Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]>CCOCC>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To thionyl chloride (300 mL) was added 3-(1-acetyl-4-piperidinyl)propionic acid (88.2 g, 0.443 mol) in small portions under ice cooling. The mixture was stirred at room temperature for 10 minutes, and then thionyl chloride was distilled off at 25° C. under reduced pressure. Diethyl ether was added to the residue and then evaporated in vacuo to give a yellow solid. Again, diethyl ether was added, and the solid was crushed with a spatula, and ether was evaporated in vacuo to give 3-(1-acetyl-4-piperidinyl)propionic acid chloride as crude light yellow powder. This light yellow powder and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (64.0 g, 0.369 mol) were suspended into 1,2-dichloroethane (200 mL), into which aluminum chloride (162 g, 1.21 mol) was added in small portions at room temperature. The mixture was stirred at room temperature for 12 hours, then added to ice-water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried on anhydrous magnesium sulfate, and evaporated in vacuo to give a light yellow oily material. The oily material was purified by silica gel column chromatography (eluted with ethyl acetate/methanol=9:1) and crystallized from ethanol-diethyl ether to give 123.5 g of 8-[3-[(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one as colorless crystals having mp. 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 31.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.022 g (31%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH2:7][C:6]([OH:25])=[O:5])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
3.89 g (9.3 mmol) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester in 35 ml CH2Cl2 were added 17 ml TFA at 0° C. The solution was stirred at RT for 2 h, concentrated and triturated with ether to yield 3 g (89%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid as white solid, MS: 362 (M−H,1Br).
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:50]>>[N:1]1([C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[C:17]([NH2:50])[C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCCn1cnc2cnc3ccccc3c21)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: Nc1nc2ccccc2c2c1ncn2CCCCCC(=O)N1CCOCC1

Procedure:
1-(6-Morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline (3.09 g, 8.79 mmol) was treated with mCPBA (3.54 g, 15.4 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (3.26 g, 17.4 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part C of Example 10 to provide 0.422 g of 1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 166-168° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:30])([F:29])[C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>CCCCO>[C:16]1([C:3]2[C:2]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:24]3[C:23]([F:30])([F:29])[F:22])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: FC(F)(F)[C@H]1CCCN1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C(F)(F)F)nc2c1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), (R)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.68 mmol, 2.36 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 3 days at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH:7]([Cl:8])[CH:6](OC)[NH:5][C:4]1=[O:11].[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH2:37])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]>CCCCCC.CC(C)=O>[C:14]([O:17][C@@H:18]1[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@@H:21]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:20][C@H:19]1[N:32]1[C:41]2[N:40]=[CH:39][N:38]=[C:36]([NH:37][CH:6]3[NH:5][C:4](=[O:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[CH:7]3[Cl:8])[C:35]=2[N:34]=[CH:33]1)(=[O:16])[CH3:15]
Reactant: COC1NC(=O)C(OC)(OC)C1Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC1(OC)C(=O)NC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)C1Cl
Yield: 63.2 %

Procedure:
3,3,5-Trimethoxy-4-chloro-2-pyrrolidinone (500 mg) was evenly admixed with adenosine 2',3',5'-triacetate (940 mg) and the mixture was melted and reacted at 170° C. for 1 hour. The reaction mixture was subjected to silica gel column chromatography using hexane-acetone (1:1) as the eluent to obtain N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (860 mg). This product was dissolved in ammonia-saturated methanol (40 ml) and allowed to stand at 5° C. for 15 hours, at the end of which time the solvent was distilled off. The residue was washed with chloroform and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(2-oxo-3,3-dimethoxy-4-chloro-5-pyrrolidinyl)adenosine (590 mg).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].Cl.[NH:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:13])=[O:12])[CH2:7]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[CH:2]([N:6]1[CH2:9][CH:8]([NH:10][S:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[S:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[O:18])(=[O:12])=[O:13])[CH2:7]1)([CH3:4])[CH3:3]
Reactant: CC(C)Br
Reactant: O=C(NCCS(=O)(=O)NC1CNC1)c1ccc(Cl)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
85.3 mg (5 equiv.) 2-Bromo-propane were added to a mixture of 50 mg (0.14 mmol) 5-chloro-thiophene-2-carboxylic acid[2-(azetidin-3-ylsulfamoyl)-ethyl]-amide hydrochloride and 38 mg (2 equiv.) K2CO3 in 5 ml DMF. The resulting mixture was stirred for 2 h at 70° C., then diluted with 15 ml dichloromethane and washed with 3 ml of a saturated NaHCO3-solution. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-azetidin-3-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19]([O:21]CC)=O)[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.O>C1COCC1>[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19](=[O:21])[NH:2][CH3:1])[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CN
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 60 °C

