Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].C[N:34](C=O)C.C(Cl)(=O)C(Cl)=O.N>C(Cl)Cl.CO>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:34])=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:31])([F:32])[F:30])#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(N)=O)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 500 mg, 1.08 mmol) in DCM was added DMF (cat., 0.1 mL), followed by oxalyl chloride (0.14 mL, 1.61 mmol). The mixture was stirred at room temperature for 4 h then concentrated in vacuo to produce a yellow residue that was further dried on a high vacuum pump. Ammonia (0.5M in dioxane, 40 mL, 20 mmol) was directly added to the residue and the mixture was stirred at room temperature overnight. MeOH was added and the mixture was absorbed onto silica gel and purified by flash chromatography (50 to 100% EtOAc/Hexanes) to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water:TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 100 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.87 (t, 1H), 7.80 (s, 1H), 7.46 (dd, 1H), 7.37 (dd, 1H), 2.69-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.00 (m, 1H), 1.58 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[N:11](OC)[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].F[C:17](F)(F)C1C=CC=C(NC(=O)N(C)C)C=1.CC1C=CC(CCOC2C=CC(NC(=O)N(OC)C)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[N:11]([CH3:17])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)C(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CON(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Agent: CON(C)C(=O)Nc1ccc(OCCc2ccc(C)cc2)cc1
Product: CN(C)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea; 3-(α,α,α-trifluoro-m-tolyl)-1,1-dimethylurea; 3-[4-(4-methylphenethyloxy)phenyl]-1-methoxy-1-methylurea; 3-(5-t-butyl-3,4-thiadiazol-2-yl)-4-hydroxy-1-methyl-2-imidazolidone; etc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:23][C:24](=[O:25])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: O=C(CBr)c1ccccc1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CC(=O)c3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 2-bromoacetophenone as described for compound 8. Purified by chromatography [ethyl acetate: petroleum ether (60-80° C.)/1:3]. Crystallized from diethyl ether. M.p. 133-135° C.
Reaction SMILES: [OH-:1].[Na+].C([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)([OH:16])[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:13]2([OH:16])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]2)=[CH:20][CH:21]=1)(=[O:1])[NH2:26]
Reactant: N#Cc1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(OCC2(O)CCNCC2)cc1

Procedure:
4N sodium hydroxide (6.8 mL) was added to an ethanol solution (30 mL) of the compound (2.2 g) obtained in Step 3 of Example 4 and the mixture was heated under reflux for four and half hours. The solvent was removed under reduced pressure and to the residue was added water (30 mL), and the precipitate was collected by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:30][O:31][NH:32][CH3:33]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[N:32]([O:31][CH3:30])[CH3:33])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid (30 g, 0.13 mol) in dichloromethane (400 mL) was added portionwise 1,1′-carbonyidiimidazole (63.3 g, 0.39 mol). After addition was complete the reaction was allowed to stir for 15 minutes before N-methoxy-N-methylamine hydrochloride (38 g, 0.39 mol) was added and the reaction allowed to stir for 16 hours. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (250 mL) and 1M HCl (150 mL). The organic phase was washed with 1M HCl solution (2×100 mL), saturated sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered and the solvents removed in vacuo to give a crude yellow oil. Purification by column chromatography (SiO2, 30% ethyl acetate in hexanes) afforded the title product as a pale yellow oil (26.5 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[CH:11]=1.[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:11]3[N:5]4[N:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]4=[N:3][C:2]=3[CH3:1])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: Cc1cn2nc(C)ccc2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4ccc(C)nn34)c(C)nc12
Temperature: 135 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture containing 2,6-dimethyl-imidazo[1,2-b]pyridazine (0.44 g, 2.99 mmol), 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.03 g, 2.99 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), PPh3 (79 mg, 0.299 mmol), Cs2CO3 (1.95 g, 6.0 mmol) in DMF (50 mL) is stirred under N2 at 130-140° C. overnight. The reaction mixture is cooled, diluted with EtOAc (300 mL), washed with H2O (3×100 mL); dried (Na2SO4); filtered and concentrated. Purification of the resulting crude material by chromatography yields the title compound (0.37 g, 1.02 mmol, 34%). 1H NMR (CDCl3): δ 0.92 (t, J=7.1 Hz, 6H), 1.80-1.95 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 2.50 (s, 3H), 3.35-3.43 (m, 1H), 6.69 (s, 1H), 6.92 (d, J=9.2 Hz, 1H), 7.82 (d, J=1H) ppm. ES-MS (m/z): calcd for C21H26N6 (M+H)+: 363.5. found: 363.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Yield: 63.7 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (5 g, 19.57 mmol)[prepared in Preparation 2], 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.28 g, 20.55 mmol)[prepared in Preparation 1], potassium carbonate (10.82 g, 78 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.500 g, 0.978 mmol) in 1,4-dioxane (82 ml) and water (16.31 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3.2 g, 12.47 mmol, 63.7% yield) as a white solid: LCMS m/e ES 257, 259 (M, M+2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH4+].[Cl-]>[Zn].CO.C1COCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[C:7]#[N:8])=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Reaction time: 0.17 h

Procedure:
Intermediate (24t) (14.3 g, mmol) and zinc dust (17.2 g, 263 mmol) were suspended in mixed solvent of MeOH/THF (1:1, 125 mL) and saturated NH4Cl (125 mL) was added. The reaction mixture became warm. There was an obvious change in the zinc suspension. The reaction was finished in 10 minutes. The reaction mixture was filtered through a silica plug and diluted with EtOAc and saturated NaHCO3. The layers were separated and the combined organics dried over MgSO4 and concentrated under reduced pressure. The crude residue (25t) was pure enough on NMR spectra.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH2:10]([NH:13][CH2:14][CH:15]=[O:16])[C:11]#[CH:12]>C1C=CC=CC=1>[CH2:10]([N:13]([CH2:14][CH:15]=[O:16])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9])[C:11]#[CH:12]
