Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C(O)(C)(C)C>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: N#CCc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1
Temperature: 25 °C

Procedure:
Phenylacetonitrile (11.7 g, 0.1 mol) and methyl acrylate (47 ml, 0.5 mol) were initially introduced into tert-butanol (60 ml) and the mixture was heated to the boiling point. The heat source was then removed. Triton B (benzyltrimethylammonium hydroxide, 40 per cent in methanol, 15.2 ml), dissolved in tert-butanol (23 ml), was added dropwise, first slowly, later swiftly. After the dropwise addition, the mixture was boiled under reflux for 4 h. The reaction mixture was cooled to room temperature overnight.—For working up, toluene (100 ml) and water (70 ml) were added to the mixture. The organic phase was separated off and washed with water (1×70 ml) and saturated sodium chloride solution (1×50 ml). After drying with Na2SO4, the solvent was distilled off in a fume cupboard because of the severe odour nuisance. Purification was carried out by a bulb tube distillation under a pressure of 7.8×10−2 mbar at a temperature of 235° C. It was possible to isolate the desired 4-cyano-4-phenylheptanedioic acid dimethyl ester in a yield of 21.45 g (72%) as a colourless, viscous substance.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]([C:27]1[N:31](COCC[Si](C)(C)C)[C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([OH:26])[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(O)C1C(SC)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O.Cl>>[F:47][C:2]([F:1])([F:46])[C:3]([C:27]1[NH:31][C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([OH:26])[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Product: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (246 mg, 0.351 mmol) was added HCl (1.25M in MeOH, 2.8 mL, 3.51 mmol) and the mixture was stirred at 60° C. After 30 minutes the reaction was cooled to room temperature, concentrated and basified with aq. NH4OH. The mixture was further diluted with MeOH. The resulting residue was purified directly by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 571.1 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13](Br)=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>C(NC(C)C)(C)C.C([O-])(=O)C.[Cu+]>[OH:28][C:24]([CH3:25])([CH3:23])[C:26]#[C:27][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22]
Reactant: Fc1c(F)c(-c2c(F)c(F)c(Br)c(F)c2F)c(F)c(F)c1Br
Reactant: C#CC(C)(C)O
Agent: [Cu+]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1c(F)c(F)c(-c2c(F)c(F)c(C#CC(C)(C)O)c(F)c2F)c(F)c1F
Temperature: 0 °C

Procedure:
To a solution of 4,4'-dibromooctafluorobiphenyl (10 g, 21.9 mmol) in degassed diisopropylamine (350 mL) was added dichlorobis(triphenylphosphine) palladium (770 mg, 1.05 mmol, 5 mol %) and copper (1) acetate (219 mg, 1.05 mmol, 5 mol %). The solution was cooled to 0° C. and to this solution was added 2-methyl 3 butyn 2-ol (2.2 equivalents, 4.0 g, 4.7 mL). The solution was allowed to warm to room temperature and was subsequently heated at 50° C. for 12 hours. The solution was cooled and filtered to remove the pecipitate of diisopropylammonium bromide. The solvent was removed at reduced pressure and the residue was chromatographed on a column of silica gel (200 g) packed with ethel acetate. An oily yellow solid was removed from the column. The addition of a couple of drops of methanol caused the oil to solidify. The resulting solid was recrystallized from a mixture of ethyl acetate/hexane (1:2) to yield 4,4'-bis(3 hydroxy-3-methyl 1-butynyl)-octafluorobiphenyl as white crytals. The yield was 8.6 (92 %), mp 119°-121° C. IR (KBr) 3400, 2960, 1475, 1365, 1210, 1170, 990, 962 cm-1. 1H NMR (80 MHz, CDCl3) δ2.7 (s, 2H), 1.53 (s, 12H); Mass Spectrum (El)(rel. intensity 462 (3.7), 447 (44.0), 432 (1.5); Anal. Calcd for C22H14F8O2 : C, 57.14; H, 3.03. Found: C,60.60; H, 4.78
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1COC[CH2:16]1.C([Mg]Br)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:14])[CH2:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C1CCOC1
Agent: CC[Mg]Br
Product: CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (1 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution cooled to −78° C. 1.0 M of Ethyl magnesium bromide in THF (7.5 mL, 7.5 mmol) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. The reaction was then quenched by the dropwise addition of saturated aqueous NH4Cl (30 mL). The resulting mixture was extracted with EtOAc (2×30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield (S)-3-(1-hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17](O)=[O:18])[N:6]2[N:5]=1)=[O:3].[CH3:24][NH:25][CH3:26].O1CCCC1.CN1CCOCC1.CN(C)C=O>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([N:25]([CH3:26])[CH3:24])=[O:18])[N:6]2[N:5]=1)=[O:3]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)O)n2n1
Reactant: CNC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reaction time: 2.5 h
Yield: 76 %

