Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl-].[NH4+].C(Cl)Cl>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 1 ml of a 1N aqueous solution of sodium hydroxide. The mixture so obtained was stirred at room temperature for 2 days. The reaction mixture was then added with 20 ml of a saturated aqueous solution of ammonium chloride and 20 ml of methylene chloride. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of methylene chloride. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 90 mg of the title compound were obtained (yield: 81.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)CCC>CN(C)C=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ccccn1
Temperature: 100 °C

Procedure:
To a solution of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.190 g, 0.528 mmol) in N,N-dimethylformamide (5 ml) was added 2-tri-n-butylstannylpyridine (0.265 g) followed by dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.187 g). The mixture was heated at 100° C. for 9 h. The solvent was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with 4% methanol in dichloromethane. The residue was then loaded onto a cartridge of strong cation-exchange resin. Elution with methanol gave non-basic impurities. Further elution with 2M ammonia in methanol gave crude product. Further purification by preparative thin-layer chromatography on silica gel using 4% methanol in dichloromethane as eluant and crystallisation of the residue from toluene/isohexane afforded 3-[4-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as yellow needles: δH (400 MHz, DMSO) 7.46 (1H, m), 7.53 (1H, d, J 7), 7.61 (1H, dd, J 11 and 9), 7.86-7.91 (2H, m), 7.95-7.99 (1H, m), 8.24 (1H, dd, J 7 and 2), 8.30 (1H, s), 8.74-8.76 (1H, m), 9.27 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CCCl)cc1

