Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B#B.[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH:19]=[CH2:20])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:6])=[O:5].[OH-:22].[Na+].OO>O1CCCC1.O>[CH3:3][S:4]([O:7][CH2:8][CH2:9][CH2:10][C:11]1([CH3:21])[CH:17]2[O:18][C:14]([CH2:19][CH2:20][OH:22])([CH2:15][CH2:16]2)[CH2:13][O:12]1)(=[O:5])=[O:6]
Reactant: [OH-]
Reactant: C=CC12CCC(O1)C(C)(CCCOS(C)(=O)=O)OC2
Agent: B#B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(CCCOS(C)(=O)=O)OCC2(CCO)CCC1O2
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of diborane in tetrahydrofuran (1 ml, 1 mM) is added slowly to a mixture of (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane (350 mg, 1.2 mM) and tetrahydrofuran (5 ml) at 0° C. under nitrogen and stirred for thirty minutes. The resulting mixture is allowed to warm to room temperature and stirred for an additional two hours. The mixture is cooled to 0° C. and 3 N sodium hydroxide (0.3 ml) is added followed by the addition of 30% hydrogen peroxide (0.3 ml). The resulting mixture is allowed to warm to room temperature and stirred for 2.5 hours. The mixture is then treated with water (10 ml) and extracted with ether (5×20 ml). The combined organic phases are dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel (30 g) with ether to give (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol (275 mg, 80%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:7]=1[Br:15])(=[O:3])[CH3:2].N1CCOCC1>CO.[Pt]=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[Br:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc([N+](=O)[O-])c1Br
Agent: O=[Pt]
Solvent: C1COCCN1
Solvent: CO
Product: CC(=O)OCc1cccc(N)c1Br
Yield: 115.5 %

Procedure:
A mixture of 5.7 grams (0.022 mole) of 2-bromo-3-nitrophenylmethyl acetate, 0.1 gram of platinum oxide and 2.0 ml of morpholine in 200 ml of methanol was hydrogenated using a Parr hydrogenator. The hydrogenation required 2.25 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 6.2 grams of 3-amino-2-bromophenylmethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH2:7][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1
Reactant: O=Cc1cc(Br)ccc1CCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Reaction time: 18 h
Yield: 89.1 %

Procedure:
5-Bromo-2-(phenethyl)benzaldehyde (1.27 g) and methyl 4-aminobenzoate (0.66 g) were heated together at 110° C. for 30 minutes and for a further 30 minutes under vacuum. The mixture was dissolved in toluene, evaporated to dryness, dissolved in ethanol (15 ml). Sodium borohydride (0.33 g) was added, the mixture stirred for 18 hours, the solvent evaporated and the residue mixed with acetic acid and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The resulting residue was purified by MPLC, eluting with dichloromethane, to give methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (1.65 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH:30]([N:33]=[C:34]=[S:35])([CH3:32])[CH3:31]>>[CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23]([NH:24][C:34]([NH:33][CH:30]([CH3:32])[CH3:31])=[S:35])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CC(C)N=C=S
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(N)(=O)=O)cc32)C1=O
Product: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(=O)(=O)NC(=S)NC(C)C)cc32)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(isopropylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR50## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(isopropylaminothiocarbonylaminosulfonyl)-7-methoxychroman is synthesized following Example 14 starting from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)methyl)6-sulfamoyl-7-methoxychroman and isopropyl isothiocyanate. Melting point: 153° C.
Reaction SMILES: [OH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9]O>CCCCCC>[OH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH3:9])=[O:4]
Reactant: CC(C)[C@@H](O)C(=O)O
Reactant: CO
Solvent: CCCCCC
Product: COC(=O)[C@H](O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of (R)-2-hydroxy-3-methylbutanoic acid (5.0 gm, 42.2 mmol) in methanol was added a solution of TMS.CH2N2 (2M) in hexane (65 mL), at 0° C., over 20 min. The reaction mixture was stirred at 0° C. for 1 h. The reaction was concentrated with a bath temperature of 20° C. and vacuum greater than 50 mm Hg. Purification via silica gel chromatography using 2-100% EtOAc in hexanes gave the ester as a yellow oil (438 mg, 12.7 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 5.30 (d, J=5.1 Hz, 1H), 3.81 (t, J=0.8 Hz, 1H), 3.63 (s, 3H), 1.94-1.86 (m, 1H), 0.88-0.82 (m, 6H).
