Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C.ClCCl.CO>[NH2:1][C:2]1[C:3]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCCCBr
Reactant: Nc1ncnc2pc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.3 %

Procedure:
7-Amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.25 g, 1.64 mmol, dried by coevaporation with dry DMF, 15 mL) was suspended in dry DMF to which sodium hydride (80 mg, 2 mmol, 60% dispersion in mineral oil) was added under argon atmosphere. The mixture was stirred at room temperature for 40 min and 1-bromopentane (0.25 mL, 2 mmol) was added. The reaction was continued for 3 h and the solvent was evaporated. The residue was coevaporated with toluene (25 mL). The solid thus obtained was dissolved in a mixture of dichloromethane and methanol (1:1, 10 mL) and impregnated onto silica gel (10 g). The solvents were evaporated under reduced pressure and the dry powder was loaded on a silica gel column (2×10 cm). The column was flash eluted with dichloromethane containing 0-5% methanol to yield 0.26 g (71%) of the title compound, mp 196-198° C. Ir (KBr): ν690 (=P-C), 1220 (-P=CH), and 3110 and 3280 (NH2) cm-1. Uv (MeOH): λmax266 nm (ε23,300). 31 p nmr (DMSO-d6): δ 62.57. 1H nmr (DMSO-d6): δ 0.83(t, 3 H, CH3), 1.25 (m, 4 H, 2CH2), 1.92 (m, 2 H, CH2), 4.27 (t, 2 H, NCH2), 8.37 and 8.67 (2s, 2 H, NH2), 8.60 (d, 1 H, C5H), and 9.03 (d, 1 H, J =54 Hz, C2H). Anal. Calcd. for C10H15N4P.0.5 CH2Cl2 : C, 47.63; H, 6.09; N, 21.17. Found: C, 47.47; H, 6.09; N, 21.86.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9].[CH2:13](O)[CH3:14]>>[Br:6][C@H:7]([CH2:11][CH3:12])[C:8]([O:10][CH2:13][CH3:14])=[O:9]
Reactant: CCO
Reactant: CC[C@@H](Br)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](Br)CC
Temperature: 25 °C

Procedure:
0.45 mL of sulfuric acid was added to ethanol (70 mL) solution of 7.0 g of (R)-2-bromobutyric acid at room temperature, and refluxed for 3 hours. The reaction mixture was cooled to room temperature, and poured into ice water (140 mL). The solution was extracted 3 times with ethyl acetate. The combined extract was sequentially washed with saturated sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, and 7.47 g of the subject compound was prepared as colorless oil. Optical purity 96% ee (HPLC)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:31])(C)C>CC(CC)=O>[ClH:31].[CH2:1]([N:8]1[C:12]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[NH:11][C@@H:10]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C1[C@H](Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-Dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (400 mg, 1.2 mmol) was dissolved in ethyl methyl ketone (3 ml), treated with water (12 μL) and with TMSCl (166 μL) and stirred overnight. The solid was filtered off, washed with ether and dried in vacuo. The product 1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 315 mg (71%).
Reaction SMILES: [S:1]([O:11][CH2:12][C:13]1([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C:14]1=[O:34])[C:17]4=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[BH4-].[Na+].CC(O)=O>CCO.C(Cl)(Cl)Cl>[S:37]([O:36][CH2:35][C:13]1([CH2:12][O:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:2])=[O:3])[CH2:26][C@@H:25]2[C@:16]34[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:24]2[CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:31][CH3:32])=[C:18]([O:33][C@H:15]3[C@H:14]1[OH:34])[C:17]4=2)([C:40]1[CH:41]=[CH:42][C:43]([CH3:44])=[CH:45][CH:46]=1)(=[O:39])=[O:38]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C(COS(=O)(=O)c4ccc(C)cc4)(COS(=O)(=O)c4ccc(C)cc4)C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
A solution of 10 (20.0 g, 30 mmole) in a mixture of 95% EtOH (200 mL) and CHCl3 (100 mL) was cooled in an ice bath and NaBH4 (3.4 g, 90 mmole) added portionwise over 10 min. The mixture was stirred for 90 min. in the cold, excess HOAc added to destroy the hydride and the solution evaporated. The residue was partitioned between CHCl3 and dilute NH4OH and further processed in the usual fashion. Evaporation gave a quantitative yield of 11 as a foam which contained traces of 6β-ol 2 and other impurities; NMR δ 4.41 (d, 1H, H5, J=5.5 Hz). This material was converted to 12 without further purification.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12][CH2:13][CH2:14]Br>>[Br:12][CH2:13][CH2:14][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: BrCCBr
Product: COC(=O)c1ccccc1OCCBr

