Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[O:23][C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:27][O:26][C:24]([C:22]1[O:23][C:17]2[CH2:16][N:15]([CH3:13])[CH2:20][CH2:19][C:18]=2[N:21]=1)=[O:25]
Reactant: COC(=O)c1nc2c(o1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc2c(o1)CN(C)CC2
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of 5-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (500 mg) in dichloromethane (15 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and dichloromethane (20 ml), triethylamine (0.495 ml), acetic acid (205 ml), formalin (0.230 ml) and sodium triacetoxyborohydride (570 mg) were added to the resultant residue at room temperature. After stirring for 15 minutes, dichloromethane (20 ml) and a saturated aqueous solution (50 ml) of sodium hydrogencarbonate were added to separate an organic layer. The water layer was extracted with dichloromethane (3×20 ml). After the resultant organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1→10:1) to obtain the title compound (257 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]([N:27]([CH3:36])[C:28](N1C=C[N+](C)=C1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane, (1:5) (69%, colourless oil) HPLC-MS m/z=403.2 (M+1), Rt: 5.11 min
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>O1CCOCC1>[CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[N:8]([C:30]([O:31][CH3:32])=[O:33])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)Cl
Reactant: CCCCNc1n[nH]c2c1c(=O)n(CCC)c1ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNc1nn(C(=O)OC)c2c1c(=O)n(CCC)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
In 60 ml of dioxane was suspended 1.40 g (4.7 mmol) of Compound 2, and 1.0 ml (7.2 mmol) of triethylamine and 0.73 ml (9.4 mmol) of methyl chlorocarbonate were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, and the residue was passed through a silica gel column and eluted with a 3:1 (by volume) mixed solvent of hexane and ethyl acetate. The main fraction collected was recrystallized from hexane-ethyl acetate to obtain 0.67 g (40%) of the titled compound as a colorless crystal.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18][CH3:19])(=[O:15])=[O:14])([CH3:11])[CH3:10])#[N:8]>O.CO>[C:7]([C:9]([NH:12][S:13]([CH2:16][CH2:17][S:18]([CH3:19])=[O:2])(=[O:14])=[O:15])([CH3:11])[CH3:10])#[N:8]
Reactant: CSCCS(=O)(=O)NC(C)(C)C#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CCS(=O)(=O)NC(C)(C)C#N
Yield: 36.5 %

Procedure:
To a stirred solution of 4.27 g (0.020 moles) sodium metaperiodate in 40 ml water which had been cooled to about 0° C. in an ice bath, 4.10 g (0.0184 mole) N-(2-cyano-2-propyl)-2-methylthioethylsulfonamide (the product of Example 27) in about 10 ml methanol was added slowly. Initially, the mixture was homogeneous, but after the addition was complete (after about three minutes), a thick precipitate formed. Additional methanol (15 ml) and water (60 ml) was added, thinning the precipitate to allow stirring. The mixture was stirred overnight in a slowly melting ice bath and then filtered. The solid was washed with methylene chloride. The filtrate was washed three times with 50 ml methylene chloride. The methylene chloride fractions were combined and evaporated to dryness to give 2.2 g of crude product, as a white solid. Recrystallization from ethanol gave 1.6 g of the above-identified product as a solid, melting point 142°-144° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1
Reactant: COCCC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1
Yield: 23.3 %

Procedure:
250 mg (0.611 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 106 mg (0.672 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 77.0 mg of the title compound from Example 277 and 70.0 mg of the title compound from Example 278 (47% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A solution of 0.65 g (5.4 mmol) 3-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 3-(2-quinolinylmethyloxy)benzaldehyde.
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].Cl[CH2:9][C:10](=O)[CH3:11]>C(#N)C>[CH3:11][C:10]1[N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[NH:7][CH:9]=1
Reactant: CC(=O)NC(=N)N
Reactant: CC(=O)CCl
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c[nH]1

