Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=O)=CC=1.CC(N(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[N+]([C:32]1[CH:33]=[C:34]([C:40]#[N:41])[C:35](=[CH:38][CH:39]=1)[C:36]#[N:37])([O-])=O>O.C1(C)C=CC=CC=1>[C:40](#[N:41])[C:34]1[C:35](=[CH:38][CH:39]=[CH:32][CH:33]=1)[C:36]#[N:37]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 160 °C
Reaction time: 18 h
Yield: 501.4 %

Procedure:
To a 100 ml, 3-necked flask equipped with a thermometer and a Dean-Stark trap was added 5.0 gm (22.9 mmol) of 4,4'-difluorobenzophenone, 8.03 gm (23.9 mmol) of bisphenol A6F, and 50 ml of dimethylacetamide (DMAC). After flushing the mixture for 30 minutes with dry nitrogen, 3.9 gm (28.7 mmol) of pulverized anhydrous potassium carbonate was added with stirring. The reaction mixture was stirred at 70° C. for 1 hour. Toluene was added to the Dean-Stark trap and to the reaction vessel (4 ml). The reaction mixture was refluxed at 145°-150° C. for 24 hours. Water which formed as a by-product was removed by azeotropic distillation. The toluene was removed by distillation while heating to 160° C. Upon cooling to 50° C., 3.10 gm (17.9 mmol) of 4-nitrophthalonitrile was added. Since the reaction mixture was somewhat viscous, the temperature of the mixture was increased to 110° C. and held at this temperature for 18 hours (overnight). FTIR spectroscopy showed the absence of hydroxy and nitro bands. The room temperature mixture was then poured into 300 ml of water with stirring to break the precipitate into a powdery form. The solid precipitate was collected by suction filtration, washed exhaustively with water, and dried to afford 11.5 gm of oligomeric phthalonitrile monomer.
Reaction SMILES: C(Cl)Cl.C[O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:21](=[O:22])[C:20]3[C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[O:13][C:12]=3[C:11]([CH3:24])([CH3:23])[C:10]=2[CH:25]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>O>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:21](=[O:22])[C:20]3[C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[O:13][C:12]=3[C:11]([CH3:23])([CH3:24])[C:10]=2[CH:25]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1oc1cnccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
DCM (0.34 ml) solution of 8-methoxy-10,10-dimethyl-10H-11-oxa-2-aza-benzo[b]fluoren-5-one (Compound GT15-11, 10 mg) was cooled to −78° C., added with the DCM solution (0.17 ml) of 1.0 M BBr3, and the mixture was stirred at room temperature overnight. To the reaction mixture, water and saturated aqueous solution of sodium bicarbonate were added, and the solid produced therefrom was filtered off. The filtrate was extracted with the mixture solution of DCM and MeOH (DCM:MeOH=9:1). The organic layer was washed with saturated brine. The filtered solid and the residues obtained after concentration under reduced pressure were combined to obtain the title compound (9.5 mg, 99%).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:41])[CH2:12][N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[CH:6][C:5]=1[CH3:42].[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:17][N:13]2[CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([CH3:42])[CH:6]=2)=[O:41])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)CN2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NC(=O)CN2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a mixture of rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-methyl-benzoic acid methyl ester (50.0 mg, 0.08 mmol) in THF/MeOH (0.6 mL/0.2 mL) was added 2 N LiOH (0.2 mL), and the reaction mixture was stirred at rt for 2 hrs. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetylamino}-methyl-benzoic acid (48.8 mg, 99.8%). HRMS (ES+) m/z Calcd for C32H31Cl2F2N3O3+H [(M+H): 614.1784; Found: 614.1783.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH2:20]([N:27]=[C:28]=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([N:17]1[CH2:16][CH2:15][N:14]([C:6]2[C:5]3[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:19][CH2:18]1)=[S:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: S=C=NCc1ccccc1
Reactant: COc1cc2c(N3CCNCC3)ncnc2cc1C
Product: COc1cc2c(N3CCN(C(=S)NCc4ccccc4)CC3)ncnc2cc1C
Yield: 37 %

Procedure:
Substantially the same procedure as in Example 1 was repeated, except that 6-methoxy-7-methyl-4-(1-piperazinyl)quinazoline was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline in Example 125, and the corresponding benzyl isothiocyanate was used in place of phenyl isocyanate, to give the desired compound.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].CO[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N:27][C:28]2[N:32]([CH3:33])[CH:31]=[CH:30][N+:29]=2[CH3:34])=[CH:22][CH:21]=1>C(OCC)(=O)C>[Cl:13]([O-:17])(=[O:16])(=[O:15])=[O:14].[N:1]1([C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N:27][C:28]3[N:29]([CH3:34])[CH:30]=[CH:31][N+:32]=3[CH3:33])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N=Nc2n(C)cc[n+]2C)cc1
Reactant: C1CNCCNC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc[n+](C)c1N=Nc1ccc(N2CCCNCC2)cc1
Temperature: 100 °C

