Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[NH:16][C:17](=[O:18])[C:12]=3[C:11]([I:25])=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([O:8][CH2:7][C@H:5]2[O:6][C@@H:1]([N:9]3[C:13]4[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[NH:16][C:17](=[O:18])[C:12]=4[C:11]([I:25])=[CH:10]3)[CH2:2][C@@H:3]2[OH:4])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:31]2[CH:48]=[CH:49][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c4c(=O)[nH]c(NC(=O)C(C)C)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Compound (59) is repeatedly dried by evaporating off anhydrous pyridine. 400 mg (0.87 mmol) of compound (59) which has been dried in this way are dissolved in 5 ml of anhydrous pyridine. After adding 4,4'-dimethoxytrityl chloride (328 mg, 0.95 mmol) at room temperature, the reaction mixture is stirred overnight. MeOH (3 ml) and 5% aq. NaHCO3 (30 ml) are then added. The aqueous phase is extracted 3 times with CH2Cl2. The organic phase is dried (Na2SO4) and evaporated, and the residue is subjected to flash chromatography (column: 10×5 cm, solvent CH2Cl2 /acetone, 9:1). Isolating the material from the main zone affords the colorless, amorphous title compound (61). (600 mg, 91%). 1H-NMR ([D6 ] DMSO: δ=1.13 (m, 4 CH3), 2.24 (m, H--C(2')), 2.77 (m, CH), 3.12 (m, H--C(5')), 3.75 (s, 2 CH3O), 3.93 (m, H--C(4')), 4.35 (m, H--C(3')), 5.30 (d, 3'-OH), 6.39 (dd, H--C(1')), 6.86-7.39 (m, aromatic H +H--C(6)), 11.54, 11.82 (2s, 2 NH). Anal. calculated for C36H37JN4O7 (764.6): C 56.55, H 4.88, N 7.33: found C 56.42, H 4.82, N 7.30.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18].[C:27](=[O:30])([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:10]2[CH:9]=[C:8]([NH2:15])[CH:7]=[C:6]3[C:11]=2[C:12]2[C:4]([C:5]4[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=4)=[C:3]([C:23]4[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=4)[C:2]([NH2:1])=[C:14]([C:23]4[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=4)[C:13]=2[C:27]3=[O:30])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc2c(c1)C(=O)c1cc(N)ccc1-2
Agent: [Cu]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc2c(c(-c3ccc([N+](=O)[O-])cc3)c1)-c1c(c(-c3ccc([N+](=O)[O-])cc3)c(N)c(-c3ccc([N+](=O)[O-])cc3)c1-c1ccc([N+](=O)[O-])cc1)C2=O
Reaction time: 96 h
Yield: 76 %

Procedure:
In dimethylformamide, 0.05 mol of 2,7-diamino-9-fluorenone, 0.3 mol of p-nitroiodobenzene, 0.12 mol of anhydrous potassium carbonate, and copper powder were added and refluxed with stirring for 4 days. After the reaction was completed, the reaction mixture was filtered, and the filtered product was thoroughly washed with dimethylformamide, water and acetone, followed by drying. Thus, 0.038 mol of reddish brown tetrakis(p-nitrophenyl)-2,7-diamino-9-fluorenone was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:43])/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1(/[CH:36]=[CH:35]/[C:34]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)/C=C/c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added trans-cinnamoyl chloride (0.235 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave a yellow syrup that was crystallized from diethyl ether/ethyl acetate/hexane to afford the title compound (0.360 g, 85%) as an off-white solid, m.p. 175° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][S:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH3:19])([CH3:18])[CH2:5][N:4]2[C:1](=[O:3])[CH3:2])=[CH:8][C:9]=1[F:17])(=[O:15])=[O:14]
Reactant: ClCCCI
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)CCCCl)cc21
Yield: 88 %

