Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[S:19])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[C:21]([N:20]1[C:2](=[O:8])[C:3](=[O:5])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]#[N:10])=[CH:16][CH:15]=2)[C:18]1=[S:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NC(=S)Nc1ccc(C#N)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)N1C(=O)C(=O)N(c2ccc(C#N)cc2)C1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Ethyl chlorooxoacetate (1.15 mL, 10.29 mmol) was added dropwise to a stirring solution of 1-(4-cyanophenyl)-3-(tert-butyl)-thiourea (0.802 g, 3.25 mmol) in dichloromethane (40 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to afford a residue which was purified by flash column chromatography (50% ethyl acetate/hexanes) to afford 0.48 g (32%) of 4-[3-(tert-butyl)-4,5-dioxo-2-thioxo-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 200.4–201.3° C.; 1H NMR (DMSO-d6): δ 8.00 (d, 2H), 7.52 (d, 2H), 2.20 (q, 2H), 1.79 (s, 9H); IR (KBr) 3500, 2220, 1760 cm−1; MS (m/z) 287 (M+).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[N:6]1([C:15](=[O:17])[CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To a suspension of NaHCO3 (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 mol) in CH2Cl2 (600 mL) cooled in an ice-water bath, was added dropwise acetyl chloride (78.5 g, 1.0 mol). The mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated to give 1-(2,3-dihydro-indol-1-yl)-ethanone (82 g, 100%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[CH2:10][CH2:9][C:8]([Cl:16])([Cl:15])[C:7](=[O:17])[C:6]=2[C:5]=1[CH2:18][CH2:19][C:20]([O-:22])=[O:21].[CH2:23](O)[CH3:24]>[BH4-].[Na+]>[OH:17][CH:7]1[C:6]2[C:5]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([CH3:3])[CH:13]=[C:12]([Cl:14])[C:11]=2[CH2:10][CH2:9][C:8]1([Cl:16])[Cl:15]
Reactant: Cc1cc(Cl)c2c(c1CCC(=O)[O-])C(=O)C(Cl)(Cl)CC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CCc1c(C)cc(Cl)c2c1C(O)C(Cl)(Cl)CC2
Reaction time: 0.25 h

Procedure:
Sodium borohydride (0.19 g, 5.02 mmoles) was added to a solution of 3-(2-methyl-8-oxo-5,6,7,8-tetrahydro-4,7,7-trichloronaphthalen-1-yl)propanoate (7.38 g, 20.3 mmoles) in ethanol (60 ml) which had been cooled in an ice-water bath. The reaction was allowed to stir for 15 minutes. Tlc (silica-CH2Cl2) showed reaction not complete. Add 20 mg of sodium borohydride first stirred in the cold for 15 minutes. Repeat addition of 20 mg of sodium borohydride with 15 minutes stirring in the cold twice more at which time tlc showed reaction complete. The reaction was then partitioned between ether (150 ml) and water (300 ml). The water was extracted with ether two times. The combined ether extracts were washed with water two times, dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave 7.25 g of title compound as a gum.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[S:6])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([CH2:19][NH:20][CH3:21])[N:15]=2)[CH:11]=[CH:12][CH:13]=1>CCO>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([CH2:19][N:20]([CH3:21])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[S:6])[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: S=C=NC1CC1
Reactant: CNCc1noc(-c2cccc(Cl)c2)n1
Solvent: CCO
Product: CN(Cc1noc(-c2cccc(Cl)c2)n1)C(=S)NC1CC1
Yield: 77.7 %

Procedure:
Cyclopropyl isothiocyanate (650 mg, 6.6 mmol) was added to 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine (1.47 g, 6.5 mmol) in EtOH (20 mL). After 3 h the formed precipitate was filtrated off and washed with cold EtOH to give 1.63 g (78%) of the title compound. LC-MS (M++1): 323.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C.O>CCOCC>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([B:23]([OH:24])[OH:22])=[CH:8][CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2ccccn2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1ccc(-c2ccccn2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
