Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)Cl>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:20](=[O:23])[CH2:21][CH3:22])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(Nc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A stirred mixture of 1.84 g (10.0 mmol, 1 eq.) of commercial N-phenyl-1,4-phenylenediamine (a black solid) and 1.18 g (14.0 mmol, 1.4 eq.) of NaHCO3 in 40 mL of CH2Cl2 was cooled to 0° C. To this suspension was added a solution of 0.96 mL (11.0 mmol, 1.1 eq.) of propionyl chloride in 10 mL of CH2Cl2 dropwise. The ice bath was removed and the mixture stirred for 1 hour and then poured into a seperatory funnel containing 50 mL of each CH2Cl2 and water. The organic phase was separated and extracted with 50 mL of saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (100 g SiO2, 1:1 ethyl acetate-hexanes) to give 1.79 g (75%) of product. 1H NMR (300 MHz, CDCl3) δ7.41 (d, 2H), 7.21-7.43 (m, 2H), 7.14 9 (bs, 1H), 6.96-7.07 (m, 4H) 6.90 (t, 1H), 5.66 (bs, 1H), 2.38 (q, 2H), 1.25 (t, 3H). MS (DCl) m/e 258 (M+NH4)+, 241 (M+H)+.
Reaction SMILES: [CH2:1]([C:3](=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])[CH:4]=O)[CH3:2].C(O)(=O)C(O)=O.[CH2:34]([O:36][P:37]([CH2:42][CH2:43][NH2:44])(=[O:41])[O:38][CH2:39][CH3:40])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH2:39]([O:38][P:37]([CH2:42][CH2:43][NH:44][CH2:4][C:3]([CH2:1][CH3:2])=[CH:6][CH2:7][C:8]1[C:9]([O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:10]2[C:14](=[C:15]([CH3:19])[C:16]=1[CH2:17][CH3:18])[CH2:13][O:12][C:11]2=[O:20])(=[O:41])[O:36][CH2:34][CH3:35])[CH3:40]
Reactant: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CCOP(=O)(CCN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCNCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CC)OCC
Reaction time: 8 h
Yield: 66.1 %

Procedure:
2-Ethyl-4-[6-ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-but-2-enal (26.6 mg, 0.068 mmol) and aminoethylphosphonic acid diethylester oxalate salt (20.4 mg, 0.075 mmol) were dissolved in DMF (0.8 mL). Acetic acid (20.5 mg, 0.342 mmol) was added, followed by sodium triacetoxyborohydride (27.6 mg, 0.137 mmol). After 8 hours, the crude reaction mixture was purified by RP-HPLC (eluent: water/MeCN) to provide 24.9 mg (65%) of the desired product after lyophilization. 1H NMR (300 MHz, CDCl3): δ=0.05 (s, 9H), 1.10-1.24 (m, 8H), 1.35 (t, J=7.5 Hz, 6H), 2.19 (s, 3H), 2.23 (m, 2H), 2.35 (q, J=7.8 Hz, 2H), 2.70 (q, J=7.2 Hz, 2H), 3.25 (m, 2H), 3.56 (m, 4H), 4.15 (m, 4H), 4.29 (m, 2H), 5.15 (s, 2H), 5.47 (m, 1H) ppm; 31P NMR (121 MHz, CDCl3): δ=27.71 ppm; MS=554 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:19][CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)c1ccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(4-tert-butyl-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14]O)=[O:6])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:33])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][F:33])=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCF)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (0.40 g) obtained in Example 113 in dichloromethane (4.5 ml) was added diethylaminosulfur trifluoride (0.18 ml) at −78° C. The reaction mixture was stirred for 5 hr while gradually heating to room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column (hexane/ethyl acetate=6/4 to ethyl acetate). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (0.024 g, 6%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10].[ClH:14]>CN(C=O)C>[C:9]([C:8]1[CH:11]=[C:4]([C:3]([Cl:14])=[N:2][OH:1])[CH:5]=[CH:6][C:7]=1[O:12][CH3:13])#[N:10]
Reactant: COc1ccc(C=NO)cc1C#N
Reactant: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(Cl)=NO)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-[(Hydroxyimino)methyl]-2-methoxybenzonitrile, 4 M hydrochloric acid and Oxon (registered trade name) were dissolved in a solution of DMF, followed by stirring at room temperature for 12 hours to obtain 3-cyano-N-hydroxy-4-methoxybenzenecaboximidoyl chloride. NMRC: 7.01 (1H, d), 8.03 (1H, dd), 8.07 (1H, d).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]23[CH2:13][N:10]4[CH2:11][CH:12]2[CH:8]3[CH2:9]4)=[N:5][S:4][N:3]=1.O.[SH2:15].[Na]>CN(C=O)C>[C:7]12([C:6]3[C:2]([SH:15])=[N:3][S:4][N:5]=3)[CH2:13][N:10]3[CH2:11][CH:12]1[CH:8]2[CH2:9]3
Reactant: Clc1nsnc1C12CN3CC1C2C3
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nsnc1C12CN3CC1C2C3
Yield: 57.5 %

