO3SiBr 464.1; found 464.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]2[CH3:18])[CH:5]=[CH:6][CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@@H:15]([CH3:17])[N:14]([C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:13][C@@H:12]2[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(CCCN2C[C@@H](C)NC[C@@H]2C)c1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: Cc1cccc(CCCN2C[C@@H](C)N(C(=O)c3ccco3)C[C@@H]2C)c1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-[3-(m-methylphenyl)propyl]-2,5-dimethylpiperazine [b.p. 125° - 132°C (4 mmHg), dipicrate, m.p. 245° - 248°C], 2-furoyl chloride and benzene.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=CC=1C)C.[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29]1[O:30]C(C)=C(CCO)N=1)[CH3:20].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[CH:29]=[O:30])[CH3:20]
Reactant: CCOc1cc(F)ccc1-c1nc(CCO)c(C)o1
Agent: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOc1cc(F)ccc1C=O

Procedure:
In analogy to the procedure described in example 7 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 34 b]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (prepared from 4-fluoro-2-hydroxy-benzaldehyde [J. Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-31] by i) treatment with ethyl iodide, potassium carbonate in N,N-dimethylformamide to give 2-ethoxy-4-fluoro-benzaldehyde; ii) conversion of 2-ethoxy-4-fluoro-benzaldehyde into 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole in analogy to the procedures described in examples 2 a] and b]; iii) conversion of 4-chloromethyl-2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazole into 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol by treatment with sodium cyanide in DMSO followed by hydrolysis of the nitrile function with sodium hydroxide in ethanol/water at reflux and reduction of the acid formed with BH3×THF in tetrahydrofuran at room temperature) in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:34]1([C:39](N2C=CN=C2)=[O:40])C=CN=[CH:35]1>>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]3[N:1]([C:2]4[CH:10]=[CH:9][C:5]5[N:6]=[CH:7][NH:8][C:4]=5[CH:3]=4)[C:39](=[O:40])[NH:34][CH2:35]3)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2ccc(OCCN3CCOCC3)cc2)N1c1ccc2nc[nH]c2c1

Procedure:
The compound was synthesized as ditrifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-(2-morpholinoethoxy)benzaldehyde (0.941 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.34 mL, 9.6 mmol), di-(imidazol-1-yl)methanone (0.582 g, 3.6 mmol) as described in method 2. The product was purified by means of preparative HPLC.
Reaction SMILES: CC(C)CC[NH2:5].[CH:7]1([CH2:12][C:13]([OH:15])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[CH:7]1([CH2:12][C:13]([NH:5][C:22]2[CH:26]=[CH:27][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)CC1CCCC1
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(CC1CCCC1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting 4-nitroaniline for 3-methylbutan-1-amine and 2-cyclopentylacetic acid for 4-nitrobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1nc(-c2cc(F)ccc2F)cs1
Product: O=C(Nc1nc(-c2cc(F)ccc2F)cs1)c1cc(Cl)ccc1O
Yield: 36.5 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,5-difluorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[F:39][C:40]1[CH:65]=[CH:64][C:43]([CH2:44][O:45][C:46]2[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=2[O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)C(O)=O)=[CH:42][CH:41]=1.C(O)(=O)/C=C/C1C=CC(O)=C(O)C=1>>[F:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][O:45][C:46]2[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=2[O:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]2[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=2)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17])=[CH:64][CH:65]=1
Reactant: O=C(O)c1ccc(OCc2ccc(F)cc2)c(OCc2ccc(F)cc2)c1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Agent: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: CC(C)(C)OC[C@H](NC(=O)c1ccc(OCc2ccc(F)cc2)c(OCc2ccc(F)cc2)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (610 mg, 1.2 mmol, example 42, step A) as described for example 42 (step B) using 3,4-di-(4-fluorobenzyloxy)benzoic acid (653 mg, 1.8 mmol, step A of this example) instead of caffeic acid. The crude material was purified by flash chromatography using successively 15%, 35% and 50% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as a yellow powder (207 mg, 27%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])OCC)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].C(O)C.[CH2:20](N)[CH2:21][NH2:22]>CCOCC>[CH2:20]1[NH:11][C:7](=[C:6]2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3](=[O:2])[CH:13]=[CH:12]2)[NH:22][CH2:21]1
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1C=CC(=C2NCCN2)C=C1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To a solution of the imidate ester HCl 34 (650 mg, 2.63 mmol) in abs. ethanol was added ethylenediamine (0.53 ml, 7.89 mmol) at 0° C. and the mixture was stirred for 16 hrs at room temperature. Ether was added and the resulting precipitates were collected by filtration and dried in vacuo to give 490 mg (90% yield) of the desired cyclic amidine 35. 1H NMR (600 MHz, DMSO-d6) δ 8.38 (d, 1H, J=3 Hz), 7.45 (dd, 1H, J=9, 2.4 Hz), 3.79 (s, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-:36].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH2:36].[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:26][CH2:27]2)=[CH:33][CH:32]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: ClCCCn1cnc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCn3cnc4ccccc43)CC2)cc1

