Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:18]2([CH:23]=[CH:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[C:10]1=[O:42]>ClCCl>[CH3:8][CH:9]1[C:18]2([CH:19]=[CH:20][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:22][CH2:23]2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:42]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)c2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)Nc2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL, 53.8 mmol) was added to a solution of benzyl 3-methyl-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (0.10 g, 0.20 mmol) in dichloromethane (2 mL). After 2 h, the reaction mixture was concentrated. The concentrated mixture was diluted in dichloromethane (2 mL) and ethane-1,2-diamine (4 mL) was added. After 1 h, the reaction mixture was concentrated and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. MS 364.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:23][S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:35][CH:34]=2)=[O:32])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 69.3 %

Procedure:
A solution of methyl 2-(4-fluorophenyl)acetate (2.35 g, 14 mmol) in THF (15 mL), at −78° C., was treated dropwise with 1 N lithium bis(trimethylsilyl)amide (14 mL, 14 mmol). After 15 minutes a suspension of 4-(methylsulphonyl)benzoyl chloride (3.3 g, 15 mmol) in THF (25 mL) was added in portions. The reaction mixture was stirred for 60 minutes at −78° C. and at 0 to 5° C. for 12 hours. The mixture was quenched with 10% citric acid, the THF removed in vacuo, and the residue triturated with hexanes to provide the desired product as a solid (yield: 3.4 g; 69%). MS (DCI-NH3) m/z 368 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ3.27 (s, 3H), 3.69 (s, 3H), 6.35 (s, 1H), 7.21 (m, 2H), 7.44 (m, 2H), 8.06 (d, J=9 Hz, 2H), 8.25 (d, J=9 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])=[O:4].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:16])=[O:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(NC(=O)C(F)(F)F)C(=O)O
Product: CC(C)(NC(=O)C(F)(F)F)C(=O)Cl

Procedure:
0.54 g (2.71 mmol) 2-trifluoroacetylamino-isobutyric acid are combined with 1.8 ml (2.47 g, 20.8 mmol) thionyl chloride and refluxed for 2 hours with stirring. The mixture is then evaporated down i. vac. and any remaining thionyl chloride is eliminating by blowing dry nitrogen over it. The residue is taken up in diethyl ether and petroleum ether and evaporated down again by blowing dry nitrogen over it.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>O1CCCC1.CN(C)C1C=CC=CC=1>[CH3:26][O:25][C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([O:13][CH3:12])[C:22]=1[O:23][CH3:24])[C:17]([NH:11][C:4]1[C:5](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=1)[C:6]([OH:8])=[O:7])=[O:18]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Product: COc1cc(C(=O)Nc2cc(F)ccc2C(=O)O)cc(OC)c1OC
Reaction time: 5 h
Yield: 60.3 %

Procedure:
In a mixture of 20 ml of tetrahydrofuran and 1.6 g of dimethylaniline is dissolved 1.6 g of 4-fluoroanthranilic acid. To this solution is added slowly a solution of 2.3 g of 3,4,5-trimethoxybenzoylchloride in tetrahydrofuran under room temperature and the mixture is strred at room temperature for 5 hours. The reaction mixture is concentrated under a reduced pressure, to the residue is added water and hydrochloric acid is added to make the mixture the weakly acidic. The precipitated crystals are collected by filtration and recrystallized from methanol to obtain 2.1 g of N-(3,4,5-trimethoxybenzoyl)-4-fluoroanthranilic acid as colorless needles.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:43][N:42]([CH3:44])[CH2:41][CH2:40][CH2:39][N:32]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:33][CH2:34][CH2:35][N:36]([CH3:37])[CH3:38]
Reactant: CN(C)CCCNCCCN(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCCN(C)C)CCCN(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 3,3′-iminobis(N,N-dimethylpropylamine) (104 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 619 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:26])[CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:34]([O:36][CH2:37][CH:38]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:35].O>C(Cl)Cl.O1CCOCC1>[CH:1]1([O:6][C:7](=[O:26])[CH2:8][N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:15][CH:16]=2)[C:34]([O:36][CH2:37][CH:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:45]3[C:50]2=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(CNCC(=O)OC2CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CN(CC(=O)OC2CCCC2)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Yield: 99.5 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-benzylamino]-acetic acid cyclopentyl ester (0.2 g, 0.55 mmol) and 1 M Na2CO3 (1.1 mL, 1.1 mmol) in DCM (2 mL), was added slowly with stirring and ice bath cooling, a solution of 9-Fluorenylmethyl chloroformate (0.14 g, 0.55 mmol) in dioxane (1.4 mL). The mixture was stirred in the ice bath for 4 h and at room temperature overnight. The mixture was poured into water (90 mL) and extracted with diethyl ether. The organic extracts were combined, dried (MgSO4) and evaporated to dryness to afford the desired product (0.32 g, 100%). m/z 607 [M++Na]+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH3:11]>>[NH2:11][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(CO)cc(Cl)n1
Reactant: N
Product: Cc1cc(CO)cc(N)n1
Temperature: 210 °C

