Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].FC(F)(F)S(O[C:9]1[C:18]2[C:13](=[C:14]([CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:22]([O:24][CH3:25])=[O:23])[CH:10]=1)(=O)=O.Cl.[C:29](OCC)(=O)C.CCCCCC>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:22]([O:24][CH3:25])=[O:23])[CH:10]=[C:9]2[CH3:29])([CH3:21])[CH3:20]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2cccc(C(C)C)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2cccc(C(C)C)c2n1
Reaction time: 1 h

Procedure:
In 30 ml of tetrahydrofuran were suspended 1.8 g of zinc chloride at room temperature under a nitrogen gas stream. A 1.4M tetrahydrofuran solution of methyl lithium (9.5 ml) was added dropwise to the resulting suspension and the resulting mixture was stirred for one hour. The reaction mixture was added dropwise to a solution of 1 g of methyl 4-trifluoromethanesulfonyloxy-8-isopropylquinoline-2-carboxylate and 153 mg of tetrakis(triphenylphosphine)palladium in 20 ml of tetrahydrofuran, followed by stirring at room temperature for 65 hours. Dilute hydrochloric acid was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 2% ethyl acetate/n-hexane), whereby 125 mg of the title compound were obtained in the form of a colorless solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.Cl>CN1CCCC1=O.C(O)C.[Ni](Cl)Cl.[Zn]>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[S:30]([N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:32])=[O:31]
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [I-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCCCC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Anhydrous nickel(II) chloride (60 mg, 0.46 mmole), triphenylphosphine (800 mg, 3.05 mmole), sodium iodide (180 mg, 1.2 mmole), and activated zinc powder (1.2 g, 18 mmole) are placed into a 25 ml flask under an inert atmosphere along with 7 ml of anhydrous N-methylpyrrolidinone (NMP). This mixture is stirred at 50° C. for about 10 minutes, leading to a deep-red coloration. A solution of 3.4 g (11.6 mmole) of 2,5-dichlorobenzenesulfonylpiperidine, which is prepared by the reaction of 2,5-dichlorobenzenesulfonyl chloride with piperidine, in 8 ml of anhydrous NMP is then added by syringe. After stirring for about 60 hours, the resulting highly viscous solution is poured into 200 ml of 1 molar hydrochloric acid in ethanol to dissolve the excess zinc metal and to precipitate the polymer. This suspension is filtered and triturated with acetone to afford, after isolation and drying, solid polyparabenzenesulfonylpiperidine.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:37])([F:36])[F:35])[CH:12]=1.C1(N(C2CCCCC2)C)CCCCC1.O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:6]([O:5][C:1](=[O:4])[CH:2]=[CH:3][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:26]=[C:25]3[C:20]([C:21]([CH3:31])([CH3:30])[CH2:22][C:23](=[O:29])[N:24]3[CH2:27][CH3:28])=[CH:19][C:18]=2[CH3:32])=[C:13]([O:33][C:34]([F:35])([F:36])[F:37])[CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(Br)cc3OC(F)(F)F)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3ccc(C=CC(=O)OC(C)(C)C)cc3OC(F)(F)F)cc21
Temperature: 80 °C

