Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8](=O)[CH:9]=[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][O:14]C2CCCCO2)[CH:7]=1.O.[NH2:30][NH2:31].[C:32](Cl)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([N:30]1[C:10]([CH2:11][CH2:12][CH2:13][OH:14])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:28])=[N:31]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: NN
Reactant: O=C(C=C(CCCOC1CCCCO1)c1ccccc1)c1cc(Br)ccc1F
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1N=C(c2cc(Br)ccc2F)CC1(CCCO)c1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 7.5 g (16.8 mmol) of 3-4 in 50 mL of pyridine was added 1.22 mL (25.2 mmol) hydrazine hydrate, and the resulting mixture was heated at 90° C. for 30 min. After cooling to room temperature, the reaction was placed in an ice bath and 5.96 mL (83.8 mmol) acetyl chloride was added dropwise. The bath was removed and the reaction was stirred overnight at room temperature before being dumped into a separatory funnel containing EtOAc and brine. The layers were separated, the organic was washed twice with 1M HCl, once with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was twice resuspended in toluene and concentrated to azeotrope off any remaining pyridine. The residue was dissolved in 200 mL of MeOH and ˜2 g of p-toluenesulfonic acid monohydrate was added. After stirring for 2 h at room temperature, most of the solvent was removed by rotary evaporation and the residue was partitioned between saturated aqueous NaHCO3 and EtOAc. After separating the layers, the organic was washed again with NaHCO3, then brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 3-5 as a white solid. Data for racemic 3-5: 1HNMR (500 MHz, CDCl3) δ 8.15 (m, 1H), 7.4-7.2 (m, 6H), 7.0 (m, 1H), 3.8-3.7 (m, 2H), 3.6 (m, 1H), 3.45 (m, 1H), 2.9 (m, 1H), 2.45 (s, 3H), 2.3 (m, 1H), 1.7-1.5 (m, 2H) ppm. HRMS (ES) calc'd M+H for C20H20BrFN2O2: 419.0765. Found: 419.0769.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[CH3:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:23][C:24]([NH2:26])=[S:25]>>[BrH:1].[Cl:22][C:21]1[C:16]([CH3:15])=[C:17]([NH:23][C:24]2[S:25][CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=3[CH3:10])[N:26]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Cl)cccc1NC(N)=S
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3cccc(Cl)c3C)n2)c(C)s1
Yield: 68.4 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-methyl-3-chlorophenyl thiourea (39 mg) as described in Example 154, step (a) to give 61.8 mg (66% yield) of methyl 4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C17H15ClN2O2S3, 410.96 (M+H), found 411.1.
Reaction SMILES: [CH2:1]([O-])C.[Na+].C(O)C.[Br:8][C:9]1[C:14]([N+]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N+:24]=[N-:25]>>[N:23](/[C:26](=[CH:1]\[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:9]=1[Br:8])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N+:24]=[N-:25]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=[N+]([O-])c1cccc(OCC2CC2)c1Br
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1cccc(OCC2CC2)c1Br)N=[N+]=[N-]
Temperature: -20 °C
Reaction time: 3.5 h
Yield: 28 %

Procedure:
A 50 mL roundbottom flask with stirbar was charged with sodium ethanolate, 21 wt % in ethanol (14 mL, 37.6 mmol), sealed and cooled to −20° C. under nitrogen. A mixture of Example 99A (6.38 g, 25.01 mmol) and ethyl 2-azidoacetate (10 g, 77 mmol) were added dropwise over 15 minutes. The solution was stirred for 3.5 hours, then poured into a separatory funnel and extracted from 100 mL water with 3×100 mL ether. The combined organics were washed with saturated aqueous sodium chloride, dried over magnesium sulfate. After filtration and solvent removal the residues were chromatographed on a 60 g silica cartridge eluting with 0-10-100% ethyl acetate/heptane to provide 2.56 g (28%) of the title compound.
Reaction SMILES: CN(C=O)C.[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=4[C:24]=3[C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Na+].C(S)C>C(O)C>[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=4[C:24]=3[C:25](=[O:34])[C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:16][CH:15]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCS
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Temperature: 75 °C