Procedure:
N-Acetylguanidine (1.516 g, 15 mmol, 3 equivalents, commercially available Aldrich) was added to 1-chloropropan-2-one (0.462 g, 5 mmol, 1 equiv) in acetonitrile (30 ml). The reaction mixture was heated to reflux for 12 hours under argon. Upon cooling, the reaction mixture was evaporated to dryness and the isolated residue was washed with water, filtered and air-dried to give 0.324 g N-(4-methyl-1H-imidazol-2-yl)acetamide. 1H-NMR (400 MHz, DMSO-d6): δ 13.3 (bs, 1H), 10.29 (bs, 1H), 6.80 (s, 1H), 2.27 (s, 3H), 2.02 (s, 3).
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[C:4]([F:23])[CH:3]=1.[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C>C1COCC1>[F:23][C:4]1[C:5]([OH:6])=[CH:13][C:14]2[CH2:15][O:16][B:29]([OH:30])[C:2]=2[CH:3]=1
Reactant: Fc1cc(Br)c(COC2CCCCO2)cc1OC1CCCCO1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB1OCc2cc(O)c(F)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of 2-(4-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (6.31 g, 16.2 mmol) in anhydrous THF (13.5 mL) was made before cooling the reaction mixture in a −78° C. bath. Reaction mixture was then treated, drop-wise, with n-BuLi (12.15 mL, 19.45 mmol) and allowed to stir for 1.0 hr before (i-PrO)3B (5.59 mL, 24.3 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 2 hr before quenching the reaction with equal volume of concentrated NH4Cl(aq) and EtOAc (1:1, 30 mL). The layers were separated and the water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (2.01 g, 73.93%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.85 (s, 2H), 6.95 (d, J=5.4 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 8.98 (s, 1H), 10.22 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([NH:27]C(=O)C)[CH:19]=[C:20]([N:22]5[CH:26]=[CH:25][CH:24]=[CH:23]5)[CH:21]=4)[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1>C(O)C.C(OCC)(=O)C>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:32]=[CH:31][C:12]3[N:13]([C:16]4[CH:17]=[C:18]([CH:19]=[C:20]([N:22]5[CH:23]=[CH:24][CH:25]=[CH:26]5)[CH:21]=4)[NH2:27])[CH:14]=[N:15][C:11]=3[CH:10]=2)[CH:6]=[N:5]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-n3cccc3)c2)cn1
Yield: 68 %

Procedure:
A mixture of 20% sodium hydroxide (5 ml) and the compound of Example 87 (1.15 g, 2.9 mmol) in 25 ml ethanol was heated at 100° C. for 2 h. The mixture was diluted with ethyl acetate (100 ml) and the organic layer was washed with water (50 ml) and brine (25 ml). The solvent was removed under reduced pressure and the crude was purified by column chromatography over silica gel to give the product in 68% yield (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:22](=O)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)=O.O>[Cl:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH:6]([C:11]3[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=3)[CH2:7][N:8]([CH3:22])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc2c(cc1Cl)CCNCC2c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: COc1cc2c(cc1Cl)CCN(C)CC2c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of benzazepine 3 (7.20 g, 19.6 mmol) in formic acid (2.3 g) was added 37% benzaldehyde (1.8 g). The mixture was heated to 90°-100° C. for four hours. After cooling the reaction mixture to room temperature, 4N hydrochloric acid solution (5.16 mL) was added. The mixture was condensed to dryness under reduced pressure. The residue was dissolved in water and then made basic with 25% sodium hydroxide solution. The mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated to obtain a solid which was purified by column chromatography (silica gel; CH2Cl2 :MeOH:NH4OH;95:5:1) to give 4, 6.0 g (80%): mp 116°-118° C.; FT-IR (KBr)λ1500, 1380, 1270 and 1060 cm-1 ; 1H NMR (CDCl3)δd 7.65-7.35 and 7.21-6.90 (AA'BB',4H, ArH'), 7.13 (S, 1H, ArH #6), 6.38 (S, 1H, ArH #9), 4.40-4.10 (m, 1H, CH), 3.70 (S, 3H, OCH3), 3.10-2.45 (m, 6H, (CH2)3), 2.37 (S, 3H, NCH3). Anal. Calcd for C18H19BrCINO: C,H,N.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:7]=1[NH2:8].[CH:18](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH:10]1([CH2:9][N:6]2[C:7]3[N:8]=[CH:18][NH:1][C:2]=3[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClC(Cl)Cl
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)[nH]c1=O
Solvent: CCOCC
Solvent: O=CO
Product: O=c1[nH]c(=O)n(CC2CCCCC2)c2nc[nH]c12

Procedure:
2 g of 5,6-diamino-1-cyclohexylmethyl-2,4-(1H,3H)-pyrimidine dione (XXII) was refluxed in 10 ml of formic acid for 1 h. 5 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 2.1 g (XXIII). The amide (XXIII) was refluxed in 15 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-n2cccn2)ccn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(-n2cccn2)ccn1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
To a stirred solution of 2-methyl-4-(1H-pyrazol-1-yl)pyridine (300 mg, 1.9 mmol) in CCl4 (25 mL), N-bromo succinimide (304 mg, 1.71 mmol) and benzoyl peroxide (23 mg, 0.09 mmol) were added and heated to reflux for 16 h. The reaction mixture was cooled to rt and precipitated succinimide was filtered. The filtrate was absorbed on silicagel and concentrated under reduced pressure. The crude product was purified flash column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound (100 mg, 45%). [TLC Rf=0.34 (ethyl acetate/hexane 30:70)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CO
Product: COc1cc(N)ccn1

