Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C([N:49]([CH2:53]C)[CH:50]([CH3:52])[CH3:51])(C)C.NC1C[CH2:60][O:59][CH2:58]C1>CN(C=O)C>[CH3:53][N:49]([CH:50]1[CH2:51][CH2:60][O:59][CH2:58][CH2:52]1)[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)C2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 4-aminotetrahydropyran (0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (231 mg, 91%) which was obtained as a white solid. MS: m/e=394.1 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10](CC2C=CC=CC=2)[C:11]=1[NH2:12])=[O:6].CO.O.[H][H]>[Pd].C(O)(=O)C>[ClH:1].[ClH:1].[NH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][NH:10][C:11]=1[NH2:12])=[O:6]
Reactant: NCC(=O)c1ncn(Cc2ccccc2)c1N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: NCC(=O)c1nc[nH]c1N

Procedure:
A solution of 1.0 g. of 2-amino-1-[5-amino-1-(phenyl-methyl)-1H-imidazol-4-yl]ethanone dihydrochloride in 100 ml. of 70:20:10 methanol:water:acetic acid is hydrogenated over 0.52 g. of 20% palladium-on-carbon at 50 p.s.i. until hydrogen uptake ceases. The catalyst is removed by filtration and the filtrate is evaporated at reduced pressure to give 2-amino-1-(5-amino-1H-imidazol-4-yl)ethanone dihydrochloride; m.p. above 250° dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([OH:23])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][CH2:20][C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:23])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)O)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccccc2CCC(=O)N2CCOCC2)=C(C)C1=O
Yield: 34.3 %

Procedure:
3-(2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.070 mmol) obtained in Example 69 and morpholine (0.009 ml, 0.11 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (10 mg, 0.024 mmol, yield 34%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:31](=[O:32])([O:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:23][CH:22]=1)[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. mixture of 9.0 g of product from Example 19, 4.44 g of pyridine and 70 ml of methylene chloride is added, dropwise, 5.28 of phenyl chloroformate. The reaction is stirred at 0° C. for 15 minutes; followed by room temperature for 30 minutes. The mixture is poured into saturated sodium bicarbonate and the aqueous layer is extracted with methylene chloride. The combined organic layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 0-5% ethyl acetate/hexane) to give 12.6 g of colorless prisms.
Reaction SMILES: ClC1C=C(C)C2N=C(C3C=CC(OCCCN4C(=O)CCNCC4)=CC=3C)NC=2C=1.[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[H-].[Na+].I[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[C:55]([CH3:61])[CH:54]=1>CN(C=O)C.O>[C:31]([O:35][C:36]([N:38]1[CH2:44][CH2:43][C:42](=[O:45])[N:41]([CH2:49][CH2:50][CH2:51][O:52][C:53]2[CH:60]=[CH:59][C:56]([CH:57]=[O:58])=[C:55]([CH3:61])[CH:54]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1cc(OCCCI)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)CC1
Agent: Cc1cc(OCCCN2CCNCCC2=O)ccc1-c1nc2c(C)cc(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCN2CCN(C(=O)OC(C)(C)C)CCC2=O)ccc1C=O
Reaction time: 0.5 h

Procedure:
4-{3-[4-(6-Chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-[1,4]diazepan-5-one. To a stirred solution of 5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.0 g, 14.0 mmol, 1.0 equiv) in DMF (45 mL) at rt was added 60% sodium hydride (560 mg, 14.0 mmol, 1.0 equiv). After stirring for 30 min, 4-(3-iodo-propoxy)-2-methyl-benzaldehyde (4.26 g, 14.0 mmol, 1.0 equiv) was added as a solution in DMF (5 mL). The mixture was stirred for 16 h and then poured into water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was partially purified by column chromatography (silica gel, 5-50% ethyl acetate in hexanes) to afford 4-[3-(4-formyl-3-methyl-phenoxy)-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a mixture with several unidentified products. This impure mixture (200 mg), 5-chloro-3-methyl-benzene-1,2-diamine (80.1 mg), and Na2S2O5 (97 mg) were stirred in DMF (1.0 mL) at 90° C. for 3 h. After cooling to rt, the reaction mixture was loaded on silica gel and was purified by Method 2 to afford 4-{3-[4-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-3-methyl-phenoxy]-propyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a mixture with several unidentified products. This mixture was dissolved in dichloromethane (1.0 mL) and TFA (1.0 mL) and stirred at rt for 1 h. The reaction mixture was loaded on silica gel and purified by Method 2 to afford 91.0 mg (42%) of the title compound. MS (electrospray): mass calculated for C23H27ClN4O2, 426.18; m/z found, 427.4 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.55 (d, J=8.5 Hz, 1H), 7.42 (br s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.5, 2.5 Hz, 1H), 4.10 (t, J=6.1 Hz, 2H), 3.67-3.56 (m, 4H), 2.98-2.89 (m, 4H), 2.72-2.66 (m, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.12-2.01 (m, 2H).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([CH3:39])[C:19]([C:21]3[C:29]4[C:24](=[C:25]([O:30][CH2:31][C:32](=[O:38])[N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[BH4-].[Na+].CO>C(#N)C.CC(O)C>[NH2:17][C@H:18]([CH3:39])[CH2:19][C:21]1[C:29]2[C:24](=[C:25]([O:30][CH2:31][C:32]([N:33]([CH2:34][CH3:35])[CH2:36][CH3:37])=[O:38])[CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: CCN(CC)C(=O)COc1cccc2c(C(=O)[C@@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Solvent: CC#N
Product: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)N)c[nH]c12
Temperature: 25 °C
Yield: 25 %

