Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+].CO>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:23]1([CH2:22][C:21]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:9]4[C:4]5[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:33]6[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=6)[C:3]=5[S:11][CH:10]=4)=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ncc(-c2ccncc2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (101 mg, 0.198 mmol), pyridine-4-boronic acid, pinacol ester (53 mg, 0.258 mmol), and PdCl2(dppf)-CH2Cl2 adduct (8 mg, 9.80 μmol) in 1,4-Dioxane (1.5 mL) and saturated aqueous sodium bicarbonate (0.6 mL, 0.600 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave for 30 min. LCMS showed complete conversion to the desired product, along with a small de-iodo by-product. The mixture was cooled, poured into water (15 mL), and extracted with ethyl acetate (2×15 mL). The extracts were washed with brine (1×15 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 24 g SiO2, 25%-100% EtOAc in hexanes gradient over 30 minutes, then EtOAc for 10 minutes, then 0-10% MeOH in EtOAc over 20 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(4-pyridinyl)thieno[3,2-c]pyridin-4-amine (66 mg, 0.136 mmol, 68.6% yield) as a beige solid. LC/MS (ES) m/z=463 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.24 (t, J=8.46 Hz, 2H), 3.90 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.74 (br. s., 2H), 7.23-7.39 (m, 7H), 7.52 (s, 1H), 7.70-7.75 (m, 2H), 8.09 (s, 1H), 8.18 (d, J=8.34 Hz, 0H), 8.65-8.72 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:11][C:4]1([CH3:12])[C:5]2[C:10](=[CH:9][C:8]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:6]=2)[C:2]([CH3:14])([CH3:1])[CH:3]1[CH3:13]
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1C(C)(C)c2ccc(C(=O)CCC(=O)O)cc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
To a solution of 11 g of 1,1,2,3,3-pentamethyl indane (0.058 mole) and 7 g of succinic anhydride (0.07 mole) in 100 cm3 of anhydrous 1,2-dichloroethane, stirred at 0° C, there are added, by small portions, 9.4 g of aluminum chloride in a manner such that the temperature remains lower than 30° C. The reaction mixture is stirred for 3 hours at ambient temperature and then poured into 250 cm3 of ice water. The organic phase is decanted and the aqueous phase is extracted twice with 1,2-dichloroethane. The organic phases are combined, washed with water and dried on magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting product is crystallized in isopropyl ether. 7 g of 4-(1,1,2,3,3-pentamethyl-5-indanyl)-4-oxo butyric acid in the form of white crystals whose melting point is 161° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=1.[Cl-].[NH4+].O>CO.C(OCC)(=O)C.CCCCCC.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cn3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N)cn3)c2cc1OC
Yield: 64 %