n-Butyllithium (1.6M in hexane, 2.67 ml) was added to dry ether (16 ml) at -78° C. under argon. A solution of 2-(4-bromophenyl)pyridine (D76, 1.0 g) in dry ether (20 ml) was added dropwise over 5 minutes and allowed to warm to -20° C. for approximately 2 minutes to give a deep red solution. After recooling to -78° C., triisopropylborate (1.18 ml) was added, stirred 30 minutes, warned to ambient temperature to give a yellow cloudy mixture. Water (4.2 ml) and 0.5 MNaOH (4.2 ml) were added with vigorous stirring and the mixture separated. The ether layer was extracted with 0.5M NaOH (2.8 ml) and the combined aqueous extracts were extracted with ether (2×30 ml). The aqueous layer was acidified to pH6 with dilute hydrochloric acid to give the title compound as a beige solid, (0.15 g, 18%).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]([CH3:20])([CH3:19])[CH3:18])/[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:17]([C:16]1[O:15][CH:14]=[N:13][C:12]=1/[CH:11]=[C:6]1/[C:5](=[O:21])[NH:4]/[C:9](=[CH:27]\[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)/[C:8](=[O:10])[NH:7]/1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)N1CC(=O)N/C(=C\c2ncoc2C(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=c2\[nH]c(=O)/c(=C/c3ncoc3C(C)(C)C)[nH]c2=O)c1

Procedure:
To a solution of 4 (50 mg, 0.17 mmol) in DMF (4 mL) was added 3-methoxybenzaldehyde (31.4 μL, 0.26 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (111.9 mg, 0.34 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was heated for 3 h at 85□. After the solvent was removed by evaporation, the residue was AcOEt, washed with water for two times and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in 70% MeCN aq and applied to reverse-phase HPLC column (μBondasphere 5C18 100 A, 19×150 mm) and eluted using a linear gradient from 30 to 100% CH3CN in 0.1% TFA aq over 30 min at a flow rate of 12 mL/min, and the desired fraction was collected and concentrated by evaporation to give a 35.3 mg (55.9%) of yellow colored KPU-201. mp 114-116° C.; 1H NMR (300 MHz, CDCl3) δ 11.40 (br s, 1H), 8.14 (br s, 1H), 7.88 (s, 1H), 6.96-7.00 (m, 2H), 6.92 (s, 1H), 6.88 (s, 1H), 6.88-6.92 (m, 1H), 3.83 (s, 3H), 1.44 (s, 9H); HRMS (EI) m/z 367.1538 (M+) (calcd for C20H21N3O4: 367.1532).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[CH3:28][C:26]1[NH:25][N:24]=[C:23]([NH:22][C:12]2[N:11]=[C:10]([O:8][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:27]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cc1cccc(O)c1
Product: COc1ccc2c(Oc3cccc(C)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methyl-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-m-tolyloxy-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:27])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[CH2:7]1.[OH-].[Na+].Cl>CO.O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[S:18][CH:19]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CSc1nc(C(=O)O)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (850 mg) of (1-4) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), 1 mol/L aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred overnight at room temperature. 1 mol/L hydrochloric acid was added to the reaction mixture, and the organic solvent alone was evaporated under reduced pressure. Saturated brine was added to the obtained residue, and the mixture was extracted with a mixed solvent of chloroform-methanol. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (479 mg) as a white solid.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:7]1[CH3:22])[CH3:5].Cl.[CH3:25][NH:26][O:27][CH3:28].C([Mg]Cl)(C)C>>[CH3:28][O:27][N:26]([CH3:25])[C:3](=[O:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[C:7]1[CH3:22])[CH3:5]
Reactant: COC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Product: CON(C)C(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 0 °C
Yield: 60.2 %

Procedure:
To a 100 mL round-bottom flask was added (±)-tert-butyl 1-(1-methoxy-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.958 g, 3.01 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.440 g, 4.51 mmol). The flask was vac/purged 3× with N2 then THF (17 mL) were added and the reaction was cooled to −40° C. isopropylmagnesium chloride (4.51 ml, 9.03 mmol) was added dropwise and the reaction was mixed at that temperature for 1 h then warmed to 0° C. for 1 h then quenched with 1N HCl, extracted with EtOAc. The org layer was washed with water then brine, dried over Na2SO4, filtered, concentrated, deposited onto silica gel with aid of DCM, and purified by CC using 25% EtOAc in Hex as eluent to provide (±)-tert-butyl 1-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.630 g, 60.3%). LRMS (M+H+) m/z: calcd 348.41. found 348.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:35]2[CH2:40][CH2:39][N:38]([CH:41]3[CH2:44][O:43][CH2:42]3)[CH2:37][CH2:36]2)=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:35]4[CH2:40][CH2:39][N:38]([CH:41]5[CH2:44][O:43][CH2:42]5)[CH2:37][CH2:36]4)=[C:26]([N:28]4[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]4)[CH:27]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: Cn1nnn(-c2cc(N)ccc2N2CCN(C3COC3)CC2)c1=O
