Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=O)[CH3:2].[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1
Yield: 64.3 %

Procedure:
A solution of 3-ethylhexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (1.5 g) in dry tetrahydrofuran was added to a stirred suspension of aluminium lithium hydride (0.48 g) and heated under reflux for 5 hours. The reaction mixture was cooled and decomposed by the addition of water and the precipitate filtered. The precipitate was washed with tetrahydrofuran and the combined filtrate and washings evaporated to a solid. The solid was dissolved in water and ammonium chloride added. The precipitated oil was extracted with dichloromethane, dried over anhydrous magnesium sulphate and evaporated to leave a solid which was recrystallised from acetonitrile to give 0.91 g of the title compound, m.p. 127.5°-133° C., identical with material prepared by an alternative route described in U.K. Pat. No. 1,285,025.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][CH:26]=1
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
2.12 g (32.5 mmol) of potassium cyanide were added to 6.90 g (16.3 mmol) of the compound from Example 52A in 345 ml of DMF. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient). 5.05 g (87% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:38])([F:37])[C:12]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:34]([N:33]([CH2:32][C:12]([OH:31])([CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([F:38])([F:37])[F:10])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:35][CH3:36]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 11 from benzoic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]2[C:10]3[N:11]([CH:23]=[CH:24][N:25]=3)[N:12]=[C:13]([CH2:15][N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)[CH:14]=2)=[CH:5][CH:4]=1.C1COCC1.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.[OH-].[Na+]>[CH2:39]([NH:46][CH:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:13]2[CH:14]=[C:9]([N:8]([CH2:7][C:6]3[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:10]3[N:11]([CH:23]=[CH:24][N:25]=3)[N:12]=2)[CH2:21][CH2:20]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(=O)CC3)nn3ccnc23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(NCc4ccccc4)CC3)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
In a 2 dram vial was added 1-((8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-yl)methyl)piperidin-4-one (0.048 g, 0.109 mmol) from (1d), THF (0.362 mL) and benzylamine (0.013 mL, 0.120 mmol). The reaction was allowed to stir at room temperature for 1 hr. Sodium triacetoxyborohydride (0.092 g, 0.435 mmol) was then added and the reaction stirred for 48 hours at ambient temperature. The mixture was diluted with ethyl acetate and 1N NaOH solution and the layers separated. The organics were washed with water and the resulting aqueous solution was back-extracted with ethyl acetate (2×). The combined organics were collected, dried over Na2SO4, filtered and concentrated to provide 6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.05 g, 86% yield) which was subsequently used without further purification m/z=(532, M+1).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)c1c(Br)ccn1N
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 89.6 %

Procedure:
The title compound was prepared from methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (9.05 g, 25.6 mmol) and (S)-2-(benzyloxycarbonylamino)propanoic acid (5.72 g, 25.6 mmol) following the experimental procedure described in Preparation 73a. 9.73 g (84% yield) of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCCC1.O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2([OH:38])[CH2:33][CH2:34][N:35]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:36][CH2:37]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCC(O)(c2ccc(Cl)cc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A stirred mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was treated with 2 g (0.01 mole) of 4-(4-chlorophenyl)-4-hydroxypiperidine added in small portions. After stirring for 30 min, a few pieces of ice were added and stirring continued for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give a water-like oil (5.16 g). A crystalline solid was obtained by cooling to -78° C. and recrystallization was accomplished by dissolving the residue in 5 ml of acetone and 75 ml of isopropyl ether and reducing the volume under nitrogen to 40 ml. Upon cooling, filtration yielded 3.6 g (79.1%) of fine white crystals, m.p. 127°-128.5° C.
Reaction SMILES: C([O:5][C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:9]=1[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11]2)CCC.S(=O)(=O)(O)O.[OH-].[Na+]>O.CCOC(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:9]2[C:10]([C:16]([CH3:18])=[CH2:17])=[N:11][C:12]3[CH:13]=[CH:14][NH:15][C:6](=[O:5])[C:7]=3[C:8]=2[CH:22]=1
Reactant: C=C(C)c1nc2ccnc(OCCCC)c2c2cc(F)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a stirred suspension of 1-butoxy-9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridine (30 mg, 0.097 mmol) in water (0.5 ml) was added sulfuric acid (0.5 ml) (CAUTION: EXOTHERM). The reaction mixture was stirred for 15 h at 100° C. The reaction was diluted with EtOAc (30 mL) and water (30 mL). To the resulting biphasic mixture was added NaOH (0.85 g, 21 mmol) portionwise to make the aqueous layer basic. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in 3 ml DMF and 100 uL of TFA, and purified by preparative reverse phase HPLC eluting with an acetonitrile/water+(with 0.05% TFA as a modified) gradient, to afford 9-fluoro-6-isopropenylbenzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6) δ 11.92 (br s, 1H), 9.74 (dd, 1H), 8.41 (dd, 1H), 7.64-7.60 (overlapping m, 2H), 6.78 (d, 1H), 5.70 (s, 1H), 5.22 (s, 1H), 2.25 (s, 3H). LRMS (ESI) calc'd for (C15H11FN2O) [M+H]+, 255.1; found 255.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:32](O)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH:6][C:32](=[O:33])[C@H:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1