Procedure:
The subtitle compound was prepared from methyl salicylate (5 g) and 1,2-dibromoethane (30.67 g) by the method of example 21 step (ii). Purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 4.9 g.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.C1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][NH:19][CH2:20][CH:21]=[O:22]>C(O)C.O>[Cl:16][CH2:17][CH2:18][N:19]([CH2:20][CH:21]=[O:22])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: O=C=Nc1ncc(Br)s1
Reactant: O=CCNCCCl
Solvent: CCO
Solvent: O
Solvent: c1ccccc1
Product: O=CCN(CCCl)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-β-chloroethylaminoacetaldehyde (13.5 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is then stirred at room temperature for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent under reduced pressure, leaving an oil. This oil is dissolved in an ethanol-water mixture, and the solution is filtered. The filtrate is then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-β-chloroethyl-3-(5-bromothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH2:11]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COC(=O)Nc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N)cc1
Reaction time: 2 h

Procedure:
Intermediate 10A (2.6 g, 9.77 mmol) was deprotected with 30% TFA in DCM (40 mL). After 2 h, the reaction was concentrated and the residue was partitioned with EtOAc (75 mL) and saturated NaHCO3 (50 mL). The organic layer was washed with brine (20 mL) and dried (MgSO4). Crude Intermediate 10B was carried onto the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (1H, s), 7.56 (2H, d, J=8.84 Hz), 7.28 (2H, d, J=8.84 Hz), 6.90 (2H, s), 3.68 (3H, s) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ncccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: ClCc1ccc(Oc2ncccn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A stirred solution of 2.0 grams (0.0099 mole) of (4-pyrimidin-2-yloxyphenyl)methan-1-ol (known compound) and 7 drops of pyridine in 50 mL of methylene chloride was cooled in an ice-water bath, and 0.94 mL (0.013 mole) of thionyl chloride was added dropwise. Upon completion of the addition, the reaction mixture was stirred for 3 hours at 10° C. to 20° C. The reaction mixture was then poured into ice-water and basified using sodium bicarbonate. The aqueous layer was separated from the organic layer, and was extracted one time with 75 mL of methylene chloride. The methylene chloride extract and organic layer were combined and passed through silicone coated filter paper. The fitrate was then concentrated under reduced pressure, yielding 2.1 grams of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH2:21](S(O)(=O)=O)C.CCCCCC>C(OCC)(OCC)OCC>[Cl:20][C:3]1[N:4]=[CH:5][N:6]=[C:7]2[C:2]=1[N:1]=[CH:21][N:8]2[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CCS(=O)(=O)O
Reactant: COc1ccc(CNc2ncnc(Cl)c2N)cc1OC
Solvent: CCCCCC
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC

