Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[CH:46]=[CH:45][C:44]=1[F:52]>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[F:52][C:44]1[CH:45]=[CH:46][C:47]2[N:48]([CH:49]=[CH:50][N:51]=2)[C:43]=1[C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[C:8]2[S:28][C:27]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]3)=[CH:26][C:9]=2[N:10]=1
Reactant: Fc1ccc2nccn2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4c(F)ccc5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 150 °C
Yield: 37.1 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (69 mg, 0.10 mmol), 5-bromo-6-fluoro-imidazo[1,2-a]pyridine (25 mg, 0.12 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and copper(I) thiophene-2-carboxylate (4 mg, 0.02 mmol) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 214 as a white solid (20 mg, 37%). LCMS (Method G) RT 4.52 min; [M+H]+ 539. 1H NMR (400 MHz, CHCl3-d): 8.20 (s, 1 H); 7.71-7.62 (m, 2 H); 7.35 (s, 1 H); 7.25-7.16 (t, J=9.5 Hz, 1 H); 7.18-6.91 (m, 1 H); 5.22 (s, 1 H); 4.05 (t, J=4.7 Hz, 4 H); 3.87 (t+m, J=4.7 Hz, 6 H); 2.62 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:36]=[N:37][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:24][S:21]([CH2:20][CH2:19][NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:33]2[CH:34]=[C:35]([NH:39][S:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)(=[O:41])=[O:42])[CH:36]=[N:37][CH:38]=2)=[CH:3][CH:4]=3)[CH2:13][CH2:14]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)CCNC1CCN(c2cnc3ccc(Br)cc3n2)CC1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)CCNC1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A slurry of a 1-(7-bromo-2-quinoxalinyl)-N-[2-(methylsulfonyl)ethyl]-4-piperidinamine (0.48 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.53 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 3 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (10% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (15 mg, 6%) as a tan solid. MS(ES)+ m/e 567.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (34 mg, yield 74%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[C:15](=[CH:18]OCC)[C:16]#[N:17])[CH3:12].C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[NH2:17][C:16]1[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:22])=[CH:18][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[N:10]=1
Reactant: NNc1cccc(Br)c1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1N
Yield: 94.2 %

Procedure:
To a solution of 3-bromophenylhydrazine hydrochloride (2.25 g, 10.1 mmol) in acetic acid (15.1 mL) and water (5.04 mL) were added ethyl(ethoxymethylene)cyanoacetate (1.88 g, 11.1 mmol) and sodium acetate (3.02 g, 22.2 mmol), and the solution was refluxed for 16 hours. The reaction was cooled and quenched with ice-water. The precipitate formed was filtered, washed with water and dried under vacuum for 24 hours to give 2.95 g of the titled compound (93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][C:21](O)=O>C(OCC)(=O)C>[CH3:16][C:14]([CH3:15])([OH:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:21]1[CH2:20][O:19][CH3:18]
Reactant: COCC(=O)O
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CCOC(C)=O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 170 °C
Yield: 9.9 %

Procedure:
3-Amino-4-(2-hydroxy-2-methylpropylamino)quinoline (7.5 g, 32 mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heated at about 170° C. for about 3 hours. The resulting solid residue was dissolved in ethyl acetate (150 mL). The ethyl acetate solution was extracted twice with 0.2N sodium hydroxide, washed with water, dried over magnesium sulfate, treated with activated charcoal and then concentrated to a volume of about 50 mL. Hexane was added to the ethyl acetate and the resulting precipitate was collected and dried to provide 0.9 g of the desired product as a crystalline solid, m.p. 145°-148° C. Analysis: Calculated: % C, 67.3; % H, 6.7; % N, 14.7; Found: % C, 67.2; % H, 6.6; % N, 14.6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCCCC#Cc1cccc(CCCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCCCC#Cc1cccc(CCCN)c1

Procedure:
tert-Butyl 3-(3-(6-methoxyhex-1-ynyl)phenyl)propylcarbamate was deprotected following the method used in Example 13 except that CH2Cl2 was used as a cosolvent in the reaction (HCl-dioxane solution: CH2Cl2 7:5). Purification by prep HPLC (Method 2P) gave 3-(3-(6-methoxyhex-1-ynyl)phenyl)propan-1-amine hydrochloride as an off white solid. Yield (0.050 g, 30%): 1H NMR (400 MHz, CDCl3) δ 8.37 (br s, 3H), 7.10-7.24 (m, 4H), 4.02 (t, J=6.4 Hz, 2H), 3.78 (s, 3H), 2.98 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H), 2.04-2.12 (m, 2H), 1.82-1.89 (m, 2H), 1.63-1.73 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:44])=[C:16]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24](=[O:33])[CH2:25][N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:45][I:46]>>[I-:46].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:44])=[C:16]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([CH2:25][N:26]5[CH2:31][CH2:30][N+:29]([CH3:45])([CH3:32])[CH2:28][CH2:27]5)=[O:33])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CI
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CC[N+](C)(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Product: [I-]