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)ccc2N2CCN(C3COC3)CC2)c1=O
Temperature: 120 °C
Yield: 55 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 1.0 eq, 0.7 mmol), 1-(5-amino-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (0.3 g, 1.4 eq, 0.9 mmol), PTSA (0.4 g, 2.0 eq, 1.9 mmol) was taken in iPrOH (50 mL) and heated at 120° C. overnight. The volatiles were removed under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product as a solid in 55% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:26]
Reactant: CI
Reactant: COc1ccc(CSc2nc(Cl)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 741 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine (2.00 g, 6.3 mmol) was dissolved in N,N-dimethylformamide (20 ml), under ice cooling, 60% sodium hydride (0.30 g, 7.6 mmol) was added and stirred for 5 minutes, then methyl iodide (1.08 g, 0.76 mmol) was added and stirred overnight. Water was added to the reaction solution, the precipitated crystals were collected by filtration and washed sequentially with water and ether to obtain 2.06 g (89% yield) of 6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O1CC[CH2:18][CH2:17]1>CS(C)=O>[Si:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:17]#[CH:18])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Solvent: CS(C)=O
Product: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 4 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
6-Bromo-1-(t-butyldimethylsilyloxy)hexane (20 g, 110.42 mmol) was dissolved in dry dimethyl sulfoxide (500 ml) and tetrahydrofuran (50 ml) and cooled to 0° C. under argon atmosphere, to which was added lithium acetylide ethylene diamine complex (28.0 g, 304.74 mmol) and the resulting solution was stirred for 1 day at 4° C. After the reaction was completed, the mixture was poured in ice-water and extracted with ethyl ether. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This crude product was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane=1:40. After removal of the solvent, 18 g of the title compound was obtained as colorless oil. (yield: 73.8%)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].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.Cl.[F:42][C:43]1[CH:51]=[C:50]2[C:46]([C:47]([C:61]3[CH:62]=[N:63][N:64]([CH:66]4[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]4)[CH:65]=3)=[CH:48][N:49]2[S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])=[CH:45][CH:44]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([N:69]1[CH2:68][CH2:67][CH:66]([N:64]2[CH:65]=[C:61]([C:47]3[C:46]4[C:50](=[CH:51][C:43]([F:42])=[CH:44][CH:45]=4)[N:49]([S:52]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)(=[O:54])=[O:53])[CH:48]=3)[CH:62]=[N:63]2)[CH2:71][CH2:70]1)=[O:7]
Reactant: CN(C)CC(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of (dimethylamino)acetic acid (165 mg; 1.60 mmol), HATU (608 mg; 1.60 mmol), and DIPEA (619 mg; 4.80 mmol) in THF (25 mL) was added 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 368 mg; 0.80 mmol) under nitrogen. The reaction mixture was stirred overnight, concentrated, dealed with saturated aqueous NaHCO3 (50 mL), extracted with EtOAc (50 ml×2). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by a silica gel chromatography (DCM/MeOH=20/1) to afford 400 mg (100%) of the title compound as a yellow oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C@@H:8]1([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[N:21]=2)[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10]>N1C=CC=CC=1>[C:9]([O:10][C@@H:9]1[C@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@@H:13]([CH2:15][O:16][C:5](=[O:7])[CH3:6])[O:14][C@H:8]1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[N:21]=1)(=[O:10])[CH3:8]
Reactant: NC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2nc(C(N)=O)cs2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
Acetic anhydride (2.0 ml) was added to an ice-cold solution of compound 1 (1.04 g, 4 mmol) in anhydrous pyridine (16 ml) and the reaction solution was stirred at room temperature for 17 h. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried (MgSO4). The ethyl acetate portion was evaporated in vacuo and the residue thus obtained was crystalized from water to provide 1.4 g (90%) of compound 2 as white needles; mp 103° C.; 1H NMR (CDCl3) 2.1 (3 s, 9, tri-O-acetyl), 6.2 and 7.15 [pair of s(br), 2, CONH2 ], 8.2 (s, 1, H5). Anal. (C15H18N2O8S) C, H, N, S.