Procedure:
To a suspension of 15.6 g (52.8 mmols) of 5-amino-4-chloro-6-(3,4-dimethoxybenzylamino)pyrimidine in 100 ml of triethyl orthoformate was added 149 mg (1.36 mmols) of ethanesulfonic acid and the resulting mixture was heated at 80° for 15 min. Upon cooling and addition of hexane to the reaction mixture, a yellow precipitate formed which was collected by filtration; yield, 15.4 g (95.6%) mp 159°-163°. Recrystallization from EtOH--H2O gave the analytical sample; yield 13.2 g (82.2%) mp 160°-164°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=[O:25].[Na+].CCOC(C)=O>C(O)(=O)C>[C:19]([C:18]1[O:23][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:25])[CH:7]=2)[CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(=O)CC(C(=O)c1ccccc1)c1ccnc(F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2cc[nH]c(=O)c2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A solution of 2-(2-fluoropyridin-4-yl)-5,5-dimethyl-1-phenylhexane-1,4-dione (200 mg, 0.6 mmol) in acetic acid (3 mL) was heated at reflux for 18 h. Upon cooling to RT the solution was slowly added to a mixture of sat'd aqueous NaHCO3 (40 mL) and EtOAc (40 mL). The mixture was stirred for 15 min. and the organic layer then collected. The aqueous layer was extracted with ethyl acetate (30 mL) and the organic layers combined, washed with sat'd aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using EtOAc-MeOH (100:0→95:5) as eluant to give the pure product as a cream solid (146 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([O:19]C)[C:11]([Cl:18])=[CH:12][C:13]=2[O:16]C)[CH2:8][O:7]1)=[O:5])[CH3:2]>C(#N)C.O.C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][C:14]2[C:13](=[O:16])[CH:12]=[C:11]([Cl:18])[C:10](=[O:19])[C:9]=2[CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(OC)cc(Cl)c(OC)c2CO1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1CC2=C(CO1)C(=O)C(Cl)=CC2=O
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a stirred solution of 1.0 g (3.7 mmol) of the chloroiso-chroman from step 6 in 20 ml of acetonitrile was added dropwise a solution containing 6.25 g (11.4 mmol) of ceric ammonium nitrate in 20 ml of water. The mixture was stirred overnight and then diluted with 50 ml of CH2Cl2. The organic layer was separated and the aqueous phase was extracted twice with 25 ml CH2Cl2. The combined organic layer was washed once with 50 ml H2O, 50 ml brine and then dried over Na2SO4. After evaporation of solvents, flash chromatography of the residue with a solvent gradient of 5 to 20% ethyl acetate in toluene yielded 495 mg (55%) of the titled compound. (MP: 83.5° C.) 1H NMR (200 MHz, CDCl3) δ: 1.27 (t, 3H, J=7.1 Hz, CH3), 2.58 (ddt, 1H, J=19.0, 8.8, 3.2 Hz, HCHaCHC=O), 2.83 (d multiplets, 1H, HCHeCHC=O), 4.17 (dd, 1H, J=8.7, 3.3 Hz, OCHC=O), 4.20 (q, 2H, J=7.0 Hz, OCH2), 4.44 (dt, 1H, J=18.8, 3.4 Hz, HCHaO), 4.78 (d multipier, 1H, J=18.8, 2.6, 1.7 Hz, HCHeO), 6.95 (s, 1H, C=CH).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]1=[O:25])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][C@@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:5]1=[O:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N=[N+]=[N-])C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O

Procedure:
0.3 g of 5% w/w palladium-on-carbon was added to 30 ml of ethanol containing 1.4 g of t-butyl α-[3(S*)-azido-2-oxo-6(R*)-phenylperhydroazepin-1-yl]acetate (Isomer A) [prepared as described in Example 1(h)], and under one atmosphere pressure of hydrogen the reaction mixture was shaken for 4 hours at 40° C. The catalyst was filtered off and the solvent was evaporated under reduced pressure, to give 1.56 g of the title compound as a gummy substance.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 73 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-ethylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-ethyl-phenyl)-1H-indole-3-carboxaldehyde (73% yield) as a light yellow solid. ESI/MS 284 (M+H); RT 4.04 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=9 Hz); 7.54 (4H, m); 7.38 (2H, m); 7.28 (1H, d); 2.77 (2H, q); 1.28 (3H, t).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)O[CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].[O:35]1CCC[CH2:36]1>>[CH3:23][Si:20]([CH3:21])([CH3:22])[CH2:19][CH2:18][C:36]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:35]
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: C[Si](C)(C)CCC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 71 %

