Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[O:4]=[C:5]([C@H:7]([CH2:9][C:10]1[CH:17]=[C:15]([OH:16])[C:13]([OH:14])=[CH:12][CH:11]=1)[NH2:8])O.Cl>>[CH3:2][CH2:1][O:3][C:5]([C@@H:7]([NH2:8])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:14])=[C:15]([OH:16])[CH:17]=1)=[O:4]
Reactant: CCO
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc(O)c(O)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
Absolute ethanol (395 g, 500 ml, 8.58 moles, 17 eq.) and L-DOPA (100 g, 0.507 moles, 1 eq.) are introduced into 1 L reactor. The batch is cooled to 15° C. and HCl(g) (37.01 g, 1.014 mole, 2 eq.) is bubbled into the reaction mixture at 15-30° C. The reaction is heated to reflux (79° C.) and kept at reflux for 3 hours. The batch is then cooled to 40° C. and 350-400 ml of solvent is distilled out under vacuum during 1.5-2 hours (50 mbar, jacket temperature 60° C.). Deionized water (220 ml) is introduced, the pH of the solution is adjusted to 2-3 with 5N NaOH solution (65 ml) and 170 ml of the reaction mixture is distilled out during 1.5-2 hours (50 mbar, jacket temperature 50° C.). Toluene (20 ml) is added to the resulting solution, the pH of the solution is adjusted to pH 4-5 with 5N NaOH solution and sodium metabisulfite (2 g, 2% w/w) is added. The operations from this stage on are done at nitrogen atmosphere. The temperature of the reaction is adjusted to 25-30° C., the pH is adjusted to 6.5-6.7 with 5N NaOH and the solution is seeded with L-DOPA ethyl ester (1 g). The precipitation is continued by controlled addition of 5N NaOH solution (70 ml/hr.) until pH 7.6-7.8, the reaction mixture cooled to 5° C. and kept at this temperature for one hour. The precipitate is collected by filtration and washed with (2×40 ml) cold water. The crude wet precipitate is dried by azeotropic distillation of the water with toluene (500 ml) under vacuum (50 mbar, jacket temperature 25-45° C.) until no more water is distilled out. The mixture is cooled to ambient temperature, L-DOPA ethyl ester (crude) is collected by filtration, washed with toluene and dried in a vacuum oven at 30-35° C. until constant weight. The yield of crude material is 85%.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[C:14]([C:21]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:39])[CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[CH:26]=[N:27][CH:28]=3)=[O:22])=[CH:13]2)[CH2:11][O:10][CH2:9]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:30]([NH:29][C:25]2[CH:26]=[N:27][CH:28]=[C:23]([C:21]([C:14]3[C:15]4[CH:20]=[N:19][CH:18]=[N:17][C:16]=4[N:12]([C:8]4([CH2:7][OH:6])[CH2:11][O:10][CH2:9]4)[CH:13]=3)=[O:22])[CH:24]=2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1(n2cc(C(=O)c3cncc(NC(=O)Cc4ccc(Cl)cc4)c3)c3cncnc32)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2cn(C3(CO)COC3)c3ncncc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(5-{7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-chloro-phenyl)-acetamide (Preparation 203 mg, 0.059 mmol) was dissolved in dry THF (0.5 mL) and tetrabutylammonium fluoride (0.065 mL of a 1M solution in THF, 0.065 mmol.) was added. The reaction was stirred for 30 min at room temperature. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were concentrated and purified by preparative HPLC to give the title compound in quantitative yield 28 mg.
Reaction SMILES: [C:1]1([C:7]2([CH2:20][O:21][CH2:22][C:23]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36]C(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O1CCCC1>[CH3:36][N:27]1[C:28]2[C:24](=[C:23]([CH2:22][O:21][CH2:20][C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3[nH]ccc23)(c2ccccc2)CC1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: Cn1ccc2c(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Reaction time: 0.08 h

Procedure:
A solution of tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1H-indol-4-yl)methoxy)methyl)piperidine-1-carboxylate (59 mg, 0.121 mmol) in tetrahydrofuran (5 ml) at 25° C. was treated with potassium tert-butoxide (13.6 mg, 0.121 mmol) and stirred for 5 minutes. Dimethyl sulfate (0.012 ml, 0.121 mmol) was added, the solution was stirred at 25° C. for 1 h, and then concentrated in vacuo. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 45 mg (90%) as a colorless oil. Mass spec.: 503.17 (MH)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:18](Br)[CH:19]=[CH2:20].[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].C[N+](CCCC)(CCCC)CCCC>[CH2:20]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:16][CH3:17])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: COC(CNC(=O)OCc1ccccc1)OC
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCN(CC(OC)OC)C(=O)OCc1ccccc1
Temperature: 16 °C
Reaction time: 0.25 h

