Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH2:5][C:6]2[CH:11]([C:12]([OH:14])=[O:13])[N:10]3[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@H:9]3[S:8][CH:7]=2)=[CH:30]1
Reactant: Cn1ccc2ccccc21
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc21
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is dissolved in a solution of 0.13 g of 1-methylindole in 0.3 ml of trifluoroacetic acid, and the solution is left to stand for 15 minutes at room temperature and diluted with an equal quantity of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-(1-Methyl-3-indolylmethyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained; in a thin layer chromatogram (silica gel), this acid shows Rf values at 0.85 (system n-butanol/acetic acid/water, 67:10:23) and at 0.58 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:32][CH2:33][C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][N:30]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)NCc2ccccn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (91.6 mg, 0.4 mmol) in DMF (4 ml) was added pycoylamine (0.045 ml, 0.44 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC), (93 mg, 0.48 mmol), 1-hydroxybenzotriazole (HOBT), (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:24]4[NH:25][C:26](=[N:29]C=O)[S:27][CH:28]=4)=[O:23])[C:18](=[O:33])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.P(Cl)(Cl)([Cl:36])=O>CO>[ClH:36].[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:32])[C:22]([C:24]4[N:25]=[C:26]([NH2:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:33])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(=NC=O)[nH]3)[C@H]2SC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Cl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-7-[2-(2-formylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (24.8 g.) in methanol (500 ml.) was dropwise added phosphorus oxychloride (16.4 g.) over 15 minutes under cooling at 5° to 10° C. with stirring, and the mixture was stirred for 2.5 hours at the same temperature. The 3/4 amount of methanol was distilled off from the reaction mixture under reduced pressure, and the residue was pulverized in diethyl ether. The powder was collected by filtration and then dried to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-imino- 2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid hydrochloride.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC=CCCCCCCC=CCC1
Agent: [Pd]
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Solvent: CCO
Product: O=C1CCCCCCCCCCCCCC1
Yield: 89.1 %

Procedure:
A flask was charged with cyclopentadeca-4E,12E-dien-1-one (0.10 g, 0.45 mmole), ethanol (5 ml) and 5% palladium-on-carbon (0.01 g). The mixture was stirred at room temperature under 1 atm of hydrogen gas for 1 hour. The reaction mixture was filtered through celite and concentrated to provide cyclopentadecanone (exaltone) (0.09 g, 88% yield). C15H28O (224.39 g/mole). 1HNMR (500 MHz, CDCl3): 1.25 (m, 20H), 1.60 (m, 4H), 2.35 (t, 4H) ppm. 13CNMR (125 MHz, CDCl3): 23.40, 26.25, 26.39, 26.69, 26.74, 27.54, 42.05, 212.50, ppm. IR (νmax(cm−1)): 2924(s), 2854(s), 1708(s), 1458(m).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH2:15]([O:14][C:12]([CH:11]=[C:18]1[C:24]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=2[N:22]([C:30](=[O:48])[C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:46])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[CH:33][C:32]=2[CH3:47])[CH2:21][CH2:20][CH2:19]1)=[O:13])[CH3:16]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To tetrahydrofuran (200 ml) is added sodium hydride (60%, 0.85 g), and thereto is added dropwise ethyl diethylphosphonoacetate (4.68 ml) with stirring under ice-cooling, and the mixture is further stirred under ice-cooling for 10 minutes. To the reaction mixture is added 5-oxo-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.10 g), and the mixture is stirred at room temperature for 6 hours. The reaction solution is poured into ice-water (200 ml), and extracted with ethyl acetate (300 ml). The extract is washed with brine (300 ml), dried over magnesium sulfate, and the solvent is distilled off. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane=1:2) to give 5-ethoxycarbonylmethylidene-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.22 g) in the form of a mixture of the E-type compound and the Z-type compound thereof, as colorless amorphous.