Procedure:
Methylamine (35 mL of a 25 wt % solution in THF) was added all at once to a solution of 1-tert-butyl 3-ethyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidine-1,3-dicarboxylate (650 mg, 1.6 mmol) in THF (30 mL). The reaction mixture was heated to 60° C. for a period 12 h then cooled to rt. Water (50 mL) was added and the resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford tert-butyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidine-1-carboxylate (620 mg) as yellow oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CC1C=CN=C(N)C=1C.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][OH:49])[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:30]([N:37]1[CH2:41][CH:40]([C:42]2[S:43][CH:44]=[C:45]([Br:47])[CH:46]=2)[CH:39]([CH2:48][O:49][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Agent: Cc1ccnc(N)c1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2cc(Br)cs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Diisopropylethylamine (20.2 g, 0.156 mol), dimethyl aminopyridine (320 mg, 2.6 mmol) and TsCl were (9.88 g, 0.052 mol) were added, respectively, to the product of step b) (9.1 g, 0.026 mol) in 150 mL of dichloromethane at 0° C. The reaction mixture was stirred overnight at room temperature and then was quenched with 75 mL of 1 M HCl and extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried with MgSO4 and evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 0-50% methanol-dichloromethane gradient to give the subtitle compound (6.7 g, yield: 51%). MS calculated for C23H24BrNO3S2 +H: 506, observed: 506 and 508.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1O)[CH:17]=[CH2:18].CC1C=CC=C(C)N=1>ClCCl>[O:8]([C:20]1[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[CH2:16][CH:17]=[CH2:18])[S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]
Reactant: C=CCc1cc([N+](=O)[O-])ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CCc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reaction time: 3 h

Procedure:
Triflic anhydride (1.63 ml) was added dropwise to a mixture of 2-allyl-4-nitrophenol (1.79 g) and 2,6-dimethylpyridine (1.18 g) in dry dichloromethane (15 ml) at -20° C. under an atmosphere of argon. The reaction mixture was allowed to reach ambient temperature over 3 hours. The mixture was partitioned between water and dichloromethane. The organic phase was separated, washed with 1M aqueous sodium hydroxide solution, water, dried (MgSO4) and evaporated to give 2-allyl-4-nitrophenyl triflate (2.71 g) as an oil; microanalysis, found: C, 38.7; H, 2.6; N, 4.2%; C10H8F3NO5S requires: C, 38.6; H, 2.59; N, 4.5%; NMR: 3.7(2H,d), 5.19-5.35(2H,m), 5.97-6.17(1H,m), 7.84(1H,d), 8.36-8.55(2H,m); m/z 311(M).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=C(O)C=CC=1C.[F:18][C:19]([F:38])([F:37])[C:20]1[O:24][C:23]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])=[CH:22][CH:21]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:28]2([OH:35])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]([CH2:25][C:23]3[O:24][C:20]([C:19]([F:38])([F:37])[F:18])=[CH:21][CH:22]=3)[C:27]2=[O:36])[CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Reactant: Oc1ccc(Br)cc1
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 4-bromophenol to replace 3,4-dimethylphenol, and 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-((5-(trifluoromethyl)furan-2-yl)methyl)indolin-2-one was obtained (62%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.49-7.37 (m, 2H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.25-7.17 (m, 1H), 7.03 (d, J=7.9 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.74-6.68 (m, 1H), 6.38-6.32 (m, 1H), 5.00-4.81 (m, 2H), 4.09 (s, 1H); MS (ES+) m/z 449.9 (M−17), 451.3 (M−17).
Reaction SMILES: C[N+](C)=CCl.[Cl-].[Cl-].[CH2:8]([NH:10][C:11]([C:13]1[S:17][C:16](SC)=[N:15][C:14]=1[NH2:20])=O)C>>[S:17]1[C:13]2[CH:11]=[N:10][CH:8]=[N:20][C:14]=2[N:15]=[CH:16]1
Reactant: CCNC(=O)c1sc(SC)nc1N
Agent: C[N+](C)=CCl
Agent: [Cl-]
Product: c1ncc2scnc2n1

