Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[NH:32]C(=O)C(C)(C)C)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.OS(O)(=O)=O>O>[NH2:32][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:26]=1[C:22]1[C:20]2[S:21][C:17]([C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][NH:13][C:12]4=[O:16])[N:4]=3)=[CH:18][C:19]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1cnccc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cnccc1-c1cccc2cc(-c3nc(NCCN4CCNC4=O)ncc3F)sc12
Temperature: 90 °C
Yield: 48 %

Procedure:
Transfer the amide intermediate to a 40 mL septum capped vial. Add a magnetic stir bar and charge water (20 mL) and concentrated H2SO4 (5 mL) to the vial. Warm the vial to 90° C. in an oil bath for 5 hours. Cool the reaction to room temperature and pass through an SCX (10 g) column. Elute with water/methanol 1:1, then 100% methanol, then 1:1 dichloromethane/methanol, and finally elute the product off with 10% 2 M ammonia in methanol/90% dichloromethane. Concentrate in vacuo. Chromatograph on silica (80 g) eluting with gradient of 0% to 10% 2 M ammonia/methanol solution in dichloromethane. Dry in vacuum oven at 42° C. for 2 hours to give the title compound (192.6 mg, 48%) as a gold solid. MS (ES) m/z 450 [M+1]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[O:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][NH2:44])[CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:44][CH2:43][CH2:42][N:39]3[CH2:40][CH2:41][O:36][CH2:37][CH2:38]3)[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(NCCN3CCOCC3)ncnc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 2-morpholino ethaneamine to obtain the title compound (see Table 1).
Reaction SMILES: C([O:8][N:9]([CH2:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([O:35]CC3C=CC=CC=3)[C:32]([NH2:34])=[O:33])=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH2:12])=[O:11])C1C=CC=CC=1.[H][H]>CN(C)C=O.C(O)C.[C].[Pd]>[OH:35][N:31]([CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]2[CH:43]=[CH:44][C:14]([CH2:13][N:9]([OH:8])[C:10]([NH2:12])=[O:11])=[CH:15][CH:16]=2)=[CH:25][CH:26]=1)[C:32]([NH2:34])=[O:33]
Reactant: [H][H]
Reactant: NC(=O)N(Cc1ccc(OCCCCOc2ccc(CN(OCc3ccccc3)C(N)=O)cc2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: NC(=O)N(O)Cc1ccc(OCCCCOc2ccc(CN(O)C(N)=O)cc2)cc1
Yield: 62 %

Procedure:
1,4-Bis[4-[(1-benzyloxyureido)methyl]phenoxy]butane (1.94 g) was dissolved in 45 ml of dimethylformamide-ethanol (8:1), mixed with 0.29 g of 10% palladium carbon and then the mixture was stirred for 22 hours at room temperature in an atmosphere of hydrogen. The catalyst was removed by filtration using Celite, and the solvent was evaporated under a reduced pressure to obtain 0.84 g of 1,4-bis[4-[(1-hydroxyureido)methyl]phenoxy]butane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].CC(C)([O-])C.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The starting 2-amino-5-nitrophenol (21.2 g, 0.14 mol) was dissolved in 350 mL THF. Solid potassium t-butoxide (15.85 g, 0.141 mol) was added slowly, with vigorous stirring. Then a solution of benzylbromide (in 150 mL THF) was added slowly and stirred at room temperature for 2 days. The solvent was removed and the crude oil poured into water (ca. 500 mL) and 3:1 ethyl acetate/methylene chloride (ca. 200 mL). The solid precipitate was filtered off and dried, then recrystallized in toluene to give 2-benzyloxy-4-nitro-phenylamine (9.1 g). The aqueous and organic layers were separated and the aqueous layer was extracted twice with 3:1 ethyl acetate/methylene chloride. The combined organic layers were washed with 5% sodium hydroxide (which formed three layers, and the middle layer contained the desired material by TLC), then the desired layer was washed twice with water, then brine, and dried over anhydrous magnesium sulfate, filtered and the solvent removed. The solid was recrystallized in toluene, filtered and dried to yield 12 g of 2-benzyloxy-4-nitro-phenylamine. (The total yield was 62%.). 1H NMR (CDCl3) 7.9-7.7 (m, 2H), 7.5-7.3 (m, 5H), 6.65 (d, 1H, J=8.68 Hz), 5.15 (s, 2H), 4.57 (br, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:22][N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:28][C:25]2[N:26]=[N:27][N:23]([CH3:22])[N:24]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Reactant: Cn1nnc(N)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC1(c2ccc(C(F)(F)F)cc2CNc2nnn(C)n2)CCCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde (118 mg, 0.393 mmol) and 2-methyl-2H-tetrazol-5-amine (148 mg, 1.49 mmol) in toluene (3 mL) was heated at reflux for 16 hours, after which solvent was removed to give a gummy solid. Ethanol (3 mL) and sodium borohydride (25 mg; 0.660 mmol) were added to the residue. The resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with water and dried over sodium sulfate and concentrated under reduced pressure. The crude was purified over 4 g RediSep (eluted with 20-60% ethyl acetate in heptane) to give 83 mg (55% yield) of title compound. MS (ES+): Calc: 383.4, Found: 352.3 (M-OMe). 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 7.48 (dd, J=8.77 Hz, 1H), 7.42 (d, J=8.30 Hz, 1H), 4.92 (d, J=6.22 Hz, 2H), 4.75 (t, J=6.22 Hz, 1H), 4.16 (s, 3H), 3.03 (s, 3H), 2.26 (m, 2H), 2.07 (m, 2H), 1.88-1.77 (m, 2H), 1.75-1.65 (m, 2H), 1.64-1.52 (m, 4H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[CH:35]1([C:38]([N:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33][CH2:34]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)C>O1CCCC1>[O:19]=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCCC(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(=O)CP(=O)(OC)OC
Temperature: -78 °C

