Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][C:24]([CH3:33])([CH3:32])[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)O)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
To a stirred suspension of tert-butyl 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoate (60 mg, 0.13 mmol) in 10 mL of dichloromethane was added drop-wise trifluoroacetic acid (4 mL) at room temperature. Then the mixture was stirred at room temperature for 16 hours. The solvent was evaporated at 40° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 40% acetonitrile/60% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 60% acetonitrile/40% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoic acid (21 mg, 40%) as a white solid. MS: (M+H)+=397; 1H NMR (300 MHz, DMSO): δ 12.93 (s, 1H), 12.52 (s, 1H), 9.13 (s, 1H), 8.55-8.54 (m, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 8.71 (dd, 1H, J=9.9, 1.8 Hz), 7.20 (t, 1H, J=2.1 Hz), 4.17 (s, 3H), 1.66 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[C:15]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br)#[N:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:11]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[C:15]#[N:16])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2C#N)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
8-Chlorotheophylline (20 g, 93.19 mmol) was dissolved in 800 ml of DMF and 2-cyanobenzyl bromide (18.28 g, 93.19 mmol), potassium carbonate (12.88 g, 93.19 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was suspended in 900 ml of water and 900 ml of EtOAc, and compound (1A) was collected by filtration of the suspension. The layers in the mother liquor were separated and the aqueous layer was extracted with 3×500 ml of EtOAc. The combined organic layers were washed with 1×500 ml of water, and the solvent was evaporated to give compound (1A) as white crystals.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[C:23](OCC)(=[O:25])C>CS(C)=O>[C:11]([O:10][C:8]([N:15]1[CH2:20][CH2:19][C:18]2([O:25][CH2:23]2)[CH2:17][CH2:16]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CCOC(C)=O
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
After dissolving 60% NaH-in-oil (5.28 g, 132 mmol) in DMSO (dimethylsulfoxide) (250 mL) cooled to 0° C., trimethylsulfonium iodide (29.0 g, 132 mmol) was added. The reaction mixture was then raised to room temperature and the mixture was stirred for 40 minutes. N-Boc-piperidone (Boc=tert-butoxycarbonyl) (25.0 g, 125 mmol) was added to the reaction mixture, which was then stirred at room temperature for 1 hour and then at 55° C. for 1.5 hours. Next, the reaction mixture was poured into ice-cooled water (500 mL) and was extracted with AcOEt (ethyl acetate) (500 ml×3 times). The organic layer obtained by combining the ethyl acetate layers was washed with water and then with saturated brine, and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to obtain 6-aza-1-oxaspiro[2.5]octane-6-carboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 26.4 g (99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:37])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(O)cc2=O)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OC)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
A solution of 35 mg (0.07 mmol) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester (example 142, step 2) in 5 ml of acetone was treated with 94 mg (0.6 mmol) of potassium carbonate and 8 ul (0.08 mmol) of dimethylsulfate. The mixture was stirred 2 hrs at RT and filtered. Evaporation of the solvent and chromatography on silica gel with AcOEt/methanol 95:5 gave 5 mg (13%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Off-white solid. 526 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([NH:14][S@@](C(C)(C)C)=O)[CH3:13])=[CH:7][CH:6]=2.Cl.O1CCOCC1>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([NH2:14])[CH3:13])=[CH:7][CH:6]=2
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc2cnc(Cl)cc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](N)c1ccc2cnc(Cl)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 213.1 %

Procedure:
A solution of (R,R)-2-methyl-propane-2-sulfinic acid [1-(3-chloro-isoquinolin-6-yl)-ethyl]-amide (932 mg, 3 mmol) in methanol (9 mL) was stirred at room temperature under nitrogen. 4M HCl in dioxane (3 mL, 12 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was triturated with ether. The orange solid was collected, washed with ether and dried to afford the title compound (777 mg). 1H NMR (300 MHz, d6-DMSO) δ 1.61 (d, J=6.7 Hz, 3H), 4.58-4.67 (m, 1H), 7.90 (dd, J=8.5, 1.4 Hz, 1H), 8.04 (br, 1H), 8.05 (br, 1H), 8.26 (d, J=8.5, 1H), 8.65-8.8 (br, 3H), 9.25 (s, 1H). LCMS (m/z) 207/209 [M+H], Tr 0.72 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[S:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccsc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccsc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 26.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 3-Thiophenecarboxaldehyde (18.2 mg, 0.163 mmol) were reacted to produce 17 mg (27%) of the title compound. mp: 238-241° C., 1H NMR (300 MHz, DMSO-d6): 13.21 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.72 (s, 2H), 7.22 (s, 1H), 7.13 (d, J=8 Hz, 1H), 6.40 (br s, 1H), 6.35 (br s, 1H), 5.19 (t, J=8 Hz, 1H), 3.31 (s, 2H), 3.29 (s, 1H), 2.88 (s, 1H), 2.76 (s, 1H), 2.61 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS: 430, 432 (M+H), HPLC: 2.44 min (G method).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][C:3]1([C:7]#[N:8])[C:2](=[O:1])[CH2:6][S:5][CH2:4]1
Reactant: N#CC1CSCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC1(C#N)CSCC1=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of 4-oxotetrahydrothiophene-3-carbonitrile (0.50 g, 3.9 mmol) in anhydrous acetone (7.8 mL) was added potassium carbonate (1.63 g, 11.8 mmol), followed by iodomethane (0.56 g, 3.9 mmol). The resulting mixture was stirred at 35° C. for 1 hour. The mixture was cooled to ambient temperature, filtered, and carefully concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH2:27][O:28][CH2:29][CH3:30]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH2:27][O:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: O=C(N=C=S)c1ccco1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=S)NC(=O)c1ccco1

