Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(O)(=O)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].O.O.O.C([O-])(=O)C.[Na+]>O>[Cl:15][CH2:16][C:17]([NH:4][C:3]1[C:5]([CH3:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)c(N)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)c(NC(=O)CCl)c1C
Reaction time: 0.5 h

Procedure:
A mixture of 7.8 g of 2,3,6-trimethylaniline R. A. Scherrer and H. R. Beatty, J. Org. Chem. 37, 1681 (1972), and 50 ml glacial acetic acid was cooled to 10° C. in a glass stoppered bottle, 7.23 g chloroacetyl chloride was added, mixed quickly and followed immediately by a cooled solution of 19.3 g sodium acetate trihydrate in 80 ml water. The mixture was shaked for 30 min. and the solid material was filtered off and washed carefully with water. After drying, a yield of 9.94 g (81%) was obtained. It melted at 145°-146° C. Analysis: Calcd. for C11H14ClNO: C 62.4, H 6.67, Cl 16.8. Found: C 62.4, H 6.78, Cl 16.8.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.O.N1(O)C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][N:17]([C:29](=[O:30])[CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:32])([F:20])[F:33])[CH:23]=4)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CNCCN3C2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)Cc4cccc(C(F)(F)F)c4)CCN3C2)cn1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
The product from Example 152C (102 mg, 0.392 mmol) was dissolved in dichloromethane (1 mL) followed by addition of 3-trifluoromethylphenylacetic acid (88 mg, 0.431 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (66.0 mg, 0.431 mmol). The mixture was stirred for 5 minutes and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (76 μL, 0.431 mmol) was added. After stirring for 18 hours at ambient temperature, the mixture was partitioned between water and dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a 24 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes and then a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound as a viscous colorless oil (101 mg, 57.7%). 1H NMR (300 MHz, CDCl3) δ ppm 1.76-2.15 (m, 2H), 2.18 (s, 3H), 2.19-2.37 (m, 2H), 2.37-2.53 (m, 1H), 2.69-2.91 (m, 1H), 2.91-3.05 (m, 1H), 3.14-3.29 (m, 1H), 3.65-3.78 (m, 1H), 3.80 (d, J=3.3 Hz, 2H), 3.93 (dd, J=12.5, 2.0 Hz, 1H), 4.64 (ddd, J=10.3, 5.9, 4.5 Hz, 1H), 4.74-4.83 (m, 1H), 5.23 (d, J=1.4 Hz, 1H), 5.39 (tdd, J=7.2, 5.2, 1.9 Hz, 1H), 5.80 (s, 1H), 7.49 (ddd, J=16.3, 4.6, 2.8 Hz, 3H), 8.14 (t, J=1.4 Hz, 1H), 8.18-8.23 (m, 1H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3C=CC=C[C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:7]1[O:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=2[CH:8]=1)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)oc1ccccc12
Product: O=C(CCCl)c1cc2ccccc2o1

Procedure:
Using dibenzofuran and 3-chloropropionyl chloride, the same procedure as in Reference Example 2 was followed, to yield the title compound as a colorless crystal having a melting point of 116° to 118° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5](I)=[CH:4][N:3]=1.[C:30]([Cu])#[N:31]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH3:10])[C:5]([C:30]#[N:31])=[CH:4][N:3]=1
Reactant: N#C[Cu]
Reactant: C[C@H](Nc1nc(N)ncc1I)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(N)ncc1C#N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-(1-((2-amino-5-iodopyrimidin-4-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one 7 (700 mg, 1.35 mmol) in DMF (40 mL), cyanocopper (243 mg, 2.7 mmol), tetrakis(triphenylphosphine) palladium(0) (779 mg, 0.68 mmol), and copper iodide (180 mg, 0.95 mmol) were added and the resulting mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to RT, quenched with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH-DCM to afford the product, (S)-2-amino-4-((1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 8.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1>CN(C=O)C>[Cl:20][C:21]1[N:26]=[C:25]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([NH:3][CH2:1][CH3:2])=[O:19])=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][N:22]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
355 μL (2.53 mmol) TEA are added to a mixture of 600 mg (2.30 mmol) N-ethyl-2-(4-piperidin-4-yl-phenyl)-propionamide (VI.1) and 377 mg (2.53 mmol) 2,4-dichloro-pyrimidine in 25 mL DMF. The mixture is stirred for 3 h at rt. Subsequently the solvent is removed in vacuo and the residue is purified using reversed phase HPLC (water, 0.3% NH4OAc/acetone) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B(O)O.[F-].[Cs+].C(N(C(C)C)C(C)C)C>C(O)CC.CCOC(C)=O>[F:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccc(Cl)nn1
Agent: [Cs+]
Agent: [F-]
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2F)nn1
Temperature: 100 °C
Yield: 14.4 %

