Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:12]>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]cc(Cl)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cnc(Cl)c(Br)c1
Temperature: 70 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a solution of 3-bromo-5-chloropyridin-2-one (84.3 g, 0.404 tool) in DMF (100 mL) was added POCl3 (56.5 mL, 0.61 tool) via dropping funnel over 3 hours at room temperature. The resulting black solution was then heated to 70° C. and allowed to stir for 3 days. After cooling to room temperature, the solution was poured into 1L of ice/water, filtered, and the solid dried in a vacuum oven to provide 81.76 g (89%) of the desired 3-bromo-2, 5-dichloropyridine as an off-white solid, m.p. 39°-41° C.: IR(CHCl3) 3867, 3663, 2989, 2734, 1812, 1606, 1547, 1400, 1366, 1230, 1155, 1129, 1074, 1027, 894, 658, 563cm ; HNMR (300 MHz, CDCl3)δ 8.0 (d, 1H, J=2.2Hz) , 8.35 (d, 1H, J=2.2Hz); 13C NMR (CDCl3)δ 120.43, 130.74, 141.46, 146.64, 148.99; exact mass calculated for C5H2NBrCl2 =224.8748; high resolution mass spec. 224.8764.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(CC)CC)[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[N+:9]([C:5]1[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:3][C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1cc(Br)cc(-n2cccn2)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cc(-c2cccnc2)cc(-n2cccn2)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromo-2-nitro-3-pyrazol-1-yl-phenylamine (200 mg, 0.71 mmol) in THF (8 mL) was added, successively, 3-pyridyl-diethyl borane (157 mg), (tetrakistriphenylphosphine) palladium(0) (84 mg), and sodium carbonate (1.1 mL, 2.2 mmom of 2M aqueous). The resulting mixture was stirred at 70° C. overnight then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried (MgSO4) then concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel eluted with a gradient of ethyl acetate:hexanes (1:3, 1:2, 1:0, 2:1, 4:1, 8:1), to afford 120 mg (60%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 6.45 (br,s 2H), 6.55 (t, 1H), 7.1 (s, 1H), 7.25 (s, 1H), 7.55 (m, 1H), 7.7 (s, 1H), 8.1 (dt, 1H), 8.3 (d, 1H), 8.7 (d, 1H), 8.9 (s, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[N:15]1[CH:27]([CH2:28][CH:29]=O)[C:26]2[C:17](=[CH:18][C:19]([CH2:31][C:32]3[CH:33]=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[C:16]1=[O:39])(C(C)(C)C)(C)C.[CH3:40][NH:41][CH3:42].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl>[Cl:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][C:19]2[CH:18]=[C:17]3[C:16](=[O:39])[N:15]([C@H:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]4[OH:8])[CH:27]([CH2:28][CH2:29][N:41]([CH3:42])[CH3:40])[C:26]3=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)=[CH:37][CH:36]=1
Reactant: CNC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCCC[C@@H]1N1C(=O)c2cc(Cc3ccc(Cl)nc3)c3cccnc3c2C1CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)CCC1c2c(cc(Cc3ccc(Cl)nc3)c3cccnc23)C(=O)N1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of {8-[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl]-5-[(6-chloropyridin-3-yl)methyl]-7-oxo-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-9-yl}acetaldehyde (see Example 22, 0.033 g, 0.058 mmol) in 1.2 mL of 1,2-dichloroethane was added dimethylamine (2 M in tetrahydrofuran, 0.059 mL, 0.12 mmol), acetic acid (0.0034 mL, 0.058 mmol), sodium cyanoborohydride (3.7 mg, 0.058 mmol), and 4 Å molecular sieves. The mixture was irradiated in a microwave reactor at 100° C. for 20 min, cooled to ambient temperature, and filtered. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 2 mL of dichloromethane and treated with hydrochloric acid (6 M aqueous, 4 drops). After 14 hr, the mixture was diluted with dichloromethane, washed 2× with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 479.2200 for [M+H]+ [calc'd for C27H32CN4O2, [M+H]+=479.2208]: 1H NMR (400 MHz, CDCl3) δ 8.97-8.96 (m, 1H), 8.34-8.28 (m, 2H), 7.78 (s, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 5.21-5.19 (m, 1H), 4.69-4.51 (m, 1H), 4.47 (s, 2H), 3.42-3.33 (m, 1H), 3.29-3.15 (m, 2H), 2.76-2.63 (m, 1H), 2.49 (s, 6H), 2.29-2.17 (m, 2H), 1.81-1.68 (m, 2H), 1.48-1.00 (m, 5H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([F:30])[CH:32]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 3-fluorobenzyl bromide according to General Procedure B. Yield 113 mg (22%), MP 135° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.22 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.44 (s, 2H), 6.98 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 7.16 (dd, J=3.6, 4.8 Hz, 1H), 7.34 (m, 2H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.56 (d, J=6.0 Hz, 1H), 9.09 (s, 1H); EIMS: 521 (M+1). Anal. (C27H25FN4O4S) C, H, N.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH2:11].[Cl:12][CH2:13][C:14](Cl)=[O:15]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][CH2:13][C:14]([NH:11][CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CC12CCC(C1)C(C)(C)C2N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC12CCC(C1)C(C)(C)C2NC(=O)CCl
Reaction time: 12 h