Procedure:
To a suspension of N-(9-fluorenylmethoxycarbonyl)-D-alanine (8.17 g, 26.3 mmol), methylene chloride (88 ml) and N,N-dimethylformamide (0.14 ml) is added dropwise oxalyl chloride (2.44 ml, 28 mmol) at room temperature with stirring, and the mixture is further stirred for one hour. The reaction solution is concentrated to dryness under reduced pressure to give an oil containing 9-fluorenylmethoxycarbonyl-D-Ala-Cl. A solution of N,N-diethyl-2-(1H-indol-7-yloxy)acetamide (4.31 g, 17.5 mmol) in methylene chloride (44 ml) is cooled to −20° C., and thereto is added dropwise a 3M solution of methyl magnesium bromide in diethyl ether (20.5 ml, 61.4 mmol). After the addition, the mixture is further stirred at −15° C. for one hour. This reaction solution is cooled to −20 to −15° C., and thereto is added dropwise a solution of N-(9-fluorenylmethoxycarbonyl)-D-alanyl chloride in methylene chloride (53 ml) obtained above, and the mixture is further stirred at −20° C. for 5.5 hours. The mixture is warmed to about −5° C., and poured into 2N hydrochloric acid. The organic layer is collected, washed with water (25 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to give an oil (13.3 g) containing (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methyl-2-oxoethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester. To a solution of the obtained oil in a mixture of acetonitrile (70 mL) and 2-propanol (4.0 ml) is added sodium borohydride (1.98 g, 52 mmol) in portions at room temperature with stirring, and the mixture is refluxed for 5 hours. The reaction solution is cooled to room temperature, and thereto is added dropwise methanol (120 ml). The reaction mixture is concentrated to dryness under reduced pressure. To the residue are added ethyl acetate and water, and the mixture is stirred. The organic layer is separated, washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (methanol/a saturated ammonia solution in chloroform=1/20) to give the desired (R)-2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-N,N-diethyl-acetamide (1.33 g, yield: 25%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][CH3:29])[C:7]2[N:8]([C:10]([C:14](OCC)=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1)=[O:3].[BH4-].[Li+].O1CCCC1>CO.O>[CH2:28]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=1[CH2:20][NH:19][C:6]1[C:7]2[N:8]([C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=[C:4]([C:2]([NH2:1])=[O:3])[CH:5]=1)[CH3:29]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C(N)=O)cn12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(CO)c(C)nc12
Reaction time: 1.33 h
Yield: 46 %