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[O-:17][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[Na+].[Na+].O.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5](=[O:17])[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)(=[O:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 77.0 g (0.74 mol) of 2-acetylfluorene in 1.1 l of acetic acid are added at 90° C and under intense stirring, 385 g (1.3 mol) of sodium bichromate during a period of 1 hr to 1 hr 15 min. Thereupon, the reaction mixture is allowed to stand under the same conditions for 4 hours, then poured into 4.6 l of water heated to 90° C and kept overnight at room temperature. The precipitate is filtered off, washed with 900 ml of a 2-percent sulfuric acid till a colorless wash solution appears, and with water until the acid reaction disappears. Then the precipitate is treated under intense stirring, with 540 ml of a 5-percent caustic soda solution heated to 90° C, and let cool down to room temperature. The precipitate is filtered off, washed with water and dried in a drying cabinet at 80° C to obtain 62.5 g of crude 2-acetylfluorenone which is then recrystallized from 1.0 l of benzene for the sake of purity. The yield of 2-acetylfluorenone equals 55.5 g (68.0 wt% as calculated for 2-acetylfluorene or 50 wt.% when calculated for fluorene), m.p. 160°-161.5° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][N:15]([CH3:21])[C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1.C(OCC)(=O)C>C1COCC1>[CH3:14][N:15]([CH3:21])[CH:16]1[CH2:20][CH2:19][N:18]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:17]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Yield: 47.5 %

Procedure:
Suspend 2-chloro-6-nitrobenzthiazole (8.49 g, 39.6 mmol) in THF (100 mL). Slowly add (3R)-(+)-3-(dimethylamino)pyrrolidine (5.24 g, 45.9 mmol). Stir the reaction overnight at room temperature. Dilute the reaction with ethyl acetate and then wash with water and brine. Concentrate the organic portion in vacuo, and triturate the resulting residue with MeOH to afford the title compound (4.94 g, 43%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (d, 1H, J=2.2 Hz), 8.14 (dd, 1H, J=9.0, 2.4 Hz), 7.52 (d, 1H, J=8.8 Hz), 4.00-3.43 (m, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.20-2.15 (m, 7H), 1.93 (m, 1H).
Reaction SMILES: C(=[N:8][C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14]([NH2:16])=[O:15])C1C=CC=CC=1.I(O[CH2:21][CH2:22][CH2:23][CH3:24])(=O)=O.C([Cl:32])C1C=CC=CC=1>>[ClH:32].[NH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:21][CH2:22][CH2:23][CH3:24])[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: CCCCO[I+2]([O-])[O-]
Reactant: ClCc1ccccc1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Product: CCCCn1cnc(N)c1C(N)=O
Product: Cl
Yield: 17 %

Procedure:
Following the same conditions as in Reference Example 2, 14.30 g (67 mmol) of 4-benzylideneamino-5-imidazole carboxamide obtained in Reference Example 1 was reacted with butyl iodate, instead of benzyl chloride in the Reference Example 2. After the post-treatment, 2.47 g of 4-amino-1-butyl-5-imidazolecarboxamide hydrochloride was obtained (yield 17%).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>O1CCOCC1>[C:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccs1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(NCc2cccs2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
The mixture of ethyl 4-phenyl-2-methanesulphonylpyrimidine-5-carboxylate (2.30 g, 7.5 mmol), 2-thienylmethylamine (2.12 g, 18.75 mmol) and dioxane (30 ml) were stirred at room temperature for 16 hours, the solvent was removed in vacuum. To the residue ethanol (10 ml) was added, the resulting crystals were filtered off in vacuum, washed with ethanol (5 ml) to obtain 1.99 g (78%) of the title ester in the form of white crystals, m.p.: 123-124° C.; [M+H]+ 340
