Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][NH2:13]>C(O)C>[C:12]([NH:5][C:4]([NH:3][CH3:2])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CN
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 4 h

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl)imidazole (1.93 g.) and dimethyl-N-cyanoimidodithiocarbonate (1.65 g.) in ethanol (33 ml.) was set aside overnight at room temperature. Ethanolic methylamine (33%, 22 ml.) was added and the solution was then set aside for 4 hours. Concentration and recrystallisation from isopropyl alcohol-ether yielded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.0 g.), m.p. 139°-140°. (Found: C, 47.5; H, 6.5; N, 33,3; S, 12.7 C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S. 12.7).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([O:27][CH2:28]C)[N:21]=1>C(#N)C>[Cl:26][C:24]1[CH:23]=[C:22]([O:27][CH3:28])[N:21]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:15])=[O:14])=[O:18])[N:25]=1
Reactant: CCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOc1cc(Cl)nc(N)n1
Solvent: CC#N
Product: CCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-propylsulfonylbenzenesulfonyl isocyanate (1.74 g, 6.00 mmol) in dry acetonitrile (25 ml) was added 2-amino-4-chloro-6-ethoxypyrimidine (1.00 g, 6.00 mmol). After stirring at room temperature overnight, the reaction mixture was filtered to yield the product as a white powder melting at 193°-195° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[N:20]([N:24]=[C:25]([NH2:27])[N:26]=3)[CH:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1>>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[C:19]3[N:20]([N:24]=[C:25]([NH:27][C:2]4[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=4)[N:26]=3)[CH:21]=[CH:22][N:23]=2)[CH:15]=[N:14]1
Reactant: CC(C)(O)c1ccc(Br)cc1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C(C)(C)O)cc4)nc23)cn1

Procedure:
2-(4-Bromophenyl)propan-2-ol and 8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine are reacted under Buchwald Hartwig conditions as described in general procedure 2.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)=[CH:35][CH:34]=2)[CH2:41][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The compound (14) synthesized in Reference Example 14 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6](=[O:16])[CH:7]([Br:20])[O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)C(C)(C)C(=O)COc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26 g (0.091 mol) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 150 ml of carbon tetrachloride. 4.7 ml (0.091 mol) of bromine in 50 ml of carbon tetrachloride were added dropwise at room temperature at such a rate that the bromine was steadily consumed. The mixture was then stirred for 30 minutes at room temperature. After distilling off the solvent in vacuo, 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester was obtained quantitatively and could directly be reacted further.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>CN(C)C=O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:4]1[C:5](=[O:6])[CH2:7][NH:1][C:2]1=[O:3]
Reactant: ClCc1ccccn1
Reactant: O=C1CNC(=O)N1
Solvent: CN(C)C=O
Product: O=C1CNC(=O)N1Cc1ccccn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
5.0 g of hydantoin, 8.2 g of 2-chloromethylpyridine and 6.9 g of potassium carbonate anhydride were dissolved into 100 ml of N,N-dimethylformamide and these were stirred under room temperature for 1 hour and at 80° C. for 30 minutes. The N,N-dimethylformamide was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluate solvant; chloroform:methanol =9:1). Thus 4.8 g of the captioned compound was thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([O:13][CH3:21])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
To a solution of 1.00 g (3.8 mmole) of (2S,3S)-3-(t-butoxycarbonyl)amino-2-hydroxy-5-methylhexaneoic acid prepared according to the method of R. L. Johnson [J. Med. Chem., 25, 605 (1982)] in 30 ml. of methanol was added, with stirring and ice-cooling, an ethereal solution of diazomethane. The mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation, and the solid thus obtained was recrystallized from hexane, to afford 952 mg. of colourless needles, melting at 84°-85° C.; [α]22 -10.2° (C=1.26, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([OH:22])=O)=[CH:16][C:11]2=[N:10][N:9]=1.S(Cl)(Cl)=O.[CH3:31][N:32]1[C:36]([NH2:37])=[CH:35][CH:34]=[N:33]1.C(N(CC)CC)C>C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([NH:37][C:36]3[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=3)=[O:22])=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Reactant: Cn1nccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccn2c(-c3ccccc3Cl)nnc2c1
Temperature: 95 °C

