Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:37][CH2:36][CH2:35]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].Cl.[F:39][C:40]1([F:44])[CH2:43][NH:42][CH2:41]1>C(#N)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:42]4[CH2:43][C:40]([F:44])([F:39])[CH2:41]4)=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])(=[O:16])=[O:15])[CH2:11][N:10]2[C:28]2[N:29]([CH:34]3[CH2:35][CH2:36][CH2:37]3)[N:30]=[C:31]([CH3:33])[CH:32]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: FC1(F)CNC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Agent: Cl
Solvent: CC#N
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CC(F)(F)C4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (example 388 g) was reacted with 3,3-difluoroazetidine hydrochloride (CAS Reg. No. 288315-03-7) in acetonitrile at 90° C. for 48 h to give the title compound as colorless oil. MS (ESI): m/z=613.1 [M+H]+.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH:13][CH2:14][CH2:15][C:16]1[S:20][CH:19]=[C:18]([CH2:21][CH2:22][N:23]2[CH2:43][CH2:42][C:26]3([O:31][CH2:30][CH2:29][N:28]([C:32]([C:34]4[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[S:37][CH:38]=4)=[O:33])[CH2:27]3)[CH2:25][CH2:24]2)[CH:17]=1.[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46].C(#N)C>C1(C)C=CC=CC=1>[CH:39]([C:36]1[S:37][CH:38]=[C:34]([C:32]([N:28]2[CH2:27][C:26]3([CH2:42][CH2:43][N:23]([CH2:22][CH2:21][C:18]4[CH:17]=[C:16]([CH2:15][CH2:14][O:13][CH2:46][CH2:45][C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:20][CH:19]=4)[CH2:24][CH2:25]3)[O:31][CH2:30][CH2:29]2)=[O:33])[N:35]=1)([CH3:40])[CH3:41]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCO)c4)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
Benzyltrimethylammonium hydroxide (40% in water, 0.27 mL) was added in one portion to a stirred solution of (9-(2-(5-(2-hydroxyethyl)thiophen-3-yl)ethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone [Example 78, step b] (0.92 g) and tert-butyl acrylate (0.38 g) in toluene (1 mL). The resultant mixture was stirred vigorously at 20° C. for 4 hours. Acetonitrile (1 mL) was added and the mixture was stirred for 18 hours and then purified without work up. The crude product was purified by flash silica chromatography, using 6% methanol in ethyl acetate with 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.84 g.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:15]([CH2:28][O:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@H:16]([O:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=2)(=[O:20])=[O:19])[C@@H:15]([CH2:28][OH:29])[O:14][C@H:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1C[C@H](OCc2ccccc2)[C@H](OS(=O)(=O)c2ccc(C)cc2)[C@@H](CO)O1
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
Methyl 3-O-benzyl-4-O-tosyl-6-O-trityl-2-deoxy-α-D-ribo-hexopyranoside (15.3 g; 23.01 mmoles) was dissolved in methylene chloride (200 ml). Aqueous trifluoroacetic acid (70% TFA in water, 9.6 ml) was added with vigorous stirring. The vigorous stirring was continued for five minutes (bright yellow color appears), then the reaction was quenched by the addition of saturated aqueous sodium carbonate solution (40 ml) with vigorous stirring (note: the reaction becomes colorless). The methylene chloride layer was separated and the aqueous layer extracted with methylene chloride. The combined methylene chloride extracts were dried (MgSO4), filtered and the solvent was evaporated in vacuo to give crude product. This product was chromatographed on 650 g of silica gel eluting with 3 L of methylene chloride to remove triphenyl carbinol from the column followed by elution with 10% (by volume) acetone in methylene chloride. When a faintly visible opaque band of product neared the bottom of the column the fractions containing the product were collected and the solvent was evaporated in vacuo to leave 8.1 g of methyl 3-O-benzyl-4-O-tosyl-2-deoxy-α-D-ribo-hexopyranoside, m.p. 100°-101° C., [α]D25 =115.07 (c, 0.48, CHCl3)