Reaction SMILES: Cl.[CH3:2][S:3][CH2:4][CH2:5][CH:6]1[NH:11][C:10](=[O:12])[CH:9]([CH2:13][CH2:14][S:15][CH3:16])[NH:8][C:7]1=[O:17].[OH2:18]>>[NH2:8][C@H:9]([C:10]([NH:11][C@H:6]([C:7]([OH:17])=[O:18])[CH2:5][CH2:4][S:3][CH3:2])=[O:12])[CH2:13][CH2:14][S:15][CH3:16]
Reactant: O
Reactant: CSCCC1NC(=O)C(CCSC)NC1=O
Agent: Cl
Product: CSCC[C@H](NC(=O)[C@@H](N)CCSC)C(=O)O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
500 l of water were introduced into a 500 l enameled tank with stirrer, 32 l of concentrated hydrochloric acid and 78.6 kg of 3,6-bis[2-(methylthio)ethyl]-2,5-piperazinedione (III) (DKP) were added, and the apparatus was closed tightly. It was then heated at 110° C. while stirring for 2 hours, during which the pressure rose to 2.5 bar and the DKP (III) virtually completely dissolved. After the reaction was complete, the mixture was cooled to 20° C., and the unreacted DKP was spun down in a centrifuge. The solid was washed with 10 l of water. The filtrate and washing water were then collected in an 800 l container and subsequently introduced into a 500 l tank with stirrer again. Addition of 2 kg of activated carbon was followed by stirring at 20° C. for 30 min. The suspension was then filtered through a filter press into a further 500 l tank with stirrer. About 28 l of concentrated ammonia solution were then added to precipitate at pH 6 the DD/LL/DL/LD-methionylmethionine (I). During this there was an initial preferential precipitation of the less soluble racemic pair of diastereomers DL/LD-methionylmethionine (DL/LD-I). This was spun down and the mother liquor was concentrated together with washing water to one quarter of the original volume in vapor pump vacuum at an internal temperature not exceeding 40° C. During this, the more soluble racemic pair of diastereomers DD/LL-methionylmethionine (DD/LL-I) crystallized together with small amounts of the slightly soluble DL/LD-I. Completion of the distillation was followed by cooling to 20° C. and centrifugation. The separated mother liquor and washing water were discarded. Both fractions were dried in vacuo at 70° C. In total, it was possible to obtain 64.2 kg (78%) of DD/LL/DL/LD-methionyl-methionine (I) as mixture of diastereomers. Purity >98% (HPLC).
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH-].[K+]>O>[CH2:1]1[CH2:12][O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:14])=[O:6])[O:2]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc2c1OCCO2
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
Into a 500 ml round bottom flask fitted with a 250 ml addition funnel and a magnetic stir bar were placed 2,3-ethylenedioxybenzaldehyde (4.07 g, 24.7 mmol) and 100 ml of water. The mixture was heated to 80° and potassium permanganate (7.84 g, 49.6 mmol) in 150 ml of water was added dropwise via the addition funnel over 20 minutes. After the addition was complete the mixture was allowed to stir at 80° for 1.5 hours. The mixture was made basic with a 10% potassium hydroxide solution and the solids filtered. The filter cake was washed with hot water. The filtrate was extracted with ether, made acidic, then extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered, and concentrated to give 2.96 g of subtitled product (66%) which was used directly in the next step.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.[CH3:39][C:40]([CH3:42])=[O:41]>O1CCCC1>[CH2:34]([O:33][CH2:32][C@H:31]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][N:22]1[CH2:21][C:17]1[C:16]([CH2:36][CH3:37])=[N:15][N:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]([C:40]([OH:41])([CH3:42])[CH3:39])=[CH:8][C:9]=2[CH3:38])[C:18]=1[CH2:19][CH3:20])[CH3:35]
Reactant: CC(C)=O
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(C(C)(C)O)cc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.16 ml, 0.39 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (180 mg, 0.35 mmol) in anhydrous tetrahydrofuran (1.0 ml) was added dropwise. After stirring at -78° C. for 10 minutes, anhydrous acetone (0.078 ml, 1.1 mmol) was added. The resulting mixture was warmed to ambient temperature, and stirred at that temperature for 1 hour. The reaction was quenched by addition of aqueous ammonium chloride (2 ml) and then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was then extracted with an equal volume solution of aqueous ammonium chloride. The combined aqueous extracts were then extracted with a fresh equal-volume portion of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with ethyl acetate/hexane=1:2 in volume) afforded the title compound (120 mg) as a faint yellow oil.
