Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH3:17])[O:9][CH2:8][CH2:7][O:6]1.[O:18]=[C:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][NH:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:5]1([O:9][CH2:8][CH2:7][O:6]1)[CH2:4][CH2:3][CH2:2][N:26]1[CH2:25][CH2:24][C:23]2([N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][NH:20][C:19]2=[O:18])[CH2:28][CH2:27]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Cc1cc(F)ccc1C1(CCCCl)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1C1(CCCN2CCC3(CC2)C(=O)NCN3c2ccccc2)OCCO1
Temperature: 0 °C

Procedure:
A mixture of 3 g of 4-chloro-1-(2-methyl-4-fluorophenyl)-1,1-ethylenedioxybutane, 2.3 g. of 4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane, 1.4 g of anhydrous potassium carbonate, 0.05 g of potassium iodide and 30 ml of dimethylformamide was refluxed for 3 hour. The resulting mixture was poured into ice water. The precipitated crystals were collected by filtration and washed with water to give 8-[4-(2-methyl-4-fluorophenyl)-4,4-ethylenedioxybutyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]decane as crude crystals (5 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[NH:11][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)[N:3]=1
Reactant: NC1CCCCC1Nc1nc(Cl)nc2[nH]ccc12
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CCCCC3N)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 9 %

Procedure:
A mixture of N1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,2-diamine (44 mg, 0.17 mmol), N-(4-aminophenyl)-N-methylacetamide (56 mg, 0.34 mmol) and trimethylsilyl chloride (0.146 mL, 1.15 mmol) in nBuOH (2 mL) was heated at 116° C. for 4 h. It was then purified by HPLC to give the titled compound (6 mg). MS 394.2 (M+H); UV 201.4, 262.7, 306.7 nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])=[CH:16][CH:15]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)ccc1CSc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-1-(bromomethyl)-2-nitrobenzene (0.60 g) in tetrahydrofuran (10 ml) was added 4-fluorothiophenol (1.2 ml) and diisopropylethylamine (0.45 ml). After stirring for 2 h the mixture was concentrated under vacuum and purified by column chromatography on silica, eluting with petroleum ether (40-60°):dichloromethane (9:1 to 8:1) to give the title compound (0.52 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)(O)[O-].[Na+].Br[CH2:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:14][CH:13]=3)[CH2:29][C:30]([OH:35])([C:31]([F:34])([F:33])[F:32])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1F
Yield: 63.5 %