Procedure:
Reaction of N-cyanobismethylthiomethyleneimine with ethyl thioglycollate gives ethyl 2-methylthio-4-aminothiazole-5-carboxamide. Cyclization with formamide or equivalent, followed by desulfurization of the methylthio gives a thiazolopyrimidone, which can be activated by Vilsmeier reagent ,and the chloride displaced by the desired amine to give the desired thiazolo[4,5-d]pyrimidine derivatives as shown above.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:54][C:55]1[CH:59]=[CH:58][N:57]([CH2:60][C:61]([CH3:64])([OH:63])[CH3:62])[N:56]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:54][C:55]2[CH:59]=[CH:58][N:57]([CH2:60][C:61]([OH:63])([CH3:62])[CH3:64])[N:56]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.9 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19, 100.6 mg, 0.30 mmol) in methylene chloride (1.70 mL, 0.18M) at 25° C. was treated with N,N-diisopropylethylamine (160 μL, 0.91 mmol) followed by N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (110.6 mg, 0.36 mmol). The resulting solution was stirred at 25° C. for 2.5 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 61.8 mg, 0.39 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. Silica gel column chromatography (ISCO 40 g, 1/1-3/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide (23.6 mg, 16.5%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O4 [M+H+] 466.2449, found 466.2450. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.00-1.76 (m, 9H), 1.91 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=3.9, J=11.2 Hz, 1H), 5.72 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.46-7.64 (m, 3H), 8.12 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]2[C:10]=1[O:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>O1CCCC1>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:22])[CH2:20][CH3:21])=[C:10]2[C:6]=1[CH:7]=[CH:8][O:9]2
Reactant: Cc1ccc(O)c2occc12
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Oc1ccc(C)c2ccoc12

Procedure:
To a stirred mixture of 7-hydroxy-4-methylcoumarone (88.0 g, 0.5 mole), triethylamine (83.4 mL, 0.6 mole) and tetrahydrofuran (1 L) was added propanoyl chloride (46.27 g 0.5 mole) dropwise. The mixture was poured into cold 0.5 N hydrochloric acid (3 L) slowly with stirring. The solid was collected, washed with water, and dried. mp. 147° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>O1CCCC1>[CH:1]1([CH2:7][N:8]2[C:12]([CH:20]=[O:21])=[CH:11][CH:10]=[N:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cnn(CC2CCCCC2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccnn1CC1CCCCC1
Temperature: -78 °C
Yield: 67.6 %

Procedure:
To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide (10=L) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol). After 5 min bromomethylcyclohexane (2.4 mL, 17 mmol) was added by syringe and the mixture was maintained overnight. The reaction mixture was quenched with methanol, diluted with water, and extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 500 mg (27%) of 1-cyclohexylmethyl-1H-pyrazole. To a solution of 1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran (10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78° C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). The reaction mixture was allowed to warm to rt, maintained overnight, and was quenched with methanol. The reaction mixture was diluted with water and was extracted with ether (2 x). The combined organic layers were died over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 390 mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:11][CH:12]=1)(=O)=O.[C:29]([C:31]1([OH:39])[CH:36]2[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]2)[CH2:32]1)#[CH:30].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:20]([C:8]1[C:7]([C:30]#[C:29][C:31]2([OH:39])[CH:36]3[CH2:37][CH2:38][N:33]([CH2:34][CH2:35]3)[CH2:32]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:9]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2O)nc1Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1ccccc1-c1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of 67.0 mg of 2-benzyl-6-(2-hydroxyphenyl)-3-pyridyl trifluoromethane sulfonate, 24.7 mg of 3-ethynyl-3-quinuclidinol, 19.0 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 68.6 μl of triethylamine and 1.5 ml of N,N-dimethylformamide was heated under stirring at 100° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 56.8 mg of the target compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1CCCNCC1
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCCC3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Fluoroindan-1-one (5 g, 33.3 mmol) and azepane (9.92 g, 100 mmol) were dissolved in pyridine (20 ml) and heated at reflux for 3 hours, stirred at ambient temperature for 16 hours, and then heated at reflux for an additional 6 hours. The solvent was removed under vacuum and the residue partitioned between methylene chloride and water. The organic layer was washed with 1N aqueous sodium hydroxide, dried with magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was filtered through a pad of silica gel with 1:1 ethyl acetate:hexanes, and the solvent evaporated under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.56 (m, 4H), 1.81 (m, 4H), 2.62 (m, 2H), 3.02 (m, 2H), 3.55 (t, 4H), 6.59 (d, 1H), 6.68 (dd, 1H), 7.61 (d, 1H); MS (DCI) 230(M+H)+.