Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][C:4]#[N:5].Cl.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CCO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]([NH2:5])=[CH:3][C:2]([CH:6]3[CH2:10][CH2:9][O:8][CH2:7]3)=[N:22]2)=[CH:17][CH:16]=1
Reactant: N#CCC(=O)C1CCOC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2nc(C3CCOC3)cc2N)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-oxo-3-(tetrahydrofuran-3-yl)propanenitrile (718 mg, 4.64 mmol) in EtOH (20 mL) was added conc. hydrochloric acid (0.387 mL, 4.64 mmol) and (4-methoxyphenyl)hydrazine hydrochloride (737 mg, 4.22 mmol). The reaction mixture was heated to 80° C. for 4 hr and was then cooled to RT and adjusted to pH8 by the addition of aq NaOH (2M, <5 mL). The resulting mixture was partitioned between water (20 mL) and Et2O (25 mL) and the aq layer was separated and extracted with ether (25 mL). The combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 0-5% MeOH in DCM, gradient elution) to afford the title compound, Intermediate A12, as a pale orange solid (503 mg, 45%); Rt 1.04 min (Method 2); m/z 260 (M+H)+, (ES+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A mixture of 2,6-dichloro-9H-purine (10.0 g, 53 mmol), 3,4-dihydro-2H-pyran (9.5 mL, 93 mmol) and p-toluenesulfonic acid monohydrate (1.0 g, 5.0 mmol) in THF (100 mL) was heated at 100° C. for 18 h, then cooled to RT and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10% ethyl acetate in cyclohexane) affording 2,6-Dichloro-9-(tetrahydro-pyran-2-yl)-9H-purine as a cream solid (10.9 g, 75%). 1H NMR (400 MHz, CDCl3): δ 8.33 (1H, s), 5.77 (1H, dd, J=10.4, 2.4 Hz), 4.19 (1H, m), 3.78 (1H, dt, J=11.6, 2.9 Hz), 2.17 (1H, m), 2.09 (1H, m), 1.98 (1H, m), 1.87-1.69 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][CH3:25]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:24][CH3:25])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCN1OC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 140 °C

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in acetonitrile (20 ml) then potassium carbonate (0.69 g), potassium iodide (0.175 g) and bromoethane (0.13 g) were added. The reaction was heated under microwave irradiation for 1 hour at 140° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine and then dried over sodium sulphate. The solvent was removed in vacuo and the crude product was purified by column chromatography (eluent cyclohexane/ethyl acetate) to afford ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester as a yellow solid. LCMS (method A) 1.29 min, MH+(-BOC) 131; 1H-NMR (CDCl3, 400 MHz): 5.10 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 3.95 (m, 1H), 3.60 (m, 2H), 1.50 (s, 9H), 1.20 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O:20][C:21](=O)C)(=O)[CH3:18]>C(OCC)(OCC)OCC>[CH2:17]([O:20][CH:21]=[N:1][C:2]1[S:11][C:5]2[CH2:6][N:7]([CH3:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:18]
Reactant: CCOC(=O)c1c(N)sc2c1CCN(C)C2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C)C2
Yield: 97 %

Procedure:
40.0 g (167 mmol) of 2-amino-3-carboethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 250 ml of triethyl orthoformate were mixed with 3.2 ml of acetic anhydride and refluxed under nitrogen for 3 h. The mixture was then completely evaporated in a rotary evaporator at 80° C. 48.0 g (97%) of crude product were isolated as a dark oil which is sufficiently pure for the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C=O)[C@H:10]([CH2:16][O:17][CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:16][O:17][CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@@H]1CN(Cc2ccccc2)CCN1C=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1CN(Cc2ccccc2)CCN1
Yield: 96.4 %

