Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.[Br-].C([O:14][C:15](=O)[CH2:16][CH2:17][Zn+])C>C1COCC1.O>[Br:8][C:6]1[N:7]=[C:2]2[CH2:17][CH2:16][C:15](=[O:14])[NH:10][C:3]2=[N:4][C:5]=1[Cl:9]
Reactant: Nc1nc(Cl)c(Br)nc1Br
Reactant: CCOC(=O)CC[Zn+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCc2nc(Br)c(Cl)nc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 3,5-dibromo-6-chloropyrazin-2-amine (step 1) (1.0 g, 3.48 mmol) and bistriphenylphosphinepalladium(II)chloride (0.122 g, 0.174 mmol) in THF (15 ml) under nitrogen was treated with (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (15.31 ml, 7.66 mmol) and the mixture was stirred at room temperature for 3 hours. A further portion of (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (7.5 mL, 3.8 mmol) was added and stirring continued for 1.5 hours. More (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (3.8 mL, 1.9 mmol) was added and the mixture was stirred at RT for 65 hours. The mixture was diluted with water (10 ml) and concentrated in vacuo. The residue was diluted with EtOAc (100 ml) the emulsion was filtered through Celite® (filter material). The phases were separated and the aqueous portion was extracted with EtOAc (50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc (˜10 ml) to afford the title compound as yellow solid.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N=C=NCCCN(C)C)C.[NH2:22][CH2:23][C:24]1[N:29]=[C:28]2[S:30][C:31]3[CH2:32][N:33]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:35][C:36]=3[C:27]2=[C:26]([C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:25]=1[Cl:54].[N:55]1([CH2:60][C:61](O)=[O:62])[CH:59]=[N:58][CH:57]=[N:56]1>O.CN(C)C=O>[CH2:37]([N:33]1[CH2:34][CH2:35][C:36]2[C:27]3[C:28]([S:30][C:31]=2[CH2:32]1)=[N:29][C:24]([CH2:23][NH:22][C:61](=[O:62])[CH2:60][N:55]1[CH:59]=[N:58][CH:57]=[N:56]1)=[C:25]([Cl:54])[C:26]=3[C:44]1[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Reactant: O=C(O)Cn1cncn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CNC(=O)Cn3cncn3)nc3sc4c(c23)CCN(Cc2ccccc2)C4)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
N-hydroxybenotriazole (HOBt) (0.427 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) (0.535 g) were added to an ice-cooled mixture of the compound (1.0 g) obtained in Example 18B, (1,2,4-triazol-1-yl)acetic acid (0.325 g) and N,N-dimethylformamide (DMF) (20 ml), the mixture was stirred at room temperature for 8 hours, poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) to yield 7-benzyl-3-chloro-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-2-(1,2,4-triazol-1-ylacetylaminomethyl)thieno[2,3-b:5,4-c']dipyridine (0.55 g, 50%), which was then recrystallized from ethyl acetate-hexane to yield a colorless powder having a melting point of 101 to 102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:28]O)=[C:6]([NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:7]=1.O=S(Cl)Cl.C([O-])([O-])=O.[K+].[K+].[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:46]([N:40]1[CH2:45][CH2:44][N:43]([CH2:28][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH2:42][CH2:41]1)(=[O:48])[CH3:47]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)Nc1cc(Br)ccc1CO
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCN(Cc2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 8.5 %

Procedure:
At room temperature, 3-(5-Bromo-2-hydroxymethyl-phenylamino)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.137 mmol) was dissolved in 2 ml dried CH2Cl2. Then SOCl2 (49 mg, 0.333 mmol) was added slowly. After stirred for about half an hour, K2CO3 (84 mg, 0.612 mmol) and 1-piperazin-1-yl-ethanone (32 mg, 0.245 mmol) were added. This solution was stirred for about 2 h, then the solution was concentrated and the crude product was purified by Prep-HPLC to obtain 7 mg white solid rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:25][CH2:26]CS([O-])(=O)=O)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:7]1.Cl.[C:33]1([C:39]2([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([CH2:25][CH2:26][N:42]2[CH2:41][CH2:40][C:39]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)([C:45]([NH2:47])=[O:46])[CH2:44][CH2:43]2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:7]1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccs3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccs3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(thiophen-2-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH:25]=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH2:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19][CH2:20]1)[CH:25]=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A solution of methyltriphenylphosphonium bromide (5.3 g, 14.8 mmol) in THF (50 mL) was cooled to 0° C. under nitrogen. Potassium hexamethyl disilazide (27.7 mL, 0.5M toluene solution, 13.9 mmol) was added and the mixture was stirred for 30 min. A solution of (1-t-butoxycarbonylpiperidin-4-yl)acetaldehyde from Step A (2.25 g, 9.9 mmol) in THF (10 mL) was added and the mixture was warmed to rt. After 30 min, the reaction was complete by tlc analysis. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine (100 mL each). The organic phase was dried over sodium sulfate and concentrated to give an oil which was purified by FC (75 g silica, 10/1 hexane/ethyl acetate) to afford the title compound (1.61 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[OH:39][C:32]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)=[C:31]1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Cl:23][C:24]1[C:33]([CH2:34][NH:1][CH2:2][C@@H:3]2[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:22])[CH2:4]2)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1COc2cc(Cl)c(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (70 mg, 0.33 mmol) in methanol (2 mL), methylene chloride (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (130 mg; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give the title compound as a solid (80 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[C:17]([O:20][CH2:21][CH2:22][O:23][CH2:24]Br)(=[O:19])[CH3:18]>CC#N>[Cl:3][C:4]1[N:5]([CH2:24][O:23][CH2:22][CH2:21][O:20][C:17](=[O:19])[CH3:18])[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: CC(=O)OCCOCBr
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)OCCOCn1c(Cl)nc2c(Cl)c(Cl)c(Cl)c(Cl)c21

Procedure:
NaH (0.12 g, 3.0 mmole, 60% oil disperson) was added to a stirred suspension of 2,4,5,6,7-pentachlorobenzimidazole (14) (1.0 g, 3.4.mmole) in dry CH3CN (120 mL) under a N2 atmosphere. The solution was stirred until H2 evolution has ceased and a clear solution was obtained (20 min.). (2-Acetoxyethoxy) methyl bromide (0.68 g, 10.66 mmole) in CH3CN (34 mL) was then added dropwise. The reaction mixture was stirred for an additional 3 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil (165). The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions gave a solid which was recrystallized from MeOH to afford 1.39 g (72%) of 165: m.p. 119° C. 1H NMR (CDCl3): d 5.93 (s, 2 H, C-1'), 4.143.92 (m, 4 H, C-3' and C-4'), 1.83 (s, 3 H, Ac). Anal. Calcd. for Cl2H9N2Cl5O3 : C,35.45; H, 2.23; N, 6.89. Found: C, 35.57; H, 2.17; N, 16.91.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:28]>>[Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([Cl:28])[CH3:9])[CH:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Product: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared according to the procedure of Example 13 step 6, using tert-butyl 3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate (racemic) and cyanuric chloride as the starting materials.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: NCCCO
Product: O=C(NCCCO)c1cc2ccccc2o1
Yield: 20.6 %

Procedure:
2-Benzofurancarboxylic acid (5.0 g, 30.8 mmol) and 3-amino-1-propanol (2.83 ml, 37 mmol) were coupled according to the procedure of example 22 to provide 1.39 g (17.2% yield) of the desired product as a yellow solid. Electrospray Mass Spec: m/z 219.8 (M+H)+.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)=O.[F:8][C:9]([F:36])([F:35])[C:10]([CH2:25][C:26]1[NH:34][C:33]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[CH:27]=1)([OH:24])[CH2:11][C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13]>CN(C=O)C>[Cl:1][C:27]1[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[NH:34][C:26]=1[CH2:25][C:10]([OH:24])([CH2:11][C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])([CH3:14])[CH3:13])[C:9]([F:35])([F:8])[F:36]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2cnccc2[nH]1)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1[nH]c2ccncc2c1Cl)C(F)(F)F
Reaction time: 48 h
Yield: 55.5 %

Procedure:
A solution of trichloroacetyl chloride (0.045 mL, 0.403 mmol) in 0.5 mL of DMF was treated with a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pentan-2-ol (33.0 mg, 0.081 mmol) in 0.5 mL of DMF at room temperature. After 2 days, the reaction was quenched with 2 mL of ice-water and 2 mL of cold 1 N sodium hydroxide solution. The resulting mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% dichloromethane to 10% methanol in dichloromethane, gradient) gave 20.0 mg of the title product (56% yield).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1>C1(C)C=CC=CC=1.CCOCC>[Br:23][C:19]1[N:18]=[C:17]([C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C#N)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
