Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(Cl)Cl>[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COCCC(=O)O
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)N1CCC(N)CC1
Reaction time: 4.5 h
Yield: 36.2 %

Procedure:
3-Methoxypropanoic acid (225 μL, 2.40 mmol) was added to a solution of 4-(N-Boc-amino)-piperidine (400 mg, 2.00 mmol) in methylene chloride (25 mL) at room temperature. N,N-diisopropylethylamine (1.30 mL, 7.49 mmol) and propylphosphonic anhydride (1.78 mL, 50 wt. % in ethyl acetate, 3.00 mmol) was added, and the solution was stirred for 4.5 h. The reaction mixture was concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic portion was washed with 0.2M HCl (2 mL), sat. Sodium bicarbonate (5 mL) and brine (5 mL). The solution was then dried over sodium sulfate and concentrated to a white solid. This solid was taken up in methylene chloride (6 mL), and trifluoroacetic acid (3 mL) was added at room temperature. After 1 h the solution was concentrated. The resulting solid was dissolved in methylene chloride (2 mL) and 1M sodium hydroxide (1 mL). This mixture was extracted with methylene chloride (4×2 mL) and ethyl acetate (4×2 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give 135 mg of the title compound, 1-(4-aminopiperidin-1-yl)-3-methoxypropan-1-one (36% over two steps). 1H NMR (300 MHz, CD3OD) δ 4.51-4.41 (m, 1H), 4.03-3.93 (m, 1H), 3.64 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 3.17-3.05 (m, 1H), 2.96-2.83 (m, 1H), 2.75-2.55 (m, 3H), 1.99-1.80 (m, 2H), 1.40-1.14 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
To a suspension of creatinine (5.66 g, 0.05 mole) in 150 ml. of dry dimethylformamide (DMF) is added 7.68 g. (0.05 mole) of m-chlorophenylisocyanate. The mixture is stirred for two hours and heated on a steam bath for 30 minutes. During this time the solution becomes clear (yellow). The solution is filtered and the filtrate cooled. Ice and ice-water are added to the filtrate. A light yellow solid precipitates and is filtered off. After recrystallizations from acetone-methanol and tetrahydrofuran-ether, the pure product, 1-m-chlorophenyl-3-(1-methyl-4-oxo-2-imidazolidinylidene)urea, is obtained, mp 180°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[H-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:12]([O:13][CH2:14][CH3:15])=[O:16]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of 2′,4′-Dichloroacetophenone (1.50 g, 7.93 mmol) in diethyl carbonate (24.0 mL, 198 mmol) at 0° C. was slowly added NaH (60% suspension in mineral oil, 0.657 g, 16.4 mmol). The mixture was then stirred at 80° C. for 90 minutes. The mixture was cooled to room temperature and then poured into an ice cold solution of 2.0 mL acetic acid in 56 mL water. The layers were separated and the aqueous phase was extracted with ether 3 times. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (1.16 g, 56%). LCMS: (FA) ES+, 262. 1H NMR (400 MHz, d1-chloroform) δ (2 sets of signals, keto and enol): 12.49 (s, 1H), 7.61-7.29 (m, 2 sets of 3H), 5.57 (s, 1H), 4.28 (q, J=7.28 Hz, 2H), 4.19 (q, J=7.28 Hz, 2H), 4.02 (s, 2H), 1.34 (t, J=7.03 Hz, 3H), 1.25 (t, J=7.03 Hz, 3H).