Procedure:
A solution of the protected methylether 23 (0.320 g, 1.29 mmol) in THF (3 mL) and 4 M H2SO4 (9 mL) was heated at 55° C. for 5 h. After cooling, the reaction contents were poured into 20 mL of cold (−10° C.) 4 M NaOH and diluted with 20 mL of saturated NaHCO3. The mixture was extracted with CH2Cl2 (4×15 mL) and the combined extracts dried (K2CO3) and concentrated to provide 24 as a pale oily solid (0.274 g, 96% yield). This product was of adequate purity for the subsequent transformations. 1H NMR (400 MHz, CDCl3): δ 1.85 (t, J=10.3 Hz, 1H), 2.11 (td, J=3.3, 11.0 Hz, 1H), 2.35 (bs, 1H, NH), 2.74 (m, 2H, triplet shape), 2.90 (m, 1H, td shape), 2.96-3.06 (m, 2H), 3.25-3.36 (m, 5H, OCH3 singlet present at 3.33), 3.50 (m, AB pattern, J=13.2 Hz, 2H), 7.22-7.33 (m, 5H); 13C NMR (100 MHz, CDCl3): δ 45.2, 53.8, 54.4, 55.9, 59.0, 63.4, 75.1, 126.9, 128.1, 129.1, 138.0. HRMS Calcd. for [C13H20N2O+H+] 221.1654. Found 221.1654. [α]D25+14.4 (c 0.030, CHCl3).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)[CH2:3][CH2:2]1>[Ni].C(O)C>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:18][CH2:19][CH2:20][CH2:21]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][CH:25]=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2nc(-c3cccc(OC(F)(F)F)c3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Agent: [Ni]
Solvent: CCO
Product: O=C(c1c(-c2cncnc2)nc(-c2cccc(OC(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 90, [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 89) was treated with Raney nickel in ethanol to give the title compound as yellow amorphous solid. MS: 527.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.Br[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=[O:16])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1cccc(Br)c1
Product: COc1ccc(C#Cc2cccc(C=O)c2)cc1

Procedure:
4-Methoxyphenylacetylene was reacted with 3-bromobenzaldehyde in the manner described in Example 1a to yield the title compound in form of white crystals melting at 52°-53° C.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([CH3:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:9]([CH3:28])=[O:8])=[CH:13][CH:14]=1
Reactant: CC(=O)COc1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)COc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 2 Trifluoroacetic acid (0.56 mL, 7.3 mmol) was added to a solution of tert-butyl 2-[4-(2-oxopropoxy)phenyl]ethylcarbamate (216 mg, 0.74 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred for 3 hr at ambient temperature, and then reaction mixture was stripped of volatiles in vacuo. The residue (143 mg) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:19][C:20]2[C:21](=[O:38])[N:22]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:30]([O:32]C)=O)[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:19][C:20]2[C:21](=[O:38])[N:22]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:30]([NH:42][CH:39]3[CH2:41][CH2:40]3)=[O:32])[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CCC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC2(c3ccccc3OCc3ccccc3)CCC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 268d, 1.46 g) in THF (40 mL) under nitrogen was treated with cyclopropylamine (0.88 mL) followed by isopropylmagnesium chloride (3.81 mL, 2.0 M in THF) dropwise over 10 min. The reaction was stirred at room temperature for 1 h then diluted with saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (×3). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle product (1.537 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:10]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:25])[CH:3]=1.[Cl:26]N1C(=O)CCC1=O>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:10]([Cl:26])=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:12]=2)=[C:4]([Cl:25])[CH:3]=1
Reactant: CC(C)(O)c1cn(-c2c(Cl)cccc2Cl)c(-c2ccc(Br)cc2Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(O)c1nc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)c1Cl
Temperature: 25 °C
Reaction time: 40 h
Yield: 76.8 %

