Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=3)[C:2]2=[NH:1])=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc2ccccc2[nH]1
Product: N=c1n(Cc2ccc(Cl)cc2)c2ccccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound was prepared from 2-aminobenzimidazole and 4-chlorobenzyl chloride by Procedure A. The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 185-187° C.). MS(ES+) m/z 382 (M+, 100). 1NMR (DMSO-d6) δ 5.08 (br s, 4H), 5.76 (s, 1H), 6.80-6.90 (m, 4H), 7.25-7.42 (m, 8H).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])[C:6](=C)[CH2:7][S:8][C@H:3]12.C[OH:26]>>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([OH:26])[CH2:7][S:8][C@H:3]12
Reactant: CO
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12

Procedure:
In a further example, p-nitrobenzyl 7-amino-3-methylenecepham-4-carboxylate 1 hydrochloride is dissolved in methanol and ozone is bubbled through the solution at a temperature of about -78° C. Excess ozone is purged from the mixture with nitrogen and the ozonide is decomposed by bubbling sulfur dioxide through the mixture. The reaction mixture is evaporated to dryness and the residue, p-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate is obtained as the hydrochloride salt.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=CN=[CH:9][CH:8]=2)[CH:2]=1.[N:13]1C=CC(C2C=CN=CC=2)=C[CH:14]=1.N1C2C(=CC=CC=2)C=CC=1.C1C2C(=CC=CC=2)C=CN=1>>[N:13]1[CH:14]=[CH:9][CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: c1cncc(-c2ccncc2)c1
Solvent: c1ccc2cnccc2c1
Solvent: c1ccc2ncccc2c1
Product: c1cncc(-c2cccnc2)c1

Procedure:
3,4'-bipyridine; 4,4'-bipyridine; quinoline; isoquinoline;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([OH:26])=[O:25])#[N:2].C[O-].[Na+:29]>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O-:26])=[O:25])#[N:2].[Na+:29]
Reactant: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(CC(=O)[O-])c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Reaction time: 0.33 h

Procedure:
5-Cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid (1.6 g.) in methanol (10 ml.) is added to a solution of sodium methoxide (0.27 g.) in methanol (5 ml.). The reaction mixture is stirred for 20 minutes and evaporated to dryness to yield sodium 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[N:16]([CH2:19][CH:20]([OH:25])[CH2:21][N:22]=[N+:23]=[N-:24])=[N+:17]=[N-:18]>C(Cl)CCl>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([O:25][CH:20]([CH2:21][N:22]=[N+:23]=[N-:24])[CH2:19][N:16]=[N+:17]=[N-:18])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: [N-]=[N+]=NCC(O)CN=[N+]=[N-]
Solvent: ClCCCl
Product: [N-]=[N+]=NCC(CN=[N+]=[N-])OC(=O)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Yield: 73.5 %

Procedure:
A solution of 25g (0.1 mole) of 4,4,4-trinitrobutyryl chloride, 14.7g (0.1 mole) of 1,3-diazido-2-propanol, and 50 ml of ethylene dichloride was refluxed for one week. The solution was cooled, washed with water, dried, and concentrated to give 25.5g (73.5%) of amber liquid. The product was purified by dissolving in carbon tetrachloride and passing through a neutral alumina column. Concentration of this solution gave a yellow liquid, nD24 = 1.5029, d25 = 1.464. The infrared spectrum showed the expected strong absorption for azide (4.7μ), carbonyl (5.8μ), and nitro (6.2μ).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C1N2CN3CN(C2)CN1C3.CO.S(=O)(=O)(O)[OH:24]>C(O)(=O)C.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Yield: 45 %

Procedure:
3.9 g of p-cyanobenzylamine, 4.2 g of hexamethylenetetramine, 15 ml of methanol, 15 ml of water and 8 ml of acetic acid were mixed and after adjusting the pH of the solvent to 3 by sulfuric acid, the mixture was reacted at 70° C. for 5 hours while stirring. The reaction solution was concentrated to a half amount in an evaporator and 20 ml of water was added to precipitate crystals. The crystals precipitated were collected by filtration, washed with water and dried to obtain 1.8 g (yield: 45%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[N:7][CH:8]=1.Br[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1>>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:27]=[C:26]2[C:22]([C:23]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:24]=3[N:25]2[S:28]([C:31]2[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=2)(=[O:30])=[O:29])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)cn6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Yield: 40.2 %

