Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[O:12])[C:8]([CH3:21])=[C:7]2[C:3]=1[C:4]1[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=1[NH:6]2.[CH:27]1([C:30]([NH:32][C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:31])[CH2:29][CH2:28]1>>[CH:27]1([C:30]([NH:32][C:33]2[CH:34]=[C:35]([C:2]3[CH:10]=[C:9]([C:11]([NH:13][CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[O:12])[C:8]([CH3:21])=[C:7]4[C:3]=3[C:4]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:5]=3[NH:6]4)[CH:36]=[CH:37][CH:38]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Nc1cccc(B(O)O)c1)C1CC1
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(-c4cccc(NC(=O)C5CC5)c4)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide and 3-(cyclopropanecarboxamido)phenyl boronic acid using an analogous procedure to that described in the preparation of compound 83. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.82 (m, 4 H) 1.53 (qd, J=11.66, 3.41 Hz, 2 H) 1.79-1.82 (m, 3 H) 1.95 (t, J=10.86 Hz, 2 H) 2.15 (s, 3 H) 2.27 (s, 3 H) 2.59 (s, 3 H) 2.74 (d, J=I1. 12 Hz, 2 H) 3.75 (m, 1 H) 6.98 (s, 1 H) 7.27 (d, J=7.58 Hz, 1 H) 7.49 (t, J=7.96 Hz, 1 H) 7.69 (d, J=2.02 Hz, 2 H) 7.91 (s, 1 H) 8.25-8.30 (m, 2 H) 10.37 (s, 1 H) 11.92 (br. s., 1 H); [M+H] calc'd for C30H34N5O2, 496.3.; found, 496.4.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:36]>C1(C)C=CC=CC=1.O>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:36])([CH3:14])([CH3:13])[CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCCCBr
Reaction time: 3 h
Yield: 77.4 %

Procedure:
To a stirred solution of compound 2 (1 g, 4.61 mmol) in toluene (30 mL) were added Ph3P (1.81 g, 6.91 mmol) and CBr4 (2.29 g, 6.91 mmol) at RT under inert atmosphere and stirred for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×60 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude. The crude was purified (silica gel; 20% EtOAc/hexanes) to afford compound 3 (1 g, 78%) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.51 (br s, 1H), 3.40 (t, J=6.8 Hz, 2H), 3.13-3.08 (m, 2H), 1.89-1.82 (m, 2H), 1.52-1.42 (m, 13H), 1.37-1.31 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:39](Cl)(=[O:41])[CH3:40]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][N:30]([C:39](=[O:41])[CH3:40])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CNCc4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CN(Cc4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(3-benzylamino-2-hydroxy-propyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and acetyl chloride.
Reaction SMILES: F[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CS(C)=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=Cc1ccncc1F
Reactant: O=S([O-])c1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccncc1S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A solution of 3-fluoroisonicotinaldehyde (0.25 mL) in dimethyl sulfoxide (2.0 mL) was treated with a solution of 4-fluorobenzene sulfinic acid sodium salt (0.5 g) in dimethyl sulfoxide (3.0 mL), and the resulting mixture was stirred at 100° C. for 3 days. The mixture was cooled to room temperature, partitioned between water and ethyl acetate (20 mL), and the aqueous phase extracted with ethyl acetate. The combined organic solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 4:1 by volume) to afford the title compound as a white solid (0.38 g).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C=O)C.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>>[NH2:2][C:3]1[N:11]=[C:10]([O:29][CH2:28][CH2:27][O:26][CH3:25])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 130 °C
Yield: 71 %

Procedure:
Sodium (66 mg, 2.9 mmol) in 50 ml of 2-methoxyethanol was added 6-amino-9-benzyl-2-chloropurine (150 mg, 0.58 mmol) and DMF (10 ml). The mixture was heated at 130° C. for 6 hour. The reaction mixture was concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and concentrated in vacuo to dryness. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (123 mg, yield 71%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH2:20][CH2:21][O:22][CH3:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:20][CH2:21][O:22][CH3:23])[N:9]=1
Reactant: COCCBr
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCn1nc(Cl)c2ccccc2c1=O
Temperature: 50 °C
Yield: 70.6 %

