Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:33]=[O:34].Cl>O1CCCC1.O>[Cl:10][C:4]1[C:5]([OH:9])=[CH:6][C:7]([F:8])=[C:2]([CH:3]=1)[CH:33]=[O:34]
Reactant: Oc1cc(F)c(Br)cc1Cl
Reactant: CN(C)C=O
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Cl)c(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To 4-bromo-2-chloro-5-fluoro-phenol (104, 2.25 g, 9.98 mmol) in tetrahydrofuran (50 mL), cooled to −78° C. under an atmosphere of nitrogen, was added n-butyllithium (2.50 M in hexane, 4.21 mL) and 1,2-bis-(chloro-dimethyl-silanyl)-ethane (1.08 g, 5.01 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was cooled to −78° C., followed by adding tert-butyllithium (1.70 M in hexane, 12.4 mL). After 30 minutes, N,N-dimethylformamide (0.97 mL, 0.0125 mol) was added to the reaction. After 30 minutes, the reaction was warmed to room temperature for 10 minutes. 5N HCl (20 mL) was added to the reaction. After 30 minutes, the reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (105, 0.50 g, 28.7). 1H NMR consistent with structure.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:30][CH3:31]
Reactant: CCI
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and ethyl iodide, white powdery 3-[2-(3-difluoromethoxy-4-ethoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:17]([O:19]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:16][O:15][CH2:14]3)[C:8]=2[N:9]=1.[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]([C:17]([NH:22][CH2:23][C:24]2[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=2[CH3:30])=[O:19])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:14][O:15][CH2:16]3)[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C1COC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2COC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (5 equivalent) was added to a solution of ethyl 6-bromo-1-(oxetan-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equivalent) in EtOH (10 times by volume) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was, then, dissolved in DMSO (10 times by volume) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (2 equivalents) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equivalents) was added to it and stirring was continued for 5 to 16 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by ether wash to provide the desired intermediate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:17]=[C:18]=[S:19])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)[CH3:16])[C:18]1=[S:19])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: CC(N=C=S)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(C(C)c2ccc(F)cc2)C1=S
Yield: 33.1 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 1-(4-fluorophenyl)-ethyl-isothiocyanate (18.1 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Crystallization from ethyl acetate afforded the title compound (8.8 g) as a light yellow solid, m.p. 93°-95° C. Anal. Calcd. for. C13H15F N2O S: C, 58.63; H, 5.68; N, 10.52. Found: C, 58.69; H, 5.64; N, 10.58. Mass spectrum (EI, M.+) m/z 266.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]([CH3:12])[CH3:11])[C:6]=2[CH:13]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[C:51]1[N:52]=[C:53]2[N:57]([C:58]=1I)[CH:56]=[CH:55][O:54]2>CN(C=O)C.O1CCOCC1.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].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[C:51]1[N:52]=[C:53]2[N:57]([C:58]=1[C:2]1[CH:3]=[CH:4][C:5]3[O:9][N:8]=[C:7]([CH:10]([CH3:12])[CH3:11])[C:6]=3[CH:13]=1)[CH:56]=[CH:55][O:54]2
Reactant: CC(C)c1noc2ccc(Br)cc12
Reactant: Fc1ccc(-c2nc3occn3c2I)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1noc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)cc12
Temperature: 90 °C
Yield: 6.3 %

Procedure:
5-Bromo-3-isopropylbenzo[d]isoxazole (0.120 g, 0.500 mmol), bis(pinacolato)diboron (0.130 g, 0.512 mmol), potassium acetate (0.098 g, 0.99 mmol) and PdCl2(dppf) (0.033 g, 0.045 mmol) in DMF (3 mL) was heated to about 90° C. for about 2 h then cooled, evaporated, triturated with DCM then filtered. The filtrate was concentrated under reduced pressure to give a dark oil which was dissolved in 1,4-dioxane (3 mL) and water (0.5 mL). Cesium carbonate (0.405 g, 1.24 mmol), PdCl2(PPh3)2 (0.035 g, 0.050 mmol) and 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (0.173 g, 0.500 mmol; Example #2, step A) were added and the mixture was heated to about 90° C. oil bath for about 16 h. The solvents were evaporated and the material was purified by reverse phase chromatography (Table 1, Method c). Evaporation of the fractions with the desired product resulted in a precipitate which was collected by filtration to give the title compound (0.012 g, 6.33% yield) as a tan solid: LC/MS (Table 1, Method a) Rt, =3.08 min; MS m/z: 380.1 (M+H)+.
Reaction SMILES: C(C1OC2CC3C=CC=CC=3C2N=1)C1OC2CC3C=CC=CC=3C2N=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[OH:51])=[CH:30][CH:29]=1.[C:66]1([N:72]=[C:73]=[O:74])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:35][CH2:36][C@H:37]2[O:41][C@@H:40]([N:42]3[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]3=[O:44])[C@H:39]([OH:50])[C@@H:38]2[O:51][C:73](=[O:74])[NH:72][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The THF solution (1 ml) containing 3aR-[2(3′aR,8′aS),3′aβ,8′aβ]]-2,2′-methylenebis[3a,8a-dihydro-8H-indeno-[1,2-d]oxazole] (0.03 mmol, 10.1 mg) and Cu(OTf)2 (II) (0.03 mmol, 11.1 mg) was stirred for 30 minutes at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1.5 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.3 mmol, 164.0 mg) and the THF solution (1 ml) of phenyl isocyanate (0.3 mmol, 35.7 mg) were added thereto. After the mixture was continuously stirred for 1 hour at 0° C. and for 1.5 hours at room temperature, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 82:18, and the transformation ratio of the reaction was 76%.
Reaction SMILES: [N:1]([CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][CH:4]([CH2:21][CH:22]=[CH2:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: C=CCC(Cc1ccccc1-c1noc2ccccc12)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(N)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Yield: 54.6 %