Procedure:
4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (200 mg, 0.830 mmol) and tert-butyl 7-bromo-9-tosyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (419 mg, 0.830 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (222 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.26 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 7.80 (br s, 2H), 7.57 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.27 (3H, under solvent peak), 7.07 (d, J=6.8 Hz, 1H), 4.91 (br m, 2H), 3.71 (br m, 2H), 2.71 (br m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([CH:30]1[CH2:32][CH2:31]1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:30]1([CH:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=3)=[O:11])[C:6]([OH:33])=[O:5])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NCC(C(=O)O)C1CC1)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
A mixture of 2-cyclopropyl-3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid tert-butyl ester (52 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h; then the mixture was concentrated and resulting residue was treated with water; the solids were collected via filtration and air dried to give desired product as white solids (37 mg). LC-MS ESI+: 393 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[N:12]O)[CH2:5]2.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]([OH:11])=[O:21])=[C:4]([CH2:5][C:6]#[N:12])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C(=NO)Cc2cc(Br)ccc21
Product: N#CCc1cc(Br)ccc1C(=O)O

Procedure:
Similar procedure as described in example 9B was used, starting from 5-Bromo-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 4-Bromo-2-cyanomethyl-benzoic acid. LC-MS: m/e 238 (M−1).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)=[O:5].[CH3:28][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:5])[CH3:28])[C@@H:7]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3S,4R)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as light brown solid. MS (m/e): 330.3 [(M+H)+].
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[N:20]4[C:21](=[N:26][CH:27]=[C:19]4[C:18]2=[O:28])[CH:22]=[CH:23][CH:24]=3)CC1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH:17]1[CH2:18][CH2:13][CH:12]([CH2:11][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[N:20]4[C:21](=[N:26][CH:27]=[C:19]4[C:18]2=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(=O)c3cnc4cccc2n43)CC1
Agent: Cl
Solvent: CCO
Product: O=c1c2cnc3cccc(n1CCCCC1CCNCC1)n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution prepared by dissolving 3.82 g (9.94 mM) of 1,2-dihydro-1-[3-(1tert-butoxycarbonylpiperidin-4-yl)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 50 ml of ethanol was added 10 ml (122 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting precipitate was recovered by filtration. The precipitate was rinsed with small amounts of ethanol and ether to provide 2.99 g (yield 84.5%) of the title compound as brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:26])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: CSc1ccc2c(c1)N(c1ccccc1)C(=O)Cc1nnc(C)n1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnc2n1-c1ccc(S(C)=O)cc1N(c1ccccc1)C(=O)C2

