Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[N:36]#[C:37]Br>CO>[NH2:36][C:37]1[N:21]([C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:31])=[O:32])[CH2:23]2)[C:3]2=[C:4]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=4)(=[O:12])=[O:13])[C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: N#CBr
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1c(N)nc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To a solution of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.200 g, 0.301 mmol, Example #23 Step I) in MeOH (3.0 mL) was added cyanogen bromide (5 M in MeCN, 0.482 mL, 2.41 mmol) dropwise. The reaction was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-((1S,3S,4R)-3-(2-amino-6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-ethylcyclopentyl)cyclopropane-sulfonamide (0.11 g, 67%) as a brown solid: LC/MS (Table 1, Method a) Rt=2.00 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].[NH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH2:21])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: N
Product: CC1(C)C(=O)C(C(N)=O)=C(O)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
Ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.19 g, 4038 μmol, see Example 2) was dissolved in ammonia (0.5M in 1,4-dioxane (40376 μL, 20188 μmol)), and the resulting mixture was heated at 70° C. for 16 hours. The reaction mixture was then concentrated, dissolved in MeOH and ammonium hydroxide, and stirred at ambient temperature for 16 hours. The reaction mixture was then heated at 80° C. for 16 hours. The reaction mixture was concentrated, suspended in DCM, filtered, and washed with DCM. The mother liquor was purified via preparatory LC to give the title compound (31 mg) as an off-white solid. MS m/e=266 (M+H)+. Calculated for C13H12ClNO3 265.09.
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18](I)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1>>[CH:1]([N:14]1[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:17](=[O:21])[NH:16][C:15]1=[O:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1I
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cn(C(c3ccccc3)c3ccccc3)c(=O)[nH]c2=O)cc1
Yield: 50.3 %

Procedure:
The title compound was obtained according to the procedure: described for the synthesis of Example 14 (Step 2), starting from 1-benzhydryl-5-iodo-pyrimidine-2,4-dione (0.11 g, 0.27 mmol) and p-tolylboronic acid (0.06 g, 0.41 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 75:25) to afford the title compound (0.05 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 7.11-7.15 (m, 3H), 7.20-7.24 (m, 6H), 7.34-7.44 (m, 6H), 8.16 (s, 1H). MS (ESI) m/z: 369 [M-H]−.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:6])=[O:5])[CH3:3].[O:14]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.O>[OH:13][C:9]1([C:24]2[CH:25]=[CH:26][C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)NC1CCCC1=O
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Into a flame dried 250 mL 3 neck flask that was fitted with a thermometer and condenser, and while stirring at room temperature under a nitrogen atmosphere, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.00 g, 4.9 mmol) in THF (40 mL) was added dropwise to 15 mL of 0.5 M 4-phenoxyphenylmagnesium bromide. The addition of 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was continued dropwise, keeping the temperature above 35° C. After the addition of 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one was complete, the reaction was stirred overnight at room temperature. Enough saturated ammonium chloride in water was then added to precipitate salts and the organic layer was decanted off. The remaining salts were washed two times with ether and the combined organic layers were concentrated under reduced vacuum. The resulting semi-solid was taken into ethyl acetate, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 2.14 g of as a dark oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 while eluting with a solvent of hexane/ethyl acetate 7:3 to provide the title compound (540 mg) as a white solid. Ion spray M.S. 374.1 (M*−1). Calculated for C20H25NO4S: Theory: C, 63.98; H, 6.71; N, 3.73. Found: C, 63.70; H, 6.77; N, 3.55.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccccc1CBr
Yield: 104.2 %

Procedure:
To 1-tert-butyl-2-methyl-benzene (940 mg, 6.34 mmol), NBS (1.24 g, 1.1 eq) and AIBN (20 mg, catalytic amount) was added CCl4 (12 mL), which was then refluxed for 1 h. The suspended particles were removed by filtration, and washed with CCl4. The organic layers were combined and concentrated under reduced pressure to give 1.5 g of a yellow liquid in a stoichiometric yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[C:29]([O:32][C:33](=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C

Procedure:
To 56 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one were added 1 ml of acetic anhydride and 1 ml of pyridine and the mixture was stirred at room temperature for one night. The reaction solution was concentrated in vacuo and purified by an NH silica gel chromatography (hexane-ethyl acetate system) to give 30 mg of the title compound.
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH3:19]O>>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:19])=[O:11])=[C:8]([C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1C(F)(F)F
Yield: 64 %

Procedure:
SOCl2 (1.1 mL, 14.62 mmol, 1 equiv.) was added to a solution of 4-amino-2-trifluoromethylbenzoic acid (3 g, 14.62 mmol, 1 equiv.) in 40 mL of MeOH and the reaction mixture was refluxed overnight. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with sat. NaHCO3 (×2), brine and dried over MgSO4, and concentrated to give 2.06 g (Yield=64%) of product as a clear oil.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:22]2[CH2:27][CH2:26][N:25](C(OCC)=O)[CH2:24][CH2:23]2)[C:11](=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:6][CH:5]=1>CC(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:11](=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)N1CCC(N(C(=O)Cc2cccc(OC)c2)c2ccc(Cl)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cccc(CC(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1