Procedure:
A suspension of 2-[2-(4-bromo-2-chlorophenyl)-1-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-propan-2-ol (230 mg, 0.50 mmol) in MeCN (4 mL, anhyd) was charged with N-chlorosuccinimide (70 mg, 0.52 mg) and then heated at 70 C. After 22 h the reaction mixture was charged with additional N-chlorosuccinimide (67 mg, 0.50 mmol) and heated at 85 C. After 40 h (total reaction time) the reaction mixture was allowed to cool to ambient temperature, concentrated and purified by chromatography (silica, EtOAc/Hex, 0:100 to 30:70) to give the title compound (0.19 g, 77%) as a white solid. 1H-NMR (DCM-d2): δ 7.61 (d, 1H), 7.42-7.45 (m, 2H), 7.36 (m, 1H), 7.27 (dd, 1H), 7.10 (d, 1H), 3.33 (s, 1H), 1.65 (s, 6H).
Reaction SMILES: CC(O)(C(C)(O)C)C.C(OCC[N:14]1[CH:18]=[C:17]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:16]=[N:15]1)C.Cl.C(N(CC)CC)C>ClCCCl.CC(OC)(C)C.O>[CH3:26][C:21]1([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23][B:19]([C:17]2[CH:16]=[N:15][NH:14][CH:18]=2)[O:20]1
Reactant: CCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: O
Product: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Temperature: 15 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
To a mixture of 2,3-dimethylbutane-2,3-diol (25.0 kg, 211.6 mol) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24, 55.0 kg, 206.7 mol) in 1,2-dichloroethane (750 kg) was slowly added a solution of HCl in MTBE (25.0 kg, 20-30% of HCl) at 0-5° C. The resulting reaction mixture was then stirred at 10-20° C. for 3-5 hours. After the selective deprotection reaction was complete as monitored by HPLC (1: below 1%), the reaction mixture was degassed and refilled with nitrogen before being cooled to −15° C. The cooled reaction mixture was then added triethylamine (TEA, 30.0 kg, 296.5 mol) to adjust pH to 7-8. The mixture was then gradually warmed to ambient temperature before being treated with water (150 kg). The two phases were separated and the organic layer was washed with brine (60 kg) and dried over sodium sulfate (Na2SO4). The drying reagent, sodium sulfate (Na2SO4), was removed by filtration and the resulting solution was concentrated under reduced pressure at 40-50° C. to a thick oil. The residue was warmed to 60-70° C. and diluted with petroleum ether (100 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred at the same temperature for 3 hours. The solids was collected by centrifugation and dried at 50-60° C. under vacuum to afford the crude desired product (1, 33.75 kg, 40.11 kg theoretical, 84.1%). The crude desired product was then suspended in 1,2-dichloroethane (30 kg) and the resulting mixture was heated to reflux until a clear solution was formed. To the hot solution was then added petroleum ether (150 kg) at the same temperature. The resulting mixture was then gradually cooled to ambient temperature and subsequently to −5° C. and stirred and the same temperature for 3 hours. The solids were collected by centrifugation and dried under vacuum at 50-60° C. to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 31.0 kg, 40.11 kg theoretical, 77.3%) as an off-white solid, which is identical in every comparable aspect to the material synthesized by the synthetic method as described above in Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The precipitated crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[S:7][C:8]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:9][C:10]=1[N:11]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:5].[O:33]1[CH:37]2[O:38][CH2:39][CH2:40][CH:36]2[C@@H:35]([O:41][C:42](=[O:52])C2C=CC([N+]([O-])=O)=CC=2)[CH2:34]1.O1CCC(O)CC1>>[O:33]1[CH:37]2[O:38][CH2:39][CH2:40][CH:36]2[C@@H:35]([O:41][C:42]([N:15]2[CH2:16][CH2:17][CH:12]([N:11]([C:10]3[CH:9]=[C:8]([C:27]#[C:28][C:29]([CH3:32])([CH3:30])[CH3:31])[S:7][C:6]=3[C:4]([OH:3])=[O:5])[C:18]([CH:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13][CH2:14]2)=[O:52])[CH2:34]1
Reactant: O=C(O[C@H]1COC2OCCC21)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Agent: Cl
Agent: OC1CCOCC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCN(C(=O)O[C@H]3COC4OCCC43)CC2)CC1

Procedure:
4-[[2-carboxy-5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-piperidine-1-carboxylic acid hexahydro-furo[2,3-b]furan-3-(R)-yl ester was prepared in a similar fashion to 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-trans-methyl-cyclohexanecarbonyl)-[4-(tetrahydro-pyran-4-yloxycarbonylamino)-cyclohexyl]-amino}-thiophene-2-carboxylic acid using method B, except the HCl salt of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester was used instead of 3-[(4-amino-cyclohexyl)-(4-trans-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester, and 4-nitro-benzoic acid hexahydro-furo[2,3-b]furan-3-(R)-yl ester was used in place of the chloroformate of tetrahydro-pyran-4-ol.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:33]5[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]3[C@:20]4([CH2:24][S:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:33]5[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A RBF was charged with tert-butyl 3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.091 g, 0.166 mmol). The material was dissolved in 0.5 mL of CH2Cl2 and TFA (0.149 mL, 1.932 mmol) was added. The reaction was heated to 50° C. and stirred for one hour. The reaction was concentrated, diluted with CH2Cl2 and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to afford (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as an off-white solid. MS m/z=447.3 [M+H]+. Calculated for C24H19FN4O2S: 446.12.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12](=[O:34])[C:13]1[CH:25]=[C:24]([C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[C:15]([C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:14]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][SH:38]>ClCCl>[CH3:10][O:11][C:12](=[O:34])[C:13]1[CH:25]=[C:24]([C:26]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:39][CH2:35][CH2:36][CH2:37][S:38]2)[CH:23]=[C:15]([C:16]([N:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[O:17])[CH:14]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccccc2)c1
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C2(c3ccccc3)SCCCS2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Add boron trifluoride diethyl etherate (0.358 mL, 2.83 mmol) to a solution of 5-benzoyl-N-methyl-N-propyl-isophthalamic acid methyl ester (0.192 g, 0.566 mmol) in dichloromethane (3 mL) at 0° C. Add 1,3-propanedithiol (0.114 mL, 1.12 mmol). Stir at room temperature overnight. Partition between water (20 mL) and dichloromethane (20 mL) and extract the aqueous layer with dichloromethane (20 mL). Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (51%).
Reaction SMILES: [CH2:1]=CC(=C)C.CN(C)C(=O)C(C)C.C(N(CC)CC)C.[CH3:21][C:22]1([CH3:30])[C:25](C)([CH:26]=[CH2:27])[CH2:24][C:23]1=[O:29]>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:30][C:22]1([CH3:21])[CH:25]([C:26]([CH3:27])=[CH2:1])[CH2:24][C:23]1=[O:29]
Reactant: C=CC(=C)C
Reactant: C=CC1(C)CC(=O)C1(C)C
Agent: CC(C)C(=O)N(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C1CC(=O)C1(C)C