Procedure:
To a stirred solution of 631 mg of 3-[2-(2-azido-4-pentenyl)phenyl]-1,2-benzisoxazole in 10 ml of anhydrous tetrahydrofuran at -40° C. under a nitrogen atmosphere was added 2.07 ml of a 1 M solution of lithium aluminium hydride in diethyl ether. The reaction mixture was warmed to room temperature then heated to 60° C. for 1 h. After cooling to room temperature and careful quenching with 4 N sodium hydroxide, 50 ml of water was added and the product extracted with 100 ml then 50 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent removed by evaporation to give crude product which was purified by chromatography on silica gel eluting with 10% methanol in dichloromethane, to give 315 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole. The product was dissolved in 1 ml of methanol and 131 mg of fumaric acid was added. Addition of diethyl ether and cooling to 4° C. led to crystallisation of 313 mg of 3-[2-(2-amino-4-pentenyl)phenyl]-1,2-benzisoxazole (E)-butenedioate, melting at 170-172° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCCl>[CH3:15][N:16]1[C:20]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of 3.95 g. (0.025 mole) of p-fluorobenzoyl chloride and 3.32 g. (0.025 mole) of aluminum chloride in 20 ml. of 1,2-dichloroethane is added dropwise to a solution of 4.52 g. (0.025 mole) of ethyl 1,4-dimethylpyrrole-2-acetate in 20 ml. of 1,2-dichloroethane at room temperature. The reaction mixture is stirred for 2 hours, and then cooled and poured into ice-dilute HCl. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over anhydrous magnesium sulfate; and the solvent evaporated. The residuc is triturated with hot hexane and crystals form upon cooling. There is obtained about 1.9 g. (25% yield) of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate as a white solid, m.p. 84-86° C. Upon recrystallization from methanol, the m.p. is 87-89° C.
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cn1
Yield: 44.5 %

Procedure:
A solution of 2,2,2-trichloroethyl {6-[acetyl(methyl)amino]pyridin-3-yl}carbamate (200 mg, 0.587 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (144 mg, 0.587 mmol), diisopropylethylamine (0.102 ml, 0.587 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (114 mg, 44.5%) as a solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[B:26]([OH:31])([OH:27])[C:17]1[CH:18]=[CH:19][C:14]([N:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A dry ethyl ether 100 ml and dry toluene 100 ml solution of 4-bromotriphenylamine 16.2 g was cooled down to −78° C. under argon atmosphere, and a hexane solution 32.8 ml of 1.6M normal butyllithium was dropwise added thereto. The reaction solution was stirred for one hour while heating up to 0° C. The reaction solution was cooled down again to −78° C., and a dry ether 50 ml solution of triisopropyl borate 23.5 g was dropwise added thereto. The reaction solution was stirred at room temperature for 5 hours. 1N hydrochloric acid 100 ml was added thereto and stirred for one hour, and then the aqueous layer was removed. The organic layer was dried on magnesium sulfate, and the solvent was distilled off. The solid matter thus obtained was washed with hexane and toluene to obtain 10.2 g of triphenylamine-4-boronic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[I:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[I:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH2:15])=[O:14])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccc(O)cc2)no1
Reactant: ClCc1ccccc1I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3I)cc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.4 %