Procedure:
A bomb was charged with 2 (30.0 g, 0.190 mol) and aqueous conc NH3 (225 mL) and the resulting mixture was heated at 210° C. for 20 h. The system was cooled to room temperature, the volatiles removed in vacuo and the residue purified by column chromatography (dichloromethane: 0.4N NH3 in MeOH 9:1) to give (2-amino-6-methyl pyridine-4-yl)-methanol as a mixture of free base and hydrochloride salt. The mixture was redissolved in dichloromethane:i-PrOH 1:1 (1 L) and treated with 20% aqueous NaOH (500 mL). The layers were separated and the organic phase extracted with dichloromethane:i-PrOH 1:1 (1×1 L). The combined organic phase was dried and the solvent evaporated to give (2-amino-6-methyl pyridine-4-yl)-methanol 3 (15.51 g, 59%) as pale orange crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:8][CH3:9].[Cl:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[F:27].Cl>CN1C(=O)CCC1.CCCCCCC.O>[ClH:20].[F:27][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:21]=1[N:10]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)[CH2:7][CH2:8][CH3:9]
Reactant: Fc1cnccc1Cl
Reactant: CCCNn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCN(c1ccncc1F)n1ccc2ccccc21
Temperature: 20 °C

Procedure:
Prepare a solution of 18.0 g potassium tert-butoxide in 53 mL NMP and stir the suspension at 20° C. until a clear solution is obtained. Cool the solution to −20° C. Add to the cooled solution a mixture of 9.3 g (53.4 mmol) N-propyl-1H-indol-1-amine, 7.4 g (53.4 mmol) 4-chloro-3-fluoropyridine and 53 mL NMP while maintaining the internal reaction temperature around −15° C. After the addition is over, the reaction mixture is stirred for ˜30 min at −20° C. The reaction mixture is then added to 100 mL water and 13 mL HCl (37%). Then, add 50 mL n-heptane (2×) and separate the phases. Add to the water phase 10 mL NaOH (32%) and extract the water phase twice with 50 mL n-butyl acetate, wash the combined n-butyl acetate phase with 50 mL water. Add to the resulting n-butyl acetate phase 4.5 mL HCl (37%). Distill the mixture using Dean-Stark trap to remove completely the water. During the distillation a solid precipitates. The suspension is cooled to 5° C. and filtered. After drying at 60–70° C., there remains 10.8 g (3-fluoro-pyridin-4-yl)-(indol-1-yl)-propylamine hydrochloride (75%) as a slightly yellow solid.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:37])[CH2:8][C:9]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)(C)(C)C.Cl>ClC(Cl)C>[OH:5][NH:6][C:7](=[O:37])[CH2:8][C:9]1([S:21]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:10][CH2:11][N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14]1
Reactant: CCOC(=O)CN1CCC(CC(=O)NOC(C)(C)C)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)CN1CCC(CC(=O)NO)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The product from Example 20A, N-tert-butoxy-2-[4-(4-phenoxyphenylsulfonyl)-1-(ethoxycarbonylmethyl)piperidin-4-yl]-acetamide, was dissolved in dichloroethane (10 ml), cooled to 0° C., and saturated with hydrochloric acid gas. The reaction vessel was then sealed and the solution stirred for two days at 25° C. Solvent was removed from the reaction mixture under reduced pressure, and the residue purified by preparative TLC, eluting with 10% methanol/methylene chloride, to give N-hydroxy-2-[4-(4-phenoxyphenylsulfonyl)-1-(ethoxycarbonylmethyl)piperidin-4-yl]-acetamide (420 mg), m/e=477.1 (MH+, FABMS).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[F:20][C:21]1[CH:22]=[C:23]([CH:28]([NH2:30])[CH3:29])[CH:24]=[CH:25][C:26]=1[F:27].C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[N+:14]([C:10]1[CH:9]=[C:8]([CH:6]([C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)[NH:30][CH:28]([C:23]2[CH:24]=[CH:25][C:26]([F:27])=[C:21]([F:20])[CH:22]=2)[CH3:29])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(N)c1ccc(F)c(F)c1
Reactant: O=C(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1ccc(F)c(F)c1
Yield: 96.1 %