Procedure:
6,7-Dimethoxy-4-((5-nitro-2-pyridyl)oxy)quinoline (654 mg, 2.00 mmol), iron powder(559 mg, 10.0 mmol) and ammonium chloride (.1.07 g, 20.0 mmol) were heated and stirred in methanol (20 ml)-water (5 ml) at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. After washing the organic layer with water and saturated brine and drying over anhydrous magnesium sulfate, the drying agent was filtered out and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals. were filtered out and washed with ethyl acetate and then blow-dried to obtain the title compound (380 mg, 1.28 mmol, 64%) as light yellow crystals.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:11]([N:23]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[N:10]([CH3:43])[N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([S:30]([N:23]([C:11]2[N:10]([CH3:43])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])(=[O:31])=[O:32])=[CH:38][CH:37]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCN(c1c(-c2ccc(C(F)(F)F)cc2)c(OCCO)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-({5-{{[4-(tert-butyl)phenyl]sulfonyl}[(2-methoxyethoxy)methyl]amino}-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}oxy)ethyl acetate (Preparation 13) (200 mg) in methanol (20 ml) was added a solution of potassium carbonate (90 mg) in water (5 ml), at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was stripped down and the residue partitioned between ethyl acetate (15 ml) and water (15 ml). The aqueous layer was extracted with ethyl acetate (2×15 ml). The combined organics were back-washed with brine (15 ml). The solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as an off white solid (170 mg).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([N:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O>[CH:8]([N:21]1[CH2:24][C:23](=[O:25])[CH2:22]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (24.7 mL) was added to a solution of 1-benzhydrylazetidin-3-ol (5 g) in DMSO (25 mL). A solution of pyridine sulphur trioxide (18 g) in DMSO (65 mL) was added dropwise and the mixture stirred at 20° C. for 90 minutes. The mixture was poured onto ice/water and extracted twice with ethyl acetate, the combined organics were washed three times with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 2% triethylamine in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 2.9 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>CCCCCC.CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 60% dispersion of NaH in mineral oil (1.07 g, 26.9 mmol) was washed with hexane, and the resulting powder was suspended in 40 mL of DMF. After cooling the stirred mixture to 0° C., ethyl 5-chloro-1H-indole-2-carboxylate (5.00 g, 22.4 mmol) was added in portions. The solution was warmed to room temperature, during which gas was released. After 15 minutes, the mixture was cooled again to 0° C., and benzenesulfonyl chloride was added dropwise (3.14 mL, 24.6 mmol). After warming to room temperature, the reaction was stirred for 1.5 hours, then poured into a mixture of EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The resulting solid was stirred in 50 mL of a 10% EtOAc/hexane solution for 30 minutes, then filtered to provide the titled product as a white powder. Proton NMR for the product was consistent with the titled compound. ESI+MS: 364.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F-].[Cs+].C[O:14][CH2:15][CH2:16][O:17][CH3:18]>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.CO>[F:10][C:4]1[CH:3]=[C:2]([C:2]2[CH2:8][CH2:7][C:18]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:4][CH:3]=2)[C:8]([CH3:9])=[CH:7][C:5]=1[NH2:6]
Reactant: COCCOC
Reactant: Cc1cc(N)c(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: Cc1cc(N)c(F)cc1C1=CCC2(CC1)OCCO2
Temperature: 130 °C

Procedure:
A mixture of 4,4,4,4-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (532.0 mg, 2.0 mmol), 4-bromo-2-fluoro-5-methylaniline (406.0 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium(0) (231.1 mg, 0.2 mmol), cesium fluoride (912.0 mg, 6.0 mmol), 1,2-dimethoxyethane (4 mL) and methanol (2 mL) was degassed for 5 min and then heated at 130° C. in a microwave reactor for 15 min. The reaction was concentrated in vacuo, and purified by silica chromatography (EtOAC/Hexanes:3/7) to afford 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline; ESMS m/z 264.1 (M+H+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CCOCC>CN(C)C=O.CCCCCC>[Si:16]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
In N,N-dimethylformamide (30 ml) was dissolved 1,3-butanediol (3.00 g, 33.3 mmol), followed by the dropwise addition of an N,N-dimethylformamide solution (30 ml) of imidazole (2.72 g, 40.0 mmol) and t-butylchlorodimethylsilane (5.29 g, 35.0 mmol). After stirring at room temperature for 24 hours, ether was added to the reaction mixture and the white solid thus precipitated was filtered off. The resulting ether solution was washed with water and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=5:1 eluate was concentrated, whereby the title compound (5.43 g, 26.6 mmol, 80%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:24])[CH2:15][CH2:14][C:13]2(OC3C=CC=CC=3[O:16]2)[CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:24])[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)Oc2ccccc2O3)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC(=O)CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 350D (1.6 g) and pyridinium p-toluenesulfonate (1.2 g) in acetone (10 mL) was added water (2 mL) and the mixture was stirred under microwave irradiation at 100° C. for 10 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.CCOCC.[CH:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[Br:31]Br>O>[Br:31][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: BrBr
Reactant: C#CCCCCCCCCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCCCCCCCC#CBr
Yield: 80 %

