Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=O)=O.O=P(Cl)(Cl)[Cl:25]>>[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:12]1[C:10]2=[N:11][C:6]([OH:5])=[CH:7][CH:8]=[C:9]2[N:14]=[C:13]1[Cl:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3Br)c2n1
Product: Oc1ccc2nc(Cl)n(-c3ccccc3Br)c2n1

Procedure:
From 3-(2-bromophenyl)-2-hydroxy-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate and POCl3, prepared in a similar manner as the one described in Example 1.136, the title compound was obtained. LCMS m/z=323.90 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 6.72 (d, J=8.6 Hz, 1H), 7.57-7.65 (m, 3H), 7.90 (dd, J1=8.1 Hz, J2=1.2 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[CH3:15].[CH:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)=[O:17].O.C(OCC)(=O)C>C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1(C)C=CC=CC=1.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>[CH3:15][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:13]=[CH:14][C:2]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:16]=[O:17])[CH:23]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1cc(OC2CCCCO2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(OC2CCCCO2)ccc1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
2-(4-Bromo-3-methylphenoxy)tetrahydro-2H-pyran (7.11 g, 25.2 mmol, including 3,4-dihydro-2H-pyran) and (3-formylphenyl)boronic acid (4.50 g, 30.0 mmol) were dissolved in a mixture of 1 M aqueous sodium carbonate solution (60 mL), ethanol (30 mL) and toluene (60 mL), and after argon substitution, tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.50 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 80° C. for 15 hrs. The reaction mixture was cooled, water and ethyl acetate were added, and insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (6.16 g, yield 82%, 2 steps) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(N)cc2oc(=O)[nH]c12
Solvent: CCCCO
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
400 mg (2.40 mmol) 6-amino-4-methyl-3H-benzoxazol-2-one, 400 mg (2.70 mmol) 4,6-dichloropyrimidine and 1.10 mL (8.00 mmol) TEA in 5 mL 1-butanol were stirred for 1 h at 100° C. After cooling to RT the reaction mixture was evaporated down and the residue was washed with water and saturated sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: C[N:2]([CH3:8])C(N(C)C)=N.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].CC(C)(O)C#N>C(#N)C>[CH3:17][O:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][CH:20]=[C:11]([CH2:10][C:8]#[N:2])[CH:12]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CN(C)C(=N)N(C)C
Agent: CC(C)(O)C#N
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Reaction time: 72 h

Procedure:
1,1,3,3-Tetramethylguanidine (3.21 ml, 25.6 mmol) was added dropwise to a solution of methyl 3-bromomethylbenzoate (2.80 g, 12.2 mmol) and acetone cyanohydrin (1.59 ml, 18.3 mmol) in acetonitrile (40 ml) at room temperature. The reaction was stirred for 3 days and the solvent then removed under reduced pressure. The resulting brown oil was purified by column chromatography on silica gel using ethyl acetate:pentane (50:50) as eluant to afford the title compound as a clear oil, 1.80 g.
Reaction SMILES: CO.[CH3:3][C:4]1[C:13]([CH2:14][CH:15]=C)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][C:9]2=[O:17].[O:18]=[O+][O-].CSC>CCOC(C)=O>[CH3:3][C:4]1[C:13]([CH2:14][CH:15]=[O:18])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][C:9]2=[O:17]
Reactant: C=CCc1ccc2c(c1C)CCOC2=O
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: CO
Product: Cc1c(CC=O)ccc2c1CCOC2=O

Procedure:
To a MeOH solution of 5-Methyl-6-(prop-2-en-1-yl)-3,4-dihydro-1H-isochromen-1-one (60 mg, 0.30 mmol) was bubbled ozone until it turned blue. Excess ozone was removed by bubbling nitrogen through. To the reaction was added DMS (0.22 ml, 3.0 mmol), and it was allowed to warm up slowly. The reaction was diluted with EtOAc, washed with water, and purified by MPLC to give the title compound. LC-MS (IE, m/z): 205 [M+1]+.