Procedure:
To a solution of 6-chloropyridazin-3-amine (0.300 g, 2.32 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.626 g, 3.01 mmol), cesium fluoride (0.915 g, 6.02 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.449 g, 3.47 mmol) in propanol (17 ml) degassed with argon was added (dppf)palladium(II) chloride dichloromethane adduct (0.0953 g, 0.116 mmol), and the reaction was heated to 100° C. in a sealed tube for 3 hours. The reaction was cooled to ambient temperature, diluted with EtOAc, and washed with water and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography on silica gel, eluting with a linear gradient of 0-10% methanol/EtOAc to yield the desired compound (0.086 g, 0.334 mmol, 14.4% yield).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(N)ccc1O
Reactant: O=Cc1ccccc1
Product: CCOC(=O)c1cc(N=Cc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 66.7 %

Procedure:
Ethyl 2-hydroxy-5-aminobenzoate (31.8 g, 0.176 mole) was mixed with benzaldehyde (17.8 ml, 0.176 mole), and the mixture was heated to 100° C. for 10 minutes and subsequently cooled with ice-water. The resulting oil was recrystallized from 96% ethanol, with activated carbon, to give the title compound (31.6 g, 67%), m.p. 63°-65° C. Found (Calc. for C16H15NO3) C 71.18 (71.38), H 5.63 (5.58), N 5.22 (5.20).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[C:26]1([CH2:25][C@@H:8]([NH2:7])[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of (R)-[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxo-ethyl]-carbamic acid tert-butyl ester (16.37 g, 37.3 mmol) in a mixture of dioxane (150 mL)/4N aqueous HCl (150 mL) was stirred at room temperature for 6 hours. The reaction mixture was then concentrated under reduced pressure and the aqueous mixture was extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the desired (R)-[1-(phenylmethyl)-2-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxoethyl]amine hydrochloride (14.0 g, 100% yield) as an off-white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[C:14]([C:18]1[CH:27]=[CH:26][C:21]([C:22](=O)[CH2:23]Br)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:23]=2)=[CH:26][CH:27]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: CC(C)(C)c1ccc(C(=O)CBr)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)cs2)cc1
Yield: 68 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 4-t-butylphenacyl bromide to obtain methyl 4-[4-(4-t-butylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 68%. Pale yellow prisms. Melting point: 154 to 155° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2ccc(F)cc2)CC1
Yield: 89.8 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.174 g, 0.506 mmol) obtained in Example 22, step 3 and 4-(4-fluorophenyl)piperidine hydrochloride (0.120 g, 0.556 mmol), the title compound (0.231 g, 90%) was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2=NCCNc3ccccc32)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCCN2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A round-bottomed flask was charged with 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (1.0 g) and tetrahydrofuran. The mixture was treated with N-bromosuccinimide (1.1 equiv.) then stirred at room temperature for 15 min. The reaction was then treated with an excess of sodium sulfite and the mixture was concentrated to dryness. The residue was dissolved in water and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered and concentrated to an oil. Solids were induced from a methylene chloride/diethyl ether mixture and collected on filter. The solids were washed with diethyl ether then air-dried to provide 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (0.60 g). H1 NMR (d6-dmso): 7.38-7.44 (m, 5H), 7.26 (dd, 1H), 6.86 (d, 1H), 6.75 (d, 1H), 6.41 (br t, 1H), 3.89 (m, 2H), 3.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[SH:9].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([S:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccc(C)c1S
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cccc(C)c1Sc1ccnc(Cl)c1
Yield: 85.7 %