Procedure:
Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 1-bromo-2-methoxyethane (462 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product. The crude material was purified via silica gel chromatography (90 g column, 5-45% EtOAc:Hex) to give the desired product 4-chloro-2-(2-methoxyethyl)phthalazin-1(2H)-one (280 mg, 70.6% yield) as a yellow solid. MS: MS m/z 223.15(M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH3:5].C[N+]1([O-])CCOCC1>C(Cl)Cl>[CH3:5][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:3][CH:2]=[O:1]
Reactant: CC(CCO)c1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(CC=O)c1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL one neck round bottom flask was added tert-butyl 4′-(3-hydroxy-1-methylpropyl)-biphenyl-2-carboxylate (197 mg, 0.604 mmol), N-methylmorpholine N-oxide (106 mg, 0.906 mmol), molecular sieves (300 mg) and methylene chloride (6 mL). The mixture was stirred while tetrabutyl ammonium ruthenate (21 mg, 0.0604 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, filtered through a stem of silica gel (5 g) and washed with mixture of ethyl acetate:hexanes (2:3). The filtrate was concentrated to afford tert-butyl 4′-(1-methyl-3-oxopropyl)biphenyl-2-carboxylate:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-1H-imidazole (15.0 g, 67.2 mmol) in DMF (150 ml) at 0° C. was added NaH (60% dispersion in mineral oil, 3.90 g, 97.5 mmol). The mixture was stirred at 0° C. for 1 hour and (2-(chloromethoxy)ethyl)trimethylsilane (14.8 mL, 84.0 mmol) was added. The resulting solution was allowed to warm from 0° C. to ambient temperature while stirring over 24 hours. The reaction mixture was diluted with 1:1 brine:H2O (500 mL), extracted with EtOAc (3×200 mL), dried over sodium sulfate, filtered and concentrated to an oil. Purification of the oil by column chromatography, eluting with 10-50% EtOAc/Hexane, afforded 2-(4-bromophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a light orange oil, (17.1 g, 70%). LCMS (APCI+) m/z 353, 355 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])[CH:2]=[CH2:3].ClC1C=C(C(OO)=[O:19])C=CC=1.S(=O)(O)[O-]>C(Cl)Cl>[O:19]1[CH2:3][CH:2]1[CH2:1][N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCN1CC(=O)NC1=O
Agent: O=S([O-])O
Solvent: ClCCl
Product: O=C1CN(CC2CO2)C(=O)N1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol) and 3-chloro-benzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml) was stirred for 2 hours at room temperature. An aqueous solution of bisulfite was added (to remove excess 3-chlorobenzenecarboperoxoic acid) and the mixture was stirred for 10 minutes. Na2CO3 was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 5 g (89%) of (±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (interm. 1).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13](Cl)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7])[CH:14]=[CH2:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCl
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O