Procedure:
L-Serine methyl ester hydrochloride, 5 g., is dissolved in 75 ml. of dimethylformamide and the solution cooled in an ice bath. Triethylamine, 4.9 ml., is added then 11.9 g. of Nα -benzyloxycarbonyl-L-tryptophan, 5.25 g. of 1-hydroxybenztriazole and finally 8.0 g of dicyclohexylcarbodiimide. The reaction is stirred with ice bath cooling overnight, allowing the temperature to rise to room temperature, then an additional twenty-four hours at room temperature. The mixture is filtered and the solid washed with dimethylformamide. The filtrate is evaporated under reduced pressure and the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid, saturated salt solution, three times with 5% sodium bicarbonate solution, saturated salt solution, and finally with water. The ethyl acetate solution is then dried over magnesium sulfate and evaporated. The residue is crystallized from 250 ml. of benzene and then from ethyl acetate and petroleum ether; 12.5 g.; m.p. 133°-135° C.; [α]D23 -12.4° (c 2, methanol); ultraviolet in methanol λmax 290 E11 115; λmax 281 E11 131; λmax 274 E11 122.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]1([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][N:24]3[CH2:25][CH2:26][N:21]([C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)[CH2:22][CH2:23]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2csc3ccccc23)cc1)CN1CCN(c2ncccn2)CC1
Temperature: 75 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
Combine 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane (200 mg, 0.708 mmol), 2-piperazin-1-yl-pyrimidine (465 mg, 2.83 mmol) and ethanol (4 mL). Apply heat (75° C.) to the homogeneous reaction mixtures and stir for 6 hours. Concentrate (in vacuo) and purify by column chromatography using a Waters Sep-Pak silica gel cartridge (10 g) and elution with graded solvent mixtures from 50% ethyl acetate in heptane to 100% ethyl acetate. Concentrate the appropriate fractions, dissolve in dichloromethane and re-evaporate under a stream of nitrogen. Dry the sample using medium heat and reduced pressure to give the title compound as a clear oil (0.285 mg, 90% Yield). Purity by LC/MS=99%, [M+H]+=447.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([Li])CCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>CCOCC>[CH3:9][C:3]1[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Br)c(C)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
A solution of 3-bromo-2,6-dimethylpyridine (5.10 g, 27.4 mmol) in anhydrous ether (160 ml) cooled to −78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.1 ml, 10 M in hexane) and stirred at −78° C. for 45 minutes. 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 54.8 mmol) in 20 ml of ether was added dropwise at −78° C. and stirred at −78° C. for 3 hours. The mixture was quenched with 10 ml of isopropanol, and allowed to warm to room temperature. 150 ml of saturated aqueous NaCl solution was added. The aqueous phase was separated and extracted with dichloromethane (100 ml×6). The combined organic phases were dried and concentrated to provide the title compound as light brown oil (6.29 g, 98.4%). 1H NMR (300 MHz, CDCl3) δ ppm 7.92 (d, J=7.46 Hz, 1H) 6.96 (d, J=7.80 Hz, 1H) 2.73 (s, 3H) 2.53 (s, 3H) 1.34 (s, 12H). MS: (M+H)+=234.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@H:15](C(=O)NC)C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C1[C@@H](NC(=O)[C@H](N2C=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=4)=[CH:65][CH:64]=3)=[CH:59]2)CC(O)=O)CC2=CN(C3C2=CC=CC=3)CCOCCN1.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:59][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[CH:74]=[CH:73][N:72]=[CH:71][CH:70]=3)=[CH:65][CH:64]=2)=[CH:61]1)[C:12]([NH:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CNC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 51 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbarnoyl)propyl)succinamic acid benzyl ester, 2(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinic 4-benzyl ester hydrochloride (prepared as described in Example 7(a)) and excess 40% aqueousueous methylamine were coupled with TBTU. The solid that precipitated from the reaction mixture was washed with water and, after drying, with ethyl acetate to give 51% of N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester as a yellow solid: 1HNMR (DMSO-d6): δ—8.58 (d, 2H, J=4.4 Hz), 7.84 (br s, 1H), 7.76-7.70 (m, 4H), 7.60 (d, 2H, J=8.5 Hz), 7.29-7.25 (m, 6H), 6.76 (s, 1H), 6.40 (s, 1H), 5.03 (s, 2H), 4.67 (t, 1H, J=6.2 Hz), 3.20 (dd, 1H, J=15.8, 6.2 Hz), 2.86 (dd, 1H, J=16.0, 8.6 Hz), 2.32 (s, 3H); Anal. Calculated for C27H25N3O3•1.3 H2O: C, 70.05; H, 6.01; N, 9.08. Found: C, 69.98, 69.97; H, 5.98, 6.00; N, 9.01, 9.00.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([OH:18])=O)=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH2:23])=[O:18])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
192 g (0.715 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 900 ml of dimethylformamide, treated at room temperature with 116 g (0.715 mol) of carbonyldiimidazole and stirred at 50° for 1/2 hr. Then, 173 ml of 25% ammonia were added dropwise at 25-30° within 1/2 hr. After stirring for 1/2 hr the reaction mixture was concentrated and the residue was dissolved in 500 ml of alcohol. After the addition of 250 ml of ether the solution was cooled to 0° and the suspension was suction filtered. There were obtained 133.6 g (69%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide; m.p. 228-230°.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][CH2:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:33])[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C@@H:15]1[CH2:21][CH2:22][CH:23]([OH:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(=O)Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CCC(O)Cc1cccc(Cl)c1
Yield: 90.9 %