Procedure:
To a stirred and warm (40° C.) solution of 12 parts of potassium hydroxide in 200 parts of 2-propanol are added at once 21 parts of ethyl 4-{N-(4-chlorophenyl)-N-[(3-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylate and the whole is stirred and refluxed for 17 hours. The reaction mixture is cooled, filtered and evaporated. The semi-solid residue is acidified with a diluted hydrochloric acid solution, washed with 1,1'-oxybisethane and the aqueous acid phase is alkalized with sodium hydroxide solution. The free base is extracted with trichloromethane. The extract is dried and evaporated. The residue is crystallized from a mixture of 1,1'-oxybisethane and hexane, yielding 7.8 parts of N-(4-chlorophenyl)-3-methoxy-N-(4-piperidinyl)benzeneacetamide; mp. 85.7° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.N1C=CC=CC=1.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[CH:5]=[CH:4]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C[C@H](CO)O1
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1C=C[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reaction time: 6 h
Yield: 90.3 %

Procedure:
(R)-(+)-5-Hydroxymethyl-2 (5H)-furanone (1.94 g, 17.0 mmol) was dissolved in anhydrous pyridine (60 mol), triphenylmethyl chloride (14.3 g, 51.2 mmol) was added to the solution at room temperature, and the mixture was stirred for 6 hr. Ethanol was added to the reaction solution at 0° C., and the mixture was stirred for one hr. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to azeotropic distillation twice with toluene and purified by column chromatographic separation on silica gel (hexane:ethyl acetate=3:1 to 2:1) to give (R)-(+)-5-triphenylmethyloxymethyl-2 (5H)-furanone (5.47 g, 90%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CO>[F:14][C:2]([F:13])([F:1])[C:3]([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH2:8]1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCOC(CNC(=O)C(F)(F)F)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 1 (6.37 g) in methanol (250 ml) under nitrogen was added benzylchloroformate (4.7 ml) and triethylamine (6.3 ml). The mixture was stirred at 22° C. for 1 h before the volatiles were removed in vacuo. The residue was purified by Biotage flash chromatography on a 90 g silica cartridge eluting with 33% ethyl acetate in cyclohexane, to give the title compound as a white solid (4.4 g).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:22]=[C:21]([C:23](=[O:26])[NH:24][CH3:25])[CH:20]=[C:19]([Cl:27])[C:18]=1[C:28](Cl)=[O:29]>>[Cl:16][C:17]1[CH:22]=[C:21]([CH:20]=[C:19]([Cl:27])[C:18]=1[C:28]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:14][CH2:15]3)=[O:12])[CH:9]=2)[NH:1][CH:2]=1)=[O:29])[C:23]([NH:24][CH3:25])=[O:26]
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Reactant: CNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: CNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3cnc(NC(=O)C4CC4)cc23)c(Cl)c1

Procedure:
3,5-Dichloro-4-({5-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)-N-methylbenzamide was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,6-dichloro-4-(methylcarbamoyl)benzene carbonyl chloride (Compound No. 20).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[CH3:24]I>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:24])[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: CI
Reactant: CSc1c(CC(=O)OC(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)C)cc(C)c2c3ccccc3n(C)c12
Yield: 80 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using isopropyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and methyl iodide as starting materials, the title compound was obtained in a yield of 80% as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=CN(C(C)C)C(C)C)[N:3]=1.[CH2:26]([CH2:28][NH2:29])[OH:27]>C(O)C>[NH2:17][C:4]1[N:3]=[C:2]([NH:29][CH2:28][CH2:26][OH:27])[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: NCCO
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Solvent: CCO
Product: Nc1ncc(C#Cc2ccc(Cl)cc2)c(NCCO)n1

Procedure:
A mixture of 0.7 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneamino-pyrimidine, 20 mL ethanol and 0.6 mL ethanolamine was refluxed for 18 hours. The green solution was evaporated in vacuo and triturated with water. The insoluble yellow residue was recrystallized by dissolving in 35 mL hot methanol, concentrating to 10 mL and chilling. The pale yellow powdery precipitate was filtered and dried to yield 0.34 g of 2-amino-5-(4-chlorophenylethynyl)-4-(2-hyroxyethylamino)pyrimidine, m.p. 197–200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=N1.Br[CH2:25]C1C=CC(C2OC3C=CC=CC=3N=2)=CC=1OC.N1C=CN=C1>>[N:10]1([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:4][C:3]=2[O:2][CH3:1])[CH:14]=[CH:13][N:12]=[CH:25]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: c1c[nH]cn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnc1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and imidazole (70 mg, 1.0 mmol) afforded the desired 2-[4-(1H-imidazol-1-ylmethyl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.57–7.86 (m, 6H), 7.26–7.40 (m, 4H), 5.53 (s, 2H), 4.02 (s, 3H). MS (ESI) 306 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[O:3][CH2:1][CH3:2])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: CCOc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4ethoxybenzoic acid (3.6 g, 0.022 mol) in chloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:13]1([C@H:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Reactant: OB(O)c1ccncc1
Product: c1ccc([C@H](Oc2ccccc2-c2cccnc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-pyridin-3-yl-phenoxy)-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and 4-pyridineboronic acid according to general procedures A and B and was isolated as a gummy oil. MS (APCI): 347 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17](F)(F)[F:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[F:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]2[N:47]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][F:18])=[CH:13][CH:12]=3)[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:46]=2)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(F)c2)nc1-c1ccc(CF)cc1