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:44][CH2:43][C:42](=O)[CH2:41]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1.[CH3:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:44][CH2:43][CH:42]([N:50]5[CH2:51][CH2:52][CH:47]([CH3:46])[CH2:48][CH2:49]5)[CH2:41]4)=[N:38][CH:39]=3)=[N:30][CH:31]=2)=[CH:22][CH:21]=1
Reactant: O=C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1
Reactant: CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1CCN(C2CCN(c3ccc(C#Cc4ccc(-c5ccc(Cl)cc5)cn4)cn3)C2)CC1
Reaction time: 8 h

Procedure:
48 mg (0.22 mmol) NaBH(OAc)3 and 27 μL (0.47 mmol) acetic acid are added to a solution of 100 mg (0.19 mmol, 70% purity) 1-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-pyridin-2-yl}-pyrrolidin-3-one and 22 μL 4-methylpiperidine (0.19 mmol) in 5 mL THF. The reaction mixture is stirred overnight and combined with saturated NaHCO3 solution. The organic phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[OH-].[Na+]>O1CCCC1.O>[CH2:25]([O:24][C:22]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(N)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-amino-2-(3-(benzyloxy)phenyl)acetate (1.09 g, 4 mmol) in a mixture of tetrahydrofuran and water (1:1, 90 mL) at 0° C. was added benzyl chloroformate (0.57 mL, 4 mmol) and aqueous sodium hydroxide (4 N, 1 mL, 4 mmol) simultaneously. The mixture was stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and ethyl acetate (100 mL) and water (30 mL) were added. The layers were separated and the aqueous phase re-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (900 mg, 56%) as a brown oil.
Reaction SMILES: [CH:1]1([C:7]2([CH2:22][OH:23])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]1([C:7]2([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:13][CH:12]3[N:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(CO)(C1CCCCC1)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1C2CCC1CC(COS(C)(=O)=O)(C1CCCCC1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-cyclohexyl-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (3-3) (0.870 g, 2.69 mmol) in methylene chloride was added diisopropylamine (0.562 mL, 3.23 mmol), dimethylaminopyridine (32.5 mg, 0.269 mmol), and methanesulfonyl chloride (0.229 mL, 2.97 mmol). The mixture was stirred at room temperature for four hours and diluted with methylene chloride, washed with water, a saturated aqueous solution of NaHCO3, and 1 N HCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated to give (3-4) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[C:8](OC)=[O:9])=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[CH2:8][OH:9]
Reactant: COC(=O)c1cc(CF)cc(CN=[N+]=[N-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cc(CO)cc(CF)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
Methyl 3-azidomethyl-5-fluoromethylbenzoate (35) (476 mg, 2.13 mmol) was dissolved in THF (21.3 mL). The air was evacuated from the reaction system, and then Ar was charged therein. In another recovery flask filled with Ar, LiAlH4 (408 mg, 10.7 mmol) was placed. To this was added THF (21.3 mL) with ice-cooling to give a suspension. To the suspension was added dropwise the solution of the compound (35), and stirred for 2 hours at 0° C. TLC was used to confirm there was no starting material in the mixture. Then, the reaction was quenched with MeOH (10 mL). The mixture was filtered through cerite to remove metals. The filtrate was evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=1:1, then EtOAc:MeOH=2:1) to isolate 3-aminomethyl-5-fluoromethylbenzylalcohol (38) (172 mg, 48%) as a yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[NH:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[C:22]([OH:33])[CH:23]=[C:24]([S:29](O)(=[O:31])=[O:30])[CH:25]=5)[C:19]=4[N:20]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].CN(C)C=O>S(Cl)(Cl)=O>[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[NH:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[C:22]([OH:33])[CH:23]=[C:24]([S:29]([Cl:1])(=[O:31])=[O:30])[CH:25]=5)[C:19]=4[N:20]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)O)cc(O)c54)[nH]3)c2)cc1C
Reactant: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccc(-c3nc4c(ccc5cc(S(=O)(=O)Cl)cc(O)c54)[nH]3)c2)cc1C
