Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][OH:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][CH2:34][OH:35])=[O:5]
Reactant: NCCO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 130 mg, 0.3 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. prior to the addition of 2-aminoethanol (27.6 mg, 0.452 mmol), 4-methylmorpholine (0.133 mL, 1.206 mmol), and HATU (149 mg, 0.392 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention=33.8 min) to give (R/S)-2-hydroxy-N-(2-hydroxyethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (34 mg, 0.065 mmol, 21.3% yield): LCMS [M+H]+=475.1; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, dd, J=8.35, 4.39 Hz), 7.64-7.77 (4 H, m), 7.47-7.64 (3 H, m), 5.10-5.21 (1 H, m), 4.46 (2 H, t, J=5.49 Hz), 3.55-3.69 (2 H, m), 3.37 (1 H, m). HPLC Peak RT=8.6 min (Analytical Method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH:15]([NH:23]C(=O)OC(C)(C)C)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:38].C(OCC)(=O)C>>[ClH:38].[NH2:23][CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate (2.7 g, 6.3 mmol) in ethyl acetate (20 mmol) under ice-cooling was dropwise added 4N HCl/ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. The resulting crystals were recovered by filtration and recrystallized from ethanol-diethyl ether to give 1-(2-amino-1-oxo-3-phenylpropyl)-4-(4-fluorophenyl)piperazine hydrochloride (2.2 g, 96.1%) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH:12]=[CH:11]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccn2-c2nccs2)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
2-Bromo thiazole (0.837 g, 5.10 mmol) was added to a solution of 5-bromo indole (1 g, 5.10 mmol) in DMF (15 mL) followed by cesium carbonate (3.32 g, 10.20 mmol), and the mixture was stirred at 90° C. for 12 h. Insoluble solids were filtered off, the filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography using 5% ethyl acetate in pet ether to afford title compound (0.75 g, 52.7%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J=8.8 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.62 (dd, J1=3.2 Hz, J2=10.4 Hz, 2H), 7.45 (dd, J1=2.0 Hz, J2=8.8 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 6.66 (d, J=4.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12]CC)=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH3:15]>>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH2:15])=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOP(=O)(CC(N)=O)OCC
Temperature: 5 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
In 400 ml of 25% aqueous ammonia is dissolved 100 g (0.446 mol) of ethyl diethylphosphonoacetate at an temperature of not higher than 10° C. The solution is allowed to stand overnight at an temperature of not higher than 15° C. and concentrated under reduced pressure. To the residue is added 25 ml of toluene and the water is azeotropically removed off under reduced pressure. To the residue is added 300 ml of toluene and 100 ml is azeotropically removed off under atmospheric pressure for complete dehydration. The residual solution is cooled and seed crystals are added at 50° C. for crystallization. After cooling to 5° C., the crystals are collected by filtration. The crystals are washed with 100 ml of toluene and dried in vacuo overnight to give 76.7 g of diethylphosphono-acetamide (a carbamoyl-containing Wittig reagent) (Yield 88.0%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[OH-].[Na+]>CO>[NH2:1][CH2:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccc(Cl)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(OCC)P(=O)(O)CC(CN)c1ccc(Cl)cc1

Procedure:
To a solution of 1.0 g of ethyl 3-amino-2-(p-chlorophenyl)-propyl(diethoxymethyl)phosphinate in 5 ml of methanol are added 2.5 ml of a 2 normal sodium hydroxide solution and the mixture is heated to a temperature of 80° for a period of 5 hours. After this time, the reaction is concentrated under reduced pressure, and the oily residue is passed down an Ion Exchange Resin (DOWEX® 50W-X8 H+) using de-ionised water as eluant. Ninhydrin-positive fractions are combined and evaporated to give 3-amino-2-(4-chlorophenyl)-propyl(diethoxymethyl)phosphinic acid, m.p. 175°-185° (dec.), 31P-NMR : δ=+31.6 ppm (D2O).