Procedure:
Prepared from 1-acetyl-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (500 mg, 1.64 mmol) and 1-chloro-3-iodo-propane (863 μL, 8.2 mmol) following similar methods to those described in Preparation 64. The title compound (502 mg) was obtained as a pale yellow oil. 1H NMR (CDCl3): 8.72 (1H, d), 7.01 (1H, d), 3.88 (2H, s), 3.75-3.57 (2H, m), 3.57-3.35 (2H, m), 2.37-2.18 (5H, m), 1.41 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13]#[C:14][C:15]2[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][C:23]([N+:30]#[C-:31])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:24].Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:7]1([C:13]#[C:14][C:15]2[S:19][C:18]([C:20]3[N:1]=[C:2]4[N:6]([C:31]=3[NH:30][C:23]([CH3:24])([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])[CH:5]=[CH:4][S:3]4)=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nccs1
Reactant: O=Cc1ccc(C#Cc2ccccc2)s1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2sccn12
Yield: 36.8 %

Procedure:
A solution of 400 mg (4.0 mmol) 2-aminothiazole, 1018 mg (4.8 mmol) 5-phenylethynyl-thiophene-2-carbaldehyde, 557 mg (4.0 mmol) (2,4,4-trimethylpentane-2-yl)-isocyanide and 400 μl of a 20% aq. perchloric acid was stirred in DCM (8 ml) for 5 d at RT. A 1 molar aq. Na2CO3 sol. was subsequently added. The phases were separated and the aqueous phase was extracted with DCM. The collected organic phases were washed with brine and dried over MgSO4. After filtering and removal of the solvent in a vacuum, a CC (AE/hexane 1:4) was performed with the residue, whereby 637 mg (1.47 mmol, 37%) 6-(5-(phenylethynyl)thiophene-2-yl)-N-(2,4,4-trimethylpentane-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:23])[C:3]([NH:5][C@@H:6]([CH3:22])[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:11]([NH2:13])=[O:12])=[O:8])=[O:4].[C:24]([NH:41][C@H:42]([C:51](O)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=1)([O:26][CH2:27][CH:28]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[NH2:13][C:11](=[O:12])[C@@H:10]([NH:9][C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:51](=[O:52])[C@@H:42]([NH:41][C:24](=[O:25])[O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=1)[CH3:23])[CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
Following the procedure described in Example 7, except using (S)-2-amino-N-((S)-1-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-1-oxopropan-2-yl)propanamide (40 mg, 0.124 mmol), Fmoc-L Tyrosine (52.6 mg, 0.130 mmol), 1-hydroxy-7-azabenzotriazole (9.5 mg, 0.070 mmol), anhydrous DMF (1.2 mL), N-methylmorpholine (16 μL, 0.146 mmol), EDC (28.5 mg, 0.149 mmol) and stirring at room temp for 4 h 15 min, 48.4 mg (47.5%) of the title compound is isolated as an off white solid. Purification is done by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 35% Solvent B to 100% Solvent B over 11 min, ret. T=8.79 min. LC/MS (Condition A): ret. T=3.46 min, (M+H)+ 708.32. Analytical HPLC: (Condition A): >99%, ret. T=21.87 min, (Condition B): >99%, ret. T=22.15 min, (Condition C): >98%, ret. T=13.82 min, (Condition D): >99%, ret. T=12.79 min.
Reaction SMILES: FS([C:5]([F:10])([F:9])C(O)=O)(=O)=O.[OH:11][CH2:12][C@H:13]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C@H:20]1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:46]C#N>>[F:9][CH:5]([F:10])[O:11][CH2:12][C@H:13]([N:19]1[CH2:24][CH2:23][C@@H:22]([CH2:25][C:26]([O:28][CH3:46])=[O:27])[CH2:21][C@H:20]1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=1)[CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)CC[C@H](CO)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: CC#N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@@H]1CCN([C@H](CCC(C)C)COC(F)F)[C@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2-(Fluorosulphonyl)difluoroacetic acid (0.040 ml, 0.385 mmol) was added to a stirred solution/suspension of methyl {(2S,4R)-1-[(1R)-1-(hydroxymethyl)-4-methylpentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 29, Step 1, 160 mg, 0.385 mmol) and Na2SO4 (11 mg, 0.077 mmol) in dry CH3CN (1 ml) at RT under N2. The reaction was then stirred and heated at 50° C. After 2 hours, the reaction was allowed to cool to RT, then partitioned between DCM/H2O. The aqueous layer was extracted with DCM (×2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 4-6-10% EtOAc/isohexanes) to give the title compound (13 mg) as an oil. M/Z 466 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C@H:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][C@@H:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC[C@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](O)C/C=C/c1cccnc1
Temperature: 135 °C
Yield: 63.3 %