Procedure:
A sealed tube was charged with Pd[P(tBu)3]2 (4 mg, 0.0075 mmol), tert-butyl acrylate (0.03 mL, 0.18 mmol) and Compound 5B (68 mg, 0.15 mmol) in 1 mL of dry dioxane. To this was added dicyclohexyl methyl amine (0.04 mL, 0.18 mmol) and the tube was sealed and heated to 80° C. overnight. After the reaction was cooled, 3 mL of water was added and the solution was passed through a 5 mL solid phase extraction (SPE) column. The SPE was washed with dichloromethane and the collected eluant was stripped on the roto vap to give crude product Compound 5C which was further purified by flash chromatography (25% EtOAc/Hexane) to yield 45 mg (60%) of product. MS (electrospray): mass calculated for C28H32F3NO4, 503.23; m/z found 504.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=1OB(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.COCCOC>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([CH2:24][O:25][CH3:26])[CH:23]=[C:18]([O:17][CH3:16])[C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-:13])=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (3.0 g, 11.1 mmol), 2,6-dimethoxy-4-(methoxymethyl)phenylboric acid (5.0 g, 22.2 mmol), palladium acetate (125 mg, 0.55 mmol), triphenylphosphine (578 mg, 2.22 mmol), tripotassium phosphate hydrate (5.3 g, 22.2 mmol) and 1,2-dimethoxyethane (30 mL) was heated to reflux for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate (100 mL) and water (50 mL) were added and the organic layer was separated off. The organic extract was then washed with 10% brine (50 mL), 1N hydrochloric acid (50 mL) and 10% aqueous ammonia (50 mL) in that order. The organic extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography to afford 3.45 g of the title compound (84% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:11]2=[O:28])[CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]1[CH:37]=[N:38][CH:39]=[N:40][CH:41]=1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:16])([CH3:15])[N:10]([CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([NH:2][C:36]4[CH:37]=[N:38][CH:39]=[N:40][CH:41]=4)[CH:8]=3)[C:11]2=[O:28])=[CH:23][CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cncnc4)c3)C(C)(C)C2=O)cc1
Temperature: 100 °C
Yield: 61.2 %

Procedure:
To a solution of 200 mg of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in stage c) below in 5 mL of dioxane are successively added under argon 11.1 mg of palladium diacetate, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine)(Xantphos), 777 mg of caesium carbonate and 86.8 mg of 5-bromopyrimidine. The reaction mixture is heated at 100° C. for 5 hours and then filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane, methanol and concentrated aqueous ammonia (95/4/1 by volume) to give 135 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-{[2-(pyrimidin-5-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione in the form of an off-white solid, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:14](Br)[CH2:15]Br>O>[CH3:13][O:12][C:9]1[C:10]2[O:11][CH2:14][CH2:15][O:1][C:2]=2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: COc1ccc(C(=O)O)c(O)c1O
Solvent: O
Product: COc1ccc(C(=O)O)c2c1OCCO2
Yield: 56.2 %

Procedure:
171.5 g of 2,3-dihydroxy-4-methoxy benzoic acid, 515 cm3 of alcohol, 280 cm3 of soda lye and 175 g of ethylene bromide were introduced into a balloon flask provided with an agitator, a thermometer and an inlet pipe for nitrogen. The mixture was heated under reflux and then cooled and poured into 2.8 liters of water. The solution was filtered and treated with 85 cm3 of concentrated hydrochloric acid. The precipitate was dried off, washed and dried. After recrystallization in dimethylformamide, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 224°-226° C.; yield: 57%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]([N:22]1[CH2:25][CH2:24][CH:23]1C(OCC)=O)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Si](C)(C)Cl)(C)(C)C.[O:39]=O.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH:9]([N:22]1[CH2:25][CH2:24][C:23]1=[O:39])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C1CCN1C(c1ccccc1)c1ccccc1
Reactant: O=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of lithium diisopropylamide (2.2 mmol) in ca. 15 ml tetrahydrofuran cooled to -78° was added, dropwise with stirring, 0.54 g (2 mmol) of N-benzhydryl-2-carboethoxyazetidine dissolved in 4 ml tetrahydrofuran. After stirring for 20 minutes at this temperature, 0.40 g (2.7 mmol) tert-butyldimethyl chlorosilane in 2 ml tetrahydrofuran was added dropwise to the orange solution over a 2 minute period. Stirring was continued at -78° for 5 minutes and the cooling bath was then removed. The solution was warmed slowly to 0° where it was maintained for 30 minutes, and then warmed to room temperature for 30 minutes with additional stirring. Photooxygenation included transferring the resulting solution to an oxygenation well containing Rose Bengal (10 mg) dissolved in 50 ml tetrahydrofuran. The solution was diluted with an equal volume of pentane, cooled to 0° and photooxygenated internally. Uptake of 1 equivalent (45 ml) of oxygen occurred over a 5 minute period. The solution was poured into 50 ml of a saturated ammonium chloride solution (pH 8), diluted and extracted several times with ether. The combined extracts were washed twice with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Removal of solvents by filtration and rotary evaporation gave an orange oil which was applied to a 10×2 cm neutral alumina column packed as a slurry in hexane. Elution with 2:1 hexane-ethyl acetate gave 0.37 g of pale yellow oil, which by NMR analysis indicated a 55% yield of the desired beta-lactam. Crystallization of some of the product was effected by dissolving the oil in 0.5 ml of tetrahydrofuran and adding the solution dropwise to 100 ml of pentane cooled to -78°. Upon warming to room temperature, most of the white solid went back into solution. The small quantity of crystalline beta-lactam so obtained was dried under a high vacuum overnight: m.p. 63°-65°; IR (oil) cm-1 1740, 1380, 1250, 1050, 760, 700; NMR(CDCl3) delta 7.25 (10H, m), 6.15 (1H, s), 3.17 (2H, t, J=4 Hz), 2.90 (2H, t, J=4 Hz); mass spectrum m/e 237 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=O)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:38][NH:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)N(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylic acid (154 mg, 0.299 mmol) synthesized in Example (28a) was dissolved in dichloromethane (10 mL), and dimethylamine hydrochloride (75.0 mg, 0.920 mmol), WSCI•HCl (115 mg, 0.600 mmol) and 4-dimethylaminopyridine (110 mg, 0.900 mmol) were added, followed by stirring at room temperature for 2 days under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (107 mg, yield 66%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]2.OC1C=C2C(=CC=1)NC(=O)C=C2.C1(S(OCCCCCl)(=O)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH2:22][CH2:21]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Agent: O=S(=O)(OCCCCCl)c1ccccc1
Agent: O=c1ccc2cc(O)ccc2[nH]1
Product: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1OC