Procedure:
Using the method of Examples 94-105, 2-furoylisothiocyanate was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 431.1846.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:36][CH3:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
(2R,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 mmol; 299 mg), morpholine (1.0 mmol; 87 mg), tris(dibenzylideneacetone)dipalladium(0) (0.025 mmol; 22.9 mg), 2-(di-tert-butylphosphino)biphenyl (0.05 mmol; 14.9 mg) and sodium tert-butoxide (1.0 mmol; 96 mg) are dissolved in toluene (2.5 mL). The mixture is stirred for 3 hours at 100° C., and then cooled to ambient temperature. The reaction mixture is quenched with saturated aqueous ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-[(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (247 mg, 82%); ESI-MS m/z: 604 [M+1]+, Retention time 4.91 min (condition C).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=O)=[N:2]1.Cl.[CH3:17][O:18][NH2:19].O>CN(C)C=O>[CH3:17][O:18]/[N:19]=[C:7](\[C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: O=C(C1=NOCCO1)c1ccccc1O
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C1=NOCCO1)c1ccccc1O
Yield: 31.2 %

Procedure:
4.4 g (0.021 mol) of (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone (III-1) and 1.87 g (0.022 mol) of O-methylhydroxylamine hydrochloride in 22 ml of dimethylformamide are heated to 100° C. for 2 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 5.7 g of crude (5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) comprising 17.5% of the E isomer and 38% of the Z isomer by HPLC are obtained. This crude product is chromatographed over silica gel using a mixture of petroleum ether/tert-butyl methyl ether (1:1). 1.55 g of Z-(5,6-dihydro-1,4,2-dioxazin-3-yl)-(2-hydroxy-phenyl)-methanone O-methyl-oxime (1) of a purity of 91.5% (HPLC)=28.27% of theory) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1>C1COCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1Oc1ccccc1
Yield: 105.5 %

Procedure:
The title compound of Example 8 (76 g, 0.3 mol) was hydogenated with RaNi in THF (2.4 L). The product was distilled to yield a yellow liquid (69.5 g, 100%), which had a boiling point of 145°-150° C./1.5 mmHg. This material was employed in Example 10 without further purication.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].O.Cl.[NH2:14]O>C(O)C>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:14]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 1 h
Yield: 73.6 %

Procedure:
In a 100 ml. round bottom flask there was placed 2 g. of pivalyl acetonitrile, 0.64 g. of sodium hydroxide, 35 ml. of water, and 25 ml. of ethanol. This mixture was heated to reflux and the pH was determined to be about 8.9. Then an aqueous solution of 1.0 g. of hydroxylamine hydrochloride was slowly added. At the end of the addition the pH was about 6.3. The pH of the reaction mixture was adjusted to about 6.5. After 1 hour, the pH was about 6.3 and was again adjusted to about 6.5. After 2 hours the pH was observed to be about 7.0 and was again adjusted to pH about 6.5. At 3 hours and again at 4 hours, the pH was determined to be about 6.5. The reaction mixture was allowed to reflux overnight and the following morning the pH was determined to be about 6.1. The ethanol was removed using a rotovapor and a yellow solid precipitated. This solid was filtered off and dried. It weighed 1.1 g. and it was determined by vpc to contain 94.2% of 3-amino-5-(t-butyl)isoxazole and 3.7% of 5-amino-3-(t-butyl)isoxazole. The product had a melting point of about 103°-105° C. Yield: 73.6% of desired isomer.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.O>[Si:30]([O:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: O=Cc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H]1C[C@@H]1C1CCN(c2ccc(C=O)cn2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
6-{4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidin-1-yl}pyridine-3-carbaldehyde (1.5 g, 5.47 mmol) was dissolved in DMF (5.47 ml), and imidazole (0.558 g, 8.20 mmol) was added. The mixture was cooled to 0° C., TBDMS-Cl (0.989 g, 6.56 mmol) added and the mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with 4:1 water:saturated sodium bicarbonate (100 ml), extracted with EtOAc (3×75 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vac. The residue was purified by column chromatography on silica gel, Biotage 50 g, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 389 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[NH:8][N:7]=1>O.C(O)(=O)C>[C:15]([C:11]1[CH:10]=[C:9]2[C:14]([CH:6]=[N:7][NH:8]2)=[CH:13][CH:12]=1)#[N:16]
Reactant: N#Cc1ccc2c(N)n[nH]c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (218 mg, 3.16 mmol) in water (1 mL) was added dropwise over 2 min to a stirred suspension of 3-amino-6-cyanoindazole (250 mg, 1.58 mmol) in water (1 mL) and acetic acid (2 mL) at 0° C. The resulting thick suspension was warmed to rt. After 16 h the mixture was cooled to 0° C. and the solids were collected by filtration, washing with cold water. The solids were suspended in 0.1 M HCl (4 mL), DME (3 mL) was added and the resulting mixture was stirred and heated to 80° C. for 1.5 h. The reaction was cooled and concentrated to ⅓ the volume. The residue was neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (5:1 chloroform/ethyl acetate) to give the title compound as a yellow solid:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH3:23])[CH2:11][CH2:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][NH:19][OH:20])=[CH:16][CH:15]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH3:23])[CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([OH:20])[C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=1
Reactant: CN(CCOc1ccc(CNO)cc1)c1nc2ccccc2o1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(O)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a mixture of N-[4-[2-(benzoxazol-2-yl-methyl-amino)-ethoxy]-benzyl]-hydroxylamine (1.5 g, 4.78 mmol) in THF (5 mL) was added acetic anhydride (0.49 g, 4.78 mmol). The mixture was stirred for 1 hour and the volatiles were removed in vacuo. Crystallization from EtOAc/hexane, gave a white solid (1.3 g, 77% yield, m.p. 135°-136° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:37])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:19]4[CH:30]=[CH:29][C:22]([C:23]([O:25]C(C)C)=[O:24])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]([CH3:38])[C:10](=[O:39])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:37])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:19]4[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:29][CH:30]=4)[CH:16]=3)[N:11]([CH3:38])[C:10](=[O:39])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)c1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3C)c2cncn2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(C(=O)O)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 10.8 %

