Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][N:1]4[C:35](=[O:36])[CH2:33][CH2:32][CH:31]4[C:30]([NH2:34])=[O:29])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1C(=O)CCC1C(N)=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495 Found: [M+H]+ 496.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:35]([C:32]3[CH:33]=[CH:34][C:29]([N:28]([CH3:27])[CH3:37])=[CH:30][CH:31]=3)[CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNc1ccc(N(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(N(C)C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in dry dimethylformamide (75 ml) was cooled in an ice bath and oxalyl chloride (2.2 g, 0.0172 mole) was added dropwise, with stirring, under nitrogen. The reaction mixture was stirred at room temperature for 3.5 hours and then N,N,N'-trimethyl-1,4-benzenediamine (2.9 g, 0.0193 mole) was added dropwise. The reaction mixture was stirred at room temperature under nitrogen overnight, poured into 400 ml of ice water and made basic with triethylamine (6 ml). The resulting white solid was collected by filtration, dissolved in hot isopropyl alcohol, treated with charcoal, and filtered while hot. Water was added to the cloud point an upon cooling, a solid precipitated. The gray solid was collected by filtration and rinsed with water to yield 6.6 g (92%) of product. A 1.0-g sample was dried under high vacuum to give 0.6 g of title compound, mp 152°-155° C.
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)NC1CCCCC1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCC1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.8 %

Procedure:
A solution of methyl magnesium chloride (3M in tetrahydrofuran, 19 ml, 57 mmol) was added to a solution of tert-butyl 2-oxocyclohexylcarbamate (4.0 g, 18.8 mmol) (Synth. Commun. (1992), 22(20), 3003–12) in tetrahydrofuran (80 ml) at −78° C. The mixture was allowed to warm to ambient temperature and was stirred for 3 h. The mixture was quenched by the addition of saturated ammonium chloride solution (20 ml) and was partitioned between water and diethyl diethyl ether. The organic phase was washed with water, brine, dried over MgSO4, and the solvent removed under reduced pressure to give a white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (98:2 to 70:30) as eluant to give the less polar diastereoisomer of tert-butyl 2-hydroxy-2-methylcyclohexylcarbamate (940 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=3[O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[O:18])[C:11]([CH3:13])=[CH:12][C:7]=2[O:6][C:5]([CH3:28])([CH3:27])[C:4]1=[O:29])[CH3:2].[CH3:30][Mg]Br.C(OCC)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:21]([O:22][C:23]([F:25])([F:24])[F:26])=[C:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]3[O:6][C:5]([CH3:28])([CH3:27])[C:4](=[O:29])[N:3]([CH2:1][CH3:2])[C:8]=3[CH:9]=2)[CH:15]=1)(=[O:18])[CH3:30]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Reactant: C[Mg]Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C(C)=O)ccc3OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of Compound 1D (200 mg, 0.49 mmol) in dry 3 mL of dry THF is cooled to −78° C. and treated with a 3M solution of methyl magnesium bromide in diethyl ether (0.17 mL, 0.54 mmol). The reaction was allowed to warm to room temperature, the reaction turned blue when it was complete. The mixture was quenched with 5 mL of a saturated aqueous solution of NH4Cl and passed through a SPE. The crude product was eluted with EtOAc. After removing excess solvent the crude alcohol was then dissolved in 2 mL of dichloromethane and treated with Dess-Martin reagent (250 mg, 0.59 mmol) and stirred at room temperature overnight. The reaction was quenched with 4 mL of saturated sodium thiosulfate solution and 4 mL of saturated sodium bicarbonate solution, the reaction mixture was stirred until clear. The reaction mixture was passed through another SPE and eluted with dichloromethane, removal of solvent yielded crude ketone which was purified with flash chromatography (25% EtOAc/hexane) to yield 95 mg (46%) of the desired product and a white solid. MS (electrospray): mass calculated for C22H22F3NO4, 421.15; m/z found 422.1 [M+H]+.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Ca+2:7].[OH-]>O>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:7].[Ca+2:7]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
Referring to the FIGURE, an acidic premix solution containing calcium phosphate is provided by diluting a good grade of low impurity commercial phosphoric acid in the dilution tank (10) to form an approximately 20-30% by weight phosphoric acid solution. Calcium hydroxide and water are added to the premix tank (11) to form a solution with excess calcium hydroxide, and the diluted phosphoric acid solution is added to the premix tank (11) with high shear agitation provided by a high speed agitator (12). The amount of water added to the premix tank (11) is variable. Depending upon the amount of calcium hydroxide present, a given amount of water is able to dissolve a specific amount of that calcium hydroxide at the temperature maintained in the premix tank (11) and the main reactor (13). The amount of water added to control the heat of reaction is such that cool conditions below about 30°C. is maintained in order to provide the highest solubility of the calcium hydroxide in both the premix tank (11) and the main reactor (13). The phosphoric acid is added gradually to the premix tank (11), and upon the formation of an interim reaction product, more calcium hydroxide can be dissolved by the given volume of water in the tank (11). Thus, more calcium hydroxide can be dissolved than would dissolve in the water initially present in the tank (11). By introducing the acid solution slowly into premix tank (11), a substantial amount of suspended calcium hydroxide is thereby dissolved to form an acidic calcium phosphate (monocal) premix.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccn1