Procedure:
A 250 ml, three-necked, round bottom flask was fitted with mechanical stirrer, thermometer, addition funnel and means for providing nitrogen atmosphere. To the flask was added 41 ml (0.10 mole) of 2.4 M butyl lithium/hexane solution and 40 ml of anhydrous ether. The resulting mixture was stirred vigorously and 17.2 g (0.090 mole) of tetradecyne was added over a period of 25 min at -10° C. After stirring at -10° to -15° C. for an additional 35 min, the reaction mixture was cooled in a Dry Ice/acetone bath. About 16.0 g (0.10 mole) of bromine was added dropwise over a period of 90 min at -60° C. to -68° C. After stirring at -40° C. for an additional 40 min, the reaction mixture was poured into 100 ml of water. The resulting mixture was extracted twice with 50 ml portions of ether. The combined ethereal layers were washed twice with 50 ml portions of sodium bicarbonate solution, dried, and concentrated, resulting in 21.9 g (80% yield) of light yellow liquid. I.R. (film/neat) in cm-1 : 2230 (C≡C), 1470 (CH2), 720 [--(CH2)n --, n≥4].
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C(=O)C.C(O)C.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:19][C:17]1[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=[C:2]([C:22]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])[CH:18]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Cc1cc(Br)cc2nnc(Nc3ccccc3)nc12
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(-c2cc(C)c3nc(Nc4ccccc4)nnc3c2)c(C)c1
Yield: 26.4 %

Procedure:
To a solution of (7-Bromo-5-methyl-benzo[1,2,4]triazin-3-yl)-phenyl-amine (10 mg, 0.032 mmol) dissolved in 2 ml N,N-Dimethylacetamide in a 20 ml vial, 2,4,6-trimethylphenylboronic acid (21 mg, 0.128 mmol) dissolved in 1 ml ethanol and potassium carbonate (6.4 mg, 0.06 mmol) dissolved in 1 ml water were added. Triphenylphosphine (1 mg, 0.0038 mmol) and tris(dibenzylideneacetone) dipalladium (0) (1 mg, 1.09 umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 3 mg [5-Methyl-7-(2,4,6-trimethyl-phenyl)-benzo[1,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 26.8%; ESI-MS: [M+H]+, 355; 1H NMR (CDCl3): δ 2.06 (s, 6 H), 2.36 (s, 3 H), 2.72 (s, 3 H), 6.99 (s, 2 H), 7.17 (m, 1 H), 7.45 (m, 2 H), 7.57 (m, 1 H), 7.89 (d, J=1.36 Hz, 1 H), 7.94(d, J=8.76 Hz, 2 H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[C:15]([F:25])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:24]3)=[C:15]([F:25])[CH:14]=2)=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)c(F)c2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Temperature: 85 °C

Procedure:
To a N-(3-tert-butyl-phenyl)-3-fluoro-4-piperazin-1-yl-benzamide (0.15 mmol) solution in dioxane was added 4-bromo-benzoic acid (0.195 mmol), NaOtBu (0.45 mmol), Xantphos (0.03 mmol) and Pd2 dba3 (0.009 mmol). The reaction vial was purged with Ar, sealed, and heated at 85° C. overnight. The reaction was worked up by diluting with methanol adding an excess of NH4Cl, and passing through a plug of silica gel (1 g) and eluting with methanol. The methanol fraction was concentrated. The residue suspended in DMSO, filtered, and purified by reverse phase liquid chromatography with increasing concentrations of CH3CN in water yielding the product 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid. LCMS calcd for C28H30FN3O3 (m/e) 475, obsd 476 (M+H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:14]2=[N:15][C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=[C:13]2[CH2:12][CH2:11][CH2:10]1)(=O)C.[OH-].[Li+]>C1COCC1.O.CCOC(C)=O>[C:19]1([C:17]2[N:18]=[C:13]3[CH2:12][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:14]3=[N:15][C:16]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
To a solution of 4-(2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butyl acetate (step 2) (410 mg, 1.021 mmol) in THF (6 ml) and water (3 ml) was added lithium hydroxide (56.9 mg, 2.375 mmol) and the mixture was heated at reflux for 18 h. The reaction mixture was diluted with EtOAc and the combined organic extracts were washed with water (2×), brine, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[OH-].[K+].[Cl:16][C:17]([Cl:21])([Cl:20])[C:18]#[N:19]>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][C:18](=[NH:19])[C:17]([Cl:21])([Cl:20])[Cl:16])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C1CC(O)CC1CC
Reactant: N#CC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1CC(OC(=N)C(Cl)(Cl)Cl)CC1CC
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.8 %