A dried 500 mL round bottom flask was charged with a solution of iso-butyronitrile (3.29 g, 4.27 mL, 47.6 mmol) in toluene (100 mL), the solution was cooled down to 0° C. and KHMDS 0.5 m in toluene (100 mL, 50.0 mmol) was added slowly. After complete addition, the reaction mixture was allowed to warm up to room temperature over 1 hour. The resulting mixture was added to a solution of 2,6-dibromopyridine (28.2 g, 119 mmol, available commercially from Aldrich) in toluene (100 mL) While adding, the light yellow solution became quickly dark reddish. The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was diluted with ether, washed with a saturated aqueous solution of ammonium chloride and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The semi-solid residue was suspended in a small amount of toluene and filtered off, the light brown solid corresponded to 2,6-dibromopyridine recovered. Filtrate was purified by flash chromatography (silica gel 50 μm, 220 g, Rediflash Teledyne-Isco) eluting with 0 to 50% over 20 min dichloromethane/hexanes to give 2-(6-bromopyridin-2-yl)-2-methylpropanenitrile (7.608 g, 28.4% yield) as a light yellow oil that solidified into a white solid upon standing. 1H NMR (CHLOROFORM-d) δ: 7.58-7.61 (m, 2H), 7.42-7.46 (m, 1H), 1.76 (s, 6H); LC-MS 225.0 226.9 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][N:2]4[CH2:3][CH2:4][CH:5]5[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:1]4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Reactant: C1CCC2CNCCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCCCC2C1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
A mixture of decahydroisoquinoline (200 mg, 1.44 mmol, 1 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (570 mg, 1.44 mmol, 1 eq) and K2CO3 (238 mg, 1.70 mmol, 1.2 eq) in DMF (15 mL) was heated at 80° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, the mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo and the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (350 mg, 49.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 499.2 (M+1); 1H NMR (CDCl3, 400 MHz) δ: 1.27-1.59 (12H, m), 1.80-1.82 (2H, m), 2.07-2.33 (2H, m), 2.40-2.51 (2H, m), 3.22-3.26 (2H, m), 4.22-4.24 (2H, m), 7.14-7.16 (1H, m), 7.23 (1H, s), 7.47 (1H, s), 7.65-7.69 (1H, m), 8.00-8.02 (1H, m), 8.64 (1H, s) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].[C:26]1(=[O:31])[CH2:30][CH2:29][CH:28]=[CH:27]1.[Li+].[OH-].O>O.C(COC)OC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:28]2[CH2:29][CH2:30][C:26](=[O:31])[CH2:27]2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CCc1ccc(C2CCC(=O)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester (preparation 2) (4.6 mmol) and [(1,4-hydroquinone)-rhodium(COD)]BF4 (Son et al., J. Am. Chem. Soc. 2005, 127, 12238) (2 mol %) in water/dimethoxyethane (1:1, 20 mL, degassed) was added 2-cyclopenten-1-one (4.6 mmol) and LiOH (8 mol %). The mixture was warmed to 50° C. and stirred overnight. Additional water was added, and the mixture was extracted with dichloromethane. The organic phase was separated, dried and concentrated in vacuo to afford the title compound as a brown oil. 1H NMR (300 MHz, DMSO) δ 7.72-7.56 (m, 2H), 7.54-7.39 (m, 1H), 3.62 (s, 3H), 3.53-3.36 (m, 1H), 3.08-2.95 (m, 2H), 2.70-2.47 (m, 3H), 2.43-2.21 (m, 4H), 2.02-1.83 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=1.N1C=CC=CC=1.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[S:25]([O:10][C:6]1[CH:5]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH:8]=[O:9])(=[O:26])=[O:24]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)cc(OC2CCCCO2)cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of 6-chloro-2-hydroxy-4-(tetrahydro-pyran-2-yloxy)benzaldehyde (10.5 g, 40.9 mmol) and pyridine (14.6 mL, 0.20 mol) in DCM (150 mL) cooled at −10˜0° C. was added Tf2O (10.3 mL, 61.2 mmol) dropwise. The reaction mixture was stirred at 0° C. for an additional 2 h and quenched with cold brine (40 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:200) to give the title compound as a yellow oil (10.5 g. Yield: 66%).
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([O:30][CH3:31])[C:22]=1[CH2:23]Br.O>CN(C)C=O>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][CH2:23][C:22]2[C:25]([O:30][CH3:31])=[CH:26][CH:27]=[C:28]([F:29])[C:21]=2[F:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1ccc(F)c(F)c1CBr
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c([N+](=O)[O-])cc1NCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a suspension of 4-fluoro-2-methoxy-5-nitroaniline (0.37 g) and potassium carbonate (0.36 g) in N,N-dimethylformamide (10 mL) was added 2,3-difluoro-6-methoxybenzyl-bromide (0.47 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 5-fluoro-2-(2,3-difluoro-6-methoxybenzylamino)-4-nitroanisole (0.32 g). This material was dissolved in N,N-dimethylformamide (9.3 mL). To the solution were added sodium hydride (55%, 45 mg) and methyl iodide (0.18 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (4 mL)-tetrahydrofuran (4 mL). To the solution were added nickel(II) bromide (11 mg) and sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.17 g).