Procedure:
To a mixture of 3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (4.15 g, 12.9 mmol) and sodium bicarbonate (2.16 g, 25.8 mmol) in isopropanol (150 mL), 3-bromo-1,1,1-trifluoroacetone (4.8 mL, 45 mmol) was added. After heating the reaction mixture at 70–75° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.8 g) was purified by chromatography (silica gel, toluene/ethyl acetate, 7/3) to give 2-(3-fluoro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (3.54 g, 64%) as a white solid: mp (DSC) 210° C. Anal. Calc'd. for C18H16N2SO4F4.0.1 PhCH3: C, 50.86; H, 3.83; N, 6.34. Found: C, 50.61; H. 3.64; N, 6.16.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:19][C:20]1[CH:27]=[C:24]([CH:25]=[O:26])[C:23]([OH:28])=[CH:22][CH:21]=1.Cl>C1COCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]([OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(Br)cc1C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
To a solution of 2-bromopyridine (5.75 g) in THF (125 ml) was added, under argon atmosphere at -78° C., a 1.6M n-butyl lithium hexane solution (40.0 ml). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 5-bromosalicylaldehyde (3.65 g) in THF (20 ml), which was stirred for 20 minutes at the same temperature, then for further 15 minutes while warming up to room temperature. The reaction mixture was poured into 3N HCl, which was washed with diethyl ether, followed by rendering the pH to alkaline side with the addition of 3N sodium hydroxide. The resultant was washed with diethyl ether, followed by being acidified to about pH 5 with 3N HCl. The weakly acodofoed reaction mixture was subjected to extraction with ethyl acetate, washed with water, dried (anhydrous sodium sulfate), and concentrated to dryness to give 5-bromo-2-hydroxy-α-(2-pyridyl)benzyl alcohol (3.50 g) (Compound D-1), whose phisical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](O)=[O:40])[CH:34]=1)C1C=CC=CC=1.[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][NH:47][CH3:48]>>[CH3:42][N:43]([CH3:49])[CH2:44][CH2:45][CH2:46][N:47]([CH3:48])[C:39]([C:35]1[CH:34]=[C:33]([C:10]2[CH:11]=[C:12]([C:23]3[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=3)[C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH:38]=[CH:37][CH:36]=1)=[O:40]
Reactant: CNCCCN(C)C
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N(C)CCCN(C)C)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and N,N,N′-trimethyl-1,3-propanediamine as described in general procedure D. LCMS: 469 [M+H].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=1>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][NH:35][CH2:34][CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[CH:42][CH:41]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1
Product: O=C(Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
The synthesis was carried out analogously to Example XVe), starting [lacuna]70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 110 mg of {4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}-acetic acid. This gave the product of molecular weight 733.82 (C40H45F2N3O8+); MS (ESI) 734.32 (M +H+).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]([CH3:39])[C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[CH:28]=[N:29][C:24]([N:23]([CH3:22])[CH3:39])=[N:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cnc(N(C)C)nc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)cyclopent-1-enyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.8 (d, 2H), 7.3 (s, 1H), 6.98-7.1 (m, 2H), 4.7 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.78-3.1 (m, 15H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O-:20])=[O:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N+:18]([O-:20])=[O:19])[CH2:28][CH2:29]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2[N+](=O)[O-])CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-nitro-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-nitro-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=429.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:5]1[CH2:6][CH2:7][N:2]([CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[S:20][C:21]5[C:22]([N:27]=4)=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][C:12]=3[O:11][CH:10]=2)[CH2:3][CH2:4]1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: c1cnc2nc(Oc3ccc4c(CN5CCNCC5)coc4c3)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a suspension of 2-(3-piperazin-1-ylmethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine hydrochloride (122 mg, 0.30 mmol) in DCM (3 mL) was added DIEA (158 μL, 0.91 mmol) and the reaction mixture was stirred (rt, 15 min). The resulting solution was treated with MsCl (26 μL, 0.33 mmol) and the resulting solution was stirred (rt, 2 h). The reaction mixture was partitioned with EtOAc and brine (20 mL each) and the organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a white solid (42 mg, 31%). MS (ESI): mass calcd. for C20H20N4O4S2, 444.54; m/z found, 445.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.6, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.74 (d, J=8.5, 1H), 7.62-7.56 (m, 2H), 7.30 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=8.0, 4.8, 1H), 3.69 (d, J=0.5, 2H), 3.32-3.21 (m, 4H), 2.79 (s, 3H), 2.67-2.54 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]#[N:6].[OH-].[Na+].C([OH:33])(C)(C)C.CO>OO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]3[CH:26]=2)[CH2:12][CH2:11]1)[C:5]([NH2:6])=[O:33]
Reactant: CC(C)(C)O
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3-chloro-4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]benzonitrile (Example 29; 0.122 g), NaOH (0.063 g), 30% hydrogen peroxide (2 drops), and tert-butanol (2 mL) is stirred at 80° C. for 4 h, after which it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The solids remaining suspended in the aqueous layer are collected, washed with water, dried under reduced pressure, and combined with the solids obtained from concentration of the organic layers. The solids are taken up in dichloromethane and methanol with warming and filtered through a cotton plug to remove insolubles. The filtrate is then concentrated and the residue is crystallized from dichloromethane/hexane to give 0.0745 g of the title compound; mp 254-256° C.; MS m/z 403, 405; IR (mineral oil) 1413, 1235, 1597, 800, 1328 cm-1. 1H NMR (DMSOd6) δ2.64, 3.05, 3.69, 7.17, 7.25, 7.37, 7.55, 7.79, 7.84, 7.89, 7.96, 8.80.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:31]([CH3:42])[CH:30]=2)[C:25]([Cl:43])=[CH:24][N:23]=1>>[Cl:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[C:31]([CH3:42])[CH:30]=2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1N1CCN(C)CC1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)c(C)c3)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.020 g, 24%). MP: 172-178° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.04-8.01 (m, 2H), 7.54-7.49 (m, 1H), 7.47 (s, 1H), 7.24-7.21 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 3.84 (s, 3H), 3.26 (s, 2H), 3.14 (s, 3H), 3.01-2.92 (m, 8H), 2.88-2.83 (m, 2H), 2.75-2.59 (m, 9H), 2.44-2.36 (m, 3H), 2.30 (s, 3H). MS: 593.29 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([Si:17]([CH3:19])([CH3:18])[N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF (250 mL) was added sodium hydride (60% suspension in mineral oil, 10.22 g, 0.255 mol) portionwise and maintaining the solution at 0° C. The reaction mixture was stirred at 0° C. for 20 min, then a solution of tert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF (20 mL) was added and the solution stirred at RT for 25 h. The reaction mixture was poured into H2O and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4), then concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, cyclohexane:DCM 100% to 50:50) to provide the title compound as a colourless oil (41.2 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>>[CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl

Procedure:
in stage d) 2-methyl-4,5-di(methylsulfonyl)benzoic acid is reacted with thionyl chloride to give 2-methyl-4,5-di (methylsulfonyl)benzoyl chloride, and
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CN(C)CCCN=C=NCC.O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([Br:21])=[CH:23][CH:24]=2)=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Reactant: Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (3.0 g) synthesized in Example 3 and 4-bromoaniline (1.63 g) were dissolved in dichloromethane (50 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (2.72 g) and 4-dimethylaminopyridine (DMAP) (1.73 g) were successively added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (4.5 g) as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[NH:11][CH:10]=[CH:9][C:8]3=[O:15].[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[OH:15])=[C:6]1[O:1][CH2:2][CH2:3][O:4][C:5]1=[CH:14][CH:13]=2
Reactant: O=c1cc[nH]c2ccc3c(c12)OCCO3
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Oc1c(Cl)cnc2ccc3c(c12)OCCO3
Temperature: 35 °C
Yield: 73.2 %

Procedure:
2,3-Dihydro-7H-[1,4]dioxino[2,3-f]quinolin-10-one (6.93 g, 34.1 mmol, 1 eq) in acetic acid (95.9 mL) was sonicated and warmed until all had dissolved, and then it was treated with N-chlorosuccinimide (5.01 g, 37.5 mmol, 1.1 eq) and the mixture was heated at 35° C. for 18 hr, cooled and the solid collected and washed with acetic acid and dried in vacuo at 40 oC overnight, to give a white solid (5.93 g, 73%). LC/MS (ES) m/z 237 (MH+ 84%); 1H-NMR (400 MHz, d6-DMSO), 8.17 (1H, d, J=6.28, CHNHC), 7.21 (1H, d, J=8.96 Hz, CHCO), 7.01 (1H, d, J=9, CHCN), 4.29-4.25 (4H, m, 2×(CH2O)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O>[CH3:21][O:20][C:18]([NH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])=[O:19]
Reactant: COC(=O)Cl
Reactant: NC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.3 %

Procedure:
To a stirred mixture of (±)-2-(4-nitrophenyl)glycine (20) (Heyns et al., Justus Lieberg's Annalen der Chimie 611:55-56 (1958)) (3.2400 g, 16.5 mmol) and NaOH (0.6611 g, 16.5 mmol) in water (150 mL) were added methyl chloroformate (1.404 mL, 18.2 mmol), 2N NaOH (9.1 mL), and water (6 mL) at 0° C. After adjusting pH to 9 with 2N NaOH (1 mL) and stirring at 25° C. for 17 h, the mixture was basified to pH 10 with 2N NaOH and washed with diethyl ether before it was acidified with 5N HCl in the presence of EtOAc. The organic fractions (1 L) were dried (MgSO4) and evaporated to yield 19 (3.62 g, 86%): mp 152° C.; 1H NMR (DMSO-d6) δ 3.53 (s, 3H, OCH3), 5.35 (d, J=8.7 Hz, 1H, CH), 7.66 (d, J=8.4 Hz, 2H, aromatic), 8.20 (d, J=8.4 Hz, 3H, aromatic and NH). MS (FAB) m/z 255.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14]2)=O)=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[NH4+:34].O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:34]=[C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:14]3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccc(Cl)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
A mixture of N-[2-(4-chlorophenyl)-2-oxoethyl]-4-(phenylmethyl)-2-morpholinecarboxamide (3.3 g, 8.85 mmol) and ammonium trifluoroacetate (5.27 g, 44.3 mmol) was heated at 150° C. for 20 minutes. After cooling, to the resulting mixture was added water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the crude title compound (2.8 g). LC-MS (ES) m/z=354 [M+H]+.