Procedure:
10.0% of pyridine-2-carboxylic acid were suspended in 150 ml of toluene and the suspension was heated to reflux for 2 hours with 17.7 ml of thionyl chloride and 3 drops of dimethylformamide. Thereafter, the mixture was evaporated to dryness under reduced pressure, the residue was treated with toluene and again evaporated to dryness. There was obtained picolinic acid chloride as dark green crystals which were used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](/B(O)O)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1CCc1ccccc1
Reaction time: 96 h

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture was chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd-C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([NH:27]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:27][C@@H:16]([CH2:15][S:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 0.50 g (1.023 mmol) of benzyl (R)-3-(2-benzyloxycarbonylaminoethyl-sulfanyl)-2-tert-butoxycarbonylaminopropionate in 5 ml of dichloromethane was mixed with the same volume of trifluoroacetic acid and left to stand at RT for 1 h. It was then concentrated and directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([CH2:24][S:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)(=[O:23])=[O:22])=[CH:33][CH:32]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(CS(=O)(=O)c2ccccn2)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CS(=O)(=O)c2ccccn2)cc1

Procedure:
500 mg of methyl 4-(bromomethyl)benzoate was reacted with pyridine-2-thiol via Procedure Q. 260 mg of methyl 4-((pyridin-2-ylthio)methyl)benzoate was reacted via Procedure R to give methyl 4-((pyridin-2-ylsulfonyl)methyl)benzoate. 275 mg of methyl 4-((pyridin-2-ylsulfonyl)methyl)benzoate was hydrolyzed via Procedure M to give 4-((pyridin-2-ylsulfonyl)methyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((pyridin-2-ylsulfonyl)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyridin-2-ylsulfonyl)methyl)benzamide. MS (Q1) 464.1 (M)+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:25])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(NCC(=O)N2CCC(Cc3ccccc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Product: O=C(CNc1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 1-(4-benzyl-piperidin-1-yl)-2-(4-methoxy-phenylamino)-ethanone (Example 220) and boron tribromide according to the method described in Example 192. Melting Point: 138-140° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[CH2:21]([C:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]>N1C=CC=CC=1>[CH2:21]([C:24]1([S:27]([NH:18][C:5]2[C:4]([O:19][CH3:20])=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:29])=[O:28])[CH2:26][CH2:25]1)[CH:22]=[CH2:23]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(OC)cc(F)c(F)c2Nc2ccc(I)cc2F)CC1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (1 eq) in anhydrous pyridine (5 ml/mmole) was added 1-allyl-cyclopropanesulfonyl chloride (1-5 eq). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica to obtain the title product. 1H NMR (CDCl3, 300 MHz): δ 7.417 (dd, 1H), 7.309 (s, 1H), 7.25 (m, 1H), 6.89 (m, 1H), 6.52 (m, 1H), 6.427 (m, 1H), 6.03 (s, 1H), 5.668 (m, 1H), 5.11 (t, 1H), 3.9 (s, 3H), 2.75 (d, 2H), 1.21 (m, 2H), 0.767 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][NH2:49]>C1COCC1>[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][NH:49][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: NNc1ccccn1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NNc1ccccn1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of N′-pyridin-2-yl-hydrazine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 534.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28]([CH:29]=O)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].N1CCCCC1.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28](/[CH:29]=[C:43]4/[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]/4)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1Cl
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1Cl
