Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1)=[O:42])[CH3:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([NH:49][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccccc1Oc1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
AMR01059 A solution of 2-(2,4-dichlorophenoxy)benzoic acid (AMR01057, 200 mg, 0.706 mmol) in dry DCM (10 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 406 mg, 2.12 mmol) and triethylamine (0.15 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and ethyl-4-amino-1-piperidine carboxylate (122 mg, 0.706 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 12 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel using DCM to DCM/MeOH 9:1 gradient as eluent gave 4-[2-(2,4-dichlorophenoxy)benzoylamino]piperidine-1-carboxylic acid ethyl ester (140 mg, 45%) as a white solid. Rf: 0.62 (DCM/MeOH 9:1) 1H NMR (300 MHz, CDCl3) 11.26 (3H, t, J=7.1 Hz, CH3), 1.40 (2H, m, CH2), 1.97 (2H, m, CH2), 3.00 (2H, m, CH2), 4.03 (2H, m, CH2), 4.13 (2H, q, J=7.1 Hz, CH3CH2O), 4.19 (1H, m, CH), 6.80 (1H, dd, J=8.2, 0.9 Hz, ArH), 6.90 (1H, d, J=8.8 Hz, ArH), 7.24 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.27 (1H, m, ArH), 7.36 (1H, br s, NH), 7.42 (1H, m, ArH), 7.53 (1H, d, J=2.5 Hz, ArH) and 8.19 (1H, dd, J=7.8, 1.8 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([NH:19][C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([NH:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:21]=1)[CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[CH2:16]([NH:19][C:20]1[C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:15])[C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH:3]=2)=[O:27])=[CH:24][N:23]=[C:22]([NH:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[N:21]=1)[CH2:17][CH3:18]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Reactant: CN(C(=O)C(F)(F)F)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)Nc1cccc(N(C)C(=O)C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 26.8 %

Procedure:
To N-(3-aminophenyl)-2,2,2-trifluoro-N-methylactamide (302 mg) synthesized according to the method described in U.S. Pat. No. 6,344,465 B1, 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 627 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (545 mg) and 1-hydroxybenzotriazole monohydrate (377 mg), N,N-dimethylformamide (15 mL) and triethylamine (766 μL) were added at room temperature, the reaction vessel was sealed, and then the mixture was stirred at 100° C. for 40 minutes by using a microwave reaction system. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 97 to 96% ethyl acetate in methanol) to obtain 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)-N-(3-(2,2,2-trifluoro-N-methylacetamido)phenyl)pyrimidine-5-carboxamide (A7, 186 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[NH:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>O=P(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:13]([Cl:20])=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1

Procedure:
A stirred mixture of 2-benzyl-5-methoxy-2H-1,2,4,6-thiatriazin-3-one-1,1-dioxide (10.5 g) and PCl5 (12.2 g) in POCl3 (35 ml) is refluxed overnight. The reaction mixture is evaporated in vacuo at 50° C. affording the crude product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.Cl[C:37]1[N:38]=[N:39][CH:40]=[C:41]([O:43][CH3:44])[CH:42]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:37]3[N:38]=[N:39][CH:40]=[C:41]([O:43][CH3:44])[CH:42]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:11]2=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3nc(-c4ccccc4F)ccc32)cc1
Reactant: COc1cnnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cnnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4ccccc4F)nc23)c1
Temperature: 105 °C
Yield: 16.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridine (102 mg, 0.208 mmol) and 3-chloro-5-methoxypyridazine (30 mg, 0.208 mmol) in p-dioxane/H2O (4:1, 1.5 mL) followed by potassium phosphate (88 mg, 0.415 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (7.35 mg, 10.38 μmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 105° C. for 1 h. The mixture was diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-35% EtOAc in Hex) to give 5-(2-fluorophenyl)-3-(5-methoxypyridazin-3-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridine (16 mg, 0.034 mmol, 16.25% yield) as a brown solid. MS (ESI, pos. ion) m/z: 475.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19].O=P(Cl)(Cl)Cl>>[Cl:19][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:16]=1
Reactant: O=c1[nH]c(-c2ccncc2)nc2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccncc2)nc2ccccc12
Yield: 60 %

