Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>OS(O)(=O)=O.CCCCC>[C:8]([C@@H:11]1[O:5][C:1](=[O:6])[C@H:2]([CH3:4])[O:3]1)([CH3:10])([CH3:9])[CH3:7]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCC
Solvent: O
Product: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Temperature: -80 °C

Procedure:
A mixture of L-Lactic acid (106 g of 85% in H2O), pivalaldehyde (220 mL), p-toluene sulfonic acid mono hydrate (2.0 g) and H2SO4 conc. (8 drops) in pentane (800 mL) was refluxed with azeotropic removal of the water formed using a Dean-Stark trap. The supernatant was decanted, washed with water, dried over MgSO4 and concentrated. The resulting residue was dissolved in hexane (800 mL) and cooled to -80° C. for 20 h. Crystals were collected by filtration in a cold room (5° C.) and washed with cold hexane (-78° C.). The crystals were dissolved in Et2O, dried over MgSO4 and concentred to give the title compound as a colorless oil. 1H NMR(CD3COCD3): δ0.95 (9H, s), 1.38 (3H,d), 4.47 (1H, m), 5.24 (1H, s).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)nc3)CC2)c(C)c1
Yield: 63.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.17 g) described in Preparation Example 145 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (834 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of ethyl isonipecotate (4.9 mL, 31.8 mmol) and pyridine (2.8 mL, 34.6 mmol) was cooled to 0° C. Methanesulfonyl chloride (2.7 mL, 34.9 mmol) was added. After 1.5 hours, the reaction mixture was diluted with CH2Cl2 (300 mL) and extracted with saturated aqueous NaHCO3 (3×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in EtOAc (400 mL), extracted with H2O (3×50 mL), dried over Na2SO4, filtered, and concentrated to give the pure product (5.42 g, 22.9 mmol, 72%) as a yellow solid. IR(CHCl3): 3027, 1726, 1331, 1158, 963.
Reaction SMILES: ClCl.Cl[C:4]1([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:9]=[C:8]([Cl:10])[C:7](=[O:11])[NH:6][CH:5]1OC>CO>[Cl:10][C:8]1[C:7](=[O:11])[NH:6][CH:5]=[C:4]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:9]=1
Reactant: COC(=O)CCC(=O)C1(Cl)C=C(Cl)C(=O)NC1OC
Agent: ClCl
Solvent: CO
Product: COC(=O)CCC(=O)c1c[nH]c(=O)c(Cl)c1

Procedure:
This compound was also obtained in 28 percent yield by chlorinating 5-succinoyl-2-pyridone methyl ester (obtained analogously to Example 7 from 5-succinoyl-2-pyridone and methanol/sulfuric acid) using chlorine in methanol. The main product obtained (70 percent yield) was methyl 4-(3,5-dichloro-2-methoxy-6-oxo-1,2,3,6-tetrahydropyridin-3-yl)-4-oxobutyrate, which was characterized by the following data:
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:23]([C:25](=[O:36])[CH2:26][C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[CH:31]=2)[CH3:24])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)(C)(C)C.Cl>ClCCl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[CH2:26][C:25]([N:23]([CH3:24])[CH:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:37])=[O:5])[CH2:16][N:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1)=[O:36]
Reactant: CN(C(=O)Cc1cc2ccccc2o1)C(CN1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)Cc1cc2ccccc2o1)C(CN1CCC(O)C1)c1cccc(OCC(=O)O)c1
Reaction time: 22 h

Procedure:
To a solution of Example 32 (0.824 g, 1.62 mmol) in dichloromethane (15 mL) was added HCl (3 mL of 4 M solution in dioxan). After stirring for 22 hours, all volatiles were removed in vacuo, and the resulting solid was washed with ethyl acetate (twice). The remaining solid was dissolved in acetonitrile and treated with diethyl ether. The precipitate was allowed to settle and the supernatant discarded. The solid was dried to give the product as an off-white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:15][C:11]1[C:10]([C:2]2[N:1]([CH2:23][C:24](=[O:33])/[CH:25]=[CH:26]/[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:14][O:13][N:12]=1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(C=Cc1ccccc1)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nonc1-c1nc2ccccc2n1CC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.275 g, 1.37 mmol), potassium carbonate (0.472 g, 3.42 mmol) and 1-chloro-4-phenyl-but-3-en-2-one (0.297 g, 1.64 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 176-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)F)cc2)cc1