Procedure:
3.36 g of 1-methyl-8-(methylthio)-6-phenyl-4-H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 2.14 g of sodium metaperiodate in 500 ml methanol is stirred at +5° C for 24 hours. The reaction is evaporated; the residue dissolved in methylene chloride, washed with water, dried and concentrated. The concentrate is chromatographed on silica gel (20-1000μ plates, 20 × 20 cm) using acetone-methanol (9:1) as eluting solvent. The band containing the product is removed, stirred with acetone-methanol (4:1) and the silica gel filtered off. The filtrate is evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH:10]([Mg]Br)([CH3:12])[CH3:11]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[Mg]Br
Reactant: O=Cc1cnccc1Br
Solvent: C1CCOC1
Product: CC(C)C(O)c1cnccc1Br
Reaction time: 0.25 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 1.0 M isopropyl-magnesium bromide solution in THF (3.23 mL). After 15 min, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purification by flash chromatography eluted with 50% ethyl acetate in hexane to yield 1-(4-bromo-pyridin-3-yl)-2-methyl-propan-1-ol as slight yellow crystals.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3Cl)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35](B(O)O)=[C:34]([O:44][CH3:45])[CH:33]=1.[OH-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.N#N>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCC>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:35]3[CH:36]=[C:37]([CH:38]([CH3:40])[CH3:39])[C:32]([F:31])=[CH:33][C:34]=3[O:44][CH3:45])[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1ccc(F)cc1Cl
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1cc(F)ccc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4-methyl-1,3-oxazolidin-2-one (100 mg, 0.22 mmol) in 1,4-dioxane (1 mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (55.8 mg, 0.26 mmol), palladium(II) acetate (10 mg, 20 mol %), potassium hydroxide aqueous solution (147 μL, 3M, 2 eq.) and tri-tert-butylphosphine (13.4 mg, 0.066 mmol, 30 mol % as a 10% w/w hexane solution). The resulting reaction mixture was N2 purged and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 140° C. for 40 min. LC-MS indicated the formation of desired product. It was quenched with water (50 mL). Volatiles were evaporated. The resulting mixture was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to an oil. The titled compound was obtained after two purifications with silica gel and one reversed phase prep-HPLC. LC-MS: 588.25 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26]([NH:37][CH:35]3[CH2:36][O:33][CH2:34]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: NC1COC1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)NC2COC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoic acid (66.0 mg, 0.150 mmol, 1 equiv), oxetan-3-amine hydrochloride (41.0 mg, 0.374 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (114 mg, 0.299 mmol, 2.00 equiv), and N,N-diisopropylethylamine (522 μL, 2.99 mmol, 20.0 equiv) in N,N-dimethylformamide (1.0 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (39 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.33 (m, 1H), 9.02 (d, J=6.5 Hz, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.50 (dd, J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.27-7.31 (m, 2H), 5.06 (q, J=7.1 Hz, 1H), 4.80 (m, 1H), 4.73 (m, 2H), 4.44 (m, 2H), 3.84 (s, 3H), 1.66 (d, J=7.1 Hz, 3H). LCMS (ESI): M+H=496.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: Nc1cnccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccncc1N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To an ice-cold suspension of 3-aminoisonicotinic acid (8 g, 58 mmol) in ethanol (36 mL) and toluene (36 mL) was added concentrated sulfuric acid (6.4 mL), and the mixture was stirred for 24 h. The solvents were removed under reduced pressure, the residue was dissolved in water, and the solution was adjusted to pH 8 with concentrated ammonium hydroxide to give ethyl 3-aminoisonicotinate (6.5 g). MS (ESI): m/z 167 [M+H]+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16](C(F)(F)F)[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C(C3C=NC=C([Cl:54])C=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:54])[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cncc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(Cl)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-chloropyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=467, obsd.=467).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])[CH3:3].C(OC([N:22]1[CH2:28][CH2:27][CH2:26][C@H:23]1[CH2:24]O)=O)(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[CH3:1][N:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH:23]1[CH2:26][CH2:27][CH2:28][NH:22]1)[C:7]([O:9][CH3:10])=[O:8])[CH3:3]
Reactant: COC(=O)c1ccc(O)c(N(C)C)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCC2CCCN2)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a stirred mixture of methyl 3-(N,N-dimethylamino)-4-hydroxybenzoate (0.817 g, 4.18 mmol), N-tert-butoxycarbonylprolinol (0.926 g, 4.60 mmol), Ph3P (1.21 g, 4.60 mmol) in THF (20 mL) was added dropwise DIAD (95%) (0.953 mL, 4.60 mmol) at 0° C. The resulting mixture was heated under reflux for 41 hr. After cooling, the mixture was evaporated off in vacuo. The residue was chromatographed on silica-gel with EtOAc-n-hexane (1:10 to 1:6, v/v) as eluent to give a syrup which was used for the subsequent reaction without further purification. This syrup was dissolved in CH2Cl2 (10 mL) and added TFA (10 mL). After the solution was stirred for 5 hr at room temp, the solution was evaporated in vacuo. Water was added to the residue and washed with CHCl3. The aqueous layer was neutralized by the addition of sat. NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and evaporated in vacuo to afford 1.03 g (89%) methyl 3-(N,N-dimethylamino)-4-(2-pyrrolidinylmethoxy)benzoate as a gum.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccco1
Reactant: O=C1CNC(=O)N1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccco2)N1
Yield: 78.6 %

Procedure:
A solution of hydantoin (10 g), fused sodium acetate (20 g), and freshly distilled furfural (12 g) in acetic acid (40 ml) was heated under reflux for 11/4 hours. The dark solution was poured into cold water (400 ml) to precipitate the dark green/yellow product, which was washed with water until neutral and then with cold ethanol to give 14 g (80% theoretical yield) of 5-furfurylidenehydantoin m.p. 232°-5° (decomp.) (H. L. Wheeler and C. Hoffman, Amer. Chem. J., 1911, 45, 368, quote m.p. 232°.) The material was used without further purification.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:27])[N:9]([CH2:25][CH3:26])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].S(=O)(=O)(O)O.O>C(#N)C>[CH2:25]([N:9]1[C:8](=[O:27])[C:7]([C:6]#[C:5]/[CH:4]=[N:40]\[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[C:10]1=[O:24])[CH3:26]
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(CC)c1=O)OCC
Reactant: N#Cc1ccc(NN)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CCn1c(=O)c(C#C/C=N\Nc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 5-(3,3-diethoxyprop-1-ynyl)-3-ethyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (2.40 g) in acetonitrile (72 ml) were added 4-cyanophenylhydrazine (1.11 g) and concentrated sulfuric acid (0.30 ml) and the resulting mixture was stirred at room temperature for thirty minutes. The resulting mixture was cooled to 0° C. and thereto was added water (140 ml) dropwise, and the solids were collected by filtration and washed with water to afford (Z)-4-(2-(3-(3-ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)prop-2-yneylidene)hydrazinyl)benzonitrile (2.50 g) as brown solid.