Procedure:
A solution of 1-(4-nitrophenyl)piperazine (10 g, 48.31 mmol) and 2-(trimethylsilyl)ethyl p-nitrophenyl carbonate (14.4 g, 50.73 mmol) in tetrahydrofuran (220 mL) is refluxed for 3 hours with magnetic stirring and then stirred for 20 hours at room temperature. The reaction mixture is concentrated, the residue is taken up in dichloromethane and the organic phase is washed 4 times with 1N sodium hydroxide and twice with water. The organic phase is then dried over sodium sulphate, filtered and concentrated; the oily residue obtained is used without further purification in the following step (12 g, yield: 71%). 1H NMR (300 MHz, δ ppm) CDCl3: 0.04 (s, 9H), 1.02 (m, 2H), 3.43 (m, 4H), 3.65 (m, 4H), 4.22 (m, 2H), 6.82 (d, 2H), 8.13 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[C@H:12]1([C:24]2[S:28][C:27]([NH2:29])=[N:26][N:25]=2)[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[S:22][C:21]([NH2:23])=[N:20][N:19]=2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:29][C:27]1[S:28][C:24]([C@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]3[S:22][C:21]([NH:23][C:8](=[O:10])[CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:20][N:19]=3)[CH2:13]2)=[N:25][N:26]=1
Reactant: COC(=O)Cc1ccccn1
Reactant: Nc1nnc([C@H]2CCC[C@H](c3nnc(N)s3)C2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nnc([C@H]2CCC[C@H](c3nnc(NC(=O)Cc4ccccn4)s3)C2)s1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture of methyl 2-(pyridin-2-yl)acetate (107.0 mg, 0.71 mmol), 5,5′-((1S,3S)-cyclohexane-1,3-diyl)bis(1,3,4-thiadiazol-2-amine) (200 mg, 0.71 mmol), cesium carbonate (762.7 mg, 1.42 mmol) in DMF (6 mL) was heated to 130° C. under nitrogen atmosphere and microwave for 45 min. The mixture was evaporated in vacuum to dryness. The residue was purified by a standard method to afford desired compound.
Reaction SMILES: C(CP(=O)(OCC)OCC)(=O)N.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][C:21]2=O)=[CH:16][CH:15]=1.C(OP([CH2:33][C:34](=[O:39])[NH:35][CH:36]1[CH2:38][CH2:37]1)(=O)OCC)C>>[CH:36]1([NH:35][C:34](=[O:39])/[CH:33]=[C:21]2\[CH2:20][CH2:19][CH2:18][C:17]3[C:22]\2=[CH:23][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:38][CH2:37]1
Reactant: O=C1CCCc2ccc(F)cc21
Reactant: CCOP(=O)(CC(=O)NC1CC1)OCC
Agent: CCOP(=O)(CC(N)=O)OCC
Product: O=C(/C=C1\CCCc2ccc(F)cc21)NC1CC1
Yield: 35.7 %

Procedure:
This compound was prepared in an analogous manner to Example 27d with the replacement of 6-chloro-1-indanone and diethyl carbamoylmethylphosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd, J=11.2 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].[SH:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:21][C:19]1[CH:20]=[C:2]([S:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[C:3]([CH3:22])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(Br)c2C)c(=O)[nH]1
Reactant: O=C1CCC(S)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
A solution of 3-bromo-5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-2-methylbenzamide (0.35 g, 0.91 mmol.), 4-mercaptocyclohexanone (0.142 g, 1.09 mmol) and DIPEA (0.235 g, 1.82 mmol) in dioxane was purged with argon for 10 min. Then, Pd(OAc)2 (0.01 g, 0.044 mmol) and Xantphos (0.052 g, 0.089 mmol) were added and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, water was added and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to afford the title compound (0.50 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:28]=[CH:27][S:26][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=4)=[O:24])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(N3CCC(C(=O)O)C3)nc3scnc23)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxylic acid (95 mg, 0.236 mmol), tert-butyl 4-aminobenzoate (59 mg, 0.306 mmol), HATU (116 mg, 0.306 mmol) and DIEA (91 mg, 0.708 mmol) in 10 mL of DMF was stirred at room temperature for 72 hours. The solvent was evaporated at 80° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1)) to give tert-butyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidine-3-carboxamido)benzoate (105 mg, 77%) as a solid. LC-MS: 577.2 [M+H]+, tR=1.69 min
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]#N)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-:16].[Na+].C[OH:19]>C[Si](C)(C)C1C=C(C=CC=1)N>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([OH:19])=[O:16])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: N#CC1=CCN(c2ncccc2Cl)CC1
Reactant: [OH-]
Agent: C[Si](C)(C)c1cccc(N)c1
Agent: [Na+]
Product: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(3-chloropyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carbonitrile (compound 23) in 1 20 ml of NaOH (5 g, 125 mmol) water solution and methanol (20 ml) (V/V=1:1) was heated to reflux, and stirred overnight. The reaction was washed by a HCl solution in an ice bath, and extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:10][C:7]1[CH:6]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:4]=[C:3]([F:2])[C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(F)c(F)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
Methyl 2-(3,4,5-trifluorophenyl)piperidine-4-carboxylate hydrochloride (2.75 g, 8.88 mmol) was dissolved into DCM (50 mL), then DIPEA (3.88 mL, 22.20 mmol) was added. Methyl carbonochloridate (0.979 mL, 12.43 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. The mixture was washed with HCl (0.1 M, 100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(3,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.77 g, 94%) as an orange oil.