Procedure:
[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid (197 mg, 0.000594 mol), 2.0 M of Dimethylamine in Tetrahydrofuran (0.400 mL, 0.000800 mol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.147 g, 0.000767 mol) 1-Hydroxybenzotriazole (0.109 g, 0.000807 mol), 4-Methylmorpholine (0.0850 mL, 0.000773 mol) and N,N-Dimethylformamide (4.9 mL, 0.063 mol) were combined and stirred for 2.5 hours. The reaction was concentrated and purified by normal phase silica gel chromatography eluting with dichloromethane /methanol/ammonium hydroxide to yield a brown solid, 2-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-N,N-dimethyl-acetamide (162 mg, 76%). LCMS: m/z=359.13 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.89 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=4.7 Hz), 7.44 (m, 1H), 7.30 (d, 1H, J=4.7 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.13 (m, 1H), 4.94 (s, 2H), 2.94 (s, 3H), 2.92 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccsc1C1OCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C2OCCO2)s1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-methylthien-2-yl)-1,3-dioxolane (intermediate 75, 1.5 g) in tetrahydrofuran (50 ml), stirred at −60° C. under a nitrogen atmosphere, was treated drop-wise with 1.6M n-butyl lithium in hexanes (6.1 ml). The reaction mixture was stirred at this temperature for 1 hour and tributyltin chloride (2.6 ml) was added; stirring was continued at −60° C. for 1 hour and then the reaction allowed to warm to ambient temperature. After 18 hours the reaction mixture was diluted with diethylether and this mixture was extracted with water and the ether layer dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (50:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][P:6]([Cl:8])Cl)#[N:2].C[Si](C)(C)[CH:11]1[CH2:15][NH:14][CH2:13][CH2:12]1>C(Cl)Cl>[Cl:8][P:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[N:14]1[CH2:15][CH2:11][CH2:12][CH2:13]1
Reactant: C[Si](C)(C)C1CCNC1
Reactant: N#CCCOP(Cl)Cl
Solvent: ClCCl
Product: N#CCCOP(Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To a solution of 2-Cyanoethyldichlorophosphite (2.0 g, 11.6 mmol, 1.5 mL) in CH2Cl2 (30 mL) was added dropwise 4-(trimethylsilyl)pyrrolidine (2.0 mL, 1.7 g, 11.6 mmol) at 0° C. The resulting mixture was stirred overnight at room temperature. The solvent was removed under the reduced pressure to give a colorless oil (2.48 g, 88%) as a product.
Reaction SMILES: [CH2:1]([N:3]([CH2:62][CH3:63])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([S:71](Cl)(=[O:73])=[O:72])=[CH:67][CH:66]=1.S(Cl)(Cl)(=O)=O>>[CH2:62]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:61])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][C:53](=[O:60])[N:54]3[CH2:59][CH2:58][N:57]([S:71]([C:68]4[CH:69]=[CH:70][C:65]([CH3:64])=[CH:66][CH:67]=4)(=[O:73])=[O:72])[CH2:56][CH2:55]3)[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:63]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCNCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=S(=O)(Cl)Cl
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCC(=O)N3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 262b according to the procedure described in Example 290 using 4-methylbenzene-1-sulfonyl chloride as the sulfonyl chloride. MS (ES, m/z) 1031.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: Cn1c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3cc4ccccc4n3C)CC1)O2
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) in 1 M Na2CO3, was stirred for 10 minutes, then extracted with DCM and treated with N-methyl-indol-2-carbaldehyde (95 mg, 0.60 mmol) and sodium triacetoxyborohydride (159 mg, 0.750 mmol) following the procedure described in Example 55, Step A, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (179 mg) as a white solid. The resulting ester was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (187 mg) as an orange solid (hydrochloride salt). The product was suspended in DCM (3 ml), TEA (0.08 ml, 0.58 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(1-methyl-1H-indol-2-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (37 mg) as a light yellow solid. The compound was then dissolved in DCM (3 ml) and treated with 4 M HCl in dioxane (0.1 ml, 0.4 mmol) as described in Example 55, Step D, giving a light yellow solid after aqueous workup and column chromatography (eluent: DCM/MeOH 99:1 to 95:5) (7 mg, free base)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-2].[Ba+2].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(Cl)(Cl)Cl.Cl.O.C(O)(=O)C.C(OCC)(=O)C>[CH2:32]([O:18][C@@H:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:15]([OH:17])=[O:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(NCC[C@H](O)C(=O)O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Ba+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC[C@H](OCc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
(S)-4-Benzyloxycarbonylamino-2-hydroxybutyric acid (5.25 g, 20.7 mmol) synthesized according to the report of Kawaguchi et al. (Journal of Antibiotics, Vol. 25, pp. 695-708 (1972)) was dissolved in 60 mL of N,N-dimethylformamide. Barium oxide (15.9 g, 103.7 mmol) was added under an ice bath. After the elapse of 2 min from the addition of barium oxide, barium hydroxide octahydrate (13.4 g, 42.5 mmol) was added thereto under an ice bath. After 10 min, benzyl bromide (7.5 mL, 63.1 mmol) was added thereto under an ice bath. After 5 min, the reaction solution was returned to room temperature and was vigorously stirred. After 1.5 hr, the completion of the reaction was confirmed by TLC (developing solvent system=chloroform:ethyl acetate:acetic acid=10:5:1), and water (0.5 mL) was added thereto under an ice bath. The mixture was diluted with chloroform (165 ml), and 4 N HCl (70 mL) was added thereto. Further, water (25 mL) was added followed by separation. The water layer was extracted with chloroform (50 mL). The organic layer and the extracted organic layer were combined and were washed with a saturated aqueous NaCl solution. The washed solution was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (silica gel 60, neutral spheres, 160 g) (chloroform: ethyl acetate=4:1→chloroform:methanol=10:1→chloroform:methanol acetic acid=10:1:0.1 (600 mL)) to give (S)-2-benzyloxy-4-benzyloxycarbonylaminobutyrylic acid (2.86 g, 8.34 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:36])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][Si](C(C)C)(C(C)C)C(C)C)=[C:19]([O:34][CH3:35])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:36])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:34][CH3:35])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reaction time: 4 h
Yield: 68.7 %