Procedure:
Prepared analogous to Example 1 from 3,4-dimethoxy-thiophenol and 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril [prepared from 6-hydroxy-carbostyril (see F. Mayer et al. in Ber. Dtsch. Chem. Ges. 60, 858 (1927) and 4-chloro-butyl benzenesulfonate].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11](O)=[O:12])=[N:6][CH:7]=1.C[Si](C)(C)[O:21][NH2:22].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(NO)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:22][OH:21])=[O:12])=[N:6][CH:7]=1
Reactant: CC(CCc1ccc(Br)cn1)(C(=O)O)S(C)(=O)=O
Reactant: C[Si](C)(C)ON
Agent: CC(CCc1ccc(Br)cc1)(C(=O)NO)S(C)(=O)=O
Product: CC(CCc1ccc(Br)cn1)(C(=O)NO)S(C)(=O)=O
Yield: 24.9 %

Procedure:
The title compound (454 mg, 25%) was prepared from 4-(5-bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (1740 mg, 5.2 mmol) and O-(trimethylsilyl)hydroxylamine (1810 mg, 15.5 mmol) by a procedure analogous to that described for the preparation of compound (IV) 4-(6-Bromophenyl-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide from Preparation 2, Step 5. MS (LCMS) m/z 351.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (s, 3H) 2.17-2.38 (m, 1H) 2.52-2.68 (m, 1H) 2.70-2.85 (m, 1H) 2.85-2.96 (m, 1H) 3.00 (s, 3H) 7.09 (d, J=8.20 Hz, 1H) 7.76 (dd, J=8.20, 2.34 Hz, 1H) 8.58 (d, J=2.34 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][N:30]=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][N:30]=[CH:29]4)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.3 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate (60 mg, 0.13 mmol) in methanol (20 mL) was added sodium hydroxide (15.8 mg, 0.40 mmol) and water (1 mL). The resulting solution was stirred for 3 h at room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (27 mg, 47%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[CH2:19]O)[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.Cl>>[CH3:8][N:5]1[CH2:6][CH2:7][C:2]2([C:9]3[C:10](=[CH:11][CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=3)[CH2:19][O:1]2)[CH2:3][CH2:4]1
Reactant: CN1CCC(O)(c2cc(C(F)(F)F)ccc2CO)CC1
Agent: Cl
Product: CN1CCC2(CC1)OCc1ccc(C(F)(F)F)cc12