Reaction SMILES: [CH:1]([C:4]([NH:6][C:7]1[C:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:11][CH:10]=[C:9]([NH:22]C(=O)C)[N:8]=1)=[O:5])([CH3:3])[CH3:2]>C(O)C>[CH:1]([C:4]([NH:6][C:7]1[C:12]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=2[Cl:21])=[N:11][CH:10]=[C:9]([NH2:22])[N:8]=1)=[O:5])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(NC(=O)C(C)C)n1
Solvent: CCO
Product: CC(C)C(=O)Nc1nc(N)cnc1-c1cc(Cl)cc(Cl)c1Cl
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
Stannous chloride (0.182 g, 0.0096 mole) was added to the suspension of 2-isopropylcarbonylamino-6-acetamido-3-(2,3,5-trichlorophenyl)pyrazine (0.13 g, 3.24×10−4 mole), in absolute ethanol (6.50 ml) and the resulting mixture stirred at 50-60° C. for 1 hr 20 min. The reaction mixture was cooled and evaporated in vacuo. The residue was extracted with ethylacetate (3×20 ml), washed with water (2×20 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using chloroform:methanol, 99:1 as the eluent. Yield 0.046 g (40%), M.p. 105-108° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:35]([NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])=[N:36][O:37][N:38]=2)=[N:31][N:30]=1>>[F:43][C:41]([F:42])([F:44])[C:40]([NH:39][C:35]1[C:34]([C:32]2[S:33][C:29]([NH:28][C:25](=[O:26])[CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH2:16][CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2])[CH2:13][CH2:12]4)[CH:19]=3)=[N:30][N:31]=2)=[N:38][O:37][N:36]=1)=[O:45]
Reactant: Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)O)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCCOc2cccc(CC(=O)Nc3nnc(-c4nonc4NC(=O)C(F)(F)F)s3)c2)CC1

Procedure:
Prepared from 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetic acid and N-(4-(5-amino-1,3,4-thiadiazol-2-yl)-1,2,5-oxadiazol-3-yl)-2,2,2-trifluoroacetamide by methods substantially similar to those described in Example 11, supra. Yield 30 mg.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[SH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1>[OH-].[Na+]>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([S:6][CH:3]=[CH:2][C:1]([OH:5])=[O:4])=[CH:8]1
Reactant: C#CC(=O)O
Reactant: Sc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=CSc1c[nH]c2ccccc12
Temperature: 95 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A mixture of 35.0 g (0.5 mole) of propiolic acid, 97 g (0.5 mole) of 3-mercaptoindole and 500 ml of 1N NaOH solution is stirred for 1 hour at 95° C. The solution is cooled and the precipitated solid washed with water and discarded. The filtrate is acidified with 4N HCl and the gummy precipitate extracted with ether. The ether is dried and evaporated and the residue recrystallized from 250 ml of acetonitrile to give 88 g of product, mp 172°-173° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(CN=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(CN)o1
Temperature: 60 °C

Procedure:
To a solution of the crude azide (500 mg, 3.03 mmol) in THF (15 mL) were added Ph3P (polymer-supported, 3.0 mmol/g, 1.5 eq.) and water (5 mL). The reaction mixture was stirred at 60° C. until reaction completion, cooled down to rt and filtered. Sat. aq. NaHCO3 and EA were then added, the layers separated and the aq. layer extracted with EA (1×). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (9:1 CH2Cl2/MeOH) and the title compound was obtained as an orange oil. LC-MS-conditions 02: tR=0.27 min; [M+AcCN+H]+=181.61.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:39]1[CH2:43][CH2:42][O:41][CH2:40]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][CH:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Reactant: OC1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OC2CCOC2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (120 mg, 0.47 mmol), triphenylphosphine (120 mg, 0.47 mmol), 3-hydroxytetrahydrofuran (45 mg, 0.50 mmol) in CH2Cl2 (7 mL) at rt was slowly added a solution of diisopropyl azodicarboxylate (100 mg, 0.50 mmol) in CH2Cl2 (2 mL). The mixture was stirred at rt overnight, and then concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:26])[N:7]([C:6]2[CH:12]=[CH:13][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:8][CH:9]([CH3:10])[CH3:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CCc1ccc(NCC(C)C)cc1
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)c(C(=O)OC)c2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (400 mg, 2.256 mmol) in pyridine (2 mL) was added methyl 2-bromo-5-(chlorosulfonyl)benzoate (707 mg, 2.256 mmol) portionwise, over 30 minutes. The reaction mixture was stirred at 20° C. for 30 minutes then stood at room temperature, in air, for 16 hours. The solvent was evaporated in vacuo to give a crude yellow solid. The crude was then triturated with methanol, filtered and dried in vacuo to give the desired product (600 mg) as a white solid. LCMS (M+1) 454/456, RT 1.41 mins.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[OH:8][C:1]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH3:21]
Reactant: COCCCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCC(O)(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A stirred solution of tert-butyl 3-benzoylpyrrolidine-1-carboxylate (489 mg, 1.78 mmol) in dry THF (10 mL) was cooled to −70° C. and 2 M 4-methoxybutylmagnesium chloride in THF (8 mL, 16 mmol) was added. The mixture was stirred at −70° C. for 1 h and poured into satd aq NH4Cl (100 mL). The mixture was extracted with ether (2×100 mL) and the combined ether extracts were dried over Na2SO4. Removal of the solvent left an oil which was purified by flash chromatography on a 40-g silica cartridge eluted with a 0 to 100% ethyl acetate in hexanes gradient to afford tert-butyl 3-(1-hydroxy-5-methoxy-1-phenylpentyl)pyrrolidine-1-carboxylate (290 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH:11]([C:29](=[O:30])[NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NN(c2ccc(Cl)cc2)C(=O)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