Procedure:
The solution of Example 4A in toluene (343 Kg) was charged to a 200-gallon reactor followed by addition of allyl bromide (41.5 Kg) and methyltributylammonium chloride (8.3 Kg). The mixture was stirred for 15 minutes, cooled to 16° C., and treated with 50% NaOH solution (296.9 Kg) slowly over 1 hour while maintaining the internal temperature below 30° C. The mixture was stirred at room temperature until there remained no more than 1.0% 1, as determined by HPLC. The mixture was allowed to settle and the layers were separated. The organic layer was washed with phosphate buffer solution made of 10 mM KH2PO4 and 10 mM K2HPO4 (2×260 Kg), followed by a water wash (256 Kg).
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[N:4].NCC(O)CC(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O.CCOCC>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC(O)CCc1ccccc1
Agent: CC(C)CC(O)CN
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: NCC(O)CCc1ccccc1

Procedure:
1b is prepared from 2-hydroxy-4-phenylbutanenitrile according to the protocol described for 1a; LiAlH4 (6.2 g, 163 mmol), Et2O (120 ml), 2-hydroxy-4-phenylbutanenitrile (12.4 g, 77 mmol), H2O (6.2 ml), 15% aqueous NaOH (6.2 ml) and H2O (18 ml). The product, an orange oil, is used with no other purification (11 g, 87%); 1H NMR (100 MHz, CDCl3) δ: 1.80 (m, 3H), 2.65 (m, 4H), 3.62 (m, 3H), 7.21 (s, 5H); 13C NMR (25 MHz, CDCl3) δ: 33.98, 36.25, 70.92, 125.46, 128.04, 141.74. Analysis calculated for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Experimental: C, 72.45; H, 9.33; N, 8.24.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]3[C:38]4[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=4)[NH:32][N:31]=3)=[O:29])=[C:23]([F:40])[CH:22]=2)[CH2:16]1)=O)(C)(C)C.[OH-].[Na+]>O.C(#N)C>[F:40][C:23]1[CH:22]=[C:21]([C@H:17]2[O:18][CH2:19][CH2:20][NH:15][CH2:16]2)[CH:26]=[CH:25][C:24]=1[NH:27][C:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[NH:32][N:31]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)c3n[nH]c4cc(F)ccc34)c(F)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc([C@@H]2CNCCO2)cc1F)c1n[nH]c2cc(F)ccc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
To a stirred solution of trifluoroacetic acid (38 μl) in water (1.5 ml) was added a solution of (R)-2-{3-fluoro-4-[(6-fluoro-1H-indazole-3-carbonyl)-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (15 mg) in acetonitrile (0.5 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: MeOH/EtOAc/heptane) to afford 6-fluoro-1H-indazole-3-carboxylic acid ((R)-2-fluoro-4-morpholin-2-yl-phenyl)-amide (9 mg, 77%) as a white solid. MS (ISP): 359.1 ([M+H]+).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([C:24](=[O:47])[N:25]([CH:44]4[CH2:46][CH2:45]4)[C:26]4[CH:27]=[CH:28][C:29]5[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[N:31]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]=5[CH:43]=4)[CH2:21][C@H:20]([NH:48]C(OC(C)(C)C)=O)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:56]>O1CCOCC1>[ClH:56].[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([C:24](=[O:47])[N:25]([CH:44]4[CH2:46][CH2:45]4)[C:26]4[CH:27]=[CH:28][C:29]5[O:34][C:33]([CH3:35])([CH3:36])[C:32](=[O:37])[N:31]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:30]=5[CH:43]=4)[CH2:21][C@H:20]([NH2:48])[CH2:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)OC(C)(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](N)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21

Procedure:
(3S,5R)-3-tert-Butoxycarbonylamino-5-{cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (3.0 g, 4.0 mmol) is treated with 4N HCl in 1,4-dioxane (15 mL). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 653 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.46 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[Cl:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncc1O
Product: O=C(CCl)Nc1ccncc1O

Procedure:
A solution of 4-amino-3-hydroxypyridine (7 g, 0.06 mol) and chloroacetyl chloride (50 ml) was refluxed for 2 hours, cooled and the excess solvent was removed by vacuum distillation. The crude material was dissolved in water, neutralized with Na2CO3 and the solid precipitated filtered and air dried to give the desired product, m.p. 155°-158° C. The structural assignment was supported by the proton NMR spectrum.
Reaction SMILES: [C:1]1([CH3:22])[C:2]([S:7]([N:10]([CH2:18][C:19](O)=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:23]([NH:30][CH2:31][CH2:32][OH:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:30]([CH2:31][CH2:32][OH:33])[C:19](=[O:20])[CH2:18][N:10]([S:7]([C:2]1[C:1]([CH3:22])=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:9])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCCNCc1ccccc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccccc2C)cc1