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[N:36]([CH2:37][C:38](O)=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:27][CH:26]=1)#[N:24].C(N(CC)C(C)C)(C)C.N>CN(C)C=O>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[N:36]([CH2:37][C:38]([NH2:7])=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:51])[F:50])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (43 mg, 0.13 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 60 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 μL, 0.29 mmol) in N,N-dimethylformamide (0.5 mL). After 20 min aqueous ammonia (32%, 8 μL, 0.13 mmol) added and the mixture is stirred at room temperature for 1 h. The mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 36 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 0.50 min (X012_S01).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2[C:45](OC=1C1C=CC=CC=1)=[C:44]1[N:54](C(C)C)[N:55]=[CH:56][C:43]1=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:54]([CH:44]([CH3:45])[CH3:43])[N:55]=[CH:56][C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Yield: 81 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-1-isopropyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a white solid (37.3 mg, 81%). LCMS (Method H): RT=4.70 min, [M+H]+=550.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 416.22 g/mol.
Reaction SMILES: [F:1][CH:2]([F:25])[CH2:3][N:4]([S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[I:24])(=[O:16])=[O:15])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([O:12]C)=O.[H-].[Na+].O.Cl>CN(C)C=O>[F:1][CH:2]([F:25])[CH2:3][N:4]1[C:5]2[N:6]=[CH:7][S:8][C:9]=2[C:10]([OH:12])=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[I:24])[S:14]1(=[O:15])=[O:16]
Reactant: COC(=O)c1scnc1N(CC(F)F)S(=O)(=O)Cc1ccccc1I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)C(c2ccccc2I)=C(O)c2scnc2N1CC(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2.0 g (4 mmol) of methyl 4-{(2,2-difluoroethyl)[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate were dissolved in 25 ml of dimethylformamide and cooled to 0° C., and 143.3 mg (6 mmol) of sodium hydride were added. After addition, the mixture was warmed to RT and stirred for 12 h. Thereafter, the reaction mixture was poured onto 100 ml of water and brought to pH 4-5 with 2N HCl. The precipitate formed was filtered off and washed with water. This gave 1.7 g of compound I-a-14.
Reaction SMILES: C([Si:10]1(C2C=CC=CC=2)[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)CCCCCCCC.[F:37][C@H:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39]O>>[CH2:11]([Si@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([O:29][CH2:39][C@@H:38]([F:37])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[C:24]([F:30])[CH:23]=3)=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[CH2:12][CH2:13][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(O)c(F)c3)cc2)CC1
Reactant: CCCCCC[C@@H](F)CO
Product: CCCCCCCCC[Si@H]1CC[C@H](c2ccc(-c3cc(F)c(OC[C@@H](F)CCCCCC)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(4-n-nonyl-4-phenyl-4-silacyclohexyl)phenyl) -2,6-difluorophenol and (R)-2-fluoro-1-octanol, thereby obtaining the intended compound.