Reaction SMILES: CC(C)([O-:4])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].CC(OO)(C)C>C1COCC1>[Cl:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:10][NH:11][C:12](=[O:4])[CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: CC(C)(C)OO
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(Cl)c([N+](=O)[O-])c[nH]1
Temperature: 35 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Anhydrous THF (50 mL) in a 500-mL round-bottom flask was cooled to −78° C. and anhydrous NH3 (gas) was bubbled into until saturated (about 20 minutes). Potassium t-butoxide (6.5 g, 57.9 mmol) was added portion wise and the mixture was allowed to warm to ˜35° C. To a solution of 4-chloro-3-nitropyridine (3.498 g, 22 mmol) in dry THF (20 mL) at 0° C. was added tBOOH (4.4 mL, 22 mmol) (5M in decane) over 10 minutes. This solution was then added dropwise to the prepared KOtBu solution over a period of 15 minutes, then stirred for 2 hours at ˜35° C., followed by quenching the reaction with 5 mL of saturated aqueous NH4Cl solution. The reaction was allowed to stir at room temperature overnight. Volatiles were removed under reduced pressure and the residue was made weakly acidic with saturated aqueous NH4Cl solution. The solid was filtered and washed with cold water. The title compound was obtained as a tan-powder, dried under high vacuum overnight, and used for the next reaction without further purification. (1.36 g, 35% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.N>C(O)C.O.C(O)(=O)C.[Fe]>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CSc1ncnc2cc([N+](=O)[O-])ccc12
Agent: [Fe]
Agent: N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CSc1ncnc2cc(N)ccc12
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Iron powder (325 mesh, 1.35 g, 52 mmol) was added portionwise to a stirred solution of 4-(methylthio)-7-nitroquinazoline (1.44 g, 6.52 mmol) in ethanol (130 ml), water (65 ml) and acetic acid (1.15 ml) at reflux over 1.5 hours. The mixture was cooled to 50° C., and a solution of ammonia (28%, 5 ml) was added. The precipitate was collected by suction filtration, washed with warm ethanol and the solvent was evaporated in vacuo. Purification by flash chromatography on by silica gel, eluting with 5% methanol in dichloromethane, yielded 4-(methylthio)-7-aminoquinazoline (1.17 g, 94% yield):
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].Cl[C:23]1[N:27]([CH3:28])[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=1.O>CN(C=O)C>[CH3:28][N:27]1[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=[C:23]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (150 mg) in DMF (2 mL) was added sodium hydride (60% in oil, 28 mg) at room temperature by small portions. After stirring for 10 min, a solution of 2-chloro-1-methyl-1H-benzimidazole (117 mg) in DMF (1.5 mL) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/THF) and recrystallized from methanol to give the title compound (194 mg).
Reaction SMILES: [CH3:1][C:2]1([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[CH:15](OCC)=[O:16].C[O-].[Na+]>C1C=CC=CC=1.C(Cl)Cl.CCOCC>[OH:16][CH:15]=[C:4]1[C:5](=[O:8])[CH:6]=[CH:7][C:2]([CH3:1])([C:9]#[C:10][Si:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]1
Reactant: CC1(C#C[Si](C)(C)C)C=CC(=O)CC1
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1(C#C[Si](C)(C)C)C=CC(=O)C(=CO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 8 (139 mg, 0.67 mmol) in dry benzene (7.8 mL) were added ethyl formate (97%, 244 mg, 3.2 mmol) and sodium methoxide (176 mg, 3.3 mmol), successively. The mixture was stirred at room temperature for 1 h. The mixture was diluted with methylene chloride/ether (1:2, 40 mL). The mixture was washed with 5% aqueous HCl solution (15 mL ×2). The acidic washings were extracted with methylene chloride/ether (1:2, 20 mL ×1). The original organic solution and the extract were combined. The combined solution was washed with water (15 mL ×2) and brine (15 mL ×1), dried over MgSO4, and filtered. The filtrate was evaporate in vacuo to give 6-(hydroxymethylene)-4-methyl-4-((trimethylsilyl)-ethynyl)cyclohex-2-enone (148 mg, 94%): 1H NMR (CDCl3) δ 13.69 (1H, brs), 7.53 (1H, s), 6.64 (1H, d, J=9.9 Hz), 6.00 (1H, d, J=9.9 Hz), 2.78 (1H, d, J=14.6 Hz), 2.47 (1H, d, J=14.6 Hz), 1.38 (3H, s), 0.14 (9H, s); 13C NMR (CDCl3) δ 187.7, 168.0, 152.3, 126.8, 110.2, 109.5, 106.1, 37.2, 37.1, 26.9, 0.2. This material was used without further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[O-:10][C:11]#[N:12].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:11]([NH2:12])=[O:10]