Procedure:
A mixture of 3-bromopyridine (11.22 g, 70.58 mmol), (2S)-4-penten-2-ol (5.00 g, 58.05 mmol), palladium(II) acetate (527 mg, 2.35 mmol), tri-o-tolylphosphine (1.79 g, 5.88 mmol), triethylamine (30 mL, 216 mmol) and acetonitrile (30 mL) was heated in a sealed glass tube at 130-140° C. for 8 h. The reaction mixture was cooled to ambient temperature. The solvent was removed under reduced pressure on a rotary evaporator. Water (20 mL) was added and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (K2CO3), filtered, and concentrated by rotary evaporation, producing a pale-yellow oil (6.00 g). The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (95:5, v/v). Selected fractions were combined and concentrated by rotary evaporation, affording 3.95 g (41.7%) of a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S>[Cl:1][C:2]1[C:3]2[CH2:14][CH2:15][CH2:16][C:17](=[O:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCc1c(Cl)cccc1-c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCCc2c(Cl)cccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Using the extreme-dilution technique described by Hedden and Brown, J. Am. Chem. Soc., 75, 3744-48 (1953), 4-(3-chloro[1,1'-biphenyl]-2-yl)butanoic acid chloride (18.9 g, 0.069 mole) was diluted in carbon disulfide (100 ml) and placed in the dropping funnel. The dilution flask was filled with carbon disulfide (approximately 700 ml). Aluminum chloride (19.8 g, 0.15 mole) in carbon disulfide (700 ml) was placed in the reaction flask and heated at reflux. The contents of the dropping funnel were added to the reaction during an eight day period. After complete addition the contents of the dilution flask were added to the reaction flask and the mixture allowed to stir at room temperature for approximately 18 hours. One liter of 2N hydrochloric acid was added to the mixture and the total stirred for 0.5 hour. The mixture was poured into a separatory funnel and the organic phase separated. The remaining aqueous phase was saturated with sodium chloride and extracted with methylene chloride (3×250 ml). The organic phase and extracts were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield an oil. The oil was subjected to column chromatography on silica gel eluted with toluene:methylene chloride (1:1). The fractions which contained the desired product were combined and evaporated under reduced pressure to give a solid. The solid was recrystallized from methylcyclohexane:n-heptane (30:70) to yield 9-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-5-one (m.p. 117.5°-118.5°). The solvent was evaporated from the mother liquor to give an oil. This oil was subjected to column chromatography on silica gel eluted with n-heptane:ethyl acetate (40:1). The fractions which contained the desired product were combined and evaporated under reduced pressure to give additional product.
Reaction SMILES: [CH2:1]1[O:33][C:4]2([CH2:9][CH2:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([CH3:23])[CH2:17]CCCCC)=[CH:12][C:11]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:5]2)[O:3][CH2:2]1.[C:34](=O)(O)[O-].[Na+].Cl[C:40]1[CH:45]=[CH:44]C=[C:42](C(OO)=O)[CH:41]=1>ClCCl>[CH2:2]1[O:3][C:4]([CH2:9][CH2:8][CH2:7][CH3:34])([CH2:5][CH2:6][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:24])([CH3:23])[CH2:17][CH2:42][CH2:41][CH2:40][CH2:45][CH3:44])=[CH:12][C:11]=2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:33][CH2:1]1
Reactant: O=C([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CCCC3(C2)OCCO3)c(OCc2ccccc2)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc(CCC2(CCCC)OCCO2)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 5.0 g. (11.2 mmole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-3-en-l-one ethylene ketal in 15 ml. of dichloromethane is added 1.26 g. (15 mmole) of sodium bicarbonate and 2.58 g. (15 mmole) of m-chloroperbenzoic acid. The reaction is stirred overnight at 0° C. and then filtered. The filtrate is diluted with 200 ml. of ether and washed with two 100 ml. portions of saturated sodium bicarbonate. The organic extract is dried over magnesium sulfate and evaporated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Reaction time: 0.67 h
Yield: 101.8 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (4.40 g) in anhydrous DMF (75 ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04 g) and the mixture stirred for 40 min. A solution of 1-[(2-[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12 g) in DMF (10 ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product extracted with EtOAc (4×100 ml). The combined organic layer was washed with water (3×100 ml) and dried (Na2SO4). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50 g). LCMS RT=3.75 min, ES+ve 529 (MH)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22](Cl)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:39])[NH:33][C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([C:24]#[N:25])[C:22]([N:36]3[CH2:37][CH2:38][C@H:34]([NH:33][C:32](=[O:39])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:35]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: N#Cc1cc2c3c(cccc3c1Cl)C(=O)N(OCc1ccccc1)C2=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(C#N)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 63.9 %