Procedure:
Phthalimide potassium salt can be alkylated with allyl chloride in DMF to produce N-allylphthalimide. Under the Heck reaction conditions (Patel et al. 1977), N-allylphthalimide reacted with aryl bromide to give N-cinnamyl phthalimide. Upon treatment with hydrazine, cinnamyl amine was obtained from N-cinnamyl phthalimide (FIG. 28).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[S:13]1C=CC=C1CC(O)=O.C(O)(=O)C>CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:12])=[S:13])=[CH:2]1
Reactant: O=C(O)Cc1cccs1
Reactant: N#CCc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=S)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of (1H-indol-3-yl)-acetonitrile (5.0 g, 32 mmol), thiolacetic acid (6.8 mL, 96 mmol) and glacial acetic acid (25 mL) was heated at 100° C. for 4 h. After cooling to room temperature the reaction mixture was diluted with EtOAc, washed with water twice and brine. The organics were then concentrated under vacuum and purified by column chromatography (SiO2, EtOAc/hexanes) to afford 2-(1H-indol-3-yl)-thioacetamide as an orange solid (2.9 g, 48%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=2)=[CH:2]1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:32][O:31][C:29]([CH2:28][NH:27][C:12]([C:11]1[CH:15]=[CH:16][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][C:10]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:14])=[O:30]
Reactant: C[Si](C)(C)CCOCOc1cc(OCc2ccsc2)ccc1C(=O)O
Reactant: COC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(3-thienylmethoxy)-2-[2-(trimethylsilyl)ethoxy]methoxybenzoic acid (3.09 g), methyl aminoacetate hydrochloride (0.99 g), 1-hydroxybenzotriazole (1.28 g), triethylamine (0.8 g) and dimethylformamide (50 mL) is stirred at ambient temperature for 16 hours. It is then concentrated in vacuo and the resulting residue is dissolved in ethyl acetate (100 mL), washed quickly with hydrochloric acid (2×50 mL; 1 N), and then washed with saturated aqueous sodium bicarbonate solution (50 mL) and with water (50 mL), then dried over magnesium sulphate, filtered and concentrated in vacuo, to give 1-[N-(methoxycarbonylmethyl)carbamoyl]-4-(3-thienylmethoxy)-2-[2-(trimethylsilyl)ethoxy]methoxybenzene, in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:5]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C2C(=O)Nc3ccc(Cl)cc32)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.15 g, 0.55 mmol) (from Example 1b supra), benzyl bromide (113 mg, 0.65 mmol), potassium iodide (108 mg, 0.65 mmol) and potassium carbonate (163 mg, 1.18 mmol) in acetone (5 mL) was heated at 60° C. for 20 hours. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloro-methane as solvent) to give two products. Lower Rf sample was recrystallized from ethyl acetate-hexanes to give rac-3-benzyl-5-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white crystals. (Yield 58 mg, 29.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1CO>CC(O)C>[CH3:33][O:34][C:35]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:36]=1[CH2:22][O:21][CH2:20][CH:19]([OH:31])[CH2:18][N:15]1[CH2:14][CH2:13][N:12]([CH2:11][C:10]([NH:9][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])=[O:32])[CH2:17][CH2:16]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: COc1ccc(CO)c(OC)c1
Solvent: CC(C)O
Product: COc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)c(OC)c1

Procedure:
Compound 19 was prepared in a similar manner to compound 7, substituting the commercially available 2,4-dimethoxy-benzylalcohol for 2-propanol in part C. MS (M+1)=472.42
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CCO>[NH:20]([C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:21]
Reactant: NN
Reactant: CN(c1ccccn1)S(=O)(=O)c1ccc(Cl)nc1
Solvent: CCO
Solvent: O
Product: CN(c1ccccn1)S(=O)(=O)c1ccc(NN)nc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
A solution of 1.4 g (4.9 mmol) of 6-chloro-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide and 0.96 mL (19.7 mmol) of hydrazine monohydrate in 8 mL of EtOH is heated for 12 hours at 80° C. The precipitate obtained, after cooling to room temperature, is filtered off, washed with 10 mL of EtOH and then dried under vacuum. 0.85 g of 6-hydrazino-N-methyl-N-pyridin-2-ylpyridine-3-sulfonamide is obtained in the form of pale yellow crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2].S(Cl)([Cl:32])=O>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:32])(=[O:13])=[O:12])=[CH:7][C:6]=1[N:15]=[N:16][CH:17]([C:27]([CH3:29])=[O:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)O)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1N=NC(C(C)=O)C(=O)Nc1ccccc1

Procedure:
α-(2-Acetoxy-5-sulfophenylazo)acetoacetanilide (20 g) was added to thionyl chloride (100 ml). After the addition of dimethylformamide (4 ml), solution was complete, then followed by precipitation of the product. It was filtered off and dried in the vacuum oven at 40° C. Yield: 16.7 g, m.p. 225 to 226° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]([F:53])([F:52])[O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[O:42][C:41]([F:40])([F:53])[F:52])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3OC(F)(F)F)sc2N)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethoxy)phenyl)boronic acid gave 266. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.28-8.20 (m, 1H), 7.78 (s, 1H), 7.57-7.43 (m, 6H), 5.00-4.77 (m, 2H), 4.22-4.06 (m, 1H), 4.06-3.92 (m, 1H), 3.75 (s, 3H), 3.29-3.21 (m, 1H), 2.18-2.09 (m, 1H), 1.95-1.54 (m, 5H). LCMS (ES+) m/z 515 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([O:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O)=O.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]1[O:6][C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:32]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(OC(=O)c1c(F)cccc1F)C(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1oc(-c2c(F)cccc2F)nc1-c1ccc(OC)cc1
Yield: 50 %