Procedure:
prepared by reaction of [(toluene-2-sulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(=O)C.[NH4+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([NH2:38])=[O:35])[CH2:32][CH2:33]3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(C(=O)O)CC2)C1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
85 mg (0.17 mmol) of 1-({3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidin-1-yl}carbonyl)piperidine-4-carboxylic acid together with 80 mg (0.21 mmol) of HATU and 34 mg (0.28 mmol) of 4-dimethylaminopyridine were initially charged in 1.3 ml of DMF, and 11 mg (0.14 mmol) of ammonium acetate were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 46 mg (53% of theory)
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[PH:9](=[O:11])[O:10][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(#N)C>[C:16]([CH2:17][CH2:18][P:9]1(=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:10]1)#[N:19]
Reactant: O=[PH]1Oc2ccccc2-c2ccccc21
Reactant: C=CC#N
Solvent: CC#N
Product: N#CCCP1(=O)Oc2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 96.6 %

Procedure:
108 g (0.5 mol) of 6H-dibenz-[c,e][1,2]-oxaphosphorin-6-one are heated to 165° C. with stirring and under an inert-gas atmosphere, and 26.5 g (0.5 mol) of acrylonitrile are added dropwise over 4 hours. The mixture is stirred further at this temperature for 1 hour and then cooled, giving 134 g of a resinous composition. Digestion with a little acetonitrile produces 130 g of 6-(2-cyanoethyl)-(6H)-dibenz[c,e][1,2]-oxaphosphorin 6-oxide, which, after recrystallization from a little acetonitrile, has a melting point of 120-123° C. The yield is 97% of theory.
Reaction SMILES: C(O[CH:6]([O:17]CCCC)[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)CCC.[CH:22]([Mg]Br)=[CH2:23].[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:11]1[CH:10]=[C:9]2[C:8](=[C:7]([CH:6]=[O:17])[CH:12]=1)[NH:14][CH:23]=[CH:22]2
Reactant: CCCCOC(OCCCC)c1cc(C)ccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c2[nH]ccc2c1
Temperature: -40 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2-Dibutoxymethyl-4-methyl-1-nitrobenzene (13.957 g, 47.373 mmol) in anhydrous tetrahydrofuran (474 mL) under nitrogen, and cool the solution to −40° C. Add vinylmagnesium bromide (190 mL, 190 mmol, 1.0 M in tetrahydrofuran) at −40° C. with stirring. Stir the reaction mixture for 40 minutes and add saturated aqueous ammonium chloride. Extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over sodium sulfate, filter, and concentrate. Dissolve the residue in tetrahydrofuran (160 mL) and cool to 0° C. Add aqueous 0.5 molar hydrochloric acid (20 mL) and stir the mixture at 0° C. for 1 hour. Add saturated aqueous sodium hydrogen carbonate (200 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure and purify by flash column chromatography (silica gel, 5% ethyl acetate/hexane) to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([Cl:8])[C:5](/[CH:9]=[CH:10]/[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]3[CH:33]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[C:31](B4OC(C)(C)C(C)(C)O4)=[CH:30][C:24]=3[C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>O>[Cl:8][C:6]1[N:7]=[C:2]([C:31]2[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:23]3[O:22][C:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)=[C:25]([C:26]([NH:28][CH3:29])=[O:27])[C:24]=3[CH:30]=2)[CH:3]=[CH:4][C:5]=1/[CH:9]=[CH:10]/[O:11][CH2:12][CH3:13]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CCO/C=C/c1ccc(Br)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1Cl
Temperature: 60 °C