Procedure:
To a suspension of 4-(2-chloroethyl)benzenecarboxylic acid (52.5 mmol; 9.7 g) in anhydrous ethanol (57 ml) was added concentrated sulfuric acid (3.0 ml). The mixture was stirred at reflux for 2 hours 30 minutes. After cooling, the ethanol was removed under reduced pressure and the crude product obtained was dissolved in chloroform (200 ml). The organic phase was washed first with 1N NaOH (100 ml) and then with saturated NaCl solution (3×100 ml). After drying over anhydrous sodium sulfate and removing the solvent under reduced pressure, 12.0 g (100%) of pure product were thus obtained as a pale yellow oil.
Reaction SMILES: CC(C)([S@]([NH:6][C@@:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])([CH3:19])[C:8]([F:18])([F:17])[CH:9]=[C:10]([F:16])[C:11](OCC)=[O:12])=O)C.C(OCC)(=O)C.Cl.C([O-])([O-])=O.[K+].[K+]>[Pd].CO>[F:16][CH:10]1[CH2:9][C:8]([F:18])([F:17])[C@:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([CH3:19])[NH:6][C:11]1=[O:12]
Reactant: CCOC(=O)C(F)=CC(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1ccccc1F
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@]1(c2ccccc2F)NC(=O)C(F)CC1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
(R)-Ethyl 5-((R)-1,1-dimethylethylsulfinamido)-2,4,4-trifluoro-5-(2-fluorophenyl)hex-2-enoate (5.1 g, 12.5 mmol) was dissolved in ethyl acetate (200 mmol) and placed in a Parr-flask. Palladium on carbon (2.65 g, 2.49 mmol, 10%) was added and the Parr-flask was placed in a Parr-shaker (H2-pressure=2.8 bar initially). After 16 h in the Parr shaker at room temperature the reaction mixture was filtered through a plug of celite using ethyl acetate for elution. The filtrate was concentrated under reduced pressure. This material was dissolved in ethyl acetate (200 ml, 3494 mmol) and the reaction mixture was split equally into two Parr-flasks. Palladium on carbon (2.65 g, 2.49 mmol, 10%) was split in two equal partitions and added to the two Parr-flasks. The flasks were placed in two different Parr-shakers (H2-pressure=2.8 bar initially) and run in parallel. After 16 h in the Parr-shaker at room temperature the two suspensions were combined and filtered through a plug of celite using ethyl acetate for elution. The filtrate was concentrated under reduced pressure. The material thus obtained was dissolved in methanol (330 ml). HCl (4.7 ml, 19 mmol, 4 M in 1,4-dioxane) was added and the reaction was stirred at room temperature for 1 h 30 min. K2CO3 (5.16 g, 37.4 mmol) was added and the reaction was stirred at room temperature for another 1 h 30 min. The reaction was concentrated to dryness under reduced pressure and the residue was partitioned between water (200 mL) and ethyl acetate (250 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (120 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→45:55) to afford (6R)-3,5,5-trifluoro-6-(2-fluorophenyl)-6-methylpiperidin-2-one (1.86 g, 57.2% yield) as a semi-solid/foam (1:1 mixture of diastereomers) LC-MS (m/z) 262.2 (MH+) tR=0.57 minutes (Method B).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CC(C)(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3,3-dimethylbutylamine (0.278 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.543 g, 63%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1921, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH3:19])[C:15]2[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6](Br)=[CH:7][CH:8]=2)[CH3:2].C([Li])CCC.CN([CH:28]=[O:29])C>C1COCC1.Cl.C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10]([C:9]3[CH:8]=[CH:7][C:6]([CH:28]=[O:29])=[CH:5][C:4]=3[C:3]2([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CCC1(CC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1(CC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
To a mechanically stirred solution of 9,9-diethyl-2,7-dibromofluorene (59.38 g, 0.1563 mol) in THF (325 ml) cooled in a dry ice-ethanol bath, n-butyl lithium (104 ml of 1.6 M solution in hexanes, 0.1664 mol, 1.06 eq.) was added drop-wise over 25 minutes. After 20 minutes, DMF (17 ml, 0.22 mol) in THF (30 ml) was added, and the mixture was stirred in the cooling bath for 1.5 hours and outside the bath for 1 hour. The reaction was then cooled to 5° C. and treated with hydrochloric acid (12.5 ml of concentrated hydrochloric acid diluted with 50 ml water). The mixture was diluted with 200 ml of toluene, and the aqueous phase was separated and extracted with 200 ml of toluene. The combined organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, and concentrated. The residual solids were recrystallized from heptane-ethyl acetate (9:1) to obtain colorless solids, 40.29 g (78.4% yield) m.p. 126-128° C. The mother liquor, after chromatography over 150 g silica gel, elution with 1:1 heptane-toluene, and trituration of residual solids in hexanes, gave additional product, 6.56 g (12.8% yield, total 91% yield), m.p. 126-128° C. Mass Spec: m/z 328, 330, (M+). A sample for analysis was prepared by recrystallization from hexanes, m.p. 127-129° C. Analysis: Calculated for C18H17BrO, C, 65.55, H, 5.20, and Br 24.27%. Found, C, 65.60, H, 5.51, and Br 24.71%.
Reaction SMILES: I.[C:2]1([N:8]=[C:9]([NH:11][NH2:12])[NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:13]([O-])(O)=O.Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[C:2]1([N:8]2[C:9]([NH2:10])=[N:11][N:12]=[N:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(N)=Nc1ccccc1
Reactant: O=[N+]([O-])O
Agent: [Ag+]
Agent: Cl
Agent: I
Solvent: O
Product: Nc1nnnn1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a warm (50° C.), stirred solution of N'-phenylhydrazinecarboximidamide monohydroiodide (86.4 g, 0.31 mol) in water (300 mL) was added in one portion 70% nitric acid (2.80 mL, 0.0435 mol) followed by dropwise addition of a solution of silver nitrate (52.66 g, 0.3100 mol) in water (70 mL). The resulting suspension was allowed to cool over 30 minutes. To the still warm (+35° C.) mixture was added concentrated hydrochloric acid (3.6 mL). The solids were filtered off and washed with hot water (60 mL). The filtrate and washings were combined and acidified with concentrated hydrochloric acid (22.3 mL). The mixture was chilled (+5° C.) and stirred while a solution of sodium nitrite (21.46 g, 0.3110 mol) in water (70 mL) was added dropwise. The temperature of the solution was kept below 8° C. by controlling the addition rate. The solution was stirred for 15 minutes. To the mixture was added powdered sodium carbonate (36.14 g, 0.341 mol) in small portions to avoid excessive foaming. The resulting precipitate was stirred for 2 days. The solids were filtered off, washed with water (3×20 mL), and dried under house vacuum/air bleed at 45° C.; yield 38.77 g (77.4%), mp=158.5°-159.5° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][SH:35])[CH2:28][CH2:27]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:35][CH2:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:27][CH2:28]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCCc3ccc(Cl)cc3)CC2)cc1

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 4-n-butylphenyl isocyanate, 5.0 g of 3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}propanethiol dihydrochloride, 1.4 g of triethylamine and 50 ml of methylene chloride, to give 2.7 g (34% of theory) of N-(4-n-butylphenyl-S-{3-[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, m.p. 270°-272° C.
Reaction SMILES: C(O[CH:5]([C:15]1[CH:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=1)[C:6]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]1)(=O)C>C(O)(=O)C.[Zn]>[O:21]=[C:17]1[CH:16]=[C:15]([CH2:5][C:6]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH2:8][O:7]2)[CH:20]=[CH:19][NH:18]1
Reactant: COC(=O)C1(C(OC(C)=O)c2cc[nH]c(=O)c2)CCCO1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)C1(Cc2cc[nH]c(=O)c2)CCCO1
Yield: 44.2 %