Procedure:
In a similar manner to that described in Example (1a), 4-fluoro-3′-nitrobenzophenone (2.0 g), 1-(3,4-difluorophenyl)ethylamine hydrochloride (3.16 g), triethylamine (6.82 ml), titanium tetrachloride (1.08 ml), sodium cyanoborohydride (2.28 g) and acetic acid (0.7 ml) were reacted, to afford the title compound (3.03 g) as a yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].C1(N2CCC3C=CC(OC4N=CC(N5CCC5=O)=CC=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:26]5[CH2:27][CH2:28][O:24][C:25]5=[O:29])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NCCO1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: O=C1CCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: O=C1OCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 220 (E220) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 1,3-oxazolidin-2-one using the method described for Example 219 (E219); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[O:6][CH:7]=1)#[N:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.CO>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:9]2)[O:6][CH:7]=1)#[N:2]
Reactant: N#Cc1coc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C#N)co2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 1-(4-cyano-1,3-oxazol-2-yl)-3-hydroxyazetidine (214 mg, 1.30 mmol) (obtained as described in Reference Example 23(2)) in a mixture of methylene chloride (10 ml) and pyridine (5 ml) were added methanesulfonyl chloride (0.50 ml, 6.50 mmol) and triethylamine (0.90 ml, 6.50 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the resulting mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, methanol (1 ml) was added thereto in an ice bath and then the resulting mixture was stirred at room temperature for 30 minutes. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-(4-cyano-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (310 mg, yield 98%) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](=N)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[C:7]1([C:6](=[N:1][CH2:2][CH2:3][CH2:4][OH:5])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Product: OCCCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
A solution of 3-amino-1-propanol [Aldrich product #A76400] (2.0 mL, 26 mmol) in dichloromethane (79 mL) was treated with benzophenone imine (4.4 mL, 26 mmol) and stirred at 25° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (6.3 g, quantitative) as an oil. This material was used without further purification. LCMS for C16H18NO (M+H)+: m/z=240.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[CH2:5][C:4](OS(C(F)(F)F)(=O)=O)=[CH:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>[Cl-].[Na+].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.C(OCC)(=O)C.C(O)C>[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:4]1[CH2:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:17])([CH3:1])[CH:3]=1)([O-:20])=[O:19]
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC1(C)C
Reactant: O=[N+]([O-])c1ccccc1B(O)O
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)C=C(c2ccccc2[N+](=O)[O-])CC1(C)C
Temperature: 90 °C
Reaction time: 6 h
Yield: 99.8 %

Procedure:
A mixture of the trifluoromethanesulfonic acid 3,3,4,4-tetramethylcyclopent-1-enyl ester (992 mg, 3.64 mmol) produced in Example (54a), 2-nitrophenylboronic acid (729 mg, 4.37 mmol), tetrakis(triphenylphosphine)palladium(0) (219 mg, 0.189 mmol), 2N aqueous solution of sodium carbonate (3.64 mL), toluene (12.5 mL) and ethanol (6.3 mL) was stirred for 6 hours at an external temperature of 90° C. under a nitrogen atmosphere. The reaction mixture was air-cooled to room temperature, and then ethyl acetate and brine were added and extraction was performed twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 891 mg of the title compound as a light brown oil.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[OH:8][C@H:9]1[C@H:14](OC2CCC(=O)C=2)[C:13]2[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:12]=2[O:11][C:10]1([CH3:29])[CH3:28].[H-].[Na+]>O1CCCC1>[OH:8][C@H:9]1[C@H:14]([O:3][C:2]2[CH2:4][O:5][C:6](=[O:7])[CH:1]=2)[C:13]2[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:12]=2[O:11][C:10]1([CH3:29])[CH3:28]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)CC2)[C@@H]1O
Reactant: O=C1COC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](OC2=CC(=O)OC2)[C@@H]1O