Procedure:
47.5 mg of solid white 3-{4-[3-(4-difluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-difluoromethoxyphenyl isocyanate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:30]=[C:29]3[C:21]([C:22]4[CH:23]=[CH:24][C:25]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:49][C:44]8([O:48][CH2:47][CH2:46][O:45]8)[CH2:43][N:42]7C(OCC7C=CC=CC=7)=O)[NH:38][C:37]=6[CH:60]=5)=[CH:26][C:27]=4[C:28]3([F:32])[F:31])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[O:48]1[C:44]2([CH2:49][C@@H:41]([C:39]3[NH:38][C:37]4[CH:60]=[C:33]([C:25]5[CH:26]=[C:27]6[C:22]([C:21]7[CH:20]=[CH:19][C:18]([C:15]8[NH:14][C:13]([C@@H:9]9[CH2:10][CH2:11][CH2:12][N:8]9[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=8)=[CH:30][C:29]=7[C:28]6([F:31])[F:32])=[CH:23][CH:24]=5)[CH:34]=[CH:35][C:36]=4[N:40]=3)[NH:42][CH2:43]2)[O:45][CH2:46][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CC7(CN6C(=O)OCc6ccccc6)OCCO7)[nH]c5c4)ccc2-3)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CC7(CN6)OCCO7)[nH]c5c4)ccc2-3)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-Benzyl 8-(6-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate (375 mg, 0.46 mmol) was dissolved in ethyl acetate (10 mL) and to it was added triethyl amine (140 mg, 1.38 mmol), followed by 10% Pd/C (Pearlman's catalyst) (196 mg, 0.09 mmol). The flask was purged with hydrogen gas three times by applying vacuum and purging hydrogen gas from a balloon and the mixture was stirred overnight at room temperature. The crude product was filtered through a 0.2 micron Nylon filter member and the filtrate was concentrated down on rotovap. (229 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1.C(Cl)(=O)C(Cl)=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)=[O:5]
Reactant: CSc1cc(C)cc(C(=O)O)c1Cl
Reactant: Cn1nnnc1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CSc1cc(C)cc(C(=O)Nc2nnnn2C)c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
500 mg (2.31 mmol) of 2-chloro-5-methyl-3-(methylthio)benzoic acid and 320 mg (3.23 mmol) of 5-amino-1-methyltetrazole and a catalytic amount of 4-(dimethylamino)pyridine were dissolved in 10 ml of pyridine. 410 mg (3.23 mmol) of oxalyl chloride were then carefully added dropwise. After ten minutes, the mixture was stirred at 80° C. for 4 h. To bring the reaction to completion, another 137 mg (1.08 mmol) of oxalyl chloride were added at RT and the mixture was stirred at 80° C. for another 4 h. For work-up, the contents were cooled to RT and freed of the solvent on a rotary evaporator, and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution and the organic phase was then freed of the solvent. The residue was purified chromatographically, giving 495 mg of 2-chloro-5-methyl-3-methylthio-N-(1-methyltetrazol-5-yl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1>O>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:19])=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Procedure as described for Amidine I using the following amounts: 4.60 mL of aniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was orange. Addition of water yielded a yellow solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 50 mL of pentane, stirred for 30 minutes, and filtered yielding 8.23 g (78%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.76 (d, 2H), 7.36 (t, 2H), 7.25 (d, 2H), 7.06 (t, 1H), 6.98 (d, 2 H), 4.79 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH:19]([NH:21][N:22]1[C:26]([SH:27])=[N:25][N:24]=[N:23]1)=[O:20].CS(O)(=O)=O.N>C(#N)C.O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:27][C:26]3[N:22]([NH:21][CH:19]=[O:20])[N:23]=[N:24][N:25]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=CNn1nnnc1S
Agent: CS(=O)(=O)O
Agent: N
Solvent: CC#N
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
2.45 g of 7β-aminocephalosporanic acid and 1.31 g of 1-formamido-5-mercapto-1H-tetrazole were dissolved in 13 ml of acetonitrile, and 4.32 g of methanesulfonic acid were added dropwise thereto at room temperature under stirring. The mixture was stirred at room temperature for 30 minutes and then at 50° C. for 4 hours. 15 ml of water were added to the reaction mixture, and said mixture was adjusted to pH 5 with 28% ammonia. The resultant precipitates were collected by filtration, washed with water and acetone, and then dried. 2.43 g of 7β-amino-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were obtained as pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[SH:12])=[O:5])[CH3:2].Br[CH2:14][CH2:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([F:18])[F:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[S:12][CH2:14][CH2:15][C:16]([F:18])([F:17])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: CCOC(=O)c1sc(C)nc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(C)nc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a solution of give 4-mercapto-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.58 g, 2.83 mmol) in acetone (10 ml) are added 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (synthesized according to the methods described in sections a) to e) of example 1) (0.72 g, 2.83 mmol) and potassium carbonate (0.78 g, 5.66 mmol) an the mixture is heated at 80° C. for 16 h. Acetone is evaporated, diluted with water (40 ml) and extracted with EtOAc (3×30 ml). The crude product is purified by column chromatography (silica gel, 10% EtOAc/hexane) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.6 g, 1.6 mmol, 56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)([OH:9])[C:6]([OH:8])=[O:7].[CH2:22]1CCN2C(=NCCC2)CC1.CI>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)([OH:9])[C:6]([O:8][CH3:22])=[O:7]
Reactant: O=C(O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(O)(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
20.15 g (0.0671 mol) of 3,3′,5,5′-tetrafluorobenzilic acid are placed in 250 ml acetonitrile, 18.6 g (0.121 mol) of DBU, and 34.4 g (0.2426 mol) of methyl iodide is added and then stirred for 6 hours at ambient temperature. The reaction mixture is evaporated to dryness, the residue extracted with ethyl acetate and water, the organic phase dried over MgSO4, evaporated to dryness. The product is recrystallized from cyclohexane. Yield: 15.11 g of beige crystals (68% of theory); melting point: 113° C.-114° C.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:63][C@H:64]([C:69](O)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:63][C@@H:64]([CH2:65][CH:66]([CH3:68])[CH3:67])[C:69]([O:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:70]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
To a solution of methyl 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (10, 180 mg, 0.45 mmol), DCC (112 mg, 0.54 mmol) and DMAP (6 mg, 0.045 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (158 mg, 0.45 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 150 mg (66%) of the title compound as a colorless semi solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]23[CH2:14][N:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([NH:1][C:2]1[O:3][C:4]([C:7]23[CH2:14][N:11]([CH2:12][CH2:13]2)[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(C23CCCN(CC2)C3)o1
Product: CC(=O)Nc1ncc(C23CCCN(CC2)C3)o1
Yield: 60 %