Procedure:
Treat a solution of 2-(4-chloro-phenyl)-5-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (0.47 g, 0.87 mmol) in THF (5.0 mL) with TBAF (1.3 mL of 1N in THF) and stir for 4 h. Acidify reaction mixture to pH 4 with 1N HCl. Filter precipitate, wash several times with water, and dry to give title compound (0.23 g, 69%). MS (ES+) 385 (M+1)+. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.11 (d, 2H, J=8.4 Hz), 7.69 (d, 1H, J=7.0 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.02-6.97 (m, 2H), 6.86-6.81 (m, 2H), 3.74 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:11]1([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C1CCCCN1N1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCCN1N1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
To a solution of 1-(4-benzylpiperazin-1-yl)piperidin-2-one (1.0 g) obtained in Example 8a) in methanol (15 mL) was added 20% palladium hydroxide on carbon (containing 50% water, 0.20 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (0.65 g, 97%) as a yellow solid.
Reaction SMILES: O=[N:2][C:3](=O)[C:4](=O)[C:5]1[NH:6]C2C(=CC=1)C=CC1=NC=CC=21.C1(C)[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>C1(C)C=CC=CC=1>[N:2]12[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH:26]=[N:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=NC(=O)C(=O)c1ccc2ccc3nccc3c2[nH]1
Reactant: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: C1=NCCCN2CCCCC12

Procedure:
The formula (XXXVI) 2-(2-imidazolin-2-yl)quinolinecarboxylate esters can also be prepared from a formula (XXXVIII) dioxopyrroloquinoline acetamide, wherein R1, R2, X, L, M, Q and R7 are as described above, by cyclization thereof with a strong base, such as 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) in the presence of an inert organic solvent such as xylene or toluene to give the crude imidazopyrroloquinolinedione of formula (XXXVII). The reaction mixture is heated to a temperature between 100° C. and 150° C., and water removed from the reaction mixture using a Dean-Stark water separator. At least one equivalent of alcohol R3OH represented by formula (V); wherein R3 is a substituent as described above, but excluding hydrogen and salt-forming cations, is then added to the reaction mixture, and the thus prepared mixture heated to a reflux at a temperature between 100° C. and 150° C. to yield the formula (XXXVI) ester. The reaction may be graphically illustrated as follows: ##STR35## wherein R1, R2, R3, X, L, M, Q and R7 are as described above.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1I)[CH3:5])=[N+:2]=[N-:3].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1cccc2nc(C(C)N=[N+]=[N-])c(I)c(=O)n12
Reactant: OB(O)c1ccccc1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3)c(=O)n12
Temperature: 110 °C

Procedure:
A solution of 2-(1-azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.28 mmol) and phenylboronic acid (48 mg, 0.39 mmol) in 1,4-dioxane (2 mL) was treated with sodium carbonate (45 mg, 0.42 mmol), water (0.50 mL), and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (2.0 mg, 28 μmol), degassed with nitrogen for 5 minutes, and heated at 110° C. for 18 hours. The reaction mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min). LCMS for C17H16N5O (M+H)+: m/z=306.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC(C)=O>[CH2:35]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:4][CH:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCc1ccccc1
Reactant: CN(C(=O)Cc1ccc(O)c([N+](=O)[O-])c1)[C@H](CN1CCCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C(=O)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound (vi) (3.2 g, 7.62 mmol) in anhydrous acetone (50 mL) was added anhydrous potassium carbonate (4.22 g, 30.5 mmol). The mixture was stirred at room temperature for 30 mins then added dropwise benzyl bromide (1.30 g, 7.62 mmol). The stirring was continued for an additional 48 h and the reaction mixture was filtered off. The cake was washed thoroughly with acetone and the combined-filtrate was evaporated to dryness. The residue was redissolved in CH2Cl2 and the organic layer was washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The removal of the solvent resulted in a yellow foam, and the product was purified on a silica gel column to give (vii) as a solid, 2.5 g (69%); MS 474 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC1)c1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCOC1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from tert-butyl 4-iodopyridin-3-yl((tetrahydrofuran-3-yl)methyl)carbamate and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (79%). MS (ESI): m/z=403.203 [M+H]+.