Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][O:12]2.C([Mg]Cl)(C)C.[Cl:23][C:24]1[N:25]=[N:26][C:27](I)=[CH:28][CH:29]=1.Cl>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CN(C=O)C>[Cl:23][C:24]1[N:25]=[N:26][C:27]([C:16]2[N:15]3[C:11]([O:12][CH:13]=[CH:14]3)=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:28][CH:29]=1
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Reactant: Clc1ccc(I)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc3occn3c2-c2ccc(Cl)nn2)c(F)c1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 35.4 %

Procedure:
To a flask was added 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (10.0 g, 28.9 mmol, Preparation #C.1) and THF (50 mL). The mixture was cooled to about −30° C. and then a solution of iPrMgCl (2.0 M in THF, 15.2 mL, 30.3 mmol) was added dropwise. The reaction mixture was stirred about 15 min at about 0° C. and then a solution of zinc chloride (4.73 g, 34.7 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at about 0° C. for about 30 min. To a second flask was added 3-chloro-6-iodopyridazine (6.67 g, 27.7 mmol, Example #9, Step A) and DMF (20 mL) and the mixture was stirred at ambient temperature until all solids were in solution. To this flask was added Pd(PPh3)4 (1.336 g, 1.156 mmol, Strem) and then the entire contents were poured in to the first reaction flask. The reaction mixture was heated to about 80° C. and stirred for about 1 h. The reaction mixture was cooled to ambient temperature and the solids were filtered. The solid was triturated with 1-propanol (25 mL) to give a solid. The solid was portioned between 1N aqueous HCl (250 mL) and DCM (250 mL). The organic layer was isolated and then extracted with 6N aqueous HCl. The acid layer was then basified with solid Na2CO3 and the precipitate filtered and dried under vacuum to give the title compound (3.26 g, 34%). LC/MS (Table 1, Method a) Rt=2.69 min; MS m/z: 333.1 (M+H)+
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][C:20]#[N:21])[C:15](=O)[CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([S:7]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCN1C(=O)COc2cc(S(=O)(=O)c3ccccc3)ccc21
Solvent: C1CCOC1
Product: NCCN1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
A solution of (7-benzenesulfonyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetonitrile (0.234 g., 0.713 mmol) in 2 mL anhydrous THF was warmed to reflux, and borane-methyl sulfide complex (0.5 mL of a 10 M solution, 5 mmol) was added dropwise over 5 minutes. Reflux was continued for 4 hours, and the reaction mixture was concentrated in vacuo. The residue was then dissolved in 2 mL ethanol and ethanolic hydrogen chloride was added (2 mL of a 2 N solution, 4 mmol.) The solution was refluxed for 18 hours then cooled to room temperature, resulting in formation of a precipitate. The solid was filtered and dried under vacuum for 18 hours to give 0.158 g (0.496 mmol, 70%) of 2-(7-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethylamine as a yellowish solid. MS: 319 (M+H)+, mp: 261.0-265.1° C. (HCl salt).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[F:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[C:28](/[N+]([O-])=O)\[CH3:29])=[CH:23][CH:22]=1>C1COCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([CH3:29])=[CH:2][NH:1][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:23][CH:22]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C(=C\c1ccc(F)cc1)[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Ethyl isocyanoacetate (4.36 mL, 42.09 mmol) and DBU (6.28 mL, 42.09 mmol) was added to a solution of (E)-1-fluoro-4-(2-nitroprop-1-enyl)benzene (6.0 g, 33.14 mmol) in THF (60 mL) at 0° C. The reaction mixture was stirred for 30 min at room temperature; quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (1×100 mL) and brine (75 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel; 60-120 mesh). The pure product was eluted with 10% EtOAc in petroleum ether to yield the desired compound (6.0 g, 73%) as pale yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[C:4]1([CH2:3][CH2:2][CH:19]([OH:20])[CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: BrCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCc1ccccc1)CCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 minutes. 3-Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2× ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g (63%) of the diphenyl alcohol, 1H NMR (300 MHz, CDCl3): δ 1.84 (m, 4H); 2.61-2.76 (m,4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)C>N1C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:21][CH:20]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Yield: 69.1 %