Procedure:
A solution of 1-(3-chloro-1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.02,6 ]heptane (3.0 g, 14 mmol) and sodium hydrogensulfide, monohydrate (3,14 g, 42 mmol) in dry DMF (80 ml) was stirred at room temperature under nitrogen for 1 h. The solvent was evaporated. Water was added and pH adjusted by addition of 4N HCl (pH 9). The mixture was cooled on ice and the product isolated by filtration to give 1,7 g (58%) of the title compound. M.p. 205-207° C. (Compound 26).
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=CC3C(=CC(C=[O:47])=C4C=3C=CC=C4)C=2C=CC=1.C(O)C(N)(CO)CO>CO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][OH:47])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CO
Solvent: CCOCC
Product: OCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and tris(hydroxymethyl)aminomethane (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol hydrochloride, mp 238°-239° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]([Cl:22])[C:11]=1[C:12]([OH:14])=[O:13].CN(C)C1C=CC=CC=1>CCOCC>[Cl:22][C:15]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reaction time: 2.67 h

Procedure:
A mixture of 10.7 g of p-toluidine, 11.8 g of 2,6-dichloro-3-nitrobenzoic acid and 25 ml of N,N-dimethylaniline was stirred at 135° for 160 minutes. The mixture was diluted with ether and extracted with 1N aqueous sodium hydroxide. Acidification of the aqueous solution, extraction with chloroform, and evaporation of the extract provided 6-chloro-2-[(4-methylphenyl)amino]-3-nitrobenzoic acid as orange prisms, mp 192°-197° C.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C:5]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=1[NH2:7].[OH-].[Na+].O.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>C1(C)C(C)=CC=CC=1>[CH3:3][N:4]1[C:5]2[C:6](=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[NH:7][C:18](=[O:19])[C:17]1=[O:21]
Reactant: CNc1ccc(OC)cc1N
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Temperature: 25 °C

Procedure:
2-Methylamino-5-methoxyaniline dihydrochloride (0.256 mol) is neutralized with sodium hydroxide (22 g., 0.5 mol) in 80 ml. of water. The free amine is extracted into 300 ml. of xylene, the solution dried over magnesium sulfate, and filtered. This solution is then added over 50 min. to a solution of oxalyl chloride (39 g., 0.307 mol) in 300 ml. of xylene held at 75°-90° C. After addition is complete, the resulting solution is heated to a bath temperature of 155° and then allowed to cool to room temperature. The flask is cooled to 0° and the gray precipitate collected by vacuum filtration. The solid product is then dried under high vacuum at 160° for two hours.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:16]=1[F:24])[CH3:31]
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)c1c(F)cccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
Potassium tert-butoxide (1 M in THF, 8,67 ml) is added (dropwise over 5 min) to a solution of N-(tert-butyloxycarbonyl)-2-fluoro-6-nitroaniline (XIX, EXAMPLE 21, 1.85 g) in THF (15 ml) cooled at 0°. After 20 min, ethyl bromoacetate (0.96 ml) is added dropwise over several minutes. The ice bath is removed and the reaction is stirred for 2 h, after which it is partitioned between ethyl acetate, aqueous sodium bicarbonate and saline. The phases are separated, the organic phase is dried over magnesium sulfate and concentrated to give the title compound, NMR (CDCl3) 1.26, 1.35, 1.50, 3.98, 4.10, 4.20, 4.42, 4.45, 7.42 and 7.39 δ.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9 g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H), 3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.29-1.20 (m, 3H). MS (APCI+) [M+H] +377. The resulting mixture of the diastereomers was purified by chiral separation HPLC (Chiralcel ODH column, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak (RT=3.73 min) gave the tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.172 g, 29%). MS (APCI+) [M+H] +377.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].CO.Cl.[CH3:27][S:28]([NH:31][NH2:32])(=[O:30])=[O:29]>O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:32][NH:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Reactant: CS(=O)(=O)NN
Agent: Cl
Solvent: O
Solvent: CO
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NNS(C)(=O)=O
Reaction time: 0.02 h