Procedure:
2-Pyridin-4-ylquinazolin-4(3H)-one (1 mmol) and PCl5 (1.5 mmol) were suspended in POCl3 (12 mmol). The reaction mixture was brought to reflux over 4 h. The solvent was concentrated to dryness and the amorphous residue was partitioned with ethyl acetate and ice water. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with 10% Na2CO3 and brine and dried over magnesium sulfate. The filtrate was concentrated and dried in vacuo to afford the desired product as a brown solid. (60% yield). 1H NMR (400 MHz, d6-DMSO): δ 8.84 (d, 2H), 8.36 (d, 2H), 8.12 (m, 2H), 7.88 (m, 2H). MS (EI) for C13H8ClN3: 242 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([OH:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:38].[N:39]1([CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:38].[CH3:37][C:2]1([CH3:1])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([O:30][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(2-eicosyl)-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: CN(C)C(=O)[O:4][CH:5]([C:12]1[N:13]([CH3:33])[C:14]([C:23]2[S:24][C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH2:32])[C:30]=3[N:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1.CN(C)C(=O)OC(C1N(C)C(C2SC3N=CN=C(N)C=3N=2)=C(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[NH2:32][C:29]1[C:30]2[N:31]=[C:23]([C:14]3[N:13]([CH3:33])[C:12]([CH:5]([C:6]4[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=4)[OH:4])=[N:16][C:15]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:24][C:25]=2[N:26]=[CH:27][N:28]=1
Reactant: CN(C)C(=O)OC(c1nccn1C)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Agent: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Product: Cn1ccnc1C(O)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C

Procedure:
The title compound was prepared by a similar process to that described for Example 104 but using [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](1-methyl-1H-imidazol-2-yl)methyl dimethylcarbamate (Intermediate 101) in place of [5-(7-amino[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1-methyl-4-phenyl-1H-imidazol-2-yl](phenyl)methyl dimethylcarbamate (Intermediate 97). Colourless solid (20 mg, 82%);
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([C@@H:16]1[NH:20][C:19](=[O:21])[CH2:18][C@@:17]1([OH:23])[CH3:22])[CH3:15].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:14]([C@H:16]1[C@:17]([OH:23])([CH3:22])[CH2:18][C:19](=[O:21])[N:20]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH3:15]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: CC[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C[C@]1(C)O

Procedure:
Using 4-iodo-2-(trifluoromethyl)benzonitrile (605 mg), (4S,5S)-5-ethyl-4-hydroxy-4-methylpyrrolidin-2-one (350 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (180 mg), 5 tris(dibenzylideneacetone)dipalladium(0) (93 mg) and cesium carbonate (929 mg), and in the same manner as in Example 62, the title compound was obtained as a white powder (yield: 422 mg, 66%).
Reaction SMILES: O.O.Cl.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.C(O[CH:20]=[C:21]([CH3:24])[CH:22]=O)C.C[O-].[Na+]>CO>[CH3:24][C:21]1[CH:20]=[N:11][C:10]([C:9]2[CH:13]=[CH:14][C:6]([C:5]([F:15])([F:16])[F:4])=[CH:7][CH:8]=2)=[N:12][CH:22]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A sample of 4-trifluoromethylbenzamidine hydrochloride dihydrate (Maybridge, 15.2 g, 58 mmol) was dissolved in 100 mL of methanol and 3-ethoxy-2-methylacrolein (Janssen, 7.8 g, 64 mmol) was added. Sodium methoxide (25% solution in methanol, 14.7 mL) was added and the mixture was heated at 50° C. for 3 h. The cooled reaction mixture was then dded to 500 ml of ice water and stirred for 30 minutes. The white solid was filtered, air dried, dissolved in 300 mL of dichloromethane and dried over magnesium sulfate. The solvent was removed under reduced pressure to yield, after trituration with hexanes, 12.5 g of the product as a white solid melting at 143-146° C. 1H NMR (CDCl3): δ2.37 (s, 3H), 7.73 (d, 2H), 8.53 (d, 2H), 8.66 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([N:14]2[C:19](=O)[CH2:18][O:17][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=3)[CH2:15]2)[CH3:13])=[CH:7][CH:6]=1.CC(C)=O>O1CCCC1.B.O1CCCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[N:22]=3)[CH2:15]2)[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(Cc1ccc(OCCO)cc1)N1CC(c2cccc(Cl)n2)OCC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(Cc1ccc(OCCO)cc1)N1CCOC(c2cccc(Cl)n2)C1
Reaction time: 20 h