Procedure:
The title compound was prepared from N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-2-(4-methyl-piperazin-1-yl)-acetamide (Ex. 18, 130 mg, 0.22 mmol) and MeI (27 μL, 0.880 mmol.) using a similar method to that employed for Example 15 (105 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19]([O:21]CC)=O)[N:10]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:9]2=[O:31])=[O:5])[CH3:2].C(OC(=O)C1C(C)=C[C:43]([NH:47]C(=O)CCC(OCC)=O)=[C:39](C(O)=O)C=1C)C.ClC1C=CC=CC=1N.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH2:17][CH2:18][C:19](=[O:21])[NH:47][CH2:43][CH3:39])[N:10]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:9]2=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Reactant: CCOC(=O)CCC(=O)Nc1cc(C)c(C(=O)OCC)c(C)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1Cl
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: CCNC(=O)CCc1nc2cc(C)c(C(=O)OCC)c(C)c2c(=O)n1-c1ccccc1Cl
Temperature: 130 °C

Procedure:
3-(2-Chlorophenyl)-2-(2-ethoxycarbonylethyl)-5,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-carboxylic acid ethyl ester: A stirred mixture of 4-(3-ethoxycarbonylpropionylamino)-2,6-dimethylisophthalic acid 1-ethyl ester (0.327 g, 0.89 mmol), 2-chloroaniline (0.28 mL, 2.66 mmol) and phosphorus trichloride (0.74 g, 5.4 mmol) in toluene (6 mL) is heated at 130° C. for 3 h. Upon cooling to room temperature, the reaction mixture is poured onto saturated sodium hydrogen carbonate solution and extracted with chloroform. The chloroform extracts are combined, washed with brine and dried over anhydrous MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography over silica gel (initial eluent: 19:1 cyclohexane:ethyl acetate; final eluent: 7:3 cyclohexane:ethyl acetate) to afford the title compound.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:37](N(CC)CC)C.[CH3:44][C:45]([CH3:50])([CH3:49])[C:46]([OH:48])=[O:47]>CN(C)C=O>[ClH:1].[CH3:44][C:45]([CH3:50])([CH3:49])[C:46]([O:48][CH2:37][O:20][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[C:13]([C:22](=[O:36])[CH2:23][N:24]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=[CH:11][C:10]=2[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21])=[O:47]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)C(=O)O
Reactant: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.00 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid hydrochloride, 1.4 ml of triethylamine, and 1.12 ml of the chloromethyl ester of trimethylacetic acid are combined with 15 ml of absolute dimethylformamide and stirred for 16 hours at room temperature. Then the mixture is concentrated, the residue dissolved in ethyl acetate, extracted three times with water, the organic phase is dried and concentrated, and the residue is chromatographed over an aluminum oxide column (activity stage II; eluent: cyclohexane/ethyl acetate 4+1). The product is recrystallized from diisopropyl ether/ethereal hydrochloric acid, yielding 0.7 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid trimethylacetoxymethyl ester hydrochloride, decomposition point 184°-185° C.
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:23])[CH2:4]2)[O:2]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O.[Cr]>[CH2:25]1[CH2:1][O:2][C:3]2([CH2:20][C@H:19]([CH3:21])[C@@:18]3([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C:12]3=[O:23])[CH2:4]2)[O:24]1
Reactant: C[C@H]1CC2(C[C@@H]3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31C)OCCO2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Cr]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CC2(C[C@@H]3CC[C@@H]4[C@H](CC[C@]5(C)C(=O)CC[C@@H]45)[C@]31C)OCCO2
Yield: 100.6 %