Reaction SMILES: C(NCC)C.Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CN(C=O)C>[NH2:20][C:16]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:17]=1[C:18]#[N:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1cc(-c2ccccc2)oc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 68.6 ml (663 mmol) diethylamine dropwise to a mixture of 60.0 g (301 mmol) bromoacetophenone and 25.89 g (391.86 mmol) malononitrile in 130 ml DMF at RT (cooling is required to maintain the temperature). Towards the end of addition, remove the cooling, stir the mixture for 1 h at RT and then add water to 385 ml. Dilute with a further 125 ml water and stir for 20 min at RT. Filter off the precipitated solids with suction, wash twice with 125 ml water each time, dry under suction and wash with petroleum ether. Dry the residue at high vacuum. 33.3 g (50.1% of theor.) of the target compound is obtained as yellowish-brown crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1NCc2ccc(O)cc21
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1NCc2ccc(OCc3cccc(F)c3)cc21
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A mixture of 6-hydroxy-2,3-dihydro-isoindol-1-one (125.0 mg, 0.84 mmol) and 3-fluorobenzylbromide (174.3 mg, 0.92 mmol) in acetone (5 mL) containing potassium carbonate (276.4 mg, 2.0 mmol) was heated under reflux for 17 h. After cooling to RT the mixture was filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 90:10) to afford the title product (180 mg, 83%) as a white solid. MS m/e=258.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>[Pd].CCO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCC(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1-ethyl-4-(4-nitro-phenyl)-piperidine (0.8 g, 4.92 mmol) and 10% palladium on carbon (0.1 g) in EtOH (10 mL) is stirred for 3 h at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound. ESI-MS: 205.1 [MH]+; TLC: Rf=0.29 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][CH:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:39]=[CH:38][C:5]=3[N:6]([CH3:37])[C:7](=[O:36])[CH:8]([CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[N:9]=2)[CH2:16][CH2:15]1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(N)CC2)c2cc(Cl)ccc21
Yield: 28 %

Procedure:
5,7-Dichloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (170 mg, 0.44 mmol) and tert-butyl piperidin-4-ylcarbamate (89 mg, 0.44 mmol) were coupled according to the corresponding procedure described in Example 14 to yield intermediate tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate. (85 mg, 35%). Tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate (85 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours. The solution was concentrated, redissolved in ethyl acetate and extracted into 1 M aqueous hydrochloric acid (3×10 mL). The extracts were neutralized with saturated sodium bicarbonate, extracted with dichloromethane (3×25 mL), then dried with sodium sulfate, filtered, and concentrated to yield 5-(4-aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (20 mg, 29% yield). MS (M+H)+447.2.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].C([O-])=O.[NH4+]>CO.[Zn]>[NH2:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(C(=O)NCC(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
To a solution of 2-(2-fluoro-4-nitrobenzamido)acetic acid (100 mg, 0.413 mmol) in methanol (15 mL) was added successively zinc dust (270 mg, 4.132 mmol) and ammonium formate (260 mg, 4.132 mmol) at rt. The reaction mixture was stirred at rt for 15 min. The reaction mixture was filtered and washed with methanol (2×5 mL). The residue obtained after evaporation of the solvents was diluted with water (5 mL) and acidified with AcOH (3 mL). The solution was extracted with EtOAc (3×50 mL) and the combined organic layer was dried over anhyd Na2SO4. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform:methanol (70:30) as eluents to give the product as a white color solid (59 mg, 67%), mp 190-194° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[F:27].[Li+].[OH-]>>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[F:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1F)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1F)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{2-fluoro-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless liquid.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][N:14]=[CH:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: CCC=O
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCC=NNc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated via filtration, washed with water and dried in air to obtain N-(3-nitro-phenyl)-N′-propylidene-hydrazine, which was used directly in the next step.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[N:32]=1>CN(C)C=O>[F:37][C:33]1[N:32]=[C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Fc1cccc(CCl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(F)n4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 14.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (40 mg, 0.14 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (28.3 μL, 0.14 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-6-fluoro-pyridine (52.7 mg, 0.36 mmol) described in manufacturing Example 45-1-1, which was stirred for 14 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (7.8 mg, 11%) as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]=1[CH2:29]Br>CN1C(=O)CCC1.CO>[F:26][C:27]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:31][C:28]=1[CH2:29][N:4]1[C:5]2[C:6](=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=2)[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Reactant: Fc1ccc(C(F)(F)F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cn1c(=O)n(Cc2cc(C(F)(F)F)ccc2F)c2ccc(-c3ccccc3C#N)nc21
Temperature: 90 °C

Procedure:
2-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (4-1) (30 mg, 0.12 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added to a microwave vial and suspended in NMP (0.5 mL) under nitrogen. 2-Fluoro-5-(trifluoromethyl)benzyl bromide (47 mg, 0.18 mmol) was added to the suspension and then heated at 90° C. overnight. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 2-{1-[2-fluoro-5-(trifluoromethyl)benzyl]-3-methyl-2-oxo-2,3-dihydro 1H-imidazo[4,5-b]pyridin-5-yl}benzonitrile (6-1). HRMS (M+H)+: observed=427.1179, calculated=427.1177.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].O[C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][S:16][C:11]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:9]1[CH:19]=[CH:18][C:12]2[NH:13][C:14](=[O:17])[CH2:15][S:16][C:11]=2[CH:10]=1
Reactant: CN(C)CCCO
Reactant: O=C1CSc2cc(O)ccc2N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc2c(c1)SCC(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N,N-dimethyl-3-aminopropanol (0.27 g, 5.2 mmol) was added to a mixture of 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (0.95 g, 5.2 mmol) and triphenylphosphine (1.37 g, 5.2 mmol) in dry tetrahydrofurane (30 ml) under nitrogen atmosphere, followed by diethyl azodicarboxylate (1 g, 5.7 mmol). The mixture was stirred at room temperature for 48 h, concentrated in vacuo, and the product was purified by silica gel chromatography using dichloromethane:methanol gradient of (9:1) to (7:3) as the mobile phase. Yield 1.1 g (75%) mp 120–121° C.