Procedure:
To a solution of 3.69 g of methyl 2-[(acetyloxy)(2-oxo-1,2-dihydro-4-pyridinyl)methyl]tetrahydro-2-furancarboxylate in 30 ml of acetic acid was added 8.17 g of zinc, and the mixture was heated under reflux for 24 hours. This procedure was repeated twice. The reaction mixture was cooled, filtered through Celite, and the Celite and the filtrate were washed with ethanol. The combined organic layers were evaporated, and the residue was purified by silica gel column chromatography, to give 1.31 g of the title compound as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[CH2:11]([Sn:15]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])Cl)[CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:21]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:17][CH2:18][CH2:19][CH3:20])[C:5]1[S:1][N:2]=[CH:3][CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cnsc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccns1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a cold (−78° C.) solution of isothiazole (100 mg, 1.175 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.808 mL, 1.292 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.380 mL, 1.410 mmol) in anhydrous THF (0.5 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a pale yellow oil (139.3 mg, 32%). 1H NMR (500 MHz, CDCl3) δ ppm 0.90 (t, J=7.32 Hz, 9H), 1.14-1.20 (m, 6H), 1.28-1.39 (m, 6H), 1.51-1.62 (m, 6H), 7.27-7.32 (m, 1H), 8.66 (d, J=1.46 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3](OCC)([O:9][CH2:10][CH3:11])[C:4](=O)[CH2:5][C:6]#[N:7].[NH2:15][NH2:16]>>[C:6]([CH2:5][C:4]1[C:3]([O:9][CH2:10][CH3:11])=[CH:2][NH:16][N:15]=1)#[N:7]
Reactant: CCOC(CBr)(OCC)C(=O)CC#N
Reactant: NN
Product: CCOc1c[nH]nc1CC#N