Procedure:
Na (0.7 g, 30 mmol) was added to methanol (10 mL) at room temperature. Once all Na had dissolved, 2-chloro-4-aminopyridine (0.5 g, 3.9 mmol) was added. The solution was heated to reflux for 16 hours. After the reaction solution cooled to room, it was partitioned between ethyl acetate and water. The aqueous layer was extracted twice with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to give the title product. MS (DCI) m/e 125 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[N:5]=[C:4]1[C:11]([O:13]CC)=O)[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[N:5]=[C:4]1[C:11]([N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:23][CH2:24]1)=[O:13])[CH3:2]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1CC
Product: CCn1cc([N+](=O)[O-])nc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1.23 g (5.06 mmol) of ethyl 1-ethyl-4-nitro-1H-imidazole-2-carboxylate (prepared in analogy to Example 10A) and 2.48 g (15.2 mmol) of N-(pyridin-2-yl)piperazine is stirred at 100° C. overnight. For the work-up, the crude mixture obtained is purified by preparative HPLC. 0.724 g (43% of theory) of product are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([OH:14])[CH:13]=2)[N:6]=[C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:4]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[C:16]([C:5]1[CH:4]=[C:3]([NH2:2])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:13]=2)[N:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1O
Agent: Cl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1O[Si](C)(C)C(C)(C)C
Yield: 86 %

Procedure:
The title compound was prepared from 5-[5-amino-3-(1,1-dimethylethyl)-1H-pyrazol-1-yl]-2-methylphenol hydrochloride (WO 03/005999, p81-p82) and tert-butyldimethylsilyl chloride, using the same method as that described for preparation 99, as a solid in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C1(=O)O[CH2:28][CH2:27][O:26]1>[I-].C([N+](CC)(CC)CC)C.CCOCC>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:28][CH2:27][OH:26])=[O:11]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: CCOCC
Product: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (7.24 g, 0.02 mole), ethylene carbonate (2.0 g, 0.023 mole) and tetraethylammonium iodide (1.0 g) was heated in an oil bath at 105°-110° C. for 10 hrs. The reaction was completed and the resulting gummy material was taken into 300 ml of ether. The ethereal solution was washed three times with water and dried over CaSO4. After the solvent had been removed, the product was crystallized from toluene/hexane and an almost quantitative yield (>95%) of the desired ester was obtained as a light brown crystalline solid; m.p. 71°-74° C., NMR (CDCl3) 3.33 (S, 1H), 3.67-4.12 (m, 2H), 4.15-4.63 (m, 2H), 7.02-8.25 (m, 6H); ir (CHCl3) 1749 cm-1. No by-product was detected by NMR analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[OH-].[K+].C(OCC)(=O)C>CS(C)=O.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Agent: [Cu]I
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCCC3)c1)N2
Temperature: 120 °C
Yield: 45.4 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), pyrrolidine (0.21 g, 3.0 mmol), copper (I) iodide (0.11 g, 0.6 mmol) and potassium hydroxide (33.6 mg, 0.6 mmol) in DMSO (2 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(3-fluoro-5-pyrrolidin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 45%) as a white solid: LC/MS m/e calcd for C24H29FN2O2 (M+H)+: 397.5, observed: 397.3.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[OH-].[Na+]>O>[CH2:20]([O:19][C:17]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
Nipecotic acid (3.93 g, 30.4 mmol) and sodium carbonate (5.10 g, 48.1 mmol) in water (40 mL) was mixed with benzyl chloroformate (5.20 mL, 36.4 mmol) under cooling with ice and stirred at room temperature for one day. After addition of water and 1 M aqueous sodium hydroxide, the reaction mixture was allowed to separate by adding diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a pale yellow oil (5.86 g, yield 73%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:30][C:28]1[CH:27]=[C:26]([F:31])[CH:25]=[C:24]2[C:29]=1[C:20]([NH:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:3]=1)=[C:21]([CH3:38])[C:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[N:23]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: N#Cc1cc(I)c(N)cc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)c(C#N)cc1I
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 4-amino-5-iodo-2-morpholinobenzonitrile (140 mg, 0.42 mmol) in dry DMF (3.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (34.7 mg, 0.87 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (185 mg, 0.64 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 2.5 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:methanol (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with methanol and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 minutes, the solid was filtered and rinsed twice with methanol to afford an off white solid as 4-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-iodo-2-morpholinobenzonitrile. Mass Spectrum (pos.) m/e: 583.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4])#[N:2].[NH2:15][OH:16].CCCCCCC>C(O)(C)C>[NH2:2]/[C:1](=[N:15]\[OH:16])/[C:3]([NH:6][C:7]([C:9]1[O:10][C:11]([CH3:14])=[N:12][N:13]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: NO
Reactant: Cc1nnc(C(=O)NC(C)(C)C#N)o1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nnc(C(=O)NC(C)(C)/C(N)=N/O)o1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
N-(2-cyanopropan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (II) (185 gms) was suspended in isopropyl alcohol (462 ml), heated to 50 to 55° C. Aqueous hydroxylamine (IIIa; 76 ml) was added and the reaction mixture stirred for 30 minutes at 60° C. After completion, reaction mass was cooled between 0 and 5° C. and heptane (462 ml) was added to the reaction mass. The resultant slurry was filtered, washed with heptane (185 ml) and the wet cake was dried to give N-[(1Z)-1-amino-1-(hydroxyimino)-2-methylpropan-2-yl]-5-methyl-1,3,4-oxadiazole-2-carboxamide (IVa).