Reaction SMILES: C[C@H:2]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[N:5](C([C@@H](NS(C2C3NCC(C)CC=3C=CC=2)(=O)=O)CCCN=C(N)N)=O)[CH2:4][CH2:3]1.O.N[CH2:38]CCCCCCCCCCC(OC)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][C:8]([O:10][CH3:38])=[O:9]
Reactant: CC1CNc2c(cccc2S(=O)(=O)N[C@@H](CCCN=C(N)N)C(=O)N2CC[C@@H](C)C[C@@H]2C(=O)O)C1
Reactant: COC(=O)CCCCCCCCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN
Reaction time: 16 h
Yield: 169.2 %

Procedure:
To a solution of argatroban monohydrate (300 mg, 0.570 mmol) and methyl 12-aminododecanoate (compound YS-004-17) (132 mg, 0.576 mmol) in anhydrous DMF (15 mL) was added HBTU (258 mg, 0.680 mmol). Stirring was continued at room temperature for 16 hours. The precipitates formed during the reaction were filtered off and DMF was removed by vacuum distillation. The residue was purified by preparative TLC using solvents CH2Cl2 /MeOH/NH3 (90/10/1, v/v) to give the titled compound (140 mg) (Yield: 28%). 1HNMR (MeOH-4, 300 MHz).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].CO.C[O-].[Na+].Cl[CH:13]=[CH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=1>C(OCC)C>[OH:30][CH:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH2:16][CH:15]=[CH:14][CH2:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1cccc(OCCC=CCl)c1
Reactant: O=C(O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(O)c1cccc(OCC=CCSCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.15 ml. (0.105 mole) 3-mercaptopropionic acid are dissolved in 70 ml. methanol and stirred with 315 ml. 1 M sodium methylate solution for 10 minutes at ambient temperature under an atmosphere of nitrogen. Subsequently, 19.79 g. (0.07 mole) 1-chloro-4-[3-(1-hydroxyhexyl)-phenoxy]-but-1-ene in 70 ml. methanol are added dropwise thereto in the course of 15 minutes. The reaction mixture is further stirred for 3 hours a ambient temperature and the solvent is then stripped off. The residue is taken up in diethyl ether and extracted several times with 2 M aqueous sodium hydroxide solution. The aqueous solution is acidified with 2 M hydrochloric acid and the desired compound is extracted with methylene chloride. After drying and stripping off the solvent, there are obtained 22.5 g. (91% of theory) of the title compound in the form of an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[C:19]1([C@@H:25]([NH2:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CCC>[C:19]1([C@@H:25]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: C[C@H](N)c1ccccc1
Solvent: CCCCO
Product: C[C@H](Nc1nnc(Cc2ccncc2)c2ccccc12)c1ccccc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 0.511 g (2 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 1.273 ml (10 mmol) (S)-1phenylethylamine and 5 ml 1-butanol is stirred for 24 h at 110° C. The reaction mixture is evaporated under vacuum and the residue distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase dried over anhydrous sodium sulfate is evaporated in the RE and then under HV and the residue purified on silica gel by flash chromatography using dichioromethane/methanol (50:1). The product-containing fractions are dissolved in 5 ml methanol, acidified with 0.75 ml 3N methanolic HCl and evaporated under vacuum. After recrystallization of the residue from methanol/acetonitrile, drying of the crystallizate under HV (8 h, 100° C.) and equilibration for 15 h at 20° C. and in room atmosphere, title compound is obtained with a water content of 10.66%; m.p. 190° C. (decomp.); ESI-MS: (M+H)+=341; [a]D20=+42.1±0.8° (c=1.272%, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15](=[CH:18]N(C)C)[C:16](=O)[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:23]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)[C:24]([NH2:26])=[NH:25].[OH-].[Na+]>C(O)(C)C.O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:18]=[N:25][C:24]([NH:23][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:34])(=[O:35])[NH2:36])[CH:28]=4)=[N:26][C:16]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CCc2sc(C(=O)OC(C)(C)C)cc2C1=O
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1cc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Yield: 53.1 %

Procedure:
5-Dimethylaminomethylene-4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid tert-butyl ester (6.21 g, 20.20 mmol), 3-guanidinophenylsulphonamide hydrochloride (5.07 g, 20.20 mmol) and sodium hydroxide (0.81 g, 20.20 mmol) were suspended in isopropanol (250 mL) and stirred at reflux overnight. The reaction was allowed to cool to room temperature and diluted with water (˜200 mL). The resulting precipitate was isolated by filtration and the solid obtained was washed with water (1×100 mL), isopropanol (1×50 mL), diethyl ether (2×50 mL) and pentane (3×100 mL). Air drying gave an ochre powder (4.92 g, 53% yield). MS (ES+)459. δH (d6 DMSO) 1.5-1.6 (9H, s), 2.9-3.0 (2H, m), 3.1-3.2 (2H, m), 7.2-7.3 (2H, br s), 7.3-7.5 (2H, m), 7.7-7.8 (1H, m), 8.1 (1H, s), 8.4 (1H, s), 8.6 (1H, s), 9.9 (1H, s).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([C:19]1[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:22]1[CH:21]=[CH:20][C:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:26]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCc1ccc(C(=O)O)cc1
Product: CCCCCCc1ccc(C(=O)N[C@@H](C)C#N)cc1

Procedure:
General procedure D was used to deprotect 0.210 g (1.23 mmols) of 4. The product was immediately carried on using general procedure F and coupled to 1.23 mmols of 10. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (1:3) to yield 0.106 g (0.41 mmols). 1H NMR (500 MHz, CDCl3) δ 7.74-7.68 (m, 2H), 7.25 (d, J=8.2, 2H), 6.61 (s, 1H), 5.20-5.11 (m, 1H), 2.70-2.61 (m, 2H), 1.66 (t, J=6.6, 3H), 1.60 (dd, J=7.3, 14.9, 2H), 1.37-1.22 (m, 6H), 0.88 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 173.95, 166.58, 148.00, 148.00, 131.31, 129.95, 128.78, 128.62, 127.20, 127.03, 119.42, 77.27, 77.02, 76.76, 52.57, 48.42, 36.24, 35.85, 31.63, 31.10, 28.87, 22.56, 19.57, 18.68, 14.07.