Procedure:
Treatment of 4-hydroxy-4-(α-hydroxy-4-trifluoromethyl-2-tolyl)-1-methylpiperidine with hydrochloric acid by the method described in Example 16d provides 1,3-dihydro-1'-methyl-6-trifluoromethylspiro[isobenzofuran-1,4'-piperidine].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8](=[O:13])[NH:9][CH:10]([CH3:12])[CH3:11])=[O:5].[F:19][C:20]1[CH:30]=[CH:29][C:23]([C:24](=N)OCC)=[CH:22][C:21]=1[Cl:31]>C(O)C>[Cl:31][C:21]1[CH:22]=[C:23]([C:24]2[N:6]([CH2:7][C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:13])[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([OH:18])[CH:14]=3)[N:1]=2)[CH:29]=[CH:30][C:20]=1[F:19]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Reactant: CCOC(=N)c1ccc(F)c(Cl)c1
Solvent: CCO
Product: CC(C)NC(=O)Cn1c(-c2ccc(F)c(Cl)c2)nc2ccc(O)cc2c1=O
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE II.1) (400 mg, 1.59 mmol) and ethyl 4-fluoro-3-chlorobenzimidate*HCl (INTERMEDIATE III.5) (1.14 g, 4.78 mmol) in ethanol (10 mL) was heated at reflux temperature for 1 h. The mixture was then cooled to room temperature and the resultant solid collected by filtration and washed with additional portions of cold ethanol (3×20 mL) to afford 2-[2-(3-chloro-4-fluorophenyl)-6-hydroxy-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.1) (380 mg, 0.97 mmol, 61%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=3)[S:13][C:6]=12>C(Cl)Cl>[F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate 267 (1 g, 2.13 mmol) in DCM (4.3 mL) TFA (4.3 mL) was added and the reaction mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure, the residue was suspended in aqueous sodium bicarbonate, the mixture extracted with DCM, EtOAc and DCM; the combined organic phases were filtered and the recovered solids dried. The organic phase was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was combined with the solid material obtained earlier to provide 268 (806 mg, 2.12 mmol, 100% yield) as a yellow solid. MS (m/z): (M+1) 372.1 (100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>CC#N>[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:27]1[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][O:5][N:6]2[C:15](=[O:16])[CH2:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]2=[O:17])[CH2:31][CH2:32]1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2(CCCC2)CC(=O)N1OCCCN1CCN(c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (5.0 g) and 1-(2-benzothiazolyl)piperazine (3.6 g) in 100 ml of anhydrous CH3CN was added diisopropylethylamine (5.7 ml). The mixture was stirred at room temperature for 18 hours.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(N(CC)CC)C.[NH2:35][CH:36]([CH3:45])[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>C(Cl)Cl.O>[CH3:45][CH:36]([NH:35][C:20]([CH:16]1[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15]1)=[O:22])[C:37](=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: CC(N)C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(NC(=O)C1CN(Cc2ccccc2)CCO1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
Oxalyl chloride (1.17 mL, 13.3 mmol) was added to the suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (2.290 g, 8.89 mmol) and DMF (0.034 mL, 0.444 mmol) in CH2Cl2 (60 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 hours, and then evaporated. CH2Cl2 (60 mL) was added to the resulting residue, and the resulting brown solution was added to a suspension of triethylamine (4.34 mL, 31.1 mmol) and 2-amino-1-phenyl-1-propanone (1.65 g, 8.89 mmol) in CH2Cl2 (60 mL) at 0° C. The reaction mixture was stirred at 25° C. overnight. Water (150 mL) was added, and the resulting mixture was extracted with EtOAc (3×80 mL). The organics were dried (Na2SO4), filtered, and evaporated. The resulting residue was purified by silica gel chromatography, eluting with EtOAc in PE from 20% to 50% to afford the title compound (1.3 g) as a yellow oil. LC-MS (ES) m/z=353 [M+H]+.