Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[CH:37]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Cc1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 3-toluidine (104 mg, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(Cl)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(Cl)cc2C(F)(F)F)CCN1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.5 g, 4.99 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (0.835 mL, 5.99 mmol). The solution was then cooled to 0° C. before 4-chloro-2-(trifluoromethyl)benzoyl chloride (1.335 g, 5.49 mmol, commercially available from e.g. 3B Scientific or APAC) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (20 mL) and the solution was washed with water (10 mL), a saturated solution of sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off to yield the desired product in 1.445 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6]>C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[O:11][C:5](=[O:6])[CH3:4])[C:5]([OH:7])=[O:6])(=[O:1])[CH3:10]
Reactant: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(C(=O)O)cc([N+](=O)[O-])c1OC(C)=O
Reaction time: 8 h

Procedure:
7.3 g of 3,4-dihydroxy-5-nitrobenzoic acid are treated with 30 ml of acetic anhydride, whereupon the mixture is held at the reflux temperature for 8 hours. The reaction mixture is poured on to ice. The separated precipitate is filtered under suction, washed with water and taken up in methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue obtained is recrystallized from methylene chloride/n-hexane in the cold. There is obtained 3,4-diacetoxy-5-nitrobenzoic acid in the form of colorless crystals of m.p. 126°-127°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:3]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[OH:15][CH2:14][C@@H:4]1[CH2:3][C@@H:2]([O:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](CO)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 48 h

Procedure:
Intermediate Compound 89A (3.41 g, 10.3 mmol) was dissolved in anhydrous pyridine (30.0 mL) and cooled to 0° C. p-Toluenesulfonylchloride (5.89 g, 30.9 mmol) was then added in portions over a 10 minute period. The flask was then placed in a refrigerator at 4° C. for 48 h. The resulting solution was poured into 1 N HCl (300 mL), extracted with methylene chloride (3×200 mL) and the organics were dried over anhydrous sodium sulfate. The crude tosylate intermediate was dissolved in THF (50 mL), to which was added H2O (0.5 mL) followed by pTSA-H2O (1.03 mmol). Once the reaction was complete as determined by TLC, the mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with methylene chloride (3×50 mL). The combined organics were dried over sodium sulfate. The crude alcohol was purified by flash chromatography on SiO2 eluting with acetone/chloroform (0-5-10% acetone) to give 2.71 g (71% for 2-steps) of intermediate Compound 89B as a clear oil.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:44])[CH2:25][CH2:26][NH:27][C:28](=[O:43])[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:31][C:30]=2[CH3:42])[CH2:20][CH2:19]1)[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:46]>>[CH2:1]([N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH2:46])=[CH:11][CH:10]=1)[CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH3:44])[CH2:25][CH2:26][NH:27][C:28](=[O:43])[C:29]2[C:34]([CH3:35])=[CH:33][C:32]([C:36]3[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=3)=[CH:31][C:30]=2[CH3:42])[CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccccc2)c2ccc(C(=O)O)cc2)CC1
Reactant: [NH4+]
Agent: [Cl-]
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccccc2)c2ccc(C(N)=O)cc2)CC1
Yield: 72.9 %