Procedure:
Treatment of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.567 g) with methanesulphonyl chloride (0.263 g) in pyridine (18 ml) according to the method of Example 1 gave the title compound, (0.50 g), m.p. 214°-215° (from ethanol).
Reaction SMILES: OC[C:3]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C]=O>CO.[Pd].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.[Fe+2]>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[C:4]2[C:3]([CH2:8][O:7][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1CO
Agent: [Fe+2]
Agent: [Pd]
Agent: [C]=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1OCc2ccc(C(F)(F)F)cc21
Temperature: 95 °C
Reaction time: 6 h
Yield: 57.8 %

Procedure:
Methyl 2-(hydroxymethyl)-5-(trifluoromethyl)benzoate (5.00 g, 21.4 mmol) in MeOH (50 mL) was added to Pd-dppf (Heraeus) (0.312 g, 0.427 mmol) and triethylamine (5.95 ml, 42.7 mmol) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with carbon monoxide (60 psi), and stirred at 95° C. for 6 hours. The mixture was filtered through Celite, and the filtrate concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford the title compound (2.5 g, 63%). MS (DCI/NH3) m/z 203 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:4]1[C:5]([OH:13])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1cc(C=O)c(O)cc1O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cc(CO)c(O)cc1O
Reaction time: 1 h
Yield: 65.3 %

Procedure:
One gram of 5-acetyl-2,4-dihydroxybenzaldehyde was hydrogenated in the presence of 1 g of 10% palladium on carbon in 150 ml of ethanol. After about 1 hour, hydrogen uptake ceased and hydrogenation was terminated. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in approximately 30 ml of ethyl acetate and cooled in the refrigerator. The resulting solid was recovered by filtration affording 0.66 g of the desired title intermediate, m.p. =151°-152° C. The same reaction when run on a 5-fold scale provide 2.76 g of material.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:19]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1

Procedure:
65 mg (0.30 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 95 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O.ClCCl>ClCCl>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of the product from step 4 (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and t-butyl bromoacetate (0.45 mL, 3.05 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.83 g, 75%);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18]3)[C:13]([Cl:23])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(OC3CCNCC3)c(Cl)cc2c1C
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2cc(OC3CCN(C4CCC4)CC3)c(Cl)cc2c1C
Reaction time: 5 h

Procedure:
The above prepared 5-chloro-3-methyl-6-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester (1.35 g, 3.32 mmol) was dissolved in 45 mL of CH2Cl2 and treated successively with cyclobutanone (0.506 g, 2 eq.), acetic acid (0.413 mL, 2 eq.) and sodium triacetoxyborohydride (1.529 g, 2 eq.), and the mixture then kept at ambient temperature for 5 h. Pouring onto crashed ice/NaHCO3, five fold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) generated 1.190 g of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CCC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:19]([O:11][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=1[F:10])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCOc1c(F)c(F)cc(F)c1F
Yield: 91.3 %

Procedure:
To 20.0 g of 2,3,5,6-tetrafluorophenol (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 21.9 g of bromohexane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 27.5 g (110 mmol) of 4-hexyloxy-2,3,5,6-tetrafluorobenzene (4).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:17][CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=1)[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)C(Br)Oc1ccc(Cl)cc1
Yield: 76 %

Procedure:
German Laid-Open Application DOS 2,720,654 discloses that alkanecarboxylic acid derivatives, for example tert.-butyl 4-chlorophenoxyacetate, can be reacted with N-bromosuccinimide in the presence of a solvent and of a source of free radicals, such as dibenzoyl peroxide or azo-bis-isobutyronitrile, to give tert.-butyl bromo-(4-chlorophenoxy)-acetate. In the case of tert.-butyl 4-chlorophenoxyacetate it is stated that a reaction time of 2 hours is required and a yield of 76 percent is obtained. If the process is carried out with the corresponding propionic acid esters, especially on an industrial scale, substantially longer reaction times, for example from 8 to 15 hours, are required to obtain yields of from 60 to 80% of theory.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].CC1N=C(NC(=O)C)SC=1[C:18]1[S:19][C:20](S(NCC#C)(=O)=O)=[CH:21][CH:22]=1.[F-].[K+].CC1(C)C(C)(C)OB(C2C=CSC=2)O1>C1(C)C=CC=CC=1.CO.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]>[CH3:11][C:3]1[N:4]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[S:6][C:2]=1[C:22]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: C#CCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccsc2)OC1(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Temperature: 120 °C
Yield: 66 %