Procedure:
34.0 g (0.5 mol) of isoprene and then, at 0°-10° C., 75.0 g (0.55 mol) of zinc chloride were added to 350 ml of the solution, prepared according to Example 1, of the amide chloride is isobutyric acid dimethylamide in methylene chloride, while cooling and stirring. Thereafter, 50.0 g (0.5 mol) of triethylamine were added dropwise at the same temperature and, after warming to 20°-25° C., the mixture was heated to reflux and worked up according to Example 2. This gave 40.4 g (58%, relative to isobutyric acid dimethylamide employed) of the ketone of boiling point 109°-110° C./100 mm Hg and nD20 of 1.4518 (contaminated to the extent of about 10% by 2,2,3-trimethyl-3-vinyl-cyclobutanone).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][O:17]C(=O)C)[CH2:11]3)[CH2:9][N:8]([C:22]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:23])[C:5]2=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15](=[O:21])[CH2:16][OH:17])[CH2:11]3)[CH2:9][N:8]([C:22]([NH:24][C:25]3[S:26][C:27]([Cl:30])=[CH:28][N:29]=3)=[O:23])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(CO)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
5-Bromo-N-(5-chlorothiazol-2-yl)-1′-(2-acetoxyacetyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (64.0 mg, 0.136 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (1 mL). Thereafter, an aqueous solution of sodium hydroxide (2 M, 0.5 mL) was added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 30 minutes. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1→7:1) to obtain the captioned compound (37.8 mg, 65%) in the form of a white solid.
Reaction SMILES: C(O)(=O)C.[Br:5]N1C(=O)CCC1=O.[CH2:13]([CH:15]([C:18]1[N:23]2[N:24]=[C:25]([CH3:38])[C:26]([C:27]3[S:31][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][N:36]=4)=[N:29][CH:28]=3)=[C:22]2[N:21]=[C:20]([CH3:39])[CH:19]=1)[CH2:16][CH3:17])[CH3:14]>C(#N)C>[Br:5][C:28]1[N:29]=[C:30]([C:32]2[N:33]([CH3:37])[N:34]=[CH:35][N:36]=2)[S:31][C:27]=1[C:26]1[C:25]([CH3:38])=[N:24][N:23]2[C:18]([CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[CH:19][C:20]([CH3:39])=[N:21][C:22]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(-c4ncnn4C)s3)c(C)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC(CC)c1cc(C)nc2c(-c3sc(-c4ncnn4C)nc3Br)c(C)nn12
Temperature: 22 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Add acetic acid (1 mL) and N-bromosuccinimide (4.1 g, 22 mmol) to a solution of 7-(1-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiazol-5-yl]-pyrazolo[1,5-a]pyrimidine (8 g, 21 mmol) in acetonitrile (80 mL). Stir the mixture 2 h at 22° C. Then evaporate the solvent and add water (50 mL) and methyl-t-butyl ether (100 mL) to the resulting residue. Separate the organic portion, dry over sodium sulfate, filter, and evaporate the solvent. Recrystallize the resulting residue from isopropyl alcohol to afford the title compound (8.7 g, 90%). ES/MS (m/z): (79Br/81Br) 460/462 (M+1)+.