Procedure:
A mixture of 3-(3-(2-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-4-methylbenzoic acid (2.44 g, 6.7 mmol) and thionyl chloride (30 ml, 411 mmol, Aldrich) was heated to 95° C. for 2 h. The volatiles were removed in vacuo. The solids were re-dissolved in CH2Cl2 (30 ml). A 10 ml aliquot of this solution (860 mg, 2.2 mmol) was treated with 1-methyl-1H-pyrazol-5-amine (656 mg, 6.7 mmol, Maybridge), followed by triethylamine (939 μl, 6.7 mmol, Aldrich). The mixture was diluted with 10% Na2CO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated over silica gel. The residue was purified using column chromatography (Acetone/Hexanes=0-50%). The mixture was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. After washing with MeOH, the title compound was eluted with 2M NH3 in MeOH. The residue was recrystallized from MeOH yielding the title compound as a white solid. HRMS (TOF) Calcd for C24H20ClN6O+: 443.1382, found: 443.1389.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[CH2:8]([O:10][CH2:11][CH2:12]Cl)[CH3:9].C(N(CC)CC)C>>[CH2:8]([O:10][CH2:11][CH2:12][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])[CH3:9]
Reactant: CCOCCCl
Reactant: CCc1ncc[nH]1
Solvent: CCN(CC)CC
Product: CCOCCn1ccnc1CC
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-ethylimidazole (19.2 g, 200 mmol) was made reacted with 2-chloroethyl ethyl ether (26.0 g, 240 mmol) at 145 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The product was a transparent liquid which has a boiling point of 171-175 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.91 (d, 1H), 6.87(d, 1H), 4.00-3.97(t, 2H), 3.63-3.60 (t, 2H), 3.44-3.39(4, 2H), 2.75-2.65(m, 2H), 1.33-1.29(t, 3H), and 1.15-1.12(t, 3H), and 1-(2-ethoxyethyl)-2-ethyl imidazole was synthesized.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[N:42]=[C:43]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])[CH:3]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: COc1cccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Yield: 57.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (190 mg, 0.81 mmol), sodium carbonate (86 mg, 0.81 mmols) and bis(triphenylphosphine)palladium(II) dichloride (24 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 20%, dichloromethane-ethyl acetate) to give 61 mg (59% yield) of the title compound. Purity 632%.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:16])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:30])C=1.CCOCC>C(Cl)Cl>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15]([CH3:16])=[O:30])=[N:7][C:6]3[C:17]([CH3:21])=[CH:18][CH:19]=[N:20][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccnc2c1N=C(S(C)=O)c1cccnc1N2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 11-cyclopropyl-4-methyl-6-methylthio-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.8 g, 0.0027 mol) in methylene chloride (10 mL) was cooled in an ice water bath. To the resulting clear yellow solution was added m-chloroperbenzoic acid (0.55 g, 0.0027 mol) in one portion and the reaction mixture was stirred at 0° C. for 30 min. A cloudy yellow solution was obtained which was quenched by the addition of Ca(OH)2 (1 g, 0.0135 mol). The reaction mixture was stirred at room temperature for 15 min., filtered through a pad of Celite, and concentrated to obtain a yellow oil. Trituration with ether afforded 0.7 g of the title compound, m.p. 188°-190° C.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH3:22]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:22])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N
Reactant: O=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1