Procedure:
The title compound was prepared from crude ethyl 3-dimethylamino-2-(4-trifluoromethyl-benzoyl)-acrylate (142 mg, 0.45 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (121 mg, 0.34 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (128 mg, 78%). Mp 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH:24]=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:30]1([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH:35][C:33]([CH:30]4[CH2:32][CH2:31]4)=[O:34])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)C1CC1
Reactant: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12)C1CC1
Reaction time: 8 h

Procedure:
A mixture of the title compound of Step B (127 mg, 0.29 mmol), cyclopropanecarboxamide (74 mg, 0.87 mmol), trifluoroacetic acid (0.07 mL, 0.87 mmol) and triethylsilane (0.14 ml, 0.87 mmol) in toluene (2 mL) was gently refluxed overnight. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title compound, a compound of this invention, as a white foamy solid (113 mg, 77% yield).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=2)[C:20]#[N:21])=[O:16])[C:12]([CH2:26][CH3:27])=[C:11]([O:28]CC2C=CC=CC=2)[N:10]=1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[CH2:26]([C:12]1[C:11](=[O:28])[NH:10][C:9](=[O:8])[NH:14][C:13]=1[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:20]#[N:21])=[O:16])[CH3:27]
Reactant: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(=O)c1cc(C)cc(C#N)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1c(C(=O)c2cc(C)cc(C#N)c2)[nH]c(=O)[nH]c1=O
Reaction time: 1.5 h
Yield: 738.8 %

Procedure:
3-(2,6-Bis-benzyloxy-5-ethyl-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (41) (4.5 g, 9.7 mmol) in anhydrous ethanol (30 ml) and THF (30 ml) was stirred with 10% palladium on carbon (250 mg) under an atmosphere of hydrogen. After 1.5 hr, the mixture was filtered through celite pad and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, chloroform:methanol (95:5)) to afford 20.3 g (84%) of a white solid; m.p. 253-254° C.; 1H NMR (200 MHz, DMSO-d6) δ: 0.84 (3H, t, J=7.0 Hz), 1.96 (2H, q, J=7.0 Hz), 2.45 (3H, s), 8.06 (1H, s), 8.11 (1H, s), 8.33 (1H, s), 11.05 (1H, s), 8.28 (1H, s); m/z (EI): 283 (M+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O-:19])=[O:18])=[C:15]([OH:20])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:27][C:28]#[N:29]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:10])=[O:18])=[C:15]([O:20][CH2:27][C:28]#[N:29])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: N#CCBr
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC#N

Procedure:
6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 120) and bromoacetonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[CH:5][CH:4]=[N:3]1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@H:30]([NH2:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)[C@H:30]([NH:41][C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[N:9][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:17]3)=[O:20])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2N)cc1
Reactant: Cn1nccc1Nc1cc2cc(C(=O)O)ccc2cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2NC(=O)c2ccc3cnc(Nc4ccnn4C)cc3c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
A 2-5 mL microwave vial equipped with a stirring bar was charged with 92 (94 mg, 0.3506 mmol, 1.1 equiv), (3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-amine (90 mg, 0.3187 mmol, 1.0 mmol, CASRN 114616-86-5), DMF (2.0 mL) and HATU (187.4 mg, 0.4780 mmol, 1.5 equiv). The reaction mixture was stirred 20 min at RT and treated with TEA (0.1347 mL, 0.956 mmol, 3.0 equiv). The microwave vial was capped, and the reaction was stirred for 2 h at RT. The DMF solution was partitioned between EtOAc and water (120 mL/40 mL). The EtOAc layer was washed twice with brine, dried, filtered, and concentrated to give a crude oil. A portion of the crude (20%) was purified by RP HPLC to give 3.5 mg of N-((3S,4R)-1-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-yl)-3-((1-methyl-1H-pyrazol-5-yl)amino)isoquinoline-6-carboxamide (purity=100%, 254 nM). The remainder of the crude (80%) was purified on a SiO2 column (ISCO) eluting with a MeOH/DCM gradient (2 to 8% MeOH) to afford an additional 48 mg (total 51.5 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.87 (s, 1H), 8.80 (d, J=7.5 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.34 (q, J=7.7 Hz, 4H), 7.26 (d, J=8.1 Hz, 3H), 6.92 (s, 1H), 6.86 (d, J=8.4, 2H), 6.23 (s, 1H), 4.49-4.43 (m, 1H), 3.76 (s, 3H), 3.70 (s, 3H), 3.62 (d, J=10.4 Hz, 1H), 3.43 (q, J=7.5 Hz, 1H), 3.04 (m, 2H), 2.60 (m, 2H). LCMS M+H+=534.