Temperature: 60 °C

Procedure:
2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonic acid hydrochloride(0.08 g, 0.18 mmol) was suspended in 1 ml thionyl chloride containing catalytic amount of N,N-dimethylformamide. The reaction mixture was heated to 60° C. for 3 hours then was concentrated to dryness to give 2-(3′,4′-dimethylbiphenyl-3-yl)-9-hydroxyl-3H-naphtho[1,2-d]imidazole-7-sulfonyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>O.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1ccc(Cl)cc1
Solvent: O
Solvent: CCOCC
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 18.0 g. of p-chlorophenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. diethyl ether. The ethereal solution was extracted with 2×50 ml. 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave 4.7 g. (29%) of analytically pure product which melted at 101°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To an N,N-dimethylformamide solution (400 ml) of 4-bromo-2-fluorobenzoic acid (50.3 g) were added at room temperature potassium carbonate (63.5 g) and benzyl bromide (27.3 ml), followed by stirring at 60° C. for 3 hours. After the precipitate was filtered off, the filtrate was concentrated to 100 ml, and then diluted with ethyl acetate. This was washed sequentially with a saturated aqueous ammonium chloride solution, water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford benzyl 4-bromo-2-fluorobenzoate (70.5 g).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.Br[CH2:14][CH2:15][CH3:16]>C1COCC1.O>[I:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:14][CH2:15][CH3:16])[N:5]=1
Reactant: CCCBr
Reactant: Ic1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1nc(I)c2ccccc21
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
NaH (60%, 197 mg, 4.92 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) in THF (20 mL) at 0° C., and the reaction stirred further for 30 min. Bromopropane (605 mg, 4.9 mmol) was added to the reaction at 0° C. The solution was heated to reflux and stirred overnight. It was then cooled, diluted with water, extracted with EtOAc (3×30 mL), and the organics were washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%-30% EtOAc/hexanes) gave 650 mg (56%) of the title compound as a yellow solid. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.93 (3H, t, J=7.2 Hz), 1.93-1.98 (2H, m), 4.35 (2H, t, J=7.2 Hz), 7.20 (1H, t, J=7.6 Hz), 7.36-7.49 (3H, m).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19].[C:20]1([C:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[NH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:31]([C:29]1[NH:28][N:27]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:30]=1)=[O:32]
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
EDCI (288 mg, 1.5 mmol) was added to a solution of 1,2-diaminobenzene (0.141 g, 1.31 mmol), 3-phenyl-1H-pyrazole-5-carboxylic acid (188 mg, 1.0 mmol) and HOBT (203 mg, 1.5 mmol) in anhydrous DMF (5 mL). The reaction was stirred under nitrogen at room temperature. After twelve hours the reaction was concentrated in vacuo and precipitated from methanol with a small amount of water. The solid was collected by vacuum filtration and further purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the corresponding amide (60 mg, 38% yield).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[C:16]4=[N:15][C:14]=3[C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:36].[NH4+].OO>CO.O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[N:17]4[CH:18]=[CH:19][CH:20]=[C:21]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[C:16]4=[N:15][C:14]=3[C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH2:33])=[O:36])=[CH:34][CH:35]=3)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccc(-c2nc3c(N4CCOCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1ccc(-c2nc3c(N4CCOCC4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a cold (0° C.) solution of 4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-8-(4-morpholinyl)imidazo[1,2-α]pyridin-2-yl]benzonitrile (16 mg, 0.03 