Procedure:
To a solution of 1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine (5 g, 26.3 mmol) in methylene chloride (20 ml) and triethylamine (4 ml) was added chloroacetyl chloride (2.1 ml, 26.4 mmol) dropwise. The resulting solution was stirred for 12 hours, then the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water, the organic layer washed with brine, and dried over magnesium sulfate. The ethyl acetate solution was absorbed onto silica gel, which was eluted with 10% ethyl acetate/hexane, to yield 2-chloro-N-(1,3,3-trimethylbicyclo[2,2,1]hept-2-yl)acetamide as a white solid. B. Preparation of a Compound of Formula (1) in which R1 is Cyclohexyl and R2 is Phenyl
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[C:20]1(=[O:21])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([O:1][S:39]([C:35]4[S:34][CH:38]=[CH:37][CH:36]=4)(=[O:41])=[O:40])=[CH:3][CH:4]=3)[CH2:9]2)[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]12
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(O)cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(OS(=O)(=O)c3cccs3)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A stirred mixture of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (2.94 g, 8.4 mmol) and triethylamine (1.4 ml, 10 mmol) in dichloromethane (75 ml) was treated with 2-thiophenesulfonyl chloride (1.69 g, 9.2 mmol). After stirring at room temperature for 18 h the mixture was washed with saturated aqueous sodium bicarbonate (100 ml). The aqueous layer was separated and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica using 30-100% ethyl acetate-pentane gradient elution to afford the title compound as a pale yellow oil (3.45 g, 83%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:8][CH:9]=3)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)nc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A stirred suspension of 6-(4-pyridyl)nicotinic acid (400 mg, 2 mmol) in dimethylformamide, DMF, (10 ml) was treated with 1-(5-chloroindol-2-ylsulphonyl)piperazine (600 mg, 2 mmol, 1 mol eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (EDAC, 460 mg, 2.4 mmol, 1.2 mol eq.). After stirring overnight the solvent was removed in vacuo and the residue chromatographed (Isolute 20 g silica cartridge, eluting with dichloromethane containing 2.5%-5% v/v of methanol) to yield 1-(5-chloroindol-2-ylsulphonyl)-4-[6-(4-pyridyl)nicotinoyl]piperazine as a colourless foam (680 mg). This was dissolved in dichloromethane/methanol mixture (40 ml of 1:1) and treated with a saturated solution of HCI in methanol until acid to indicator paper (slight excess). The resulting solution of hydrochloride salt was evaporated to dryness and the residue boiled in 2-propanol (100 ml, incomplete solution). Filtration and cooling gave 1-(5-chloroindol-2-ylsulphonyl)-4-[6-(4-pyridyl)nicotinoyl]piperazine hydrochloride as a colourless solid, (220 mg), 1H NMR (d6-DMSO) 3.0-3.3 (broad d, 4H), 3.6-4.0 (broad d, 4H), 7.05 (s, 1H), 7.35 (dd, 1H), 7.5 (d, 1H), 7.8 (d, 1H), 8.1 (dd, 1H), 8.35 (d, 1H), 8.5 (m, 2H), 8.8 (d, 1H), 8.95 (d, 2H), 12.4 (s, 1H), signals were also present due to 2-propanol (0.5 mol equiv.); MS (M+H)+ 481/483; mp 186-190° C. (not sharp).
Reaction SMILES: C[O:2][C:3](=[O:5])[O-:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8].O>CO>[C:3](=[O:2])([O-:5])[OH:4].[CH3:6][N+:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: CO
Solvent: O
Product: O=C([O-])O
Reaction time: 3 h