Procedure:
0.7 g of N-[2-(4-(2-hydroxyethoxy)-phenyl)-1-methylethyl]-2-(6-chloro-pyridin-2-yl)-morpholin-5-one are dissolved in 20 ml of tetrahydrofuran and over a period of 3 hours at ambient temperature 3 times 4 ml of a 1 molar borane/tetrahydrofuran solution are added. Then 30 ml of acetone are added and the mixture is evaporated down. The residue is dissolved in 100 ml of methanol and stirred for 20 hours. The solvent is distilled off in vacuo and the residue is purified over a silica gel column with ethyl acetate as eluant.
Reaction SMILES: CO[C:3]([CH:5](Br)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:13]([NH2:16])[CH2:14][NH2:15].C[O-].[Na+]>CO>[C:6]1([CH:5]2[NH:16][CH2:13][CH2:14][NH:15][C:3]2=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: NCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCCNC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
Methyl bromophenyl acetate (25 g, 109 mmol) and ethylene diamine (13.1 g, 218 mmol) were mixed in dry MeOH (180 mL) and stirred at room temperature for 15 minutes under nitrogen. Sodium methoxide (6.5 g, 120 mmol) was added in one portion and the mixture heated to reflux for 3.5 hr. The mixture was left stirring overnight at room temperature. The solvent was evaporated in vacuo to give a pale yellow gum, which was partitioned between water (100 mL) and chloroform (100 mL), the pH of the aqueous phase was adjusted with 2M HCl to pH 7.5 and extracted with more chloroform (100 mL). The combined organic phases were dried (MgSO4) and evaporated to give the title compound as a pale yellow solid (17 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=1.CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][C:13]2[CH:12]=[C:11]([CH3:10])[NH:15][N:14]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2C)n[nH]1
Temperature: 70 °C

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (1.25 g, 7.8 mmol) in EtOH (30 ml) was added 5-methyl-1H-pyrazol-3-ylamine (756 mg, 7.8 mmol) and DIPEA (2.8 mL). The mixture was heated at 70° C. overnight. LC/MS showed the completion of the reaction. The title compound was obtained by filtration under vacuum as a white solid (700 mg). m/z 224.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:16]([CH:17]=O)=[N:15][N:14]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C:11]2=[N:12][CH:13]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[NH2:32].[S]>CN(C=O)C>[N:32]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[NH:25][C:17]=1[C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:9]=2)[N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1
Reactant: Nc1ccncc1N
Reactant: Cc1ccncc1-c1cnc2c(c1)c(C=O)nn2C1CCCCO1
Agent: [S]
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1cnc2c(c1)c(-c1nc3ccncc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C

Procedure:
A solution of 5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (LVII) (0.120 g, 0.37 mmol), 3,4-diaminopyridine (LVIII) (42 mg, 0.39 mmol) and sulfur (13 mg, 0.39 mmol) in dry DMF (5 mL) was heated at 140° C. under nitrogen for 12 h. The solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water (1×20 mL). The organic layer was dried over MgSO4, filtered and concentrated to yield 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (LIX). The crude product was used directly for step 3 without further purification. ESIMS found for C23H21N7O m/Z 412.7 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20](I)[CH:19]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:27]([C:29]1[N:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]2=[N:31][CH:30]=1)#[CH:28]>>[N:1]1([C:6]2[CH:7]=[C:8]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:28]#[C:27][C:29]4[N:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]5=[N:31][CH:30]=4)[CH:19]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12