Procedure:
A solution of 100 g. of dimethyl methylphosphonate in 670 ml. of anhydrous tetrahydrofuran is cooled to -78°C. under an argon atmosphere. To the cold solution are added dropwise under stirring and under argon atmosphere, 495 ml. of a 0.1M solution of n-butyllithium in tetrahydrofuran, maintaining the temperature at -70°C. When the addition is complete the reaction mixture is maintained under the same conditions for 10 additional minutes, a solution of 58 ml. of methyl caproate dissolved in 187 ml. of tetrahydrofuran is then carefully added, maintaining the temperature at -78°C. The reaction mixture is stirred at -78°C. for 2 hours followed by stirring for 4 hours at room temperature. The excess base is neutralized with acetic acid and the solvent is evaporated under high vacuo. The residue is dissolved in ether-water (1:1, 950 ml. each), the ethereal phase is separated, washed with water and dried over magnesium sulfate. The ether is evaporated and the residue is purified by vacuum distillation, thus obtaining the pure dimethyl 2-oxoheptylphosphonate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:7]([OH:9])=[O:8])([O-])=O.[H][H].[Na]>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:24])(=[O:25])[NH2:23])[C:12]=1[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1S(=O)(=O)c1ccccc1
Agent: [Na]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1S(=O)(=O)c1ccccc1

Procedure:
A suspension of 3-nitro-4-phenylsulphonyl-5-sulphamyl-benzoic acid (6 g) in water (300 ml) was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after addition of Pd-on-carbon catalyst (0.3 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the reaction mixture was neutralized by addition of 2N sodium hydroxde, and the catalyst was removed from the resulting suspension by filtration. The filtrate was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid, and the precipitated 3-amino-4-phenylsulphonyl-5-sulphamyl-benzoic acid was collected by suction. After recrystallization from aqueous ethanol, the acid had a melting point of 278°C (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 145 °C
Yield: 97.4 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), 1-(4-fluorophenyl) ethanone (1.406 g) and K2CO3 (2.3 g, 16.64 mmol) in DMF (18 mL) was heated with a microwave condition at 145° C. for 4 h. The solution was diluted with EA and washed with water twice, dried over Na2SO4 and concentrated in vacuo to afford the title compound (3.12 g, 97% yield) as a brown oil. LCMS: rt=3.83 min, [M+H]=315
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH3:2]
Reactant: CCOC(=O)CCNCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A solution of 1.04 g (0.005 mole) of 3-benzylamino-propanoic acid ethyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) gave 1.70 g of 3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propanoic acid ethyl ester (IV-22).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:33]=[CH:32][C:27]4[C:28](=[O:31])[O:29][CH2:30][C:26]=4[CH:25]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.[C:34]([Cu])#[N:35].O>CN(C=O)C>[O:15]=[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[C:28](=[O:31])[O:29][CH2:30][C:26]=3[CH:25]=2)[CH2:18][CH2:17]1)[CH2:13][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[C:2]([CH:3]=1)[C:34]#[N:35]
Reactant: N#C[Cu]
Reactant: O=C1OCc2cc(CCN3CCN(C(=O)Cc4ccc(-n5cnnn5)c(I)c4)CC3)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(CC(=O)N2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1-n1cnnn1
Temperature: 110 °C