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:43])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([CH2:25][C:26]2[C:31]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:29]=[C:28](Cl)[N:27]=2)[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[CH:8][CH:7]=1.[CH2:44]([OH:48])[CH:45]([CH3:47])[CH3:46]>C1COCC1.CC(O)=O.O>[CH2:32]([C:31]1[C:26]([CH2:25][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:4])=[O:43])=[CH:7][CH:8]=2)[CH2:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)=[N:27][C:28]([O:48][CH2:44][CH:45]([CH3:47])[CH3:46])=[N:29][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1c(CN(Cc2ccc(C(=O)OC)cc2)Cc2ccc3c(c2)OCCO3)nc(Cl)nc1-c1ccccc1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1c(CN(Cc2ccc(C(=O)O)cc2)Cc2ccc3c(c2)OCCO3)nc(OCC(C)C)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (60% dispersion in mineral oil) (40 mg) is added to a solution of 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (46 mg, 0.0804 mmol) in THF (3 mL) containing isobutyl alcohol (0.5 mL) at room temperature. The mixture is stirred at room temperature for 5 minutes and then at reflux for 2 hours. Next, H2O (0.5 mL) is added and heating is continued for an additional 30 minutes. After cooling to room temperature, the reaction mixture is treated with a few drops of AcOH until pH 4–5. The mixture is then diluted with H2O and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated. The residue is purified by preparative TLC, eluting with 20:1 CHCl3-MeOH. The band containing the product affords 28.4 mg 4-{[(5-butyl-2-isobutoxy-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid as a colorless gum. 1H NMR (CDCl3, 300 MHz) δ 8.02 (br, 2H), 7.39 (br, 7H), 6.87 (br s, 1H), 6.78 (br s, 2H), 4.21 (br s, 4H), 4.12 (br d, J=6.3 Hz, 2H), 3.70 (br, 4H), 3.54 (br s, 2H), 2.54 (br m, 2H), 2.13 (br, 1H), 1.02 (d, J=6.3 Hz, 6H), 0.94 (br 4H), 0.60 (br, 3H) ppm. MS: m/z 596 [M+1].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[N:6][CH:7]=1.[Cl:14][CH:15]([Cl:34])[C:16]([NH:18][C@H:19]([CH2:32][F:33])[C@H:20]([OH:31])[C:21]1[CH:26]=[CH:25][C:24]([Sn](C)(C)C)=[CH:23][CH:22]=1)=[O:17].[Cl-].[Li+]>>[Cl:14][CH:15]([Cl:34])[C:16]([NH:18][C@H:19]([CH2:32][F:33])[C@H:20]([OH:31])[C:21]1[CH:22]=[CH:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1)=[O:17]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CS(=O)(=O)NCc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cn1
Temperature: 100 °C

Procedure:
N-((5-bromopyridin-2-yl)methyl)methanesulfonamide (previously described in WO9528400) (240 mg, 0.90 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (400 mg, 0.90 mmol) in 2-methylpyrrolidinone (5 mL) are treated with lithium chloride (115 mg, 2.7 mmol) and degassed and purged with nitrogen. Bis(triphenylphosphine)-palladium(ii) chloride is added and the mixture heated at 100° C. for 3 hours. The mixture is cooled, diluted with water and extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase chromatography to give the title compound (324 mg): 1H NMR (400 MHz, CDCl3) δ: 2.96 (s, 3H), 4.2-4.3 (m, 3H), 4.4 (m, 0.5H), 4.57 (m, 0.5H), 4.58 (m, 0.5H), 4.70 (m, 0.5H), 4.90 (bs, 1H), 6.00 (s, 1H), 6.52 (s, 1H), 7.47 (d, 2H), 7.52, (d, 1H), 7.69 (d, 3H), 8.1 (m, 1H), 8.85 (m, 1H), 8.82 (bs, 1H). m/z (Cl) 464.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[CH:14]1([CH2:13][CH2:12][N:8]2[C:5]3[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][C:4]=3[C:31]3[CH2:30][N:29]([CH3:28])[CH2:34][CH2:33][C:32]2=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCC1CCCCC1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CCC2CCCCC2)CCN(C)C1
Yield: 16.1 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (500 mg, 3.1 mmol), 1-bromo-2-cyclohexylethane (602 mg, 3 mmol), triethyl amine (303 mg, 3 mmol) and N-methyl-4-piperidone hydrochloride (589 mg, 4.5 mmol) were combined in ethanol (3 ml) to obtain 150 mg of 5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole after purification on neutral alumina using ethyl acetate-hexane gradient.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH:10]=[O:11])[CH3:9].[C:12]([NH:18][NH2:19])(=[O:17])C(C)(C)C.[CH2:20]([N:22](CC)[CH2:23]C)C>C(Cl)Cl>[CH3:7][N:8]([C:10]([N:19]=[N:18][C:12]([N:22]([CH3:23])[CH3:20])=[O:17])=[O:11])[CH3:9]
Reactant: CCN(CC)CC
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)N=NC(=O)N(C)C
Reaction time: 1 h
Yield: 61 %

Procedure:
To the solution of acid (63) (330 mg, 0.74 mmol) in CH2Cl2 (10 mL) was added oxalyl chloride (77 μL, 0.88 mmol) and the catalytic amount of DMF. The reaction mixture was stirred for 1 hr and concentrated in vacuo. The residue (crude acyl chloride) was diluted with CH2Cl2 (10 mL) and pivalohydrazide (128 mg, 1.10 mmol) and triethylamine (0.31 mL, 2.21 mmol) was added. The reaction mixture was stirred for 2 hrs at room temperature. The reaction mixture was concentrated in vacuo and diluted with EtOAc (50 mL). The organic layer was washed with aq. 1N HCl and aq. sat'd NaHCO3 solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by Prep-LC (Gilson) provided 244 mg (61%) of desired diamide as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:30]([CH3:32])[CH3:31])[NH:11]1.[NH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:33][N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)=[O:28])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:30]([CH3:32])[CH3:31])[NH:11]1