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:3]2)[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1Nc2ccccc2OCC1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OCC1N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 0.989 g of 3-chloro-2,3-dihydro-1,5-benzoxazepin-4(5H)-one and 1.0 g of potassium phthalimide in 5 ml of dimethylformamide is warmed to 90° overnight. The reaction mixture is poured into 20 ml of water and stirring is continued for 1 hr. Isolation by vacuum filtration and drying at 60° in vacuo affords 3-phthalimido-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; m.p. 188°-193°; NMR (DMSO, d6) δ 7.95 (s, 4), 6.61-7.40 (m, 5), 4.92 (d of d, 1), 4.01 (d, 2).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:19](=[C:20]([CH2:25]Cl)[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:25][C:1]#[N:2])[C:19]=3[CH:18]=[CH:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: ClCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1cccc2c(-c3ccc(Br)cc3)nccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 2.5 g of sodium cyanide and 150 ml of dimethylsulfoxide was added 14 g of 1-(4-bromophenyl)-5-chloromethylisoquinoline little by little. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate and a dilute aqueous solution of sodium bicarbonate. The organic layer was separated, dried, and recrystallized from dichloromethane-hexane to afford 8.5 g of 1-(4-bromophenyl)isoquinoline-5-acetonitrile as colorless prisms having a melting point of 121.5° to 122.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].N1C=CC=CC=1>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[N:35]/[OH:36])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(/C=N/O)cc2n1Cc1ccccc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 12 mg, 0.027 mmol) in MeOH (6 ml) was hydroxylamine hydrochloride (6.0 mg, 0.081 mmol) and pyridine (3 mg, 0.16 mmol). The mixture was stirred at 65° C. for 12 h, and then added concentrated in vacuo. The residue was purified by chromatography on silica gel (0→40% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:6]2[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]2=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C=Nc1nc(=O)n(S(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
To a 25 mL screw-cap vial were added dichloromethane (CH2Cl2; 10 mL), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (250 mg, 1.36 mmol), and triethylamine (Et3N, 300 mg, 3 mmol). To this mixture was added 4-chlorobenzenesulfonyl chloride (315 mg, 1.5 mmol), and the resulting mixture was shaken at room temperature for 3 h. The crude reaction mixture was partitioned between CH2Cl2 and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by reverse phase chromatography to yield the title compound as a white solid (321 mg, 66%): mp 207-210° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.08-8.02 (m, 3H), 7.53-7.47 (m, 2H), 3.23 (s, 3H), 3.21 (s, 3H); ESIMS m/z 360 ([M+H]+).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](O)=[O:31].CCCP(=O)=O>CC1CCCO1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=1)=[O:31]
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 85 °C
Yield: 75.8 %

Procedure:
Pyridine (12.9 mL, 161 mmol) was added to a solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (9.32 g, 40.3 mmol) and 5-bromo-2-chlorobenzoic acid (10.4 g, 44.3 mmol) in 2-methyl-tetrahydrofuran (100 mL). The reaction was heated to 85° C. before the addition of propylphosphonic anhydride (38.5 mL, 60.4 mmol, 50% solution in EtOAc) drop-wise. The reaction was heated at 85° C. for 16 hours before cooling to room temperature. The organic solution was washed with saturated aqueous sodium hydrogen carbonate solution (3×25 mL), saturated brine (30 mL) and concentrated in vacuo. The resulting solid was triturated with TBME (5×50 mL) to afford the title compound (13.7 g, 76%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:27][C:26]([F:29])([F:28])[CH2:25]2)=[CH2:23])[N:16]=3)=[C:9]([F:30])[CH:8]=1.[I-].[CH3:32][S+](C)(C)=O.