Procedure:
Sodium borohydride (2 mg, 0.053 mmol) followed by MeOH (0.1 mL) was added to a solution of (4-{(R)-2-[4-(3-chlorophenyl)-3-oxo-butyl]-6-oxo-piperidin-1-yl}-but-2-ynyloxy)-acetic acid methyl ester (5 mg, 0.012 mmol) in CH2Cl2 (0.3 mL) at 0° C. After 10 min at 0° C. the reaction was quenched with aqueous HCl (0.25 M, 3 mL). The reaction mixture was extracted with CH2Cl2 (3×4 mL), then the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2) afforded 4.6 mg (92%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[O:24])=[CH:25][CH:26]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(-n3ncc4c(=O)n(-c5ccc(Cl)cc5)c(-c5ccc(Cl)cc5Cl)nc43)cc2)CC1
Reaction time: 1 h

Procedure:
4-[5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzoic acid (54.1 mg, 0.106 mmol) is dissolved in 1 mL of thionyl chloride and stirred for 1 h at reflux. The thionyl chloride is then removed under a stream of dry nitrogen and the resulting solid is dissolved in 2 mL of dry dichloromethane. N-methylpiperazine (500 mg, 5.00 mmol) is then added to the solution and the reaction mixture is stirred for 2 h. After the volatiles are evaporated, the resulting residue is dissolved in 1 M NaOH and extracted with ethyl acetate. The crude product is purified by column chromatography. 1H NMR (CDCl3, 400 MHz) δ 8.36(s, 1H), 8.28 (d, 2H), 7.57 (d, 2H), 7.36-7.29 (m, 3H), 7.23-7.16 (m, 2H), 7.03 (m, 1H), 3.97 (m, 3H), 3.48 (m, 2H), 2.83 (m, 6H). HPLC-MS calculated for C29H23Cl3N6O2 (M+H+) 593.1. Found: 593.1.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].Br[CH2:9][C:10]1[C:11]([CH2:16]Br)=[CH:12][CH:13]=[CH:14][CH:15]=1>CN(C)C=O>[CH3:3][S:4]([N:7]1[CH:16]=[C:11]2[C:10]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9]1)(=[O:6])=[O:5]
Reactant: BrCc1ccccc1CBr
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1cc2ccccc2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.88 g) was suspended in 3 ml dimethyl formamide. To this stirred solution was added methanesulfonamide (0.95 g, 10 mmol) in 5 ml dimethyl formamide dropwise under nitrogen. After stirring at 60° C. for 0.5 hours, a solution of 2.64 g (10 mmol) α,α'-dibromo-o-xylene in 7 ml DMF was added at a rate appropriate to maintain the temperature at 60-70° C. The mixture was stirred at room temperature for another hour, then quenched by pouring into water. The resulting precipitate was collected and washed with water, petroleum ether and ether successively. Weight 1.57 g (80%). 1H-NMR δ2.37 (s, 3H, --CH3), 4.709 (s, 4H, 2CH2). 7.25-7.35 (m. 4H, ArH).
Reaction SMILES: [C:1]1([C:11]2[N:12]=[C:13]([CH2:18][CH2:19][CH3:20])[NH:14][C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([C:11]2[N:12]=[C:13]([CH2:18][CH2:19][CH3:20])[N:14]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[N:39]([C:40]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:38]=[N:37][N:36]=4)=[CH:27][CH:28]=3)[C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1nc(-c2cccc3ccccc23)c(C=O)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-(naphth-1-yl)-2-n-propylimidazole-5-carboxaldehyde (0.90 g, 39.7 mmol, 1 eq), 4-bromomethyl-2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl (2.03 g, 43.7 mmol), 1.1 eq), dry DMF (20 mL), and 3.0 g of potassium carbonate was stirred at room temperature for 18 h. The reaction mixture was filtered, the precipitate was washed with methylene chloride and evaporated under reduced pressure. The residue was chromatographed in 98:2 methylene chloride/ethyl acetate over silica gel to yield a yellow foam. Yield: 1.50 g. NMR (CDCl3) δ 9.45 (s, 1H); 7.85 (m, 1H); 6.86-7.45 (m, 29H); 5.55 (s, 2H); 2.60 (t, 2H); 1.80 (m, 2H); 0.95 (t, 3H). ##STR78##