Procedure:
108.0 g of tetramethylammonium monomethylcarbonate, 72.0 g of water and 32.0 g of methanol were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 100° C., the reaction was continued for 3 hours at 100° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 98.5 mol %.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][C:12]3=[CH:15][NH:16][N:17]=[C:11]3[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:14][CH2:13]3)=[N:17]2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: c1ccc(CN2CCc3c[nH]nc3CC2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1ccc(-n2cc3c(n2)CCN(Cc2ccccc2)CC3)cn1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 6-(phenylmethyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 5) (200 mg, 0.88 mmol), (6-bromo-3-pyridinyl)boronic acid (355 mg, 1.76 mmol), copper acetate (478 mg, 2.64 mmol), pyridine (0.142 ml, 1.76 mmol) and molecular sieves (600 mg) in dichloromethane (10 ml) was allowed to stir at room temperature in a flask open to the atmosphere for 240 hours. The reaction mixture was filtered through a pad of celite, washing with dichloromethane and methanol. The filtrate was evaporated, redissolved in methanol and passed down a 10 g SCX cartridge, eluting with methanol, then a 2 M solution of ammonia in methanol. The basic fractions were combined, evaporated and purified by column chromatography, eluting with a mixture of 2M ammonia in methanol and dichloromethane (0-10%). The impure product was re-purified using reverse phase chromatography, eluting with a mixture of acetonitrile and water (5-100% and 3-60%) to afford the product (D15); MS (ES+) m/e 383 & 385 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:47][CH2:48][CH2:49][N:50]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:51]1[CH2:57][C:54]2([CH2:56][CH2:55]2)[O:53][CH2:52]1)(=O)=O>CN(C)C(=O)C>[CH2:55]1[C:54]2([CH2:57][CH:51]([N:50]([CH2:49][CH2:48][CH2:47][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[N:17][CH:18]=5)=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[CH2:52][O:53]2)[CH2:56]1
Reactant: CC(C)(C)OC(=O)N(CCCOS(C)(=O)=O)C1COC2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCCCN(C(=O)OC(C)(C)C)C5COC6(CC6)C5)ccc34)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (200.6 mg, 0.44 mmol) and cesium carbonate (684.6 mg, 2.1 mmol, Aladdin) in N,N-dimethylacetamide (1 mL) was added (N-(4-oxaspiro[2.4]heptane-6-yl)-tert butoxycarbonylamino)propyl methanesulfonate (0.63 mmol) in N,N-dimethylacetamide (5 mL). After stirring at 40° C. for 2 days, the reaction mixture was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:4 (v/v) n-hexane/EtOAc) to give the title compound as a white solid (200 mg, 62.5%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.Cl.[NH:14]=[C:15]1[CH2:19][CH2:18][CH2:17][NH:16]1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH:2]=1
Reactant: N=C1CCCN1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 2-bromo-1-(2,4-difluorophenyl)ethanone (7.05 g, 30.0 mmol, prepared using General Procedure A.1 from 1-(2,4-difluorophenyl)ethanone), 2-imino-pyrrolidine hydrochloride (10.9 g, 90 mmol, prepared following the procedure in J. Med. Chem., 2002, 45, 999-1001) and Na2CO3 (21.1 g, 199 mmol) in DMF (30 mL) was stirred overnight at about 80° C. The reaction mixture was cooled to ambient temperature, poured into water and extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude title compound (6.61 g, 100%): LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 221.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:10])=[CH:4][C:3]=1[CH3:17].BrC1C=CC(N)=CC=1C.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][CH2:36][C:29]2[C:30]3[C:35](=[N:34][CH:33]=[CH:32][CH:31]=3)[NH:27][CH:28]=2)=[O:10])=[CH:4][C:3]=1[CH3:17]
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Cc1cc(NC(=O)c2sccc2N)ccc1Br
Agent: Cc1cc(N)ccc1Br
Product: Cc1cc(NC(=O)c2sccc2NCc2c[nH]c3ncccc23)ccc1Br

Procedure:
EXAMPLE 9 was prepared according to the procedure described in EXAMPLE 5 using N-(4-bromo-3-methylphenyl)3-aminothiophene-2-carboxamide (prepared as described in EXAMPLE 1, part 1, using 4-bromo-3-methylaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 441, 443 [MH+]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Cl[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:15]1[C:10]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[N:11][CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1
Reactant: Nc1cc(O)ccn1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(N)c1
Yield: 44.7 %