The stirred suspension of 4.2 g of 1-(p-chlorophenyl)-3-methyl-2-pyrazolin-5-one in 100 ml of benzene is gently warmed with 2.4 g of triethylamine until all solid is dissolved. The deep red solution is combined with 2.4 g of phenylisocyanate, and after 2 hours' standing at ambient temperature, a lower layer is present. The mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with water, dried, evaporated, the residue is triturated with diethyl ether and recrystallized from methanol to yield the 1-(p-chlorophenyl)-3-methyl-4-phenylcarbamoyl-2-pyrazolin-5-one of Formula II with R'=R"=H and R=Cl, melting at 212°-215° (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][C:11]([C:12](O)=[O:13])=[C:4]2[CH2:3]1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][C:11]([C:12]([Cl:23])=[O:13])=[C:4]2[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCn2c(-c3ccccc3)nc(C(=O)Cl)c2C1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of intermediate 64C (0.12 g, 0.44 mmol) in 3 mL DCM was added thionyl chloride (0.16 mL, 2.21 mmol), followed by catalytic amount of DMF. The resulting mixture was stirred at 50° C. for 30 minutes, concentrated and the residual thionyl chloride was azeotroped with toluene. The resulting material 64D was dried under vacuum and used in the next step without purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.[Cl:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41]>C1COCC1>[Cl:36][CH2:37][CH2:38][NH:39][C:40]([NH:17][C@H:14]1[CH2:15][CH2:16][O:12][CH2:13]1)=[O:41]
Reactant: N[C@H]1CCOC1
Reactant: O=C=NCCCl
Agent: CC[NH+](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C(NCCCl)N[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A solution of (S)-(−)-tetrahydro-3-furylamine p-toluenesulfonate salt (0.5 g, 1.928 mmol) in THF (20 mL) was gently agitated with MP-Carbonate Resin (1.825 g, 5.78 mmol, 3.17 mmol/g loading) for 36 h, the resin removed via filtration and the filtrate cooled to 0° C., treated drop-wise with chloroethyl isocyanate (0.224 g, 2.121 mmol), warmed to RT and stirred overnight. The mixture was washed with satd. NH4Cl (1×), satd. NaHCO3 (1×), then brine (1×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (S)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (0.11 g, 30%). 1H NMR (400 MHz, DMSO-d6): δ 6.31 (d, J=6.9 Hz, 1 H), 6.01 (t, J=5.9 Hz, 1 H), 4.11-4.08 (m, 1 H), 3.69-3.67 (m, 3 H), 3.55 (t, J=6.2 Hz, 2 H), 3.36 (dd, J=8.8, 3.8 Hz, 1 H), 3.32-3.26 (m, 2 H), 2.03 (dq, J=12.6, 7.6 Hz, 1 H), 1.59-1.61 (m, 1 H); MS (ESI) m/z: 193.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]1[C:25](=[O:48])[CH2:26][NH:27][C:28](=[O:47])[NH:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([O:39]CC2C=CC=CC=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]1[C:25](=[O:48])[CH2:26][NH:27][C:28](=[O:47])[NH:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2-c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2-c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 21.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 1.36 g of benzyl (2R,4R)-3-[3-{2-[4-tert-butoxycarbonyl-2-(2-phenylphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido]phenylacetate, 0.44 g of ammonium formate and 0.6 g of palladium on charcoal (10% Pd). 0.25 g of (2R,4R)-3-[3-{2-[4-tert-butoxycarbonyl-2-(2-phenylphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido]phenylacetic acid, melting point 128° C., is thereby obtained; [α]D25 =-26.2°±0.9° (C %=0.56; MeOH).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>O1CCCC1>[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[NH:12][CH:11]=2)=[C:2]([F:1])[N:7]=1)=[O:27]
Reactant: COc1ncc(F)cc1C(=O)Cl
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ncc(F)cc1C(=O)Nc1ccc(Cc2c[nH]c3ncc(C)cc23)c(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a reaction flask, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 100 mg, 0.3902 mmol) was combined with 5-fluoro-2-methoxy-nicotinoyl chloride (151, 81.37 mg, 0.4292 mmol), 3.00 mL of tetrahydrofuran, and pyridine (0.06312 mL, 0.7804 mmol). The reaction was stirred at room temperature overnight, then poured into aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 1-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-2168, 100 mg). MS (ESI) [M+H+]+=409.9.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15]=2[N:16]=1>C(O)(=O)C.CO>[Cl:4][C:5]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:6]=1[CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([O:2][CH3:1])[N:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:15]=2[N:16]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(Nc2ccc(C(F)(F)F)cc2)c2nc(Cc3c(Cl)cccc3Cl)sc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To solution of NaOMe (15 mg, 0.3 mmol) and MeOH (1.5 mL) was added [2-(2,6-dichloro-benzyl)-5-methanesulfonyl-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (25 mg, 0.05 mmol) and the resulting mixture was heated to 60° C. After 4 h, the resulting solution was acidified with 1 drop of acetic acid and purified directly by reverse phase HPLC to afford a colorless solid (10.3 mg, 45%). MS (ESI): mass calcd. for C20H13Cl2F3N4OS, 484.0; m/z found, 485.0 [M+H]+. 1H NMR (CDCl3): 8.01 (s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.30-7.25 (m, 1H), 4.74 (s, 2H), 4.05 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:71]([S:73][CH2:74][CH2:75][NH2:76])[CH3:72]>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:76][CH2:75][CH2:74][S:73][CH2:71][CH3:72])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CCSCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(ethylthio)ethyl]amine hydrochloride (14.2 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (7 mg, 23%). LC-MS m/z 607 (M+H)+.