Procedure:
5 g of homopiperazine (0.05 mol) and 6 ml of dry DMF are charged to a fully equipped round-bottomed flask. The mixture is brought to 100° C. 1.65 g of 2-(4-methoxyphenylazo)-1,3-dimethyl-3H-imidazol-1-ium perchlorate are added over 20 min. The reaction mixture is maintained for 1 hour at 100° C. with stirring and then it is allowed to cool. The reaction mixture is then poured, with stirring, into 150 ml of ethyl acetate. A precipitate forms and it is separated from a gum. This precipitate is recovered by filtration and it is washed 3 times with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1Cc2cc(-c3cccc(Cl)c3)ccc2N1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol) in dimethoxyethane (10 cm3) was stirred under N2 for 20 min. To this mixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol) and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm3). The solution was brought to reflux for 6 h then cooled to RT, poured into water and extracted with EtOAc (×3). The combined organic extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, ethyl acetate: hexane 1:3) to afford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p. 169-171° C., 1H NMR (THF-d8) δ 3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25 (d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5 (br s, 1H); 13C NMR (THF-d8) δ 36.39 (t), 109.80, 123.97, 125.55, 127.19 (d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s); MS (EI) m/z 243, 245 (M)+; Anal. (C14H10ClNO) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]/[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)/[C:4]([O:6]CC)=[O:5].Cl>O1CCCC1.CO.[OH-].[Na+]>[CH3:1][CH:2]([CH3:32])/[C:3](=[N:9]/[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:17]=1)/[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
Ethyl Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (580 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1N aqueous solution of sodium hydroxide (3 ml) was added and the mixture was stirred for 3 hours at room temperature. 1N HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystals were recrystallized from ethyl acetate-hexane to obtain Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (523 mg, yield 96%) as colorless crystals. m.p. 140-142° C.
Reaction SMILES: C(=O)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([K])([CH3:27])[CH3:26].CC([O-])(C)C.[K+].C(NC(C)C)(C)C.[Li]CCCC.[CH:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1)([CH3:49])C.[NH4+].[Cl-]>C1COCC1>[CH3:26][C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1)([CH3:27])[CH:52]([C:53]1[CH:49]=[CH:47][CH:50]=[CH:55][CH:54]=1)[NH2:51]
Reactant: CC(C)c1ccccn1
Reactant: CC(C)([K])c1ccccn1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CC(C)(c1ccccn1)C(N)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a stirred solution of benzaldehyde (3.44 mL, 33.92 mmol) in THF (35 mL) is added a THF solution of lithium bis(trimethylsilyl)amide (37.3 mL, 37.32 mmol) at 0° C. The mixture is stirred at 0° C. for 2 hours. To the resulting solution is added (2-(pyridin-2-yl)propan-2-yl)potassium (6.48 g, 40.71 mmol) at −20 to −15° C. drop wise prepared in the following manner: in a dried, nitrogen-flushed flask was placed potassium 2-methylpropan-2-olate (61.9 mL, 61.89 mmol) (1.0 M in THF) and diisopropylamine (8.75 mL, 61.89 mmol). The mixture is cooled to −20° C. and BuLi (30.9 mL, 49.51 mmol) is slowly added to give a yellow solution. The reaction mixture is then cooled to −50° C. and 2-isopropylpyridine (5 g, 41.26 mmol) is added and the mixture stirred 30 minutes. The mixture is then stirred at −20° C. for 30 minutes, and sat. NH4Cl is added. The mixture is extracted with EA (3×). Combined EA are washed with sat. NaCl, dried over Na2SO4, filtered and concentrated by ISCO column (24 0 g), eluting with 0-70% EA/Hex, then 5% MeOH/DCM to give 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine (6.07 g, 79%) as an yellow oil. This oil is dissolved in isopropyl acetate (50 mL) and a solution of 5-6 N HCl in isopropyl alcohol (4.0 mL) is added. The mixture is concentrated, dissolved in methanol, concentrated and triturated in ether to yield 1 (4.0 g, 60%) as a white solid. M.p.=188° C. 1H NMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H); 13C NMR (75 MHz, CD3OD): δ 22.2, 22.6, 43.7, 62.4, 126.2, 126.4, 128.1, 128.9, 129.6, 133.3, 142.9, 146.9. MS: m/z 227.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl.[CH3:20]O>>[CH3:20][O:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][CH2:6][C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:16]
Reactant: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
50 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid are suspended in 700 ml of methanol and the solution saturated with gaseous hydrogen chloride. The saturated solution is refluxed for 31/2 hours and most of the methanol is removed under reduced pressure. The concentrate is poured into ice water and the mixture neutralized with sodium bicarbonate. It is extracted with ethyl acetate-diethyl ether (1:1), the organic phase washed with water, dried and evaporated. The residue is crystallized from ethyl acetate-diethyl ether (1:5), to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid methyl ester melting at 107°-108.5°.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>>[F:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1ccc(F)c2cccnc12
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1cc(F)c2cccnc2c1O
Temperature: 170 °C
Yield: 43.8 %