Procedure:
To a stirred solution of 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate (0.082 g, 0.22 mmol) in acetic acid (3 mL) was added ammonium acetate (0.125 g, 1.62 mmol) and the reaction mixture heated to reflux for 3 hours. A further portion of ammonium acetate (0.017 g, 0.22 mmol) was added the reaction mixture heated to reflux for 1 hour. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 15% EtOAc in hexanes as eluent to afford ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate (0.041 g, 0.11 mmol, 53%) as a white crystalline solid. 1H NMR (CDCl3) δ 1.41 (3H, t), 3.87 (3H, s), 4.43 (2H, q), 6.99 (2H, d), 7.07 (2H, t), 7.49 (1H, m), 8.15 (2H, d). LCMS (1) Rt: 2.46 min; m/z (ES+) 360.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](OS(C)(=O)=O)[CH3:8].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:21].CCN(C(C)C)C(C)C>CC#N.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:22]([CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH3:8]
Reactant: CC(NCCCCN1C(=O)c2ccccc2C1=O)c1ccccn1
Reactant: CC(OS(C)(=O)=O)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccccn1)N(CCCCN1C(=O)c2ccccc2C1=O)C(C)c1ccccn1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
Using General Procedure A: To a stirred solution of methanesulphonic acid 1-pyridin-2-yl-ethyl ester (269 mg, 1.34 mmol) and 2-[4-(1-pyridin-2-yl-ethylamino)-butyl]-isoindole-1,3-dione (356 mg, 1.10 mmol) in CH3CN (5 mL) at room temperature was added DIPEA (0.30 mL, 1.72 mmol) and KI (13 mg, 0.078 mmol). After 3 hours the temperature was increased to 60° C. and the mixture stirred for another 17 hours. KI (23 mg, 0.139 mmol) and DMAP (35 mg, 0.286 mmol) were added and the reaction stirred for a further 2 hours. Work up and purification by flash chromatography (35:1:1 CH2Cl2: MeOH: NH4OH) afforded pure 2-{4-[bis-(1-pyridin-2-yl-ethyl)-amino]-butyl}-isoindole-1,3-dione as a mixture of diastereomers (139 mg, 30%). 1H NMR (CDCl3) δ 1.18-1.49 (m, 10H) containing 1.27 (d, 3H, J=7.0 Hz) and 1.42 (d, 3H, J=7.1 Hz), 2.51-2.80 (m, 2H), 3.44-3.52 (m, 2H), 4.03-4.12 (m, 2H), 6.98-7.07 (m, 2H), 7.31 (d, 1H, J=7.9 Hz), 7.45-7.61 (m, 3H) containing 7.47 (d, 1H, J=7.9 Hz), 7.66-7.70 (m, 2H), 7.76-7.81 (m, 2H), 8.43-8.48 (m, 2H). ES-MS m/z 429 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=S)=S.[Br:15]Br>O>[Br:15][C:6]1[CH:5]=[C:4]([OH:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: BrBr
Reactant: COc1ccc(O)c(OC)c1
Solvent: S=C=S
Solvent: O
Product: COc1cc(OC)c(Br)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution comprising 8.6 g of 2,4-dimethoxyphenol and 80 ml of carbon disulfide (CS2) was added dropwise 2.86 ml of bromine at 10° to 15° C. After stirring the mixture at room temperature for one hour, water was added to the reaction mixture and the reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue and the precipitated crystals were collected by filtration to give 12.0 g of 3-bromo-4,6-dimethoxyphenol (yield: 92%, melting point: 78°-80° C.).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12].[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([NH:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)(CO)CO
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CO)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzaldehyde (17.4 ml) was added dropwise to a solution of 2-amino-2-methyl-1,3-propanediol (20 g) in methanol (200 ml) at 0° C. and the whole was stirred at room temperature for 2 hours. Sodium borohydride (11.5 g) was added thereto in portions at 0° C. and the mixture was stirred for 10 minutes. 1N Sodium hydroxide solution and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give 2-benzylamino-2-methyl-1,3-propanediol (28.54 g).