Procedure:
Using the method of Example 3, Step A, 2,6-dimethylbenzenethiol (0.872 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2,6-dimethylphenylthio)pyridine (1.35 g, 86% yield) as a white solid. 1H NMR (CDCl3) δ 8.07 (d, 1H), 7.22-7.34 (m, 3H), 6.75 (s, 1H), 6.71 (d, 1H), 2.40 (s, 6H).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].S(Cl)(Cl)=O.[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH2:28]O)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH2:28][CH2:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:30])=[CH:19][CH:20]=1)(=[O:26])=[O:25])=[O:9])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A mixture of 3-(chlorosulfonyl) benzoic acid (Intermediate 73, 5.51 g, 0.025 mol) and thionyl chloride (17.85 g, 11 mL, 0.15 mol) was refluxed for 1 hr. Excess thionyl chloride was distilled off at atmospheric pressure and finally at reduced pressure to give crude acid chloride. To a mixture of the crude acid chloride and 2-(p-tolylsulfonyl)ethanol (4.8 g, 0.024 mol) in dichloromethane (50 mL) was added triethylamine (2.52 g, 0.025 mol) at room temperature. TLC showed the reaction mixture was complete after 1 hr. The reaction mixture was washed with water (2×25 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give 10 g of a viscous oil. The oil was purified by flash chromatography (silica gel, 25 to 50% ethyl acetate in hexane) to give 6.1 g (63%) of the title compound as a white solid.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])C.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[C:16]1([C:15]2[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]([CH2:5][CH2:6][CH3:7])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCCC(=Nc1ccccc1)SCC
Solvent: CCCCO
Product: CCCc1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 130 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Next, 5.40 g of N-[1-(ethylsulfanyl)butylidene]aniline, 3.19 g of benzoylhydrazine, and 30 mL of 1-butanol were put in a 100 mL three-neck flask and heated and stirred at 130° C. for 12 hours. After the stirring, butanol was distilled off under a reduced pressure to give a brown solid. This solid was washed with ethyl acetate, and subjected to suction filtration to give a solid. The given solid was purified by silica gel column chromatography. As developing solvents, first, hexane:ethyl acetate=1:9 was used, and then ethyl acetate was used. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of hexane and ethyl acetate, so that 3,4-diphenyl-5-propyl-4H-1,2,4-triazole (abbreviation: HPrptz) was prepared (a white solid, yield: 28%). The synthetic scheme of Step 4 is shown by (d-7).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13]C2CCC(C)CC2)[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1)#[CH:26]>>[CH:3]1([CH2:8][CH2:13][N:12]2[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:26]#[C:25][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: CC1CCC(Cn2c(-c3ccccc3Br)nc3ccccc32)CC1
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3ccccc3n2CCC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-(4-methyl-cyclohexylmethyl)-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). White solid (43%). MS (Turbo Spray): m/z=430.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]2[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]3[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:32]#[N:33])=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1-n1cccc1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-methoxy-4-pyrrol-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M18) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (10 mg).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of acryloyl chloride (0.057 mL, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 mL, 0.73 mmol) in CH2Cl2 (40 mL), which was cooled in an ice/water bath to 0° C. The mixture was stirred while in the ice/water bath for 1 h and was then allowed to warm to r.t. The mixture was then held at r.t. for 18 h, and was then diluted with CH2Cl2 (100 mL). This solution was then washed with sat. NaHCO3 (200 mL) and the aqueous wash solution was extracted with CH2Cl2 (2×100 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with an impurity (172 mg, 50%) as a pale yellow solid. 120 mg of this material was purified by crystallisation from CH3CN to give the title compound (85 mg, 0.164 mmol) as a yellow solid without evidence of the impurity by NMR analysis. The mother liquors from the crystallization and a further impure fraction from the FCC (containing a 75:25 mixture of product:starting material) were combined, concentrated in vacuo and was purified by crystallisation from CH3CN to give more of the title compound (40 mg, 12%) as a tan solid; 1H NMR: 2.09 (6H, s), 3.03-3.12 (1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s), 8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 518.23.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:16]([CH2:15][CH:2]([OH:1])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(O)CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To DMF solution (400 ml) of N-(2,3-epoxypropyl)phthalimide 58.8 g (0.29 mol), sodium azide 37.6 g (0.58 mol) and ammonium chloride 18.5 g (0.35 mol) were added, and stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and then filtered. The filtrate was evaporated to dryness. The residue was dissolved in benzene (800 ml), washed with water, brine and water sequentially and then dried over sodium sulfate. The solvent was removed in vacuo. The desired product was further purified by silica gel chromatography. 66.3 g of desired product was obtained. The NMR spectra were consistent with the desired title intermediate.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: C#CCC(C)OC1CCCCO1
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)OC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(pent-4-yn-2-yloxy)tetrahydro-2H-pyran (3.33 g, 19.80 mmol) were dissolved in diethyl ether (20 ml) and the mixture was stirred vigorously. Triethylamine (0.920 ml, 6.60 mmol) diluted with diethyl ether was added dropwise. The reaction mixture was extracted with water and the organic phase dried with MgSO4, filtered and evaporated. The product was used in the next step without further purifications. LC-MS: [M+1]=284.32.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:4]3[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=3[Cl:2])[N:13]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1
Agent: Br
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-amine hydrobromide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (16.5 mg) with purity >90%. 1H-NMR (DMSO-d6) δ 13.43 (s, NH), 8.46 (d, J=2.8 Hz, 1 H), 8.29 (d, J=2.8 Hz, 1 H), 7.96 (dd, J=1.1 Hz, J=8.0 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.70 (dd, J=1.1 hz, J=8.0 Hz, 1 H), 7.42 (t, J=8.0 Hz, 1 H), 7.52 (s, 1 H), 2.67 (s, 3 H); MS (pos) m/z 442.2,444.2.