Procedure:
Ethyl 6-(aminocarbonyl)-8-(2-ethyl-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-carboxylate (280 mg, 0.71 mmol) and lithium borohydride (16 mg, 0.71 mmol) were added to tetrahydrofuran (10 ml) and the reaction mixture was refluxed for 70 min. Additional amounts of lithium borohydride (16 mg) and methanol (45 mg, 1.42 mmol) were added and the mixture was refluxed for 80 min. Additional amounts of lithium borohydride (16 mg) and methanol (22 mg, 71 mmol) were added and the mixture was refluxed for 4 h. The reaction mixture was allowed to reach R.T. and water (1 ml) and methanol (5 ml) and was stirred for 40 min. at R.T. The solvents were evaporated under reduced pressure and the residue was added to water and was stirred for 80 min. The crystals were filtered off and washed with water, ethyl acetate/ethanol and diethyl ether to give the desired product (115 mg, 46%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[CH:17]([OH:20])([CH3:19])[CH3:18]>NC1C=C(O)C=CC=1>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:6][C:5]1[CH:4]=[CH:3][CH:19]=[C:17]([OH:20])[CH:18]=1
Reactant: CC(C)O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Agent: Nc1cccc(O)c1
Product: COc1cc2nccc(Nc3cccc(O)c3)c2cc1OC
Yield: 47 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline hydrochloride (540 mg, 2.08 mmol), (prepared as described for the starting material in Example 2), in 3-aminophenol (1 ml) and isopropanol (15 ml) was heated at reflux for 2 hours. The mixture was allowed to cool and the solid product was collected by filtration, washed with acetone and dried to give 6,7-dimethoxy-4-(3-hydroxyanilino)quinoline hydrochloride (336 mg, 47%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To the solution of tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate (700 mg, 1.641 mmol) in chloroform (2 mL) was added trifluoroacetic acid (2 ml, 26.0 mmol). The reaction mixture was stirred at the room temperature for 1 hr. The reaction was evaporated, and then 2 ml of 1 M Na2CO3 (2 mL) were added followed by 10 mL of ethyl acetate. The organic layer was separated, washer with brine, dried over MgSO4, filtered and evaporated. 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (450 mg, 1.310 mmol, 80% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30-7.38 (m, 2H), 7.27 (d, J=7.33 Hz, 1.5H), 7.08 (d, J=7.33 Hz, 1.5H), 3.35-3.49 (m, 1.7H), 3.10-3.22 (m, 2H), 2.97-3.09 (m, 0.8H), 2.52-2.67 (m, 2H), 2.30-2.44 (m, 0.8H), 1.75-2.10 (m, 2.3H), 1.59-1.75 (m, 2.4H), 1.39-1.58 (m, 2H), 1.13-1.38 (m, 2.5H); LC-MS Rt=0.70 min; MS (ESI): 327.2 [M+H]+.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: OC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC1CNCCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 100 %

Procedure:
A mixture of 27.8 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)-3-piperidinol hydrochloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 21.9 parts (100%) of 4-[bis(4-fluorophenyl)methylene]-3-piperidinol hydrochloride; mp.>260° C. (intermediate 24).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16]CC2C=CC=CC=2)[C:10]=1[C:24](=[O:26])[CH3:25])C1C=CC=CC=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH:37]=O>>[OH:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[C:10]=1[C:24](=[O:26])[CH2:25][CH2:37][C:28]1[CH:29]=[CH:30][C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=2[CH:27]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1c(OCc2ccccc2)cc(C)cc1OCc1ccccc1
Product: Cc1cc(O)c(C(=O)CCc2ccc3c(c2)CCCC3)c(O)c1

Procedure:
The intermediate, 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treated with 2-naphthaldehyde as described in Example 1, Part B. Subsequent catalytic hydrogenation as described in Example 1, Part C, provided 1-(2,6-Dihydroxy-4-methyl-phenyl)-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Further treatment of this by-product as described in Example 1, Part D and E, afforded the title compound. 1HNMR (400 MHz, CD3OD) δ 7.02 (s, 1H), 6.93 (m, 2H), 6.87 (s, 1H) 6.61 (s, 1H), 5.24 (d, J=7.73 Hz, 1H), 3.94 (d, J=12.05 Hz, 1H), 3.75–3.34 (m, 5H), 3.25–2.72 (m, 8H), 2.43 (s, 3H), 1.81–1.77 (m, 4H). MS: m/z (MH+) 469.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[C:13]#[N:14])=[CH:6][CH:5]=1.C(Br)Br.[NH:26]1[CH:30]=CN=[N:27]1.C[N:32]([CH:34]=O)[CH3:33]>>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)([CH2:30][N:26]1[CH:34]=[N:32][CH:33]=[N:27]1)[C:13]#[N:14]
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1c(F)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: BrCBr
Product: N#CC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 3 neck 200 ml round bottom flask was charged with 2.4 gms of 60% NaH (0.048 mole, 1.2 eq.), washed twice with 25 ml of hexanes, in 40 ml of DMF. At room temperature 12.28 gms (0.04 mole, 1.0 eq.) of alpha-[2-(4-chlorophenyl)ethyl]-2-chloro-6-fluorophenylacetonitrile was added dropwise over 0.5 hour in 30 ml of DMF. Then 10.43 gms of CH2Br2 (0.60 mole, 1.5 eq.) in 20 ml of DMF was added dropwise and the reaction was stirred at room temperature for 0.5 hour after which gas liquid chromatography indicated that the reaction was complete. The reaction was quenched after 1 hour by adding 20 ml of water and 200 ml of ether which was separated. After washing with water, drying and concentrating 14.84 gms (92.9% yield) resulted which was used directly in the triazole coupling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[N:11]#[C:12][NH2:13].[Na].[CH3:15]I>C(O)C>[C:12]([NH:13][C:9](=[N:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:10][CH3:15])#[N:11]
Reactant: CI
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: CSC(=Nc1ccc(Cl)cc1)NC#N