Procedure:
Boil (under reflux) 5 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde together with 7.6 g of activated manganese dioxide and 300 ml of toluene with the introduction of ammonia using a water-trap. Filter after 5 hours and then evaporate the filtrate to dryness in vacuo before recrystallizing three times from dimethylformamide and water to obtain 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile [m.p. 190° to 192° C].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][N:37]=[C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:35]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:36]6[CH:35]=[C:34]([CH3:33])[O:38][N:37]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cc(C2(N)CC2)no1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cc(C)on5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methylisoxazol-3-yl)cyclopropanamine (0.074 g, 0.5 mmol, 1.1 eq), HOBT (0.094 g, 0.69 mmol, 1.5 eq), EDC.HCl (0.0.13 g, 0.69 mmol, 1.5 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Preparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.1 g (39.22%). 1H NMR (400 MHz, CD3OD): δ 1.39-1.48 (m, 4H), 2.36 (s, 3H), 2.380-2.382 (d, 3H, J=0.8 Hz), 2.96 (s, 3H,), 4.05, (s, 3H), 6.05 (d, 1H, J=0.8 Hz), 7.12 (s, 1H), 7.26-7.34 (m, 3H), 7.58-7.59 (d, 1H, J=1.2 Hz), 7.62-7.64 (d, 1H, J=8.8 Hz), 7.81 (s, 1H), 7.96-7.98 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)+
Reaction SMILES: N1C=C[CH:3]=[C:2]1[C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[NH:8][N:7]=1.[N:17]1[CH:22]=C(B(O)O)C=[N:19][CH:18]=1>>[N:19]1[CH:3]=[C:2]([C:6]2[C:14]3[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH:22]=[N:17][CH:18]=1
Reactant: OB(O)c1cncnc1
Reactant: O=Cc1ccc2c(-c3ccc[nH]3)n[nH]c2c1
Product: O=Cc1ccc2c(-c3cncnc3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of 3-(1H-pyrrol-2yl)-1H-indazole-6-carbaldehyde, except substituting pyrimidin-5-ylboronic acid (34 mg, 0.15 mmol), the title compound was obtained as a beige solid (8.1 mg, 30%). 1H NMR (400 MHz, CD3OD) δ ppm 10.15 (s, 1H), 9.44 (s, 2H), 9.21 (s, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.23 (t, J=1.3 Hz, 1H), 7.84 (dd, J=8.5, 1.3 Hz, 1H); MS ESI 225.0 (100) [M+H]+, calcd for [C12H8N4O+H]+ 225.07.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (100 mg) in CHCl3 (3 mL) was treated with Et3N (0.090 mL), N-(tert-butoxycarbonyl)-D-phenylalanine (122 mg), EDCI (89 mg) and HOBt (62 mg). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was washed with 1 N aqueous NaOH solution (2 mL×2) and brine (2 mL). The organic layer was dried and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(tert-butoxycarbonyl)-D-phenylalanyl}aminomethyl]piperidine.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].C(OC([NH:26][CH2:27][CH:28]1[CH2:31][CH2:30][NH:29]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][N:29]1[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CC(C)(C)OC(=O)NCC1CCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC3CN)nc21
Yield: 51.5 %

Procedure:
A suspension of 1.08 g (4.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.93 g (5.0 mmol) of 2-[(t-butoxycarbonylamino)methyl]azetidine, 1.01 g (10 mmol) of triethylamine and 50 ml of acetonitrile was stirred at reflux for two hours. The solvent was removed in vacuo and the residue was dissolved in 25 ml of trifluoroacetic acid. After stirring at room temperature for two hours, the solvent was removed in vacuo. The residue was suspended in water and the pH adjusted to 11 with 10% sodium hydroxide. The resulting solution was filtered through a fiber glass pad to clarify and the filtrate acidified to pH 7.2 with 1 M hydrochloric acid. The resulting precipitate was removed by filtration, washed successively with water, ethanol, ether and dried in vacuo to give 0.66 g (52%) of the title compound, mp 198°-200° C.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.[Cl:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:25][CH2:26][S:27]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=2)[C:10](=[O:15])[CH2:11]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)CCl
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)CCl)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (3.78 g) and triethylamine (6.27 ml) in dichloromethane (50 ml) was added a solution of chloromethanesulfonyl chloride (2.68 g) in dichloromethane (10 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of 4-chloromethylsulfonyl-1-(4-cyanobenzyl)-2-piperazinone (4.01 g).
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=2[N:9]=1.Br[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17]>C(N(CC)CC)C>[C:19]1([CH:15]([S:4][C:5]2[S:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=2)[C:16]([OH:18])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Sc1nc2c(s1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C(Sc1nc2c(s1)CCCC2)c1ccccc1
Yield: 77 %

Procedure:
A methylene chloride solution of 5.13 g (0.03 m) 2-mercapto-4,5,6,7-tetrahydrobenzothiazole, 6.45 g. (0.03 m) α-bromophenylacetic acid and 6.0 g (0.06 m) triethylamine is heated to gentle reflux overnight. The solution is extracted twice with a dilute hydrochloric acid solution, once with water and is then dried over anhydrous MgSO4. The residual solid after solvent removal is recrystallized from acetonitrile. 7.0 g (77% yield) of title compound, melting at 118°-20° C., is obtained
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:36])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C(C)=O)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-acetylpiperazine. ES-MS m/e (%): 519 (M+Na+, 32), 497 (M+H+, 100).