Procedure:
A mixture of (±)-1-methylethyl 4-[[4(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoate (described in Example B12) (0.00369 mol) and LiOH. H2O (0.00369 mol) in THF (15 ml) and H2O (8 ml) was stirred at room temperature for 72 hours, poured out into H2O and washed with EtOAc. The aqueous layer was evaporated, taken up in 2-propanone/H2O and acidified with HCl/diethyl ether. The aqueous layer was evaporated. A part of the residue (0.3 g) was taken up in EtOH/diethyl ether. The precipitate was filtered off and dried, yielding 0.2 g (71%) of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzoic acid, mp. >260° C.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:12][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([CH3:17])[O:16][C:9]=2[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:17][C:15]1[O:16][C:9]2[CH2:8][CH2:7][N:6]([CH3:4])[CH2:12][CH:11]([OH:13])[C:10]=2[CH:14]=1
Reactant: CCOC(=O)N1CCc2oc(C)cc2C(=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(o1)CCN(C)CC2O
Temperature: 0 °C
Yield: 82.4 %

Procedure:
A solution of 6-ethoxycarbonyl-2-methyl-4,5,7,8-tetrahydrofuro[2,3-d]azepin-4-one (27 mg) prepared in the step 6 in 1 mL of dry THF was slowly dropped into an ice-cooled solution of 6.4 mg of lithium aluminum hydride in 1 mL of dry THF. The reaction solution was gradually heated followed by heating to reflux for 2 hours. Then the reaction solution was cooled, ice was gradually added thereto so that an excess amount of lithium aluminum hydride was decomposed and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 17 mg of the objective compound.
Reaction SMILES: [Ca:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[OH-].[Na+]>>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Ca+2:1].[Ca+2:1]
Reactant: [Ca]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: [Ca+2]

Procedure:
The calcium solution was added rapidly with stirring to the phosphate solution. All solutions were adjusted to pH 10 with concentrated NaOH prior to mixing. The initial solid phase formed immediately on mixing was filtered, washed (with distilled water+NaOH, pH 10), and then freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:14]2([CH3:17])[CH2:16][O:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.Cl([O-])(=O)(=O)=O.[Na+]>C(#N)C>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][CH2:16][C:14]([OH:15])([CH3:17])[C:12]([NH:11][C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[O:13])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: Cc1cc(NC(=O)C(C)(O)CNc2ccc(F)cc2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.2 g, 0.85 mmol), 4-fluoroaniline (0.18 g, 1.7 mmol) and sodium perchlorate (0.21 g, 1.7 mmol) in 2 ml of acetonitrile was boiled under reflux for 6 hours. After a workup of the reaction mixture, the crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.41 (3H, s), 2.51 (3H, s), 3.10 (1H, dd, J=12.7 Hz, J=4.6 Hz), 3.41 (1H, dd, J=12.7 Hz, J=7.7 Hz), 5.26 (1H, m), 6.02 (1H, s), 6.62-6.66 (2H, m), 6.84-6.89 (2H, m), 7.79-7.83 (2H, m), 8.02 (1H, d, J=8.9 Hz), 9.99 (1H, s).