Procedure:
The titled compound was made as for example 1 using N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide and 3-ethynylimidazo[1,2-a]pyridine: MS (M+H)+ 486. The titled compound can also be prepared according to the alternative synthesis described in example 1 from 3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-methylbenzoic acid and 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (as prepared in Example 1). The 3-(imidazo[1,2-a]pyridin-3-ylethynyl)-4-methylbenzoic acid is prepared in a manner similar to that described in Example 1 using 3-Ethynylimidazo[1,2-a]pyridine and 3-iodo-4-methylbenzoic acid as Sonogashira coupling partners.
Reaction SMILES: [CH2:1]([N:8]([O:20][CH3:21])[C:9](=[O:19])[CH:10]=[C:11]1[C:15](=[O:16])[O:14]C(C)(C)[O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]([O:20][CH3:21])[C:9]([CH:10]=[C:11]([OH:12])[C:15]([OH:16])=[O:14])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(Cc1ccccc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CON(Cc1ccccc1)C(=O)C=C(O)C(=O)O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of N-benzyl-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.267 g, 0.917 mmol) in tetrahydrofuran (10 ml) was treated at 22° C. with 2 ml (2 mmol) of 1 M aqueous sodium hydroxide. After 1 h, the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and the solvent evaporated in vacuo to give 0.220 g (95% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm) : 3.70 (3H, s), 4.85 (2H, s), 6.57 (1H, s), 7.32-7.37 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[Cl:21]C1C=CC(NC2C=CC=CC=2)=C(C=1)C(O)=O.C1(NC2C=CC=CC=2C(O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][C:10]([Cl:21])=[CH:9][CH:8]=2)=[O:4]
Reactant: O=C(O)c1cc(Cl)ccc1Nc1ccccc1
Reactant: COC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Agent: O=C(O)c1ccccc1Nc1ccccc1
Product: COC(=O)c1c(O)c2cc(Cl)ccc2n1-c1ccccc1

Procedure:
Prepared in a manner analogous to the multistep procedure described [P. Friedlander and K. Kunz, Chem. Ber., 55, 1597 (1922)] for the preparation of 3-hydroxy-1-phenyl-1H-indole-2-carboxylic acid methyl ester, with 5-chloro-2-(phenylamino)benzoic acid substituted for 2-(phenylamino)benzoic acid in the first step of the synthetic sequence. The final indole product was recrystallized from aqueous 2-methoxyethanol to yield analytically pure product, mp 170°-173° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:14]([CH2:18][C:19]#[CH:20])[C:15](=O)[CH3:16])(C)(=O)=O>CO>[NH2:8][C:7]1[C:2]2[N:3]([C:14]([CH2:18][C:19]#[CH:20])=[C:15]([CH3:16])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1N
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Solvent: CO
Product: C#CCc1c(C)nc2c(N)cccn12
Yield: 17.3 %

Procedure:
A mixture of 2,3-diaminopyridine (62.8 g) and 3-mesyloxy-5-hexyn-2-one (109.5 g) in methanol (126 ml) was refluxed for 20 hours. After methanol was evaporated in vacuo, sodium bicarbonate aqueous solution was added to the residue and then the mixture was extracted with ethyl acetate, washed with water and sodium chloride aqueous solution, and evaporated in vacuo. The resultant residue was subjected to column chromatography on silica gel (310 g) and eluted with a mixture of methylene chloride and acetonitrile. The eluates containing the object compound were combined and evaporated in vacuo. The residue was suspended in diethyl ether and the resultant precipitates were collected by filtration to give 8-amino-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (18.42 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][C:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)=[CH:28][CH:27]=1)([OH:25])[CH2:23][OH:24]>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:22]([OH:25])([CH2:21][OH:20])[CH2:23][OH:24])=[CH:31][CH:30]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(O)(CO)CO)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred THF (10 mL) solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (102 mg, 0.33 mmol, 1.0 eq), TEA (0.1 mL, 0.66 mmol, 2.0 eq) followed by compound phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (100 mg, 0.33 mmol, 1.0 eq) was added at RT and the mixture stirred for 16 h, then it was concentrated under vacuum and the residue was purified by CC using MeOH/CHCl3 (3:17) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,2,3-trihydroxypropan-2-yl)phenyl)urea (120 mg; 75%, white solid; TLC system: MeOH/CHCl3 (1:4); Rf: 0.3).