Reactant: N#C[O-]
Reactant: Cc1ccc(Cl)c(N)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A solution of 2-chloro-5-methylaniline (10 g, 70.6 mmol) and potassium cyanate (14.3 g, 176 mmol) in a mixture of acetic acid (340 mL) and water (34 mL) was stirred at room temperature during 4 hours. The solvent was evaporated and the residue taken into a mixture of CH2Cl2 and an aqueous saturated solution of NaHCO3. The precipitate was filtered, washed with dichloromethane and dried under vacuum to give 12.6 g (97%) of intermediate 7.
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[C:25]([O:28][CH2:29][C:30]([CH2:32]Cl)=[O:31])(=[O:27])[CH3:26]>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:32][C:30](=[O:31])[CH2:29][O:28][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OCC(=O)CCl
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (5.3 g) was dissolved in N,N-dimethylformamide (70 ml) and thereo 1-acetoxy-3-chloroacetone (2.2 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove insoluble materials. After the filtrate was evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. The extract was washed with a NaCl solution and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give the title compound (6.0 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:4]=2[C:3]=1[F:24].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C>[CH3:25][N:26]([CH3:31])[S:27]([N:12]1[C:5]2[C:6]3[O:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([F:1])=[C:3]([F:24])[C:4]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:13]1=[O:23])(=[O:29])=[O:28]
Reactant: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(I)cc3F)c2o1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: Cc1nc2c(F)c(F)c3c(c2o1)n(S(=O)(=O)N(C)C)c(=O)n3-c1ccc(I)cc1F
Yield: 61 %

Procedure:
Intermediate I-23a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-2-methyl-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-18a: 80 mg, 0.178 mmol), N,N-dimethylaminosulfonyl chloride (38.5 mg, 0.269 mmol), TEA (54.5 mg, 0.534 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford the 60 mg of the product (61.2% yield). H1NMR (CDCl3, 300 MHz): δ 7.70-7.64 (m, 2H), 7.30-7.22 (m, 1H), 3.20 (s, 6H), 2.72 (s, 3H). LCMS: 70.3%, m/z=552.9 (M+1). HPLC: 81.3%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].O.[C:32](OCC)(=[O:34])C>CO.N1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([O:34][CH3:32])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: I[Cu]I
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: COc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A solution of Intermediate 1 (337 mg) obtained in Example 1, Step A in methanol (2.7 ml) and pyridine (2.7 ml) is added with a solution of 28% sodium methylate (847 mg) in methanol, and then with copper iodide (70 mg), and the mixture is stirred at 65° C. for 30 hours. The reaction mixture is cooled to room temperature, and added with water (30 ml) and ethyl acetate (30 ml), and the insoluble matters are removed by filtration through Celite. The organic layer of the filtrate is separated, and the aqueous layer is extracted 3 times with ethyl acetate (20 ml for each time). The combined organic layer is washed 3 times with saturated brine (30 ml for each time), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound (98 mg (predictive yield)).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:12]2[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=2[C:9]2[CH2:18][CH2:17][C:16](=[N:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]1=2
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a stirred suspension of 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]-indol-3(2H)-one (6.0 g) in toluene (50 ml) was added benzylamine (9.2 g) and the mixture was heated at reflux temperature with azeotropic removal of water using a Dean Stark trap. After 4 hours, TLC analysis indicated complete conversion to product. The mixture was allowed to cool to room temperature and filtered, and the solid material was washed with acetonitrile. The filtrate and washings were combined, concentrated and purified by flash chromatography on silica gel (2:1 hexane/acetone as eluent). The crystals which formed in the product-containing fractions were collected via filtration to give 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (1.1 grams) and the filtrate was concentrated to give an oil (3.0 grams) which crystallized upon standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 73.1 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)hexanoic acid (3.50 g) and ethyl 4-aminophenylacetate (1.61 g) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.47 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from isopropyl alcohol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.36 g).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3]/[CH:4]=[C:5](/[F:18])\[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1>Cl>[ClH:1].[NH3+:2][CH2:3]/[CH:4]=[C:5](/[F:18])\[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(OC/C(F)=C\CN)cc1
Agent: Cl
Product: [NH3+]C/C=C(/F)COc1ccc(C(=O)[O-])cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A stirred solution of (E)-Methyl 4-(4-amino-2-fluorobut-2-enyloxy)benzoate hydrochloride (0.050 g, 0.18 mmol) in ethereal HCl solution (1 M; 3 mL) was stirred at reflux for 20 hours. The reaction mixture was allowed to cool to RT and the volatiles were removed under reduced pressure to afford the title compound (0.040 g, 98%) as a fine white powder; m.p.=256-257° C.; 1H-NMR (200 MHz, D2O): δppm: 3.77 (2H, d, J 8.4 Hz), 4.91 (2H, d, J 18.8 Hz), 5.65 (1H, dt, J 18.6, 8.0 Hz), 7.08 (2H, d, J 8.4 Hz), 8.00 (2H, d, J 8.4 Hz).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:7]([CH3:18])=[C:8]([N:12]2[C:16](=[O:17])[CH2:15][NH:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.O>[Cl:25][CH2:26][C:27]([N:14]1[CH2:15][C:16](=[O:17])[N:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=2[CH3:18])[CH2:13]1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(Cl)cccc1N1CNCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O

Procedure:
To a mixture of 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one acetic acid salt (75) (422 mg, 1 equiv) and K2CO3 (552 mg) in 5 mL of DCM/water (1:1 v/v) was added chloroacetyl chloride (240 μL, 1.5 equiv). One hour later, the organic layer was separated and dried over sodium sulfate to give 1-(2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3]1=[S:14].[C:15]([O-])([O-])=O.[Na+].[Na+].CI>CC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[S:14][CH3:15]
Reactant: Cn1c(=S)[nH]c2cc([N+](=O)[O-])ccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cc([N+](=O)[O-])ccc2n1C

Procedure:
A mixture of 1-Methyl-5-nitro-1,3-dihydro-benzoimidazole-2-thione (5.16 g, 24.7 mmol), Na2CO3 (2.88 g, 27.2 mmol) and MeI (3.68 g, 25.94 mmol) in acetone (150 ml) was refluxed overnight. The mix was filtered hot and the filtrate was concentrated to about 50 ml, the product was collected by filtration and washed with a small amount of cold CH2Cl2, drying left 4.58 g as a mustard yellow solid: LC/MS(m/e) at 224.0 [M+H]+, Rt at 1.55 min.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:11]4[O:12][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:9][N:10]=4)=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(Cc2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (5-benzyl-[1,3,4]oxadiazol-2-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C1CNCCN1
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
A heterogenous reaction mixture containing 2-bromo-nitrobenzene (2.02 g, 10.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100° C. for 10 hours. The orange-red solid was extracted with ethyl acetate and washed thoroughly with 3 N NaOH solution followed by brine. The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting red oil was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield 1-(2-nitrophenyl)-piperazine as an orange-red oil (1.90 g, 92%). It was characterized as a hydrochloride salt. Analysis calculated for C10H14N3O2Cl0.10 CHCl3: C, 47.46; H, 5.56; N, 16.44. Found: C, 47.63; H, 5.69; N. 16.42.