Temperature: 85 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To 5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (79 mg, 0.184 mmol) in EtOH (3 mL) was added piperidine (22 uL 0.221 mmol) followed by hydantoin (21 mg, 0.202 mmol). The reaction mixture was stirred at 85° C. for 6 h. The solvent was removed by rotary evaporation and the residue was diluted with 3 mL of water. The suspension was sonicated and the resulting solid was filtered off and washed with water followed by a 1:1 mixture of EtOH/water. The material was Dried under vacuum to provide 62 mg of (Z)-5-((5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione LCMS (ES): m/z 511 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][CH:23]1[O:27][C:26](=O)[C:25]2[S:29][CH:30]=[CH:31][C:24]1=2.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:26]1[C:25]2[S:29][CH:30]=[CH:31][C:24]=2[CH:23]([CH3:22])[O:27]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC1OC(=O)c2sccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1OC(=C2C(=O)Nc3ccc(F)cc32)c2sccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one in THF is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 4-methyl-4H-thieno[2,3-c]furan-6-one (0.15 mmol), in THF is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution. The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (35% EtOAc-Hexanes) to give the title compound as a yellow solid (38 mg, 87%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:25].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)Cl>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N+:15]([O-:43])=[CH:16][CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]=2[C:8]1=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2c(-c3ccccc3)ccnc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C1c2c(-c3ccccc3)cc[n+]([O-])c2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
5-[3,5-Bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 5; 729 mg) was dissolved in methylene chloride (10 mL). To the resulting solution, 3-chloroperbenzoic acid (524 mg) was added, and then the mixture was stirred at room temperature for 24 hours. The reaction mixture was purified on a silica gel column chromatography (ethyl acetate:methanol=5:1) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine 10-oxide (411 mg, 54%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[NH:14][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[CH:9]=1.Br.Br[CH2:21][C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]2[N:14]([CH2:21][C:22](=[O:23])[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C@H:13]([C:15]([F:16])([F:17])[F:18])[CH2:12][CH2:11][N:7]2[C:8](=[O:10])[CH:9]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 750 mg (15.77 mmol) of sodium hydride in 50 mL of DMF is cooled to 0° C. under argon. A solution of 2 g (7.89 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 50 mL of DMF is added dropwise. The mixture is stirred for 10 minutes at room temperature. After cooling the reaction medium to 0° C., 2.92 g (9.86 mmol) of 3-(bromoacetyl)pyridine hydrobromide are added portionwise. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction medium is evaporated to dryness and the residue is taken up in water and extracted with EtOAc. The organic phase is dried over magnesium sulfate and evaporated to dryness. The crude product obtained is purified by chromatography on silica gel (eluent: 100% EtOAc). After evaporating the fractions under reduced pressure, 1.90 g of (8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:14])=[CH:8][C:9]([CH:12]=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([CH3:14])=[CH:8][C:9](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C=O)ncc1OCC1CC1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC1CC1
Yield: 90 %

Procedure:
The title compound is prepared in 90% yield (688 mg, yellow oil) from 5-(cyclopropylmethoxy)-4-methylpicolinaldehyde (495 mg, 2.59 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (471 mg, 3.88 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:6][CH2:7][CH3:8].CS[C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1>>[CH2:6]([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:17]1[NH:22][C:21](=[O:23])[C:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:7][CH3:8]
Reactant: COc1ccc(Cc2cnc(SC)[nH]c2=O)cc1
Reactant: CCCN(CCCN)c1ccccn1
Product: CCCN(CCCNc1ncc(Cc2ccc(OC)cc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(3-aminopropyl)-N-propylamino]pyridine (1.0 g) and 2-methylthio-5-(4-methoxybenzyl)pyrimid-4-one (0.88 g) were fused together on an oil bath at 160° C. for 2.5 hr. On cooling the residue was crystallized from ethanol/water to give a white solid which on recrystallization from acetone/water gave 2-[3-(N-propyl-N-pyrid-2-ylamino)propylamino]-5-(4-methoxybenzyl)pyrimid-4-one 1 H2O; 1.27 g (79%) m.p. indeterminate.