Procedure:
5-Fluoro-8-hydroxyquinoline (3.00 g) and potassium carbonate (7.62 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl and cooled. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.67 g of the title product as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO.[CH2:15](Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: -10 °C
Reaction time: 20 h

Procedure:
6.2 g (27.1 mmol) of 3-bromo-5-formylbenzoic acid (J. Org. Chem., 2002, 67, 3548-3554) are dissolved in 110 ml of acetonitrile under argon. 330 mg (2.7 mmol) of 4-dimethylaminopyridine and 1.73 ml (54.2 mmol) of methanol are added thereto. The mixture is cooled to −10° C., and 6.23 g (32.5 mmol) of EDC are added. The mixture is slowly allowed to reach RT and is then stirred for 20 h. The solvent is then evaporated in vacuo, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate (6:1)).
Reaction SMILES: CO.[CH3:3][C@H:4]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C(Cl)Cl>[OH:15][C@@H:6]([CH2:5][C@H:4]([CH3:3])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CCCC[C@@H](C)CC(=O)CC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CCCC[C@@H](C)C[C@H](O)CC(=O)OC(C)(C)C
Yield: 73 %

Procedure:
In a 200 ml autoclave were charged 50 ml of methanol, 14.0 g of t-butyl (R)-5-methyl-3-oxononanoate obtained in Step 5, and a solution of 0.49 g of (S)-di[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]tetrachlorodiruthenium triethylamine in 40 ml of methylene chloride, and the mixture was allowed to react under a hydrogen pressure of 60 kg/cm2 for 18 hours. The solvent was removed by distillation under reduced pressure to obtain 13.6 g of a crude product, which was then purified by silica gel column chromatography to obtain 10.3 g (72.5%) of the titled compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:2].Cl>O1CCOCC1>[CH2:45]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([OH:18])=[O:17])=[O:12])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:44])[NH:33][C@@H:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37][CH2:36][CH2:35]3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:46]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ((S)-tert-butyl 3-((4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoate (4.31 g) was added 4M HCl in dioxane (20 mL). The mixture was stirred at room temperature for 5 h, concentrated to give a yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-(R)Methyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a solution of methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoate (4.7 g, 12.2 mmol) obtained in example 2 in methanol (50 mL) was added aqueous 10% sodium hydroxide (28 mL). The mixture was stirred at 25° C. for 3h. The solvent was removed under reduced pressure and the residue was acidified with 2N hydrochloric acid extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with water (75 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using ethyl acetate to give the title compound (3.0 g, 66%) as a syrupy liquid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:21]1[S:25][C:24]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=2[C:22]=1[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN1C(=O)CCC1.O.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]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:21]3[S:25][C:24]4[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=4[C:22]=3[CH3:31])=[C:14]([C:16]([F:18])([F:19])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2cc(C(F)(F)F)nc12
Reactant: Cc1c(Br)sc2ccc(F)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(F)cc4c3C)c(C(F)(F)F)nc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a dry 10 ml round bottom flask with reflux condenser containing 8-(1-ethyl-propyl)-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (150 mg, 0.690 mmol), 2-bromo-5-fluoro-3-methyl-benzo[b]thiophene (186.1 mg, 0.759 mmol), and Cs2CO3 (472 mg, 1.45 mmol) in NMP (1.1 ml). The mixture is degassed with bubbling N2 for 15 min. Then add Pd2(dba)3 (32 mg, 0.0345 mmol) and PPh3 (36.2 mg, 0.138 mmol). Heat the reaction mixture at 130° C. and stir overnight. Dilute with H2O; extract with EtOAc (3×20 ml); dried (Na2SO4), filter and purify by HPLC to give title compound (29.5 mg, 0.068 mmol, 10%). 1H NMR (CDCl3): 0.931 (t, J=7.6 Hz, 6H), 1.912 (m, 4H), 2.286 (s, 3H), 2.552 (s, 3H), 3.386 (m, 1H), 6.877 (s, 1H), 7.224 (td, J=2.4, 9.0 Hz, 1H), 7.50 (dd, J=2.9, 9.8 Hz, 1H), 7.842 (dd, J=4.9, 9.0 Hz, 1H) ppm. ES-MS (m/z): calcd for C22H21F4N3S (M+H)+: 435.39. found: 436.2.