Procedure:
A solution of (±)5-(2-amino-1,3-oxazol-5-yl)-1-azabicyclo[3.2.1]octane (E3) (0.25g, 1.3 mmole) in acetic anhydride (8 ml) was refluxed for 1h under nitrogen. The reaction mixture was concentrated in vacuo and the residue treated with saturated aqueous potassium carbonate solution (10 ml). After extraction into chloroform (3×10 ml) the organic extracts were dried over sodium sulphate and concentrated in vacuo. Trituration of the resulting gum with ether afforded the title compound (E14) as a solid (180 mg, 60%) m.p. 142°-143° C. (from methanol-ether).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[C:23]([CH3:26])([CH3:25])[CH3:24])[C:9]=2[C:10]=1[CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:9]=2[C:10]=1[CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(C(=O)OCC)oc2cccc(OCCCNC(C)(C)C)c12
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a dichloromethane (0.5 ml) solution of 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-propyl-benzofuran-2-carboxylic acid ethyl ester (5.0 mg) was added trifluoroacetic acid (0.5 ml) at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol to give 4-(3-tert-butylamino-propoxy)-3-propyl-benzofuran-2-carboxylic acid ethyl ester (2.4 mg) as a pale yellow oil. FAB-MS: m/z 362 (MH+); 1H-NMR (CDCl3): δ 0.91 (3H, t, J=7.3 Hz), 1.34 (s, 9H), 1.25-1.45 (5H, m), 1.64 (2H, quintet, J=7.3 Hz), 2.23 (2H, quintet, J=7.3 Hz), 3.07 (2H, t, J=7.3 Hz), 3.16 (2H, t, J=7.3 Hz), 4.09 (2H, t, J=5.9 Hz), 4.42 (2H, q, J=6.9 Hz), 6.52 (1H, d, J=8.3 Hz), 7.12 (1H, d, J=8.3 Hz), 7.28 (1H, dd, J=8.3 Hz, 8.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].O>P(=O)(O)(O)O>[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([OH:14])[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cc1ccccc1N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1cccc2c(O)cc(C(F)(F)F)nc12
Temperature: 105 °C
Reaction time: 5.5 h
Yield: 17.4 %

Procedure:
2-Methylaniline (5.00 g) was dissolved in 75% phosphoric acid (20 mL), and ethyl trifluoroacetoacetate (8.60 g) was dropwise added thereto at 105° C. The mixture was stirred at 105° C. for 5.5 hr. After allowing to cool, the reaction mixture was added to water. The precipitated solid was collected by filtration to give 2-trifluoromethyl-4-hydroxy-8-methylquinoline (1.84 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:23])=[O:8].CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:23])=[O:8]
Reactant: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)O

Procedure:
A solution of 500 mg. of isopropyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate in 15 ml. of methanol is treated with a solution of 1.05 g. of potassium carbonate in 8 ml. of water. The reaction mixture is refluxed under nitrogen atmosphere for 30 minutes, cooled, and evaporated to dryness. The residue is taken up in 10 ml. of 10% aqueous hydrochloric acid and 50 ml. of water and the resultant mixture extracted with ethyl acetate (3 × 50 ml.). The combined extracts are dried over magnesium sulfate and evaporated to dryness under reduced pressure, to give 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid [(A), R and R1 = CH3 ].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C([BH3-])#N.[Na+]>CCO.CC(O)=O>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[CH:16]2[CH2:17][CH2:18]2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:20])[C:7](=[O:19])[NH:8][N:9]=2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A solution of 6-amino-7-cyclopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.860 g, 3.16 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (2.703 g, 15.79 mmol) in EtOH (25 mL) and HOAc (2.5 mL) was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and sodium cyanoborohydride (0.073 g, 1.159 mmol) was added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by preparative HPLC (Table 3, Method 3) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.560 g, 41%). The racemic product was separated by chiral SFC (Table 2, Method 6) to give 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 22%) and 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 20%).