Procedure:
A mixture of 4.9 parts of 1-(3-chloropropyl)-1H-benzimidazole, 5.76 parts of 1-[bis(4-fluorophenyl)methyl]piperazine, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1H-benzimidazole hydrate; mp. 108.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[CH:36][CH:37]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COc1cc(OC)nc(Oc2ccc(I)cc2)n1
Product: COC(=O)C(C/C=C/c1ccc(Oc2nc(OC)cc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 56.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (30 mg) was reacted with 2-(4-iodophenoxy)-4,6-dimethoxypyrimidine (40 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4,6-dimethoxypyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (30 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:30]3[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (495 mg) was reacted with Boc-piperazine via General Procedure B-3 to give tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](SC)=[N:9][CH:10]=1)=[O:4].[CH:13]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:24][S:25]([O-:28])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([S:25]([CH3:13])(=[O:28])=[O:24])=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(SC)nc1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(S(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of 2-methylsulfanyl-pyrimidine-5-carboxylic acid methyl ester (1 g, 5.43 mmol) in DCM (60 mL) is added MCPBA (2.81 g, 16.29 mmol) portion wise at rt. The resulting solution is stirred at rt overnight. A solution of Na2S2O3 (1.6 g) in water (60 mL) is added. The mixture is stirred at rt for 20 min. The organic layer and aqueous layer are separated, and the aqueous layer is extracted with DCM (2×20 mL). The combined organic layer is washed with saturated aqueous NaHCO3 (3×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester (1.05 g, 90%) as a solid. MS: 217 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.41 (s, 3H), 4.06 (s, 3H), 9.44 (s, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(O)C3)o2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reaction time: 7 h
Yield: 177.9 %

Procedure:
A suspension of 4A (5.45 g, 19. 8 mmol) in dichloromethane (100 mL) was cooled in an ice-bath. Triethylamine (4.4 mL, 31.7 mmol) was added followed by methanesulfonyl chloride (2.3 mL, 29.7 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The mixture was transferred to a separatory funnel and was washed with water followed by aqueous NaHCO3 (sat.). The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was filtered. The product was washed twice with diethyl ether and then dried in vacuo. There was obtained 5.03 g (72%) of 4B as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 3.90 (s, 3H), 4.42 (dd, 1H), 4.64 (dd, 1H), 4.86 (dd, 1H), 5.11 (dd, 1H), 5.40 (m, 1H), 7.02 (d, 2H), 8.09 (d, 2H), MS (APCI+) m/z 354 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24](O)=[O:25])[N:21]=1)=[CH:5]2.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][C:24]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: CN1CCNCC1
Reactant: O=C(O)CC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CN1CCN(C(=O)CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Yield: 28 %

Procedure:
The compound (150 mg, 0.38 mmol) prepared in Example 149 and 1-methylpiperazine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (50 mg, Yield 28%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=S)[CH3:2].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)CCC>O>[CH3:2][C:1]1[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=1
Reactant: CC(=S)Nc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1nnc(-c2ccccc2)n1-c1ccccc1
Yield: 18 %

Procedure:
First, 5.04 g of thioacetanilide, 5.44 g of benzoylhydrazine, and 50 mL of 1-butanol were put in a round-bottomed flask provided with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with a microwave (2.45 GHz, 100 W) for 2 hours and 45 minutes to be heated. Then, water was added to this solution and an organic layer was extracted from dichloromethane. The organic layer was washed with water and dried with magnesium sulfate. After the drying, the solution was filtrated. The solvent of this solution was distilled off, and the resulting residue was purified by silica gel column chromatography which uses ethyl acetate as a developing solvent, so that 3-methyl-4,5-diphenyl-4H-1,2,4-triazole (abbreviation: HMptz) was prepared (light yellow powder, yield: 18%). The synthetic scheme of Step 1 is shown by (a-1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27][N:28]1[CH2:33][C@H:32]2[CH2:34][C@@H:29]1[CH2:30][NH:31]2.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:31]3[CH2:30][C@H:29]4[CH2:34][C@@H:32]3[CH2:33][N:28]4[CH3:27])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: CN1C[C@H]2C[C@@H]1CN2
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C[C@H]2C[C@@H]1CN2C(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (26 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 63 as a solid (11 mg).
Reaction SMILES: [Br-].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)#[N:34].O>COC(C)(C)C>[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#CC1CCC(C=O)CC1
Agent: [Br-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A mixture of 2.51 g (p-pentylphenyl)methyl-triphenylphosphonium bromide and 615 mg of 4-cyanocyclohexanecarboxaldehyde (cis/trans mixture about 1:1) in 30 ml of t-butyl methyl ether was placed at 0° C. in a sulphonation flask while gassing with argon, the mixture was treated within 2 minutes with 673 mg of solid potassium t-butylate and the mixture was subsequently stirred at 0° C. for a further 1.5 hours. The red-brown, heterogeneous mixture was then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was suspended in 150 ml of hexane, freed from precipitated triphenylphosphine oxide by filtration (back-washing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.4 bar) of the resulting oil (1.36 g) on silica gel with 3% ethyl acetate/petroleum ether as the eluant gave 1.02 g (81%) of 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile as a colourless oil; Rf values of this isomer mixture (10% ethyl acetate/petroleum ether): 0.27 and 0.36.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A solution of 3-chloroquinoxaline-2-carbonyl chloride (1.0 g, 4.40 mmol) in dichloromethane (9.2 mL) was added dropwise to a mixture of tert-butyl 4-aminobenzoate (851.0 mg, 4.40 mmol), pyridine (1.07 mL, 13.21 mmol) and dichloromethane (13.8 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 40 minutes. To the reaction, water (10 mL) was added. The two layers were separated. The organic layer was washed with water (2×10 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The product was slurried in hexanes at 40° C., and the solid was isolated by filtration to yield tert-butyl 4-[(3-chloroquinoxaline-2-carbonyl)amino]benzoate (1.34 g, 79%) as a yellow solid. ESI-MS m/z calc. 383.10, found 384.4 (M+1)+; Retention time: 1.88 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.27 (dd, J=7.5, 2.1 Hz, 1H), 8.22-8.11 (m, 1H), 8.11-8.01 (m, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.7 Hz, 2H), 1.56 (s, 9H) ppm.