Procedure:
Heterocyclic molecules are also derived from the above polyfunctional small molecules, which behave similarly. For example, 5-bromo-4,4-diethoxy-3-oxovaleronitrile is reacted with hydrazine, forming (via hydrazone formation, cyclization and ethanol elimination) 3-cyanomethyl-4-ethoxypyrazole; and acetimido 3-bromo-2,2-diethoxypropionate is cyclized on warming to produce 3-methyl-5-(2-bromo-1,1-diethoxyethyl)-1,2,5-oxadiazole. The latter is deketalized by warming in 95% formic acid to produce the corresponding 3-methyl-5-(2-bromoacetyl)-1,2,5-oxadiazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[CH:22]([C:23]([O:25]C)=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1.I[CH3:30].[H-]>CN(C=O)C.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:30])[C:12]=3[CH2:11]2)=[O:9])=[CH:27][CH:28]=1
Reactant: CI
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CC(C(=O)O)N(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (0.96 g, 40.0 mmol) in dry DMF (150 ml) was added portionwise methyl 2-(4-chlorobenzoyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (7.3 g, 20.0 mmol) at 0° C. to 5° C. After being stirred for 15 min, iodomethane (2.8 g, 20.0 mmol) was added and the reaction mixture was stirred for additional 1 h in an ice bath. The mixture was then stirred at room temperature for 9 h. The excess of hydride was decomposed with methanol and the reaction mixture was then evaporated to dryness in vacuo. The residue was recrystallized from MeOH to give 2-(4-chlorobenzoyl)-9-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]indole-3-carboxylic acid, 5.4 g (74%); mp 262-263° C. 1H NMR (Acetic acid-d4) δ 3.18 (1H, m, CH2), 3.56 (1H, m, CH2), 3.45 and 3.68 (3H, s, NMe), 4.64 and 5.40 (1H, d, J=15.8 Hz, NCH2), 4.70 and 4.93 (1H, d, J=17.1 Hz, NCH2), 5.02 and 6.12 (1H, d, J=5.4 Hz, CH), 7.04-7.07 (1H, m, ArH), 7.15-7.18 (1H, m, ArH), 7.31-7.33 (1H, m, ArH), 7.45-7.47 (1H, m, ArH), 7.50-7.55 (3H, m, 3×ArH), 7.59-7.61 (1H, m, ArH). Anal. Calcd for (C20H17ClN2O3): C, 65.13; H, 4.65; N, 7.60. Found: C, 64.77; H, 4.79; N, 7.68.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16]CC)=[O:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C#CC>C(#N)C>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1onc(-c2cccc(Cl)c2F)c1C
Agent: CC#CC(=O)OCC
Solvent: CC#N
Product: Cc1c(-c2cccc(Cl)c2F)noc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
Ethyl 3-(3-chloro-2-fluorophenyl)-4-methylisoxazole-5-carboxylate: Ethyl but-2-ynoate (0.725 ml, 6.22 mmol) and Intermediate 46A (0.36 g, 2.074 mmol) were dissolved in acetonitrile (10.37 mL). Magtrieve (1.742 g, 20.74 mmol) was added and the reaction mixture was stirred in a sealed tube at 80° C. After 2 h, the reaction was cooled to rt and then it was filtered through CELITE®, rinsing with EtOAc. The filtrate was concentrated and purified by reverse phase HPLC to afford the desired product (0.009 g, 2% yield) as a white solid. MS(ESI) m/z: 284.0 (M+H)+. 1H NMR (500 MHz, MeOD) δ 7.70 (ddd, J=8.0, 7.2, 1.7 Hz, 1H), 7.49 (ddd, J=7.8, 6.3, 1.7 Hz, 1H), 7.35 (td, J=7.8, 1.1 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.25 (d, J=1.9 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H) ppm. The other regioisomer, ethyl 3-(3-chloro-2-fluorophenyl)-5-methylisoxazole-4-carboxylate (0.083 g, 14%) was also obtained as a colorless oil. MS(ESI) m/z: 284.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].[OH-].[Na+].COC1C=CC(O)=CC=1.Cl>>[C:10]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: O=C(O)C1CCNCC1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Product: C=C(C)C(=O)N1CCC(C(=O)O)CC1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
The procedure of Example A is used in this example. Isonipecotic acid 43 g, (0.33 mol), 39 g (0.39 mol) of methacryloyl chloride, 29.6 g (0.79 mol) of sodium hydroxide and a trace amount of p-methoxyphenol are charged to the reaction vessel. The reaction mixture is run at 0°-5° C. for a period of three hours and acidified with 2N HCl to pH 3.5. White precipitate is formed and extracted with ethyl acetate. The combined organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to yield crystalline material which is recrystallized from ethyl acetate, to produce 52.9 g (81%) of the product. Found: melting point 90°-93° C. NMR (CDCl3), 4.9 gamma (s, 1H, =CH2), 4.7 gamma (s, 1H, =CH2), 3.8 gamma (br s, 2H, NCH2), 1.7.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:3]1.[OH-].[Na+].CO>O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 16 h

Procedure:
A mixture of 0.240 part of methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate, 10 parts by volume of 0.1 N sodium hydroxide and 7.9 parts of methanol is allowed to stand at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The aqueous layer is acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. Chromatography of the crude product on silica gel with 50% ethyl acetate-benzene affords 3-hydroxy-5-oxocyclopent-1-eneheptanoic acid, melting at about 47°-48.5°. That compound is characterized further by absorption in the ultravoilet spectrum at about 222 millimicrons with a molecular extinction coefficient of about 7700 and a maximum in the nuclear magnetic resonance spectrum at about 87.2 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18]([C@:20]3([NH:25][C:26]([C:28]4[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[N:32][CH:33]=4)=[O:27])[CH2:24][CH2:23][O:22][CH2:21]3)=[O:19])=[N:14][CH:15]=2)=[C:5]([C:42]([F:45])([F:44])[F:43])[CH:4]=1.Cl>O1CCOCC1>[NH2:34][C:30]1[CH:31]=[N:32][CH:33]=[C:28]([CH:29]=1)[C:26]([NH:25][C@@:20]1([C:18](=[O:19])[NH:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:42]([F:44])([F:45])[F:43])=[CH:15][N:14]=2)[CH2:24][CH2:23][O:22][CH2:21]1)=[O:27]
Reactant: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(NC(=O)OC(C)(C)C)c4)CCOC3)nc2)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc(CNC(=O)[C@]3(NC(=O)c4cncc(N)c4)CCOC3)nc2)c(C(F)(F)F)c1

Procedure:
tert-Butyl(S)-[5-(3-{[5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamoyl}-tetrahydrofuran-3-ylcarbamoyl)-pyridin-3-yl]-carbamate (product from Example 5e, 1.2 mmol) was stirred with a 4N HCl solution in dioxane (20 mL) for two hours at ambient temperature. Then the mixture was evaporated to dryness, the residue was triturated with approx. 20 mL diethyl ether and suction filtered.