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:24]4[CH2:27][C:26]([F:29])([F:28])[CH2:25]4)[CH2:32][CH2:23]2)[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CC(F)(F)C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CC(F)(F)C4)CC3)nc2s1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)vinyl)thiazolo[5,4-b]pyridine (299.1 mg, 0.692 mmol) in THF (13.33 mL) was added a solution of trimethylsulfoxonium iodide (913 mg, 4.15 mmol) and potassium 2-methylpropan-2-olate (466 mg, 4.15 mmol) in DMSO (8.0 mL) under argon, and the resulting solution was stirred at 60° C. for 2.5 h. The reaction mixture was then cooled to 25° C., THF was removed in vacuo, and the residual mixture was diluted with DCM (200 mL). The resulting solution was sequentially washed with sat. aq. NH4Cl and brine). The combined aqueous layers were extracted with DCM, and the combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-70% EtOAc/hexanes) furnished 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 446.1; Observed: 447.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23]C(S)=[CH:21][CH:20]=1)=[O:17]>C(O)(C)(C)C>[F:13][C:14]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:15]=1[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:12]([S:9][C:4]2[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[N:5]=2)=[CH:23][CH:24]=1)=[O:17]
Reactant: O=C(Nc1ccc(S)cc1)c1c(F)cccc1F
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 12 h
Yield: 34.8 %

Procedure:
A 250 ml round bottom flask equipped with a condenser was charged with 4,6-dichloro-2-methanesulfonyl pyrimidine (4.2 g, 18.8 mmol), 2,6-difluoro-N-(4-mercapto-phenyl)-benzamide (4.98 g, 18.8 mmol) and tert-butanol (75 ml) under nitrogen. The reaction mixture was degassed thoroughly and then heated at 90° C. for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution and brine. The organic was dried over magnesium sulfate, filtered and concentrated until the product began to precipitate. The mixture was then cooled and aged for 12 hrs. The product was collected by filtration, washed with cold ethyl acetate and dried. This gave the title compound as an off-white solid (2.7 g, 35%). 1H NMR (DMSO) 7.32 (2H, m), 7.61 (3H, m), 7.79 (1H, s), 7.82 (2H, d), 10.9 (1H, s). MS (ES+): 412.19
Reaction SMILES: [C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@@H](NC(C)=O)C(=O)O)cc1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To a solution of 52 (900 mg, 3.25 mmol) in THF/water, 3:1 (10 mL) was added lithium hydroxide monohydrate (273 mg, 6.5 mmol), and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed in vacuo. The aqueous layer was extracted with diethyl ether (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined DCM fractions were dried and evaporated to yield the title compound (750 mg, 2.85 mmol, 88%) as a white solid. [α]D23 −23.2 (c. 0.1, EtOH). Mp 75° C. 1HNMR (D6 acetone, 300 MHz): δ 7.27 (d, J=7.8 Hz, 1H, NH); 7.17 (d, J=8.7 Hz, 2H, ArH2′ and ArH6′); 6.86 (d, J=8.7 Hz, 21H, ArH3′ and ArH5′); 6.06 (m, 1H, H2″); 5.40 (dd J=1.5 Hz, 17.5 Hz, 1H, H3a″); 5.23 (dd, J=1.5, 10.5 Hz, 1H, H3b″); 4.67 (dd, J=5.1, 8.1, 10.5 Hz 1H, H2); 4.53 (d, J=5.1 Hz, 2H, H1″); 3.11 (dd, J=5.4, 14.1 Hz, 1H; 3Ha); 2.93 (dd, J=8.1, 14.1, 1H, 3Hb); 1.89 (s, 31H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH+]. HRMS calcd for C14H18NO4 264.123583, found 264.123770.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[C:10]([C:12]2[CH:16]=[C:15]([Si](C)(C)C)[O:14][N:13]=2)[N:11]=1)=[O:5].[F-].[Cs+]>C(O)C.C(Cl)Cl>[F:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)=[C:10]([C:12]2[CH:16]=[CH:15][O:14][N:13]=2)[N:11]=1)=[O:5]
Reactant: C[Si](C)(C)c1cc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)no1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: CCO
Product: O=C(Nc1nc(-c2ccon2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Into a solution of Compound 105 (55.0 mg, 0.10 mmol) in ethanol (2.0 mL) at room temperature was added cesium fluoride (152 mg, 1.0 mmol). The mixture was stirred at room temperature for 1 hour, diluted with CH2Cl2, washed with water (2×), dried (Na2SO4), filtered and concentrated. The residue was purified on silica to give Compound 106 (39 mg).