Procedure:
Following the procedure of Example B2, 2-benzyloxy-6-chloro-5-cyano-benzo[de]isoquinoline-1,3-dione (0.20 g, 0.55 mmol, from Example A2), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.11 g, 0.60 mmol), triethyl amine (0.11 g, 1.1 mmol) were reacted at ambient temperature for 5 hours. Column chromatography of the crude product on silica using chloroform/methanol (20:1) gave 0.18 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2([OH:17])[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][O:21][C:22]1[C:27]2[O:28][C@H:29]([CH2:32]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:30][O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[C:27]2[O:28][C@@H:29]([CH2:32][N:16]3[CH:11]4[CH2:12][CH2:13][CH:14]3[CH2:15][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=3)([OH:17])[CH2:10]4)[CH2:30][O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: OC1(c2cccc(C(F)(F)F)c2)CC2CCC(C1)N2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1cccc(C(F)(F)F)c1)C3)CO2
Yield: 68 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(3-trifluromethylphenyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 68%, white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:37][C:36](=[O:38])[NH:35][N:34]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][N:35]=[C:36]([O:38][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:37]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCCN5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Yield: 0 %

Procedure:
Using a procedure analogous to that described in Example 14, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (350 mg, 1 mol), (prepared as described for the starting material in Example 14), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (380 mg, 2 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (215 mg, 43%).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O.O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:5]2[CH:6]=[N:7][C:8]3[C:4]2=[N:3][CH:2]=[N:1][C:9]=3[NH2:10])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
In 100 ml of dimethyl sulfoxide, 4.05 g (30.0 mmol) of adenine was dissolved, and 3.5 g (31.0 mmol) of potassium tert-butoxide and 5.0 g (35.0 mmol) of 4-fluoronitrobenzene were added thereto, and the mixture solution was stirred at 80° C. for three hours. The solution was diluted with 200 mL of water and the precipitate formed was collected by filtration, washed with 100 mL of water and 30 mL of methanol in the order named and vacuum dried to obtain 7.2 g (84%) of a target product as a yellow solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[C:10]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:9]2)=CC=1.O>C(O)(C(F)(F)F)=O>[CH3:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:15]2[S:16][CH:17]=[C:13]([C:11]3[C:10]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:9][NH:8][CH:12]=3)[N:14]=2)[N:24]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4nccc(C)n4)n3)c(-c3ccccc3)n2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(Nc2nc(-c3c[nH]nc3-c3ccccc3)cs2)n1
Yield: 52.9 %

Procedure:
According to Scheme 12 Step 2: A solution of 4-(1-(4-methoxybenzyl)-3-phenyl-1H-pyrazol-4-yl)-N-(4-methylpyrimidin-2-yl)thiazol-2-amine (0.17 mmol, 77 mg) in TFA (1 mL) was stirred at 150° C. for 5 minutes under microwave heating. Water was added and was extracted with DCM. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using DCM/AcOEt (100:10 to 50:50) to yield N-(4-methylpyrimidin-2-yl)-4-(3-phenyl-1H-pyrazol-4-yl)thiazol-2-amine (90 μmol, 30 mg, 50%) as a yellow solid.