Procedure:
A mixture of 5-[2-(4-{[3-iodo-4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (190 mg, 034 mmol) and CuCN (47 mg, 0.52 mmol) in 2 ml of anhydrous DMF was heated to 110° C. under N2 for 30 min. The reaction was cooled to ambient temperature, and then 15 ml of water was added. Extracted with DCM and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified via prep-TLC to afford 5-(2-oxo-2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(1H-tetrazol-1-yl)benzonitrile. 1H-NMR (400 MHz, CD3CN) δ ppm 9.36 (s, 1H), 7.85 (s, 1H), 7.72˜7.79 (m, 3H), 7.44˜7.50 (m, 2H), 5.30 (s, 2H), 3.87 (s, 2H), 2.49 (t, J=7.5 Hz, 21H), 2.64 (t, J=7.2 Hz, 2H), 2.65˜2.70 (m, 2H), 2.46˜2.53 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(F)cc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in dry DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added all in one portion. The mixture was stirred for 10 minutes at room temperature before 4-fluorobenzenesulfonyl chloride (12 mg, 0.062 mmol) was added. The reaction mixture was stirred for 10 minutes, and TFA (1 mL) was added dropwise. The reaction mixture was heated at 50° C. overnight and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.8 mg) in the form of the trifluoroacetate salt. MS m/z 381 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(N5CCN(C)CC5)CC4)c3c2)cc(Cl)c1O
Yield: 48 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (102 mg, 0.225 mmol was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (16.8 mg, 48%) as an orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (2, 1H), 8.30 (d, J=1.4 Hz, 1H), 8.08-8.00 (m, 2H), 7.33 (d, 0.1=2.1 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 4.00 (s, 3H), 3.57 (d, J=12.9 Hz, 2H), 3.34 (s, 3H), 3.24-3.16 (m, 2H), 2.79-2.52 (m, 7H), 2.36 (s, 3H), 2.11 (d, J=11.3 Hz, 2H), 1.96-1.83 (m, 2H), 1.34-1.28 (m, 2H), 126-1.19 (m, 2H); ESI MS m/z 535 [C30H35ClN4O3+H]+; HPLC>99% (AUC), tR=10.13 min.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]([CH:10]=O)[CH:8]=O)[N:4]=[CH:3][CH:2]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]1[CH:10]=[C:7]([C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=2)[CH:8]=[N:14]1
Reactant: O=CC(C=O)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: c1ccc(-c2cn[nH]c2)nc1
Temperature: 25 °C

Procedure:
2-(2-Pyridyl)-malondialdehyde (7.8 g, 52 mmol) and hydrazine hydrate (3.7 mL) were heated at 75° C. in ethanol (75 mL) for 18 h. After cooling to ambient temperature and concentration in vacuo, recrystallization from EtOAc/Hexane gave 2-(1H-pyrazol-4-yl)pyridine as gold crystals. MP=136° C. 1H NMR (CD3Cl, 300 MHz) δ 6.48-8.51 (1H, m), 8.30 (1H, br. s), 8.07 (1H, br. s), 7.74 (1H, ddd), 7.68 (1H, d), 7.15 (1H, ddd). MS (ESI) 146 (M+H)+
Reaction SMILES: COC[O:4][C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[S:15][C:16]=2[CH3:17])=[CH:8][N:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:6]=1.Cl>CO>[OH:4][C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[S:15][C:16]=2[CH3:17])=[CH:8][N:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:6]=1
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C
Agent: Cl
Solvent: CO
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-(4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (1.1 g) in methanol (20 mL) was added concentrated hydrochloric acid (0.3 mL) at room temperature, and the mixture was stirred at 50° C. for 2 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (15 mL), di-tert-butyl dicarbonate (1.4 g) and saturated aqueous sodium hydrogen carbonate (15 mL) were added, and the mixture was stirred for 30 min. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane to give tert-butyl 4-{4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (0.97 g, yield 88%) as pale-yellow prism crystals. melting point: 221-223° C.
Reaction SMILES: C1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2C([O:12][C:13](=[O:14])[C:3]=2C=1)=O>ClC1C=CC=CC=1Cl>[C:13]([OH:14])(=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Clc1ccccc1Cl
Product: O=C(O)CCCCC(=O)O
Yield: 150 %

Procedure:
A solution is formed by mixing 38.4 grams of trimellitic acid anhydride and 132.5 grams of p,p' diphenyl methane diisocyanate and 214.7 grams of o-dichlorobenzene by heating the mixture. At approximately 160°C. a clear, homogeneous solution is obtained. Once clarity is obtained 43.8 grams of adipic acid is added slowly. The temperature of the mixture is raised to approximately 160°C. and slow reflux is maintained. After approximately 35 minutes, a viscous resin is obtained and 486.3 grams of phenol are added to quench and stop the reaction. The solution is maintained at 130°C. until all the resin is dissolved. The resultant solution is cooled to room temperature and filtered. The viscosity of the product at 25°C. was measured at about 200 cps, utilizing a Brookfield viscometer, and a resin solution of approximately 30% weight resin.