Procedure:
Using general procedure E, 4-(benzyl-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 91) (60 mg, 0.10 mmol) and ammonium chloride (22 mg, 0.41 mmol) afforded COMPOUND 92 as a white solid (43 mg, 71%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5.7 Hz), 1.06-1.35 (m, 2H), 1.51-1.62 (m, 1H), 1.69-1.86 (m, 3H), 2.13-2.31 (m, 1H), 2.40 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.20-3.40 (m, 2H), 3.62-3.71 (m, 1H), 3.89 (s, 2H), 5.79 (br s, 2H), 6.49 (d, 2H, J=8.1 Hz), 6.84-6.93 (m, 2H), 7.12-7.22 (m, 3H), 7.25-7.33 (m, 2H), 7.41-7.48 (m, 2H), 7.57 (d, 2H, J=8.1 Hz), 8.20 (br s, 1H), 8.60-8.67 (m, 2H). 13C NMR (CDCl3) δ 13.45, 19.34, 29.05, 30.40, 31.30, 39.60, 43.73, 48.18, 51.98, 55.72, 60.12, 111.66, 120.60, 121.49, 125.76, 126.06, 126.75, 128.51, 129.11, 135.24, 138.06, 139.02, 139.21, 147.61, 150.35, 151.34, 169.08, 169.34. ES-MS m/z 590 (M+H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(Cl)(Cl)Cl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (18 ml) in chloroform (80 ml) was added dropwise at 10°-15° C. over 1.5 hours to a stirred solution of the above 1-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone (89.6 g) in a mixture of methanol (120 ml) and chloroform (20 ml). When the addition was complete, the mixture was stirred at ambient temperature for 1 hour, then poured onto an excess of ice-water. The aqueous layer was separated and the product extracted into dichloromethane (2×150 ml). The combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×200 ml) then with water, dried over calcium chloride and the solvent removed in vacuo to yield an oil. The oil was distilled to give 2-bromo-l-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone (88.31 g), b.p. 148°-154° C./0.66 mbar.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=2)[CH2:4][O:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:22])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=2)[NH2:19])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](COc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](COc2cc(N)cc(C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.1 %

Procedure:
(4R)-2,2-dimethyl-4-{[3-nitro-5-(trifluoromethyl)phenoxy]methyl}-1,3-dioxolane (0.7770 g, 2.4 mmol) was dissolved in EtOAc (30 mL) and Pd (77 mg, 10% on carbon) was added. The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen for 6 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The solvents were evaporated to give 3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-(trifluoromethyl)-aniline (700 mg, 100%) as a white solid. LCMS: (FA) ES+291.9.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)#[CH:10]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:10][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=2)=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(C#Cc2ccc(F)cc2)c1
Yield: 24.9 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-bromo-5-methylpyridine, (prepared as described in PREPARATION 1), (196 mg, 1.14 mmol) and 1-ethynyl-4-fluorobenzene (150 mg, 1.25 mmol) to give the title compound (60 mg, 25%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][OH:11].[H-].[Na+].[C:16]([NH2:20])(=[O:19])[CH:17]=[CH2:18].S(=O)(=O)(O)O>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][O:11][CH2:18][CH2:17][C:16]([NH2:20])=[O:19]
Reactant: CN(C)CCOCCN(C)CCO
Reactant: C=CC(N)=O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOCCN(C)CCOCCC(N)=O

Procedure:
A 50 ml 3 neck round bottom flask was fitted with the following: magnetic stirrer, reflux condenser, air bubbler, and a temperature controlled oil bath. The flask was charged with 19.0 g of 2-{[2-(2-dimethylaminoethoxy)ethyl]methylamino}ethanol. Sodium hydride, 0.03 g, was then added carefully to the 2-{[2-(2-dimethylaminoethoxy)ethyl]methylamino}ethanol solution with stirring. The mixture was stirred at a constant rate for two minutes before 7.10 g of acrylamide was added. After the addition of acrylamide, the reaction mixture was stirred at 55° C. for 6 hours. The mixture was cooled to ambient temperature and neutralized with 0.80 g of concentrated sulfuric acid. The resulting mixture was filtered through a Celite layer. The filtrate was collected for foam application without further purification. Quantitative 1H NMR showed that the product was 94% pure.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:3](=[O:9])[N:4]([CH3:12])[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(=O)[nH]cc(F)c1=O
Reaction time: 24 h