Procedure:
Mix 2-aminopyridin-4-ol (3.3 g, 30 mmol), 2-chloro-3-methyl-5-nitropyridine (5.17 g, 30 mmol) in anhydrous DMF (50 mL), add K2CO3 (8.28 g, 60 mmol). Stir the reaction at 90° C. overnight. Concentrate under reduced pressure to give crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (3.3 g, 45%). MS: (M+1): 247.1.
Reaction SMILES: N[C@H](C(N1CCC[C@H]1C(O)=O)=O)CC(C)C.N[C@H](C(N1CCC[C@H]1C(O)=O)=O)CC1C=CC=CC=1.[NH2:36][C@H:37]([C:42]([N:44]1[CH2:52][CH2:51][CH2:50][C@H:45]1[C:46]([O:48][CH3:49])=[O:47])=[O:43])[CH2:38]CSC.N[C@H](C(N1CCC[C@H]1C(OC)=O)=O)CCCC>>[NH2:36][C@H:37]([C:42]([N:44]1[CH2:52][CH2:51][CH2:50][C@H:45]1[C:46]([O:48][CH3:49])=[O:47])=[O:43])[CH3:38]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCSC
Agent: CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC
Agent: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N

Procedure:
Instead of Z-Ala-OH, (a) Z-Val-OH, (b) Z-Leu-OH, (c) Z-Phe-OH, (d) Z-Met-OH and (e) Z-norLeu-OH were used as starting compounds to obtain (a') H-Val-Pro-OMe, (b') H-Leu-Pro-OH, (c') H-Phe-Pro-OH, (d') H-Met-Pro-OMe and (e') H-norLeu-Pro-OMe as oils, respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH:16]=O)[CH2:11]2.[C:19]1([N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26](=[O:29])[NH:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26](=[O:29])[NH:27][N:28]=[CH:16][CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[CH:15][C:6]=3[O:5][CH2:4][C:3]([O:2][CH3:1])=[O:18])[CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NNC(=O)N(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1CCC(C=O)C2
Solvent: CCO
Product: COC(=O)COc1cccc2c1CCC(C=NNC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of methyl(2-formyl-1,2,3,4-tetrahydronaphthalen-5-yl)oxyacetate (248 mg), prepared by the same procedure as reference example 1, m ethanol (10 ml) was added 4,4-diphenylsemicarbazide (0.27 g) under an atmosphere of argon. After stirred for 1 h at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:methylene chloride=3:100) to give the title compound (444 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(c2ncc(Br)cn2)CC1
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5 g, 25.8 mmol), piperidin-4-ol (2.88 g, 28.4 mmol) and triethylamine (5.40 mL, 38.8 mmol) in EtOH (51.7 mL) was heated at 90° C. for 0.5 h. The solvent was evaporated, the residue was diluted with 1N HCl (20 mL) and extracted with EtOAc (3×15 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated. The product was recrystallized from CH2Cl2/hexanes, filtered and washed with hexanes to afford the title product.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=1>>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[N:18][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Nc1ccc(N)nc1
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(N)nc2)n1

Procedure:
The title compound was prepared following the procedure of Example 49, utilizing 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine and 2,5-diaminopyridine (Aldrich). LCMS (API-ES) m/z 295 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.52 (s, 1H); 8.75 (d, J=7.83 Hz, 1H); 8.74 (dt, J=7.83, 1.08 Hz, 1H); 8.34 (d, J=2.74 Hz, 1H); 8.27 (d, J=1.76 Hz, 1H); 8.26 (d, J=2.15 Hz, 1H); 7.87 (d, J=8.80 Hz, 1H); 7.88 (dt, J=9.00, 1.08 Hz, 1H); 7.68 (br. s., 1H); 6.83 (dd, J=7.82, 4.70 Hz, 1H); 6.62 (d, J=8.80 Hz, 1H); 2.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(Cl)nn1
Product: Clc1ccc(OCc2ccccc2)nn1

Procedure:
3,6-Dichloropyridazine (10.0 g, 67.12 mmol) was reacted analogously to example 4a with benzyl alcohol (6.95 ml, 67.12 mmol). Yield: 12.82 g (87%), M+H+: 221.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)[N:16]=2)=[O:14])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (77)(100 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.