Procedure:
35 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol is stirred in 350 ml of dimethylformamide with 70 g of pyridinium dichromate for 17 hours at room temperature. The reaction solution is stirred into ten times the amount of ethyl acetate, then the thus-separated chromium salts are left behind by decanting, and the organic phase is washed with water. After drying and evaporation, 35 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one is produced, mp 154° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10]2[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=2[C:12](=[O:14])[CH2:13]1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccccc2Br)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccnc2c1C(=O)CC(c1ccccc1Br)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a mixture of 5-(2-bromophenyl)cyclohexane-1,3-dione (1.5 g), 1-amino-2-butyne hydrochloride (0.59 g) and tetrahydrofuran (30 ml) was added triethylamine (0.57 g). The mixture was stirred at room temperature for 1 hour, refluxed for 13 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and to the residue was added diphenylether. The mixture was stirred at 250° C. for 12 hours and cooled, and to the mixture was added diethylether. The mixture was extracted with 1N hydrochloric acid, and the aqueous layer was washed with diethylether, neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals of 7-(2-bromophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.52 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Br:17][C:18]1[CH:19]=[C:20]([F:37])[C:21]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31](Cl)[N:30]=2)=[C:22]([CH:27]=1)[C:23]([NH:25][CH3:26])=[O:24]>>[Br:17][C:18]1[CH:19]=[C:20]([F:37])[C:21]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:30]=2)=[C:22]([CH:27]=1)[C:23]([NH:25][CH3:26])=[O:24]
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
5-Bromo-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as an off-white foam (22 mg, 12%). LCMS (m/e) 577 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.07 (s, 1H), 7.48 (s, 1H), 7.44 (d, 1H, J=9.3 Hz), 7.19 (s, 1H), 7.06-6.97 (m, 2H), 6.91 (d, 1H, J=8.1 Hz), 6.28-6.18 (m, 1H), 3.57 (t, 2H, J=5.6 Hz), 3.38 (s, 3H), 2.90 (d, 3H, J=4.9 Hz), 2.92-2.84 (m, 2H), 2.83-2.65 (m, 8H); 19F-NMR (CDCl3, 400 MHz) δ −109.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]([Sn](CC)(CC)CC)[CH3:15]>CCOC(C)=O>[CH2:14]([C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[CH3:15]
Reactant: O=[N+]([O-])c1cc(Br)c2scnc2c1
Reactant: CC[Sn](CC)(CC)CC
Solvent: CCOC(C)=O
Product: CCc1cc([N+](=O)[O-])cc2ncsc12
Yield: 75.9 %

Procedure:
A solution of 7-bromo-5-nitrobenzothiazole (0.15 g, 0.58 mmol), tetraethyltin (0.18 mL, 0.87 mmol) and catalytic amount of Cl2Pd(PPh3)2 in a sealed tube was stirred for 12 h at 90° C. The reaction mixture was diluted with EtOAc and washed with brine several times. Organic solution was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (EtOAc, neat) to provide 91 mg (0.44 mmol, 75%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=O.CC([O-])=O.[Na+].Cl.[OH:26][NH2:27]>CO>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[N:27][OH:26]
Reactant: NO
Reactant: COc1c(C=O)ccc2c1ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C=NO)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A 1 L three-necked round bottom flask equipped with a magnetic stirrer was dried and cooled under a stream of nitrogen then charged with 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (15 g, 0.057 mol, 1.0 equiv.), NaOAc (15.67 g, 0.12 mol, 2.0 equiv.), hydroxyamine hydrochloride (8.01 g, 0.12 mol, 2.0 equiv.) and MeOH (300 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then concentrated and the residue was dissolved in EtOAc (1000 mL). The organic layer was washed with water (2×300 mL) and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde oxime (14.5 g, 93% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
The compound of formula 3a was prepared according to the procedure of Shani, J. etal., J. Med. Chem, 1985, 28, 1504. Thus, a mixture of 4-nitrobenzoyl chloride (90 g, 0.48 mol) and anisole (57.24 g, 0.53 mol) in carbon disulfide (450 mL) was stirred in a three neck round bottom flask equipped with nitrogen inlet, condenser and mechanical stirrer that was being cooled in an ice bath. Aluminum chloride (84.0 g, 0.63 mol) was added in portions and stirring continued at ice bath temperature for 30 minutes, then at room temperature for an additional 1 hour. The reaction mixture was cooled, treated with concentrated hydrochloric acid (150 mL), diluted with cold water (250 mL). The product was collected, filtered, washed, dried, and crystallized from ethyl acetate to give 4-(4-methoxybenzoyl)-nitrobenzene as an off-white solid, m.p. 120-122° C.; Analysis for C14H11NO4: Calc.: C, 65.3; H, 4.31; N, 5.44; Found: C, 65.22; H, 4.16; N, 5.69.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]1CCN2C(=NCCC2)CC1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([O:12][CH3:28])=[CH:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Product: COC1=CC(=O)OC(CCc2ccc(C(C)(C)C#N)c(F)c2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A magnetically stirring solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile (− rotation, 0.15 g, 0.40 mmol) was cooled to 0° C. DBU (0.18 mL, 1.21 mmol) was added followed by Mel (0.076 mL, 1.21 mmol) and reaction was stirred at 0° C. for 1 hour. The reaction mixture was partitioned between 1N HCl and EtOAc. The layers of the resulting reaction mixture were separated and the organic layer was washed with brine (1×10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography (20% EtOAc in Hexanes) to give the desired product as a yellow oil (0.062 g, 41%). 1H NMR (400 MHz, CDCl3): δ 1.18 (d, J=6.5 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H), 1.50–1.78 (m, 8 H), 1.94–2.05 (m, 2 H), 2.18 (s, 3H), 2.64–2.73 (m, 3 H), 3.75 (s, 2 H), 5.17 (s, 1 H), 6.89–6.97 (m, 2 H), 7.35–7.40 (m, 1 H). MS (ESI): 386 (M+H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 80 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and [(tert-butoxycarbonyl)amino]acetic acid, the title compound was obtained in 80% yield (78.2% purity by HPLC).