Procedure:
5-Fluorouracil, namely Compound (5) (1.30 g; 10 mmol), methyl iodide (CH3I) (2.13 g; 15 mmol) and potassium carbonate (0.69 g; 5 mmol) were added to acetone (20 ml), and the resulting mixture was stirred at 60°-70° C. for 24 hours. The reaction solution obtained was filtered to remove potassium carbonate, and the filtrate was concentrated under reduced pressure. To the resulting residue was added a small volume of chloroform, and then the residue was fractionated by column chromatography on silica gel (eluent: chloroform) to isolate 5-fluoro-3-methyluracil, namely Compound (6) shown above (355 mg) as white needle-like crystals.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:9])N2[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1N=CC(COP(O)(O)=O)=C(C=O)C=1O.[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][C@H:57](N)[CH2:58]2)=[CH:53][CH:52]=1>Cl>[CH3:49][O:50][C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][C:57](=[O:9])[CH2:58]2)=[CH:53][CH:52]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: COc1ccc2c(c1)C[C@@H](N)CC2
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc2c(c1)CC(=O)CC2
Temperature: 30 °C
Reaction time: 28 h

Procedure:
The recombinant E. coli obtained in Example 2 was inoculated into 5 mL of a 2× YT medium containing 200 μg/mL of ampicillin and cultured with shaking at 30° C. for 28 hours. To 500 μL of the resulting culture liquid was added 500 μL of a 0.2 M potassium phosphate buffer (pH 7.5) containing 1 mM pyridoxal phosphate, and the mixture was sonicated so that a cell-free extract was obtained. Subsequently, 100 μL of the cell-free extract was added to 305 μL of a substrate solution having the composition shown below. After the mixture was allowed to react at 30° C. for 1 hour, 50 μL of 6 N hydrochloric acid was added to stop the reaction. The optical purity of the produced (S)-7-methoxy-2-aminotetralin was measured using HPLC under the conditions shown below. As a result, the modified enzymes shown in Table 2 had stereoselectivity higher than that of the wild-type.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]1[O:20][CH2:19]1>C(O)(=O)C>[CH2:1]([N:8]([CH2:18][CH2:19][OH:20])[C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1NCc1ccccc1
Reactant: C1CO1
Solvent: CC(=O)O
Product: NC(=O)c1ccccc1N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
o-Benzylaminobenzamide (62 g) was added to a cold solution of 85 ml ethylene oxide in 500 ml acetic acid, the mixture stirred 22 hours at room temperature and concentrated on the rotovap to remove 250 ml acetic acid. The remainder was made alkaline with 10% NaOH and the solid filtered washed with water and recrystallized from 300 ml ethyl acetate to give 48.5 g. product, m. 133-7.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH:19][CH2:20][CH:21]([CH2:23]O)[OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOC(C)=O.CCCCCC>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:23][CH:21]([CH2:20][OH:19])[OH:22])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CO
Reaction time: 8 h

Procedure:
CBz-L-valine (4.35 g, 17.3 mmol) was added to a fivefold excess of glycerol (8 ml, 86.9 mmol) together with dicyclohexylcarbodiimide (4.29 g 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) at room temperature. After stirring overnight the suspension was filtered and DMF removed in vacuo from the filtrate. The residue was redissolved in CH2Cl2, washed successively with saturated NaHCO3, brine, and water and then dried. The crude material was chromatographed on silica gel with 4/1 EtOAc-hexane as eluent to yield 2.465 g. Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH2C2-methanol) 0.12.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[S:30]
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCOC(=O)CC1(C)C(=S)Nc2cccc([N+](=O)[O-])c21