Procedure:
To ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (3.52 g, 18.9 mmol, Preparation #P.1) in DCM (21 mL) at about 0° C. was added aqueous potassium hydroxide (50%, 21 mL, 189 mmol), tetrabutylammonium hydrogen sulfate (0.64 g, 1.891 mmol) and 2,2,2-trichloroacetonitrile (9.5 mL, 95 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for about 14 h. The layers were separated and the aqueous layer was extracted with DCM (4×60 mL). The combined organic layers were washed with water (2×50 mL), brine (60 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 15-50% EtOAc in heptane to afford ethyl 2-ethyl-4-(2,2,2-trichloro-1-iminoethoxy)cyclopentanecarboxylate (2.80 g, 45%) as a colorless oil: LC/MS (Table 1, Method b) Rt=2.91 min; MS m/z: 330 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:14]=[CH:13]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:40]([CH:45]1[CH2:50][CH2:49][CH:48]([CH:51]=O)[CH2:47][CH2:46]1)[CH2:41][CH2:42][CH2:43][CH3:44].CC(C)([O-])C.[K+]>COC(C)(C)C>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:20]=[CH:51][CH:48]3[CH2:47][CH2:46][CH:45]([CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:50][CH2:49]3)[CH:16]=2)[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COc2ccc3cc(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2)cc1
Reactant: CCCCCC1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCCCCC1CCC(C=Cc2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 74 %

Procedure:
The solution of (6-benzyloxy-naphthalen-2-ylmethyl)-triphenyl-phosphonium bromide (19) (1 equi.), 4-pentyl-cyclohexanecarboxaldehyde (22), and potassium tert-butoxide (1.3 equi.) in tert-butyl methyl ether (6 mL/mmole) was stirred at room temperature for 24 h, then quenched with water, extracted with diethyl ether, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (1.25% EtOAc/hexane) afforded 2-benzyloxy-6-[2-(4-pentyl-cyclohexyl)-vinyl]-naphthalene (23) as a white solid (74%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[CH:25]([C@@H:27]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:28]([CH3:30])[CH3:29])=[O:26]>C1COCC1.C(O)(=O)C>[CH2:34]([O:33][C:32]([NH:31][C@@H:27]([CH:28]([CH3:30])[CH3:29])[CH:25]([OH:26])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Under an argon atmosphere, a solution (315 mL) of diisopropylamine (31.2 g) in dehydrated THF was cooled to −10° C., 1.6 mol/L butyllithium-hexane solution (175.3 mL) was added at −5° C. or below, and the mixture was stirred at the same temperature for 30 min. Then the mixture was cooled to −78° C., and a solution (65 mL) of ethyl acetate (24.7 g) in dehydrated THF was added dropwise at −70° C. or below. After stirring at the same temperature for 1 hr, a solution (70 mL) of benzyl [(1S)-1-formyl-2-methylpropyl]carbamate (16.5 g) in dehydrated THF was added dropwise at −65° C. or below. After stirring at −70° C. for 1 hr, acetic acid (36 g) was added, and the mixture was warmed to 0° C. The reaction mixture was poured into ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1→3/2) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate as colorless oil (yield: 15.4 g).