Procedure:
To a mixture of (E)-6-bromo-2-chloro-3-(2-ethoxyvinyl)pyridine (3.37 g, 12.84 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (6.45 g, 12.84 mmol), cesium carbonate (10.46 g, 32.1 mmol), and 1,1′ Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.524 g, 0.642 mmol) was added 1,4-Dioxane (83 mL) followed by H2O (8.34 mL). A steady stream of N2 was bubbled through the reaction mixture for 7 minutes then the mixture was heated to 60° C. for 16 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed successively with H2O (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The solid residue was triturated with EtOAc and further purified by silica gel column chromatography using a gradient of 0-30% EtOAc/CH2Cl2 as eluent. Further purification by silica gel column chromatography with a gradient of 0-100% EtOAc/Hexanes as eluent provided the title compound as a tan solid. 1H NMR δ (ppm) (CHCl3-d): 8.03˜7.97 (3H, m), 7.79 (1H, d, J=7.96 Hz), 7.69 (1H, s), 7.52 (1H, d, J=7.50 Hz), 7.28˜7.00 (2H, m), 7.11 (1H, d, J=13.00 Hz), 6.12 (1H, d, J=13.00 Hz), 5.91 (1H, br s), 4.04 (2H, q, J=7.04 Hz), 3.24 (3H, s), 3.03 (3H, d, J=4.87 Hz), 2.89 (3H, s), 1.44 (3H, t, J=7.00). MS (M+H): 557.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18]C)[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:4]=1.Br>O>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:18])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:4]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(NS(C)(=O)=O)cc1C2=O
Agent: Br
Solvent: O
Product: CS(=O)(=O)Nc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O

Procedure:
N-(9,10-Dihydro-4,5-dimethoxy-9,10-dioxoanthracen-2-yl)methanesulphonamide (1.45 g) was suspended in a 48% solution of hydrobromic acid in water (30 ml) and heated to reflux under an atmosphere of nitrogen for 60 hours. The mixture was poured into water (100 ml) generating a precipitate which was collected by filtration. Drying in vacuo over silica gel yielded N-(9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracen-2-yl)methanesulphonamide at 92% purity (HPLC) as a brown powder, m.p. >300° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH3:33][CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:35])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)=[CH:28][CH:27]=1)[C:30]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:32]
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: C1COCCN1
Product: CC(C(=O)N1CCOCC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and morpholine. LCMS (M+H)+: m/z=553.3
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[ClH:10].[N:11]([O-])=O.[Na+]>[OH-].[Na+]>[ClH:10].[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1c(F)cccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NNc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-6-fluoroaniline (2.0 g, 10 mmol) was dissolved in hydrochloric acid (7.0 mL, 12 N aqueous, 8.0 equiv) and cooled to 0° C. An aqueous solution (10 mL) of sodium nitrite (0.80 g, 11 mmol, 1.1 equiv) was added dropwise over 30 minutes via addition funnel and the mixture was stirred for an additional 30 minutes at 0° C. A hydrochloric acid solution (10 mL, 12 N aqueous) of stannous chloride (7.1 g, 31 mmol, 3.0 equiv) was then added to the mixture over 45 minutes via addition funnel and the mixture was stirred for an additional 1 hour at 0° C. To the mixture, sodium hydroxide (30 mL, 1 N aqueous) was added slowly until basic (pH>8). The mixture was warmed to ambient temperature, poured into sodium hydroxide (50 mL, 25% aqueous) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic extracts were dried with sodium sulfate, filtered and partially concentrated in vacuo. The mixture was diluted with diethyl ether (200 mL) and treated with gaseous hydrochloric acid until saturated, resulting in a white precipitate, which was filtered and washed with diethyl ether (2×50 mL), providing the titled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]([C@@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]3)[CH2:19][CH2:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1ccc2cc(O)ccc2n1
Product: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
6-hydroxy-2-methylquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-((trans)-4-tert-butylcyclohexyloxy)-2-methylquinoline, which in turn was oxidized with tert-butyl hydrogen peroxide and selenium dioxide in dioxane, providing 6-((trans)-4-tert-butylcyclohexyloxy)-2-formylquinoline. This aldehyde was then treated with t-butyl 3-aminopropionate and sodium cyanoborohydride in dichloroethane to afford t-butyl 3-(((6-((trans)-4-tert-butylcyclohexyloxy)-quinolin-2-yl)methyl)amino)propionate. Treatment with lithium hydroxide in methanol/THF gave the title compound, 3-((6-((trans)-4-tert-butylcyclohexyloxy)quinolin-2-yl)methylamino)propanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18]>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Si-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:17]([F:19])([F:18])[F:16])[CH:5]=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[Si-](F)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1cncc(Br)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (10.75 mmol) and tetrabutylammonium difluorotriphenylsilicate(IV) (6.38 g, 11.83 mmol) in THF (53.8 ml) was cooled to −78° C. Then (trifluoromethyl)trimethylsilane 2M solution in THF (6.45 ml, 12.90 mmol) was added dropwise, and the mixture stirred at −78° C. for 2 h. Brine was added and the precipitate removed and washed with AcOEt. The filtrates were dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (0-15% MeOH/CH2Cl2; SNAP50 column) giving the title compound (2.96 g, 77%) as a light yellow solid. LC-MS (M+1) 361.0.