Procedure:
A mixture of (±)-ethyl (3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetate (1.08 g, 3.88 mmol, described in Intermediate 17) and Lawesson's reagent (942 mg, 2.33 mmol) was heated at reflux in xylenes (30 mL) for 90 min. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=295 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH2:21])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:39](O)=[O:40])=[CH:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[CH:12]([NH:15][C:16]([C:18]4([NH:21][C:39]([C:36]5[CH:35]=[N:34][C:33]([O:32][CH3:31])=[N:38][CH:37]=5)=[O:40])[CH2:20][CH2:19]4)=[O:17])[CH2:13][O:14][C:10]=3[CH:9]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)OCC3NC(=O)C2(N)CC2)no1
Reactant: COc1ncc(C(=O)O)cn1
Product: COc1ncc(C(=O)NC2(C(=O)NC3COc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)CC2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-6-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-2,3-dihydro-benzofuran-3-yl}-amide (example 45) has been coupled with 2-methoxy-pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 565.1 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]2[C:13](=[O:28])[C:14](C(OCC)=O)=[C:15]([C:19]([F:22])([F:21])[F:20])[N:16]([CH3:18])[CH:17]=2)=[C:4]([F:29])[CH:3]=1.[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([C:12]2[C:13](=[O:28])[CH:14]=[C:15]([C:19]([F:20])([F:21])[F:22])[N:16]([CH3:18])[CH:17]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)n(C)cc(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(-c2cn(C)c(C(F)(F)F)cc2=O)c(F)cc1Cl
Temperature: 190 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
0.7 g (1.6 mmol) of 5-(4-chloro-2-fluoro-5-isopropoxyphenyl)-3-ethoxycarbonyl-1-methyl-2-trifluoromethyl-4(1H)-pyridone, 0.15 g (2.5 mmol) of sodium chloride and 0.1 ml of water were added to 5 ml of dimethylsulfoxide, followed by stirring at 190° C. for 3 hours. After cooling, this reaction solution was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.10 g (yield: 17%) of the desired product. Melting point: 150-151° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[N:13]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][N:15]=[CH:14]1>>[N:13]1([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: NCCCn1ccnc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc([N+](=O)[O-])ccc1NCCCn1ccnc1
Yield: 52 %

Procedure:
Starting with 36.5 g (0.2 mol) of 2-chloro-5-nitrobenzonitrile and 31.3 g (0.25 mol) of 3-imidazol-1-ylpropylamine, and after purification by recrystallization from refluxing at 96 ° ethanol, 28.2 g of yellow crystals melting at 177° C. (Kofler) were obtained, the elemental analysis of which, calculated for C13H13N5O2, was:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.[NH3:26]>CO>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:21]([C:22]([NH2:26])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCN4)cc3F)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
Methyl 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (200 mg, 1.40 mmol) was added to ammonia in methanol (10 mL) and the mixture was stirred at room temperature for 3 days. The mixture was concentrated, and then purified by prep-HPLC to obtain 2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (34.6 mg, yield 18%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.50-1.55 (m, 1H), 1.74-1.79 (m, 2H), 2.18-2.23 (m, 1H), 2.95-3.02 (m, 2H), 4.19-4.23 (m, 1H), 7.42-7.51 (m, 3H), 7.74-7.80 (br s, 1H), 7.80-7.82 (d, J=6.8 Hz, 2H), 7.96-7.98 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 8.22 (t, J=8.4 Hz, 1H); LC-MS (ESI) m/z: 326 (M+1)+.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([F:32])[CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].[CH2:33]([N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O)[CH3:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([F:32])[CH:27]=3)=[N:13]2)[CH2:17][CH2:18][N:19]([CH2:40][C:36]2[N:35]([CH2:33][CH3:34])[CH:39]=[CH:38][N:37]=2)[CH2:20][CH2:21]1)#[N:24]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC[NH2+]CC1
Reactant: CCn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCn1ccnc1CN1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a reaction vial was added 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-4) (0.020 g, 0.058 mmol), 1-ethyl-1H-imidazole-2-carbaldehyde (0.0072 g, 0.058 mmol), Na(OAc)3BH (0.062 g, 0.29 mmol), TFA (0.030 g, 0.26 mmol) suspended in DMF (0.97 mL). The reaction vessel was sealed and heated to 50° C. with stirring for 12 hours. The completed reaction was directly purified by reverse phase preparative HPLC (using a gradient elution of 0-95% ACN/water with 0.1% v/v NH4OH modifier) to afford the title compound, Example #22-1.