Procedure:
601 mg of tetronic acid and 1.01 g of the epoxide of example 1 are reacted analogously to example 6 with 180 mg of sodium hydride (80%) and 747 mg of borontrifluoride-diethyletherate in tetrahydrofurane. Usual work up yields white crystalls of the title compound. m.p. 111°-114° C. (dichloromethane/ether)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[C:21]([C:25](=[O:28])[NH:26][CH3:27])[CH:22]=[CH:23]3)=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]=2[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[CH3:43])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[CH3:27][NH:26][C:25]([C:21]1[CH:22]=[CH:23][N:24]2[C:19]([CH:20]=1)=[C:18]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[CH3:43])=[C:16]2[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[O:28]
Reactant: CNC(=O)c1ccn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccn2c(C(=O)N3CCNCC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
The compound of step 7 (0.065 g, 0.11 mmol) was dissolved in 1.1 ml of DCM and cooled to 0° C. and a 4 N solution of hydrogen chloride in dioxane (0.54 ml, 2.20 mmol) was added. The mixture was stirred at room temperature overnight and then evaporated to dryness under reduced pressure. The obtained solid was triturated several times with diethyl ether and dried in vacuo at 40° C. 0.053 g of the title compound were obtained in the form of 2-(3-fluoro-2-methyl-benzyl)-1-phenyl-3-(piperazine-1-carbonyl)-indolizine-7-carboxylic acid methylamide hydrochloride as a light yellow solid with the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:6]=1[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.O>ClCCl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:13]
Reactant: COC(=O)Cc1ccc(OC)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)Cc1ccc(O)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Methoxy-2-methyl-phenyl)-acetic acid methyl ester (1.5 g, 7.72 mmol) is stirred in dichloromethane (50 mL) at 0 deg. C. Aluminum chloride (4.13 g, 31 mmol) is added followed by ethane thiol (2.9 mL, 38.6 mmol). The resulting mixture is stirred at room temperature for 2 hr. Water (50 mL) is added and the product is extracted into ethyl acetate (3×50 ml), the extracts are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound as a colorless oil, 1.4 g, 100%. MS M++1 181. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:18]([C:20]1[NH:24][C:23]([CH3:25])=[N:22][CH:21]=1)=[O:19])[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(Cl)(Cl)Cl>C1COCC1.O>[CH3:25][C:23]1[N:24]2[CH2:2][CH2:3][N:4]([CH:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:9][CH2:10]3)[C:18](=[O:19])[C:20]2=[CH:21][N:22]=1
Reactant: Cc1ncc(C(=O)N(CCO)C2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ncc2n1CCN(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Yield: 43.7 %

Procedure:
tert-Butyl 4-((2-hydroxyethyl)((2-methyl-1H-imidazol-5-yl)carbonyl)amino)-1-piperidinecarboxylate (0.94 g) obtained in Example 91b) and triethylamine (0.72 ml) were dissolved in THF (30 ml). Methanesulfonic acid chloride (0.24 ml) was added dropwise under ice-cooling, and then mixed at room temperature for 3 hours. To the reaction solution were added chloroform and water, and the organic layer was collected by separation and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a colorless solid (0.39 g, 44%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[NH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: NN1CCCCC1
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NN2CCCCC2)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A mixture of 200 mg (0.76 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.86 g (18.53 mmol) of 1-aminopiperidine was stirred at room temperature for 2 hours. Water was added to the reaction solution followed by extraction with ethyl acetate, washing brine, and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 100 mg (40.3%) of the title compound.