Procedure:
To the ester of Example 4, Step B (0.5 g, 1.6 mmol) was added 10 ml MeOH, 0.4 ml 1N HCl and 0.37 ml H2O. The mixture was stirred one minute followed by addition of CH3SO2NHNH2 all at once. After overnight stirring, the MeOH was evaporated and additional water was added. This aqueous phase was twice extracted with CH2Cl2. The organic phase was concentrated to a crude solid and purified by flash chromatography using CH2Cl2 --EtOAc 95-5 as eluent. The product 0.33 g, was obtained as a solid m.p. 80°-82° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]1[CH2:14][O:13][S:10](=[O:12])(=[O:11])[CH2:9][CH2:8]1>C(O)(C)C>[N:1]1([CH2:14][CH2:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCCCO1
Reactant: C1COCCN1
Solvent: CC(C)O
Product: O=S(=O)(O)CCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 18 %

Procedure:
Morpholine (3.56 g) was dissolved in isopropanol (25 ml) and treated with 1,4-butane sultone (5.58 g) at 10° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 days. The white precipitate that had formed was filtered and dried to give the title compound (1.64 g). Mass spec MH+ (found) 224 MH+ (calc) 224.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH:8]([CH3:12])[C:9](Br)=[O:10]>C1(C)C=CC=CC=1>[Br:7][CH:8]([CH3:12])[C:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10]
Reactant: CC(Br)C(=O)Br
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)N1CCCCC1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Piperidine (73.3 grams; 0.91 moles) is dissolved in 400 cc of toluene and the solution is cooled to -10° C. There is added dropwise, (45.3 cc; 0.45 moles) of 2-bromopropionyl bromide while the temperature is not allowed to exceed -5° C. over a period of three hours. The mixture is stirred again for four hours, while the temperature is allowed to rise, then the mixture is filtered and the filtrate is evaporated under reduced pressure. The product boils at 102° C. (0.3 mm); IR (neat) νmax: 2940, 2860, 1650, 1450, 1380, 1260, 1140, 1020 cm-1. The product is a liquid very irritating to the skin and mucosae.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([Br:18])[CH:12]=2)C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[Br:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Br:18])[CH:14]=1)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1cc(Br)cc(Br)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCOc1cc(Br)cc(Br)c1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
1-(4′-phthalimidobutoxy)3,5-dibromobenzene (1.0 g, 2.20 mmol) was dissolved in ethanol (45 mL) for 5 minutes under nitrogen. Hydrazine monohydrate (610 mg, 12.1 mmol) was added and the reaction was refluxed at 80° C. for 2 hours. To the reaction aqueous 1M HCl (17.7 mL, 17.7 mmol) was added and refluxed at 105° C. for another 2 hours. The aqueous layer was extracted with dichloromethane (2×150 mL). The organic layers were combined, washed with saturated NaHCO3 (3×), water, and brine, then dried over MgSO4, and filtered. Removal of solvent yielded a yellow oil (560 mg, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>ClCCl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 107 %