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added concentrated ammonium hydroxide (1 mL, 28%) followed by hydrogen peroxide (0.1 mL, 30%). The cold bath was removed and the mixture was stirred at room temperature for 2 hours at which time an additional 0.1 mL of 30% hydrogen peroxide was added. After an additional 14 hours, the reaction was quenched by the addition of saturated aqueous sodium thiosulfate. Ether was added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3% to 10% methanol in dichloromethane) provided 4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-8-(4-morpholinyl)imidazo[1,2-α]pyridin-2-yl]benzamide (17 mg, 99%) as a white solid. 1H NMR (CDCl3): δ 9.03 (broad, 1H), 8.15 (d, 1H), 7.89–7.82 (m, 4H), 6.85 (t, 1H), 6.64 (d, 1H), 6.44 (d, 1H), 6.22–5.79 (broad, 2H), 5.36 (m, 1H), 4.37 (m, 1H), 4.02 (m, 4H), 3.61 (m, 4H), 2.20–2.11 (m, 2H), 1.84–1.57 (m, 6H); MS m/z 484 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[C:23](Cl)(=O)[CH2:24][CH3:25]>>[Cl:21][C:19]1[C:18]([Cl:22])=[CH:17][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=3)[C:23]([CH2:24][CH3:25])=[N:1][C:2]=2[CH:20]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)c(Cl)cc2N)cc1
Reactant: CCC(=O)Cl
Product: CCOC(=O)Cc1ccc(-n2c(CC)nc3cc(Cl)c(Cl)cc32)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from ethyl [4-(2-amino-4,5-dichloroanilino)phenyl]acetate (step 2) and propionyl chloride.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>>[C:45]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(C(C)=O)C3)cc1
Reaction time: 8 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.251 g, 0.611 mmol) in dry N,N-Dimethylformamide (3.00 mL, 38.7 mmol) was added N,N-Diisopropylethylamine (0.310 mL, 1.78 mmol) followed by Acetyl chloride (0.0650 mL, 0.913 mmol). The reaction mixture was stirred for overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.68 (s, 1H), 8.17 (d, J=7.6, 2H), 7.48 (d, J=7.9, 2H), 6.22 (d, J=6.1, 1H), 4.78-4.63 (m, 1H), 4.44 (dd, J=82.7, 18.2, 1H), 3.97 (s, 1H), 3.85 (d, J=11.1, 1H), 3.78 (d, J=11.6, 1H), 3.67 (d, J=7.4, 2H), 3.45 (dd, J=38.1, 25.8, 3H), 3.29 (m, 1H), 3.16-3.07 (m, 2H), 2.68 (dd, J=47.0, 37.1, 2H), 2.12 (s, 3H), 1.78 (ddd, J=27.5, 13.8, 7.0, 2H), 1.06 (t, J=7.2, 3H), 0.83 (dd, J=12.0, 7.4, 3H). LC/MS-m/z+453.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1.Cl>CC#N>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][C:7]2[C:20]3[C:19](=[CH:18][CH:17]=[C:16]([S:15][CH3:14])[CH:21]=3)[NH:22][C:8]=2[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)COc1ccc(Cl)cc1
Reactant: CSc1ccc(NN)cc1
Agent: Cl
Solvent: CC#N
Product: CSc1ccc2[nH]c(C)c(Oc3ccc(Cl)cc3)c2c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(4-Chloro-phenoxy)-propan-2-one (2.66 g) was added to a stirred solution of [4-(methylthio)phenyl]-hydrazine hydrochloride (2.5 g) in MeCN (15 ml)/HCl (0.5M, 15 ml) at RT. The reaction was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction was partitioned between ethylacetate/water, the organics were separated, washed with aq sodium hydroxide (1 M), dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-20% ethylacetate/iso-hexane. The resulting hydrazone was dissolved in THF (80 ml). Sodium bicarbionate solid (1.04 g) was added followed by phosphorus trichloride (0.41 ml) dropwise, and the reaction stirred at RT for 2 h. Further phosphorus trichloride (1.20 ml) was added dropwise, and the reaction stirred at RT for 16 h. The reaction was quenched with water. The mixture was extracted with ethylacetate, the organics washed with aq. sodium hydrogencarbonate, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-10% ethylacetate/iso-hexane. Yield 0.45 g.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]3=[CH:11][C:10]=2[CH3:23])=[O:8])=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][C:10]=2[CH3:23])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)cc1

Procedure:
A solution of 500 mg. of isopropyl 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-p-toluoyl-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R = CH3, R1 = p-CH3 ].