Reactant: Cc1nnc(N=C=O)s1
Reactant: C#CCNCC=O
Solvent: c1ccccc1
Product: C#CCN(CC=O)C(=O)Nc1nnc(C)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-propargylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-propargyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[N:30][C:31](Cl)=[N:32]2)=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[N:30][C:31]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)=[O:11])=[N:32]2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ncc2ccc(Br)cc2n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3ccc(Br)cc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 7-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+, [M+2]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>[Pd].C1COCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:27]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Br)cc3)c(C3CCCCC3)c(=O)n2n1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc2[nH]c(-c3ccc(Cc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986, 27, 6369–6372) a mixture of 43 mg (0.1 mmol) of 5-(4-bromo-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester, 7.3 mg (0.01 mmol) of Pd catalyst, 0.4 mL (0.2 mmol) of B-Benzyl-9-BBN 0.5 M solution in THF, and 63 mg (0.3 mmol) of potassium phosphate, was purged with argon, 1 mL of 1,4-dioxane was added, and the resulting mixture was shaken at 80° C. in a sandbath overnight. The reaction mixture was then diluted with dichloromethane, filtered through a small pad of Celite, dried over sodium sulfate and evaporated to give a residue, which was purified via reverse-phase chromatography (Gilson) to afford desired 5-(4-benzyl-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a solid as indicated by LC-MS—calcd for C27H27N3O3 [M++H]+: 442.21, found: 442.2. This material was then converted to 5-(4-benzyl-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (581) via a LiOH saponification (33% yield over 2 steps); LC-MS—calcd for C26H25N3O3 [M++H]+: 428.19, found: 428.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>ClCCl>[CH3:52][S:53]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[CH2:21][CH:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])[CH2:10][CH2:9]1)(=[O:55])=[O:54]
Reactant: CC(C)(C)CC1CN(C(=O)NC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid piperidin-4-ylamide trifluoroacetic acid prepared in Example 24 (50 mg, 0.08 mmol) in dichlormethane (10 mL) at 0° C. was added triethylamine (0.026 mL, 0.19 mmol) and methanesulfonyl chloride (10 mg, 0.08 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (70% EtOAc in hexanes) to give as rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide as a white solid (30 mg, 63%)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH:7]1([CH:12]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:13][CH:14]=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.O>[CH:7]1([CH:12]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:13][C:14]#[CH:1])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C4CCCC4)c3)ncnc21
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of potassium carbonate (38.4 mg, 0.278 mmol) in methanol (2.0 mL) at 0° C. was added a solution of 3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (prepared as in Example 727, step 4) (61.0 mg, 0.139 mmol) in methanol (1.0 mL), followed by a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (Tetrahedron, 62 (2006), pp 6673-6680) (40.0 mg, 0.208 mmol) in methanol (1.0 mL). The mixture was slowly warmed to ambient temperature and stirred for 16 hours. The mixture was then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, saturated ammonium chloride, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product, which was used without further purification (52 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)[nH]c2c(Cl)nc(C)nc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(-c2ccc(C(C)C)cc2SC)c2nc(C)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
In 5 ml of dimethylformamide, 0.70 g of 6-chloro-9-(4-isopropyl-2-methylthiophenyl)-2-methyl-8,9-dihydropurin-8-one was dissolved, and 80 mg of sodium hydride in an oil was added thereto with ice-cooling, followed by stirring for 40 minutes. Subsequently, 0.39 g of ethyl bromoacetate was added thereto, and the reaction mixture was warmed up to room temperature and was stirred for 20 minutes. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to yield 0.85 g of ethyl 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([NH:28]C(OCC1C=CC=CC=1)=O)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:39])[CH:7]([NH2:28])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(N)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-Benzyloxycarbonylamino-3-{1-[(cis-4-ethoxycarbonylcyclohexyl)carbamoyl]cyclopentyl}-propanoic acid t-butyl ester (8.11 g, 15 mmole) in 10% aqueous ethanol (320 ml) was hydrogenated at 30 p.s.i. (2 bar) for 4 hours over 10% palladium on carbon. The catalyst was removed by filtration and the filtrate evaporated under vacuum. The residue was azeotroped with dichloromethane (3×50 ml) and dried to give the crude title compound as a gum (6.86 g). Rf. 0.6 (silica; methanol, dichloromethane 5:95).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[CH3:37][N:38]=[C:39]=[S:40].O>C(#N)C>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:39](=[S:40])[NH:38][CH3:37])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN=C=S
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=S)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.5 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 1 and Et3N (0.16 ml) in acetonitrile (10 ml), methyl isothiocyanate (0.083 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound as colorless oil (0.22 g, 99%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Cl:22][C:23]1[C:32]([CH2:33][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CSc2cc(Cl)c(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 10 mL of a chloroform solution containing 325 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 234 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 64 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 367 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 478 mg of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale brown foam.