Procedure:
3-Nitrobenzoyl chloride (2 g, 10.77 mmol) was loaded into a round bottomed flask, placed under a N2 atmosphere and dissolved in anhydrous dichloromethane (10 mL). The mixture was cooled to 0° C. and N,N-dimethylethylenediamine (0.98 mL, 8.98 mmol) was added to the reaction. The reaction was allowed to warm to room temperature and left to stir for 18 h. After 18 h the reaction had given a precipitate which was isolated by filtration and washed with dichloromethane to give 2.28 g of a white solid, which was partitioned between dichloromethane and a saturated aqueous NaHCO3 solution. The organic layer was removed under educed pressure and the aqueous layer was then re-extracted dichloromethane. The organic layers were combined, dried over Na2SO4 and the solvent was removed under reduced pressure to afford the title compound as a yellow solid. MS: 193, 238; 1H NMR (400 MHz, dmso-d6): 2.19 (6H, s), 2.42 (2H, t, J 6.8 Hz), 3.39 (2H, q, J 12.4 Hz, 6.7 Hz), 7.78 (1H, t, J 7.9 Hz), 8.29 (1H, ddd, J 7.9 1.8, 1.1 Hz), 8.38 (1H, ddd, J 8.1 Hz, 2.3, 1.0 Hz), 8.68 (1H, t, J 1.8 Hz), 8.81 (1H, t, J 5.7 Hz).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[H][H]>C(O)(C)C>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(-c2ccncc2)nc1
Reactant: [H][H]
Agent: BrCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=CCNCC2)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Benzyl bromide in an amount of 10.5 g was added to a solution of 10 g of 5-methyl-2,4′-bipyridine in 70 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. To the resulting reaction solution, 1.0 g of 2% palladium-S carbon and 6.0 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 4,200 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 18.0 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 4.1 g of the intended compound as light yellow crystals. Yield rate: 40%, EI-MS: (m/z) 174 (M+), melting point: 78-80° C.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[Cl:16])[CH2:5]2)[CH2:3][O:2]1.CS(O[CH:22]1[CH2:25][N:24]([C:26]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][N:32]=2)=[O:27])[CH2:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:3]1[C:4]2([CH2:5][N:6]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:22]4[CH2:23][N:24]([C:26]([C:28]5[O:29][C:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[N:31][N:32]=5)=[O:27])[CH2:25]4)=[CH:11][C:10]=3[Cl:16])[CH2:7]2)[CH2:1][O:2]1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reactant: Oc1ccc(CN2CC3(COC3)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC4(COC4)C3)c(Cl)c2)C1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
1A (0.30 g, 1.25 mmol) was dissolved in dry DMF (10 mL) and 1C (0.61 g, 1.88 mmol) was added followed by Cs2CO3 (0.82 g, 2.50 mmol). The reaction mixture was stirred at 90° C. for 24 h. The mixture was filtered and approximately half the volume of solvent was evaporated. The product was purified by preparative RP HPLC (gradient: 15-55% acetonitrile over 30 min, 0.2% ammonia buffer). The pure fractions were combined and concentrated. Dichloromethane was added and the solution was dried (phase separator) and concentrated in vacuo. There was obtained 0.26 g (44.5%) of 1 as a solid. 1H NMR (500 MHz, CDCl3): δ 3.57 (s, 4H), 3.73 (s, 2H), 4.33 (d, 1H), 4.65 (dd, 1H), 4.73 (m, 1H), 4.77 (s, 4H), 5.06 (m, 1H), 5.14 (dd, 1H), 6.70 (d, 1H), 6.80 (s, 1H), 7.37 (m, 1H), 7.54 (m, 2H), 7.59 (m, 1H), 8.16 (d, 2H), MS (APCI+) m/z 467 [M+H]+. LC purity: 96%. A slurry experiment was performed by weighing 2.5 mg of Example 1 into a vial and adding ethanol (100 μL). The slurry was shaken for 7 days at ambient temperature and then crystals were collected using a small spatula. The crystals were dried in a hood for one hour and then analyzed using DSC (differential scanning calorimetry). A sample was weighed into an aluminium pan with a pierced lid and heated from 0° C. to 300° C. with a ramp of 5° C./min and modulated with the amplitude of ±0.6° C. every 45 seconds. The instrument was purged with nitrogen at 50 mL/minute; melting point 119±5° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:30][C:31]#[N:32]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:30][C:31]#[N:32])[CH2:23][C:24]5([CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: N#CC=C1CC2(CCOCC2)C1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCOCC5)C4)c3)n2)cn1
Yield: 60.3 %

Procedure:
This was prepared from 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (40 mg; 0.151 mmol) and 2-(7-oxaspiro[3.5]nonan-2-ylidene)acetonitrile (37 mg; 0.226 mmol) in analogous fashion to Example 148, Step D to give the desired product (39 mg). MS (apci) m/z=429.2 (M+H).