Procedure:
p-Chlorophenyl isothiocyanate (XXXIa) (50.7 grams) is added to a suspension of sodium cyanamide (19.2 g) in ethanol (30 mL) with stirring which slowly dissolves and precipitates the sodium salt of N-cyano-N'-p-chlorophenylthiourea (XXXIIa) which is filtered off, washed with ethanol and dried to yield 36.2 grams which are suspended in 200 mL of ethanol and combined with 37.6 grams of methyl iodide with rapid stirring at ambient room temperature. The product separates as heat is evolved. The suspension is cooled in an ice bath, the solids filtered, washed with water and dried to give N-cyano-N'-p-chlorophenyl-S-methylisothiourea (XXXIIIa).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl.C1(OC)C=CC=CC=1>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][NH:2][NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)COc1ccc(C(=O)NN(C)C(=O)OC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNNC(=O)c1ccc(OCC(=O)OC)cc1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of the product of step (a) (2.9 g) in a mixture of dichloromethane (20 ml) and anisole (2 ml) at 0°-5° C. was added trifluoroacetic acid (27 ml). The resultant solution was stirred at low temperature for 20 minutes and then at ambient temperature for 2.5 hours. The reaction mixture was evaporated and the residue was triturated with dry ether. The solid was collected and washed with ether to give methyl 4-(3-methylcarbazoyl)phenoxyacetate trifluoroacetate salt (2.9 g), as a white solid; m.p. 121°-123° C.; NMR Spectrum (DMSO-d6) 2.80 (3H, s), 3.70 (3H, s), 4.93 (2H, s), 7.10 (2H, d), 7.85 (2H, d), 10.80-11.70 (1H, br s); Mass Spectrum m/Z 239 (M+H)+.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1.C(N)(=S)C1C=CC=CC=1.ClCC(CCl)=O>CC(C)=O.O.COC(C)(C)C>[I:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1
Reactant: [I-]
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: NC(=S)c1ccccc1
Agent: O=C(CCl)CCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: ICc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
2 g (13.35 mmol) of sodium iodide were added to a solution of 0.56 g (2.67 mmol) of 4-chloromethyl-2-phenyl-thiazole (prepared from thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in 10 ml of acetone and the suspension was stirred at reflux for 2 hours. After cooling to ambient temperature, 30 ml of tert-butyl methyl ether and 10 ml of water were added and the mixture was transferred to a separatory funnel. The organic phase was washed with water and brine, dried with anhydrous sodium sulfate and finally evaporated, leaving 0.8 g of 4-iodomethyl-2-phenyl-thiazole as light yellow solid (99% of theory).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[CH3:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][N+:12]=1[O-:19].[OH-].[Na+]>O>[N+:1]([C:15]1[C:14]([CH3:18])=[CH:13][N+:12]([O-:19])=[C:11]([CH3:10])[C:16]=1[CH3:17])([O-:4])=[O:2]
Reactant: Cc1cc(C)c(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[n+]([O-])c(C)c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a cooled solution of fuming HNO3 (50 ml) and conc. H2SO4 (50 ml) in an ice bath was added 2,3,5-trimethylpyridine-N-oxide (35.67 g) and the reaction mixture was stirred at 40°-50° C. for 18 h. After which time, the reaction was cooled to rt, poured into water/crushed ice (250 ml), alkalized with NaOH pellets and extracted with CH2 Cl2 (3×100 ml). The extracts were combined and washed with sat. NaCl (1×50 ml), dried (MgSO4) and the solvent removed in vacuo to give 4-nitro-2,3,5-trimethyl-pyridine-N-oxide (45.5 g, 96%) as an orange solid; mp 69°-71° C. (ether), orange plates.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[CH2:7]1[O:10][CH:8]1[CH3:9]>C(O)(C)(C)C>[CH3:1][N:2]([CH2:7][CH:8]([OH:10])[CH3:9])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CNS(C)(=O)=O
Reactant: CC1CO1
Solvent: CC(C)(C)O
Product: CC(O)CN(C)S(C)(=O)=O

Procedure:
N-Methylmethanesulfonamide (21.8 grams; 0.2 mol), t-butylalcohol (50 ml) sodium hydride (0.5 grams; 50% in mineral oil), and propylene oxide (11.6 grams; 0.2 mol) were placed into a 3-necked glass reaction flask equipped with stopper, stirrer, thermometer, and reflux condenser. The mixture was heated at 50°-60° C. for three hours, cooled, and concentrated on a rotoevaporator. The concentrate was neutralized with concentrated hydrochloric acid (1 ml) and distilled under reduced pressure. Fractions 4 and 5 (13.2 grams; boiling point (140°-142° C./1.5 mm Hg) analyzed for the described product as follows: