Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:36]([C:28]2[NH:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCNC(=O)c2nc3ccccc3[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure G: A mixture of N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-butane-1,4-diamine (121 mg, 0.35 mmol), 1H-benzimidazole-2-carboxylic acid (70%, 97 mg, 0.42 mmol) (Eur. J. Med. Chem. 1993, 28, 71), HOBT (61 mg, 0.46 mmol), EDCI (91 mg, 0.46 mmol), and DIPEA (90 μL, 0.53 mmol) in DMF (5 mL) was stirred at room temperature overnight. Workup and purification gave the product as a pale yellow oil. (71 mg, 41%). 1H NMR (CDCl3) δ 1.40-1.47 (m, 2H), 1.56-1.63 (m, 2H), 2.06 (s, 3H), 2.25 (s, 3H), 2.62 (t, 2H, J=7.5 Hz), 3.30 (q, 2H, J=6.0 Hz), 3.81 (s, 2H), 4.18 (s, 2H), 7.21 (s, 1H), 7.30-7.33 (m, 2H), 7.49-7.55 (m, 3H), 7.70-7.75 (m, 3H), 7.99 (d, 1H, J=6.0 Hz), 8.21 (s, 1H), 8.40 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.32, 23.96, 27.56, 39.69, 53.84, 54.24, 59.72, 59.87, 112.7, 120.80, 120.88, 123.66, 125.22, 126.83, 127.24, 128.12, 130.18, 132.31, 133.15, 134.62, 136.64, 139.13, 141.77, 143.22, 145.43, 146.90, 154.28, 159.30, 159.68. ES-MS m/z 515 [M+H]+. Anal. Calcd. for C30H32N6O.1.6CH2Cl2: C, 60.39; H, 5.64; N, 13.37. Found: C, 60.20; H, 5.52; N, 13.54.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].CN1CCCC1=O>C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cn1cc(Br)nc(Nc2ccc(F)c([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (10 g; 37.5 mmol), 4-fluoro-3-nitroaniline (5.9 g; 37.5 mmol), and 1-methyl-2-pyrollidinone (30 mL) was heated at 140 degrees for 1 hr. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered to give 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1) as a yellow solid (8.9 g).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[N:5]=1)=[O:3]
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reactant: COC(OC)N(C)C
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 3-acetyl-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.39 g, 4.45 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in AcOEt. The organic solution was washed with half-saturated brine, and the aqueous solution was extracted with AcOEt four times. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (1.46 g, 89% yield) as orange crystals: mp 176-178° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, J=13.2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, br s), 7.84-7.90 (2H, m), 7.96 (1H, s). Anal. Calcd for C17H16F3N3O3: C, 55.59; H, 4.39; N, 11.44. Found: C, 55.32; H, 4.51; N, 11.30.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[NH:12][CH:13]=2)[O:3]1.Br[CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:24]([O:23][CH2:22][CH2:21][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)[CH:10]=[C:11]1[C:14]([O:16][CH3:17])=[O:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c[nH]1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cn1CCCOCc1ccccc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A mixture of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (Compound 38F, 600 mg, 2.39 mmol) and 1-bromo-3-benzyloxypropane (575 mg, 2.51 mmol) in DMF (2.19 mL) was charged with cesium carbonate (778 mg, 2.39 mmol). The reaction mixture was allowed to stir at 70° C. for 16 hrs. The reaction mixture was diluted with water and then extracted with EtOAc (2×). The organic layer was washed with water (2×), brine (1×), dried over Na2SO4, filtered, concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→4% Ethanol in DCM] to afford 442 mg of the title compound (46%). 1H NMR (400 MHz, CD3OD) δ 7.26-7.37 (m, 5H), 7.25 (d, J=1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 4.45 (s, 2H), 4.42 (t, J=6.8 Hz, 2H), 3.78 (s, 3H), 3.38 (t, J=5.9 Hz, 2H), 2.01 (t, J=6.2 Hz, 2H), 1.31 (s, 12H). MS (ESI): m/z 440.59 [M+H]+. UPLC: tR=1.60 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C1C=CC=CC=1.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(4-Nitro-phenyl)ethanone (10 g, 60.5 mmol), malononitrile (4 g, 60.5 mmol), NH4OAc (4.66 g, 121 mmol) in benzene (100 mL) and acetic acid (6.4 mL) was refluxed overnight using a Dean Stark to collect water. The reaction was allowed to cool to r.t., partitioned between water and EtOAc (3×). the combined organic were washed with brine, dried (Na2SO4), concentrated and purified via silica gel chromatography eluting with 3 to 1 hexanes:EtOAc to give 3.71 g (29%) of the title compound. Rf=0.22 (4:1 hexanes: EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([C@H:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[C:7]1=[O:22].[CH:28](OCC)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[N:8]([C@H:17]2[CH2:21][CH2:20][N:19]([CH:28]=[O:29])[CH2:18]2)[C:7]1=[O:22]
Reactant: CCOC=O
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Product: COc1ccc(Cn2c(=O)n([C@H]3CCN(C=O)C3)c3ccc(C#N)cc32)cc1Cl

Procedure:
A solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (80 mg) in ethyl formate (2 mL) was heated under reflux for 10 hours. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (15:1) to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-formylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (52 mg) as amorphous powders.
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[Cl:23][C:24]1[C:25]([F:35])=[C:26]([O:33][CH3:34])[C:27]([C:30](=[CH2:32])[CH3:31])=[CH:28][CH:29]=1.[F:36][C:37]([F:46])([F:45])[C:38](=[O:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[CH2:31])[CH2:32][C:38]([OH:44])([C:37]([F:46])([F:45])[F:36])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:26]([O:33][CH3:34])[C:25]=1[F:35]
Reactant: C=C(C)c1ccc(Cl)c(F)c1OC
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Temperature: 25 °C
Yield: 14.9 %

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5](F)=[CH:4][C:3]=1[F:10].O.FC1C=C(F)C=C(F)C=1.[NH3:21]>[Cu].CO>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([F:8])[CH:2]=1)[NH2:21]
Reactant: N
Reactant: Fc1cc(F)c(Cl)c(F)c1
Agent: [Cu]
Agent: Fc1cc(F)cc(F)c1
Solvent: CO
Solvent: O
Product: Nc1cc(F)cc(F)c1

Procedure:
EP 460 639 describes a three-stage preparation of 3,5-difluoroaniline. Starting from 5-chloro-2,4,6-trifluoroisophthalic acid, this is decarboxylated to give 2-chloro-1,3,5-trifluorobenzene. By reaction of the 2-chloro-1,3,5-trifluorobenzene with copper and water at 300° C., 1,3,5-trifluorobenzene can be prepared. According to Example 6 of EP 460 639, 1,3,5-tri-fluorobenzene is reacted with methanol saturated with ammonia at 200° C. for 60 hours and 3,5-difluoroaniline is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23](Br)=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Cu][C:37]#[N:38].[Cu](C#N)C#N.C(OCC)(=O)C>CN(C)C=O>[CH3:1][C:2]1([CH3:35])[CH2:10][C@H:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]3[C:21]([F:34])=[CH:22][C:23]([C:37]#[N:38])=[C:24]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)[CH:25]=3)[N:13]=2)[CH2:8][C@H:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2Br)c1=O
Reactant: N#C[Cu]
Agent: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnn(-c2cc(Nc3ncc(F)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2C#N)c1=O
Temperature: 100 °C
Yield: 43 %

Procedure:
1-(5-(4-((7R,8aS)-octahydro-5,5-dimethylindolizin-7-ylamino)-5-fluoropyrimidin-2-ylamino)-2-bromo-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (54.3 mg, 0.10 mmol) was added to a tared reaction vial with magnetic stir bar and weighed. This was dissolved in 2 mL dimethylformamide and copper(I) cyanide (18.0 mg, 0.20 mmol) was weighed out and added. The reaction was heated at 100° C. for three hours, recharged with additional copper cyanide (37.7 mg, 0.42 mmol) and heated overnight at 115° C. The reaction was diluted into ethyl acetate and washed in succession with brine and water to remove DMF. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated onto silica. Product was purified by column chromatography. After drying, 21.1 mg was obtained of the title compound (43% yield).
Reaction SMILES: C(C1C=C([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=2)=[O:12])N(C2C=C(C=CC=2)C(OCC)=O)N=1)(C)(C)C.O=S(Cl)Cl>CCl>[C:14]1([NH:13][C:11](=[O:12])[NH2:10])[C:15]2[C:16](=[CH:19][CH:14]=[CH:15][CH:16]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cl)cc2)c1
Agent: CCl
Solvent: O=S(Cl)Cl
Product: NC(=O)Nc1cccc2ccccc12
Yield: 451.1 %

Procedure:
A solution of Example C (1.66 g, 4.0 mmol) and SOCl2 (0.60 mL, 8.0 mmol) in CH3Cl (100 mL) was refluxed for 3 h and concentrated in vacuo to yield 1-{3-tert-butyl-1-[3-chloromethyl)phenyl]-1H-pyrazol-5-yl}-3-(naphthalen-1-yl)urea (1.68 g, 97%) was obtained as white powder. 1H NMR (DMSO-d6): δ 9.26 (s, 1H), 9.15 (s, 1H), 8.42–7.41 (m, 11H), 6.40 (s, 1H), 4.85 (s, 2H), 1.28 (s, 9H). MS (ESI) m/z: 433 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[N:7]=1)=[CH2:5])C.[Br:14]N1C(=O)CCC1=O>C1COCC1.O>[Br:14][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[N:7]=1)=[O:5]
Reactant: C=C(OCC)c1ccc(F)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)CBr)ccc1F
Reaction time: 0.17 h

Procedure:
A solution of 2-(1-ethoxy-ethenyl)-5-fluoro-6-methyl-pyridine obtained from Step A (15.3 g) in THF (200 mL) and water (8 mL) was treated with N-bromosuccinimide (12.02 g) at room temperature. After stirring for 10 min, the reaction was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluted with a gradient of ethyl acetate in hexanes) to give 2-bromoacetyl-5-fluoro-6-methyl-pyridine, together with an unidentified impurity. This product was used in the next step. 1H NMR (500 MHz, CDCl3): δ 7.98 (dd, 1H), 7.44 (t, 1H), 4.83 (s, 2H), 2.57 (d, 3H).
Reaction SMILES: [Cl-:1].[Li+].[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@H:17](Br)[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4].O>CN(C)C=O>[C:3]([O:6][C:7]1[C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:25])[C@@H:17]([Cl:1])[CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([O:27][CH3:28])[CH:8]=1)(=[O:5])[CH3:4]
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@H](Br)C[C@H]3[C@@H]1CC2
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)[C@@H](Cl)C[C@H]3[C@@H]1CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of lithium chloride (1.3 g, 31 mM) in 9 ml of anhydrous dimethylformamide is heated to 70° and then cooled to room temperature. 1-Acetoxy-16α-bromo-3-methoxyestra-1,3,5(10)-trien-17-one (0.50 g) is added to the solution as a solid using Gooch tubing. The resulting suspension is heated to 50° to effect solution. The solution is then stirred at room temperature for 5 hr, poured into 100 ml of H2O, filtered and dried in vacuo to give a white solid. Recrystallization from methanol gives 1-acetoxy-16β-chloro-3-methoxyestra-1,3,5(10)-trien-17-one, yield 0.40 g (89%); m.p. 164°-166°.
Reaction SMILES: [I:1]I.[C:3]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[I:1][C:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1ccc(N2CCCC2)cc1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
Iodine (6.09 g) was added slowly to a stirred solution of phenylpyrrolidine (3.21 g) and sodium bicarbonate (2.75 g) in water (30 ml). The reaction was stirred for 1 h and then left to stand overnight. The solid was isolated by filtration, dissolved in ethanol (50 ml) and discoloured with aqueous sodium thiosulfate. The product was then isolated by filtration and recrystalised from ethanol to give the desired product as a brown/red powder (1.17 g).
Reaction SMILES: [Na].Cl.[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1.[CH2:29]=O>CO.C1COCC1>[Cl:3][CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([CH3:29])[CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[CH:11][CH:12]=2)[N:7]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:6]1
Reactant: C=O
Reactant: CS(=O)(=O)N1CC(CCl)c2ccc(NCc3ccc([N+](=O)[O-])cc3)cc21
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)N(S(C)(=O)=O)CC2CCl
Yield: 73 %

Procedure:
Sodium cyanoborohydnide (40 mg, 0.64 mmol) then 2N HCl (0.5 mL) were added to a solution of 30 (96 mg, 0.24 mmol) and formaldehyde (0.18 mL of a 40% w/v aq. solution, 2.4 mmol) in MeOH (15 mL) and THF (5 mL) and the mixture stirred at 20° C. for 45 min. The solvent was evaporated, the residue was diluted with water and extracted with CH2Cl2 (×2), and the extracts dried (Na2SO4) and evaporated. Dry column chromatography (eluting with 1:2 EtOAc:petroleum ether) gave 3-(chloromethyl)-1-(methanesulfonyl)-6-[N-methyl-N-(4-nitrobenzyl)amino]indoline (31) (73 mg, 73%), mp (benzene-petroleum ether) 138-139 C. 1H NMR (CDCl3) a 8.18 (d, J=8.8 Hz, 2 H, ArH o to NO2), 7.39 (d, J=8.8 Hz, 2 H, ArH m to NO2), 7.05 (d, J=8.4 Hz, 1 H, H-4), 6.82 (d, J=2.4 Hz, 1 H, H-7), 6.3 5 (dd, J=8.4 2.4 Hz, 1 H, H-5), 4.63 (s, 2 H, NCH2Ar), 4.04 (dd, J=10.8, 8.8 Hz, 1 H, CHHN), 3.93 (dd, J=10.8, 4.7 Hz, 1 H, CHHN), 3.71 (dd, J=10.4, 4.1 Hz, 1 H, CHHCl), 3.68-3.61 (m, 1 H, H-3), 3.55 (dd, J=10.4, 7.8 Hz, 1 H, CHHCl), 3.11 (s, 3 H, NCH3), 2.81 (s, 3 H, NSO2CH3). 13C NMR a 150.3, 147.1, 146.5, 143.5, 118.9 (C-6,8,9,1,4), 127.4, 123.9 (C-2 and 6, 3 and 5), 125.5, 107.7, 97.9 (C-4,5,7), 56.5, 54.7 (C-2, NCH2Ar), 46.9 (CH2Cl), 41.8 (C-3), 39.5 (NCH3), 34.5 (SO2CH3). Anal. Calculated for C18H20ClN3O4S): C, 52.8; H, 4.9; N, 10.3; Cl, 8.7. Found: C, 52.6; H 5.1; N, 10.1; Cl, 8.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][C:41]3=[N:42][O:43][N:44]=[C:40]3[CH:39]=2)O1>CN(C=O)C.O>[N:42]1[O:43][N:44]=[C:40]2[CH:39]=[C:38]([C:2]3[CH:3]=[C:4]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([Cl:13])[C:7]=3[O:8][CH2:9][CH:10]3[CH2:12][CH2:11]3)[CH:46]=[CH:45][C:41]=12
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC2CC2)c(-c2ccc3nonc3c2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 45.5 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (0.5 g, 1.240 mmol) in a mixture of DMF (20 mL) and water (5 mL) were added Cs2CO3 (1.4 g, 4.342 mmol), Pd(TPP)4 (286 mg, 2.480 mmol) and 5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (355 mg, 1.364 mmol) at RT under N2 atmosphere and the resulting mixture was stirred at 80° C. for 14 h. After completion of starting material (by TLC), the solids were removed via filtration through a bed of Celite™ was washing with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL), brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford ethyl 2-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-5-chloro-4-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (250 mg) as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=COc2ccccc2C(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2.0 g of 3-methyl-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 120 ml of dimethylformamide, then 548 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was stirred at room temperature for 1 hour, then 4.1 ml (3 equivalents) of 1,4-dibromobutane was added and the mixture was stirred for 3 hours. Ice water was added to the reaction solution and extraction was performed with ethyl acetate. The ethyl acetate extract was washed with saline, then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.0 g of the above-identified compound (yield 84%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:30][C@@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNC[C@@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.30 (m, 6 H) 2.41 (s, 3 H) 2.79 (dt, J=12.95, 6.54 Hz, 2 H) 2.94-3.10 (m, 2 H) 3.13 (d, J=11.37 Hz, 1 H) 3.23 (dd, J=13.14, 8.34 Hz, 1 H) 3.46 (br. s., 1 H) 3.61-4.25 (m, 2 H) 7.59 (d, J=7.33 Hz, 1 H) 7.91-8.00 (m, 1 H) 8.03 (s, 1 H) 8.30 (d, J=13.14 Hz, 1 H) 8.45-8.57 (m, 2 H); ESI-MS m/z [M+H]+ 449.3.