Reactant: CN1CCN(N)CC1
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(C(=O)O)cc3)nc(=O)c1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(C(=O)NN4CCN(C)CC4)cc3)nc(=O)c1-2
Temperature: 45 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
Part F: To a stirred solution of 49 mg (0.10 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.06 mL (0.5 mmol) of 1-amino-4-methylpiperazine in 1 mL of DMF was added 0.052 mL of DIEA followed by 48 mg (0.15 mmol) of TBTU. The solution was stirred 16 h at 45° C., cooled to RT, and poured into water. The mixture was extracted with EtOAc, and the organic extract was concentrated under reduced pressure. Chromatography with 4:1 chloroform-MeOH afforded 34 mg (58%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid. Mass spec: (ESI+) 588 (M +H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[S:14]1[CH:18]=[CH:17][C:16]2[C:19]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]4[CH:42]=[C:41]5[C:36]([CH2:37][CH2:38][CH2:39][NH:40]5)=[CH:35][CH:34]=4)[CH2:25][CH2:24]3)=[CH:20][CH:21]=[CH:22][C:15]1=2.C(Cl)[Cl:44]>>[ClH:44].[C:1]([N:40]1[C:41]2[C:36](=[CH:35][CH:34]=[C:33]([O:32][CH2:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][N:23]([C:19]4[C:16]5[CH:17]=[CH:18][S:14][C:15]=5[CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:27]3)[CH:42]=2)[CH2:37][CH2:38][CH2:39]1)(=[O:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)OC(C)=O
Reactant: c1cc(N2CCN(CCCOc3ccc4c(c3)NCCC4)CC2)c2ccsc2c1
Solvent: c1ccncc1
Product: CC(=O)N1CCCc2ccc(OCCCN3CCN(c4cccc5sccc45)CC3)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Acetic anhydride (0.34 ml, 3.6 mmol) and pyridine (0.34 ml, 4.3 mmol) were added to a solution of 7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline (0.49 g, 1.2 mmol) in methylene chloride (10 ml) with cooling in an ice-bath, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate the organic phase from the water phase. The organic phase was washed with water, saturated sodium hydrogencarbonate aqueous solution and brine in this order, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=1:1), and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (10 ml), and 1N-HCl-ethanol solution was added thereto. Then, crystals precipitated were filtered out and dried to obtain 1-acetyl-7-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1,2,3,4-tetrahydroquinoline hydrochloride (0.27 g, yield: 52%) as white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.N([O-])=O.[Na+].[I:19]I>C(O)(=O)C.Cl.O>[I:19][C:11]1[CH:13]=[CH:14][C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc(Cc2ccncc2)cc1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
A solution of 4-(pyridin-4-ylmethyl)aniline (679 mg, 3.7 mmol) in acetic acid (1.84 mL) and concentrated hydrochloric acid (0.787 mL) was cooled to 0° C. NaNO2 (280 mg, 40.7 mmol) in water (1.23 mL) was added dropwise and the reaction mixture was allowed to stir for 30 min. A solution of KI (737 mg, 4.44 mmol) and iodine (563 mg, 2.22 mmole) in water (3.7 mL) was added dropwise to the above solution. The solution stirred for 30 min at 0° C. and for 1 h at rt. The reaction was quenched by the addition of aq. NaS2O4 and the solution was extracted with EtOAc. The combined organic solutions were washed with sat. NaHCO3, brine and 1% NaOH, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (140 mg, 18%). LCMS: (FA) ES+ 296.1 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>[Cl-].C[N+](C)(C)C.C1(C)C(C)=CC=CC=1>[OH:16][CH:15]([CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)[CH2:17][OH:18]
Reactant: OCC1CO1
Reactant: Oc1ccc(Cn2cccn2)cc1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: OCC(O)COc1ccc(Cn2cccn2)cc1

Procedure:
A mixture of 4-(1-pyrazolyl)methylphenol [this was obtained by the same method as described in the square parentheses in Production Example 1] (2 g), glycidol (936 g), dry xylene (10 ml) and a catalytic amount of tetramethylammonium chloride was stirred at 60° C. for 6 hours. The reaction mixture was then subjected to silica gel chromatography, which afforded 941 mg of 2-hydroxy-3-[4-(1-pyrazolyl)methylphenoxy]-propanol.