Procedure:
In a microwave tube, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (564.2 mg; 2 mmol; 1 eq) and Pd(dppf)Cl2 (73.2 mg; 0.10 mmol; 0.05 eq) are suspended in Toluene (7 ml). A solution of potassium fluoride (464.8 mg; 8 mmol; 4 eq) in MeOH (7 ml) is added. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene (630.3 mg; 3 mmol; 1.50 eq) is finally added as a solid. The resulting solution is flushed with argon, the tube is closed and heated under microwave action at 120° C. for 15 minutes. The reaction mixture is filtered over Celite and the solvents are evaporated. The resulting crude product is dissolved in EtOAc, washed with water and brine and dried over MgSO4. It is then purified by preparative HPLC, affording the title compound as white-off solid (316.7 mg; 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1)=[CH:8]2)=[O:4]
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 100 °C
Yield: 79.6 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (220 mg, 0.57 mmol), 3-methoxyphenylboronic acid (129 mg, 0.85 mmol), K3PO4 (240 mg, 1.13 mmol), H2O (20 mg, 1.13 mmol), SPhos (12 mg, 0.028 mmol) and Pd(OAc)2 (11 mg, 0.017 mmol) in toluene (10 mL) was heated at 100° C. under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., brine (15 mL) and EtOAc (30 mL) were added. 1 M HCl was added with stirring until pH was about 3, and the aqueous layer extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH) to give 189 mg of the title compound as a yellow solid. MS: (+) m/z 417.36 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH3:18])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COc1ccccc1CN
Solvent: COCCOC
Product: COc1ccccc1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (88 mg, 68%).
Reaction SMILES: [OH:1][C:2]1(CO)[CH:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[NH:11][C:10]2=[CH:29][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[O:31])[CH2:6][CH:5]2[CH2:40][CH:3]1[C:4]2([CH3:42])[CH3:41].I([O-])(=O)(=O)=O.[Na+].C([O-])(O)=O.[Na+]>Cl>[CH3:41][C:4]1([CH3:42])[CH:3]2[CH2:40][CH:5]1[CH2:6][CH:7]([CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[NH:11][C:10]1=[CH:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=1)=[O:31])[C:2]2=[O:1]
Reactant: CC1(C)C2CC(CN3C(=O)C(Cc4ccncc4)(Cc4ccncc4)NC3=CC(=O)c3ccc(C#N)cc3)C(O)(CO)C1C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)C2CC(CN3C(=O)C(Cc4ccncc4)(Cc4ccncc4)NC3=CC(=O)c3ccc(C#N)cc3)C(=O)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.7 %

Procedure:
4-{[1-(2-Hydroxy-2-hydroxymethyl-6,6-dimethyl-bicyclo[3.1.1]hept-3-ylmethyl)-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene]-acetyl}-benzonitrile (540 mg, 0.914 mmol), as prepared in example 48, was dissolved in 0.1 N HCl (5 ml). To this solution was added sodium periodate (235 mg, 1.10 mmol). After stirring at ambient temperature for 16 hours, the pH of the reaction was adjusted to 8 using NaHCO3. The reaction was then partitioned between CH2Cl2 and saturated NaHCO3. The CH2Cl2 was dried over Na2SO4, filtered and concentrated under vacuum to give a golden foam which was then chromatographed on silica gel using 60% acetone in hexanes to give 331 mg of the titled compound as a brown foam: C.I. m/z 560 [M+1]; 1H NMR (CDCl3)δ 10.36 (br s, 1H), 8.48 (m, 4H), 7.94 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.14 (m, 4H), 5.49 (s, 1H), 3.46 (m, 2H), 3.29 (m, 2H), 3.09 (m, 2H), 2.52 (m, 2H), 2.24 (m, 1H), 2.18 (m, 1H), 1.49 (m, 1H), 1.29 (s, 3H), 1.19 (d, J=8.9 Hz, 1H), 0.89 (m, 1H), 0.76 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH2:31][CH2:29][OH:30])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: NCCO
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCO)C1(C)C

Procedure:
The product from Example 173 and ethanolamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.47 (s, 3H), 0.90 (t. J=7.0 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.48 (m, 4H), 1.57 (s, 9H), 1.57-1.67 (m, 3H), 1.96-2.08 (m, 1H), 2.62-2.68 (m, 2H), 2.71-2.82 (m, 1H), 3.00-3.10 (m, 1H), 3.14-2.25 (m, 1H), 3.33-3.39 (m, 2H), 4.62 (t, J=4.6 Hz, 1H), 7.52 (t, J=5.7 Hz, 1H), 8.50 (s, 1H). MS (ESI+) m/z 438 (M+H)+.