Procedure:
3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 50 mg, 0.24 mmol), K2CO3 (37 mg, 0.27 mmol) and tetrabutylammonium iodide (9 mg, 0.024 mmol) were taken up in DMF (2.4 mL). 2-Iodobenzyl chloride (61 mg, 0.24 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by high-throughput purification to give 3-[4-(2-iodo-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.4 mg, 1.3%). HRMS Calcd. for C17H14IN2O3 (M+H)+, 421.0044. Found: 421.0040.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([I:27])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(I)c2)c(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: COc1cc(Nc2c(C#N)cnc3cc(I)c(OC)cc23)c(Cl)cc1Cl
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide (720 mg, 1.39 mmol) in 40 mL of acetonitrile was added 0.2 mL of methanol. The mixture was heated to reflux and phosphorous oxychloride (1.24 mL, 13.9 mmol) was added dropwise, via syringe. This solution was heated at reflux overnight. After 24 hours, the mixture was cooled in an ice-bath and the solid was collected by filtration, washed with cold acetonitrile (40 mL) and then suspended in tetrahydrofuran (100 mL). To both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×50 mL) and the mixtures were stirred for 1 hour. Water (2×800 ml) was added and stirring was continued for 2 hours. The resulting solids were combined, washed with hot water and dried under reduced pressure at ˜40° C., overnight, to provide 200 mg (29%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodo-6-methoxy-3-quinolinecarbonitrile, as yellow solid, mp 253-254° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 4.00 (s, 3H), 7.33(s, 1H), 7.74(s, 1H), 7.86 (s, 1H), 8.39 (s, 1H), 8.43 (s, 1H), 9.61 (s, 1H); MS (ES) m/z 500.0, 502.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[C:14]1(N)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.Cl>[Cl:1][C:2]1[C:7]([C:8]2[NH:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:9]=2)=[CH:6][CH:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(-c2nc3ccccc3[nH]2)c(Cl)n1
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
A mixture, homogenised in a mortar, of 19.5 g (100 mmol) of 2-chloro-3-cyano-6-tert-butylpyridine (S28), 36.2 g (200 mmol) of o-phenylenediamine and 38.0 g (200 mmol) of p-toluenesulfonic acid monohydrate is heated at 220° C. (oil-bath temperature) for 3 h. After cooling, the black, glassy sinter cake is taken up in a mixture of 100 ml of ethanol and 100 ml of 1N hydrochloric acid with vigorous stirring. After stirring for 30 min., the grey-green solid is filtered off with suction, washed three times with 50 ml of water each time and dried in vacuo. The solid is taken up in 200 ml of ethyl acetate, chromatographed on silica gel (ethyl acetate/heptane 1:1, Rf about 0.7) in order to remove 2-tert-butyl-6,11-dihydrobenzo[b]pyrido[2,3-e]-1,4-diazepin-5-one and brown by-products. The crude product obtained in this way is dissolved in ethyl acetate at the boiling temperature, and four times the amount of cyclohexane is added dropwise. After stirring at room temperature for 18 h, the crystals formed are filtered off with suction, washed with n-heptane and dried in vacuo. Yield: 7.5 g (26 mmol), 26%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)=O.O=[C:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21]>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:19]([CH:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH3:21])[C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[C:9]2[C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Reactant: Cc1cccnc1C(=O)c1cc(F)ccc1N
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cccnc1-c1c(-c2ccccn2)c(C(C)NC(=O)OC(C)(C)C)nc2ccc(F)cc12
Reaction time: 48 h

Procedure:
A solution of (2-amino-5-fluorophenyl)(3-methylpyridin-2-yl)methanone (0.29 g, 1.26 mmol), (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.366 g, 1.386 mmol), and sodium tetrachloroaurate(iii) dihydrate (0.025 g, 0.063 mmol) in 2-propanol (5.0 mL) was stirred at 80° C. for 24 h under an argon atmosphere, then at room temperature for an additional 48 h. The solution was purified by silica gel column chromatography eluting with a gradient of 10-40% EtOAc in hexane to afford tert-butyl 1-(6-fluoro-4-(3-methylpyridin-2-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate as a dark solid: LC-MS (ESI) m/z 459.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41].CN(C=O)C.C(Cl)CCl>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:41][C:37]3[S:36][CH:40]=[CH:39][N:38]=3)[CH2:16][CH2:15]2)=[O:7])=[CH:34][CH:35]=1
Reactant: Nc1nccs1
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(/N=c1\[nH]c2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)Nc2nccs2)CC1)c1ccc(F)cc1
Reaction time: 48 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (50 mg, 0.104 mmol), N,N-dimethylpyridin-4-amine (31.9 mg, 0.261 mmol), thiazol-2-amine (15.69 mg, 0.157 mmol), and DMF (2 mL). To this mixture was added EDC (40.1 mg, 0.209 mmol), and the reaction was stirred for 48 hours. The resulting mixture was diluted with water (10 mL) and DCM (30 mL). The organic layer was collected, dried over sodium sulfate and concentrated to afford a brown oil. The residual oil was purified by HPLC (10-70% ACN/H2O; 0.1% TFA) to afford (E)-4-fluoro-N-(6-(piperidin-1-ylmethyl)-1-(cis-4-(thiazol-2-ylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (0.027 g, 46.1% yield). MS m/z=561.2 [M+H]. Calc'd for C30H33FN6O2S: 560.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.36 (m, 1H) 1.36-1.48 (m, 2H) 1.50-1.60 (m, 4H) 1.68-1.84 (m, 2H) 1.86-2.01 (m, 2H) 2.26-2.37 (m, 2H) 2.40-2.50 (m, 3H) 2.75-2.90 (m, 2H) 2.98-3.10 (m, 1H) 3.63 (s, 2H) 4.77-5.08 (m, 1H) 7.18-7.24 (m, 1H) 7.24-7.32 (m, 2H) 7.36 (d, J=3.62 Hz, 1H) 7.52-7.59 (m, 2H) 7.66 (s, 1H) 8.30-8.42 (m, 2H) 12.21 (s, 1H) 12.83 (s, 1H).