Procedure:
To 50 ml. of dry DMF were added 1.2 g. (2.6 mmole) of the product from Example 16. Sodium hydride (625 mg.; 26 mmole) was added to the mixture under a nitrogen atmosphere. To the resulting mixture then were slowly added by syringe 620 mg. (10 mmole) of ethyl mercaptan. A vigorous effervescence occurred. When the effervescence had ceased, the reaction mixture was heated at 75° C. in an oil bath for 12 hours. Ethanol (5 ml.) then was added dropwise. The resulting mixture was evaporated to dryness, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with 50 ml. of aqueous sodium chloride solution, and then repeatedly with 15 ml. portions of 1N hydrochloric acid. The hydrochloric acid extracts were combined, washed with ether, and rendered alkaline by addition of cold 1N sodium hydroxide. The alkaline mixture then was extracted with ethyl acetate, and the ethyl acetate extract, after drying over magnesium sulfate, was evaporated to obtain 0.54 g. of a yellow oil. The yellow oil was chromatographed to obtain 400 mg. of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.N1C=CC=CC=1>O>[C:18]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Oc1ccc(Cl)cc1C(=O)c1ccccc1)c1cccnc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
15 g (64.5 mmol) of p-chlorobenzoylphenol and 12 g (68 mmol) of nicotinic acid chloride hydrochloride was mixed with 200 ml dry pyridine and stirred for 24 hours at 40° C. After cooling 200 ml water were added and the precipitated product washed twice with 80 ml of water and recrystallized from methanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[NH:27][CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:25][N:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:22][CH:21]=1)[CH2:36][C:32]1[NH:31][CH:35]=[CH:34][N:33]=1
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)Cc1ccc(NCc2ccc(CNCc3ncc[nH]3)cc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (199 mg) obtained in Example 43-1 was dissolved in methanol (6 ml) and then added with 2-imidazole carboxaldehyde (57.1 mg) and sodium cyanoborohydride (65.4 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (231 mg) of the subject compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: COc1ccccc1C1CC(O)c2cc(O)ccc2O1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: COc1ccccc1C1CC(O)c2cc(Oc3ccc([N+](=O)[O-])cn3)ccc2O1

Procedure:
2-(2-Methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(2-methoxyphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.49 (dd, 1H, J 7.6, 1.7 Hz), 7.34 (dt, 1H, J 8.3, 7.5, 1.7 Hz), 7.24 (d, 1H, J 2.8 Hz), 7.22 (d, 1H, J 9.1 Hz), 7.07 (d, 1H, J 8.3 Hz), 7.03 (d, 1H, J 7.5 Hz), 7.01 (dd, 1H, J 8.7, 2.8 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.62 (d, 1H, J 6.3 Hz), 5.52 (d, 1H, J 10.4 Hz), 4.93-4.99 (m, 1H), 3.84 (s, 3H), 2.30-2.35 (m, 1H), 1.85-1.94 (m, 1H).
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:7])[CH3:6].[Si:8]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:47][C@H:46]([CH3:48])[O:45][C@H:44]([CH3:49])[CH2:43]2)=[C:29]([F:41])[C:30]2[O:34][N:33]=[C:32]([C:35](OCC)=[O:36])[C:31]=2[CH:40]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Si:8]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:43][C@H:44]([CH3:49])[O:45][C@H:46]([CH3:48])[CH2:47]2)=[C:29]([F:41])[C:30]2[O:34][N:33]=[C:32]([C:35]([NH:7][CH2:5][CH3:6])=[O:36])[C:31]=2[CH:40]=1)([C:21]([CH3:22])([CH3:24])[CH3:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCNC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, trimethylaluminum (2M in toluene, 1206 μl, 2.41 mmol) was slowly added (gas evolution) to an ice cooled solution of ethylamine (2M in THF) (1206 μl, 2.41 mmol) in 7 ml of toluene. The reaction was allowed to warm to room temperature and stirred for 2 hours. Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate, (Intermediate 204, 190 mg, 0.32 mmol) was added as a solution in toluene (3 ml). The reaction was stirred at 45° C. for 18 hours. The reaction was quenched drop wise (vigorous gas evolution) with 2 ml of 1N HCl. The crude reaction was filtered to remove solids, diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over MgSO4 and concentrated to give an oil. The oil was purified by silica gel column chromatorgraphy using a gradient of hexanes to ethyl acetate. Fractions were combined and concentrated to give the title compound. (170 mg, 0.288 mmol, 90%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([CH:39]=O)[S:36][C:35]=2[CH:41]=1>O1CCCC1>[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([CH2:39][CH:2]=[O:4])[S:36][C:35]=2[CH:41]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc2ccc(Br)cc2s1
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCc1cc2ccc(Br)cc2s1
Reaction time: 0.33 h
Yield: 82.4 %

Procedure:
To a 0° C. solution of potassium tert-butoxide (2.50 g, 21.4 mmol) in tetrahydrofuran (100 mL) is added (methoxymethyl)triphenylphosphonium chloride (7.49 g, 21.4 mmol). The reaction mixture is stirred for 20 minutes. 6-Bromo-benzo[b]thiophene-2-carbaldehyde (2.58 g; 10.7 mmol) is added and the ice-bath is removed. The mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with AcOH (5 mL). The mixture is treated with water (50 mL) and concentrated to a residue under reduced pressure. The residual aqueous solution is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to a residue. The residue is dissolved in THF (50 mL) and treated with HCl (5 N, 5 mL). The mixture is stirred at 70° C. for 60 minutes and neutralized with NaOH (5 N, 5 mL). The mixture is concentrated to a residue under reduced pressure. The residual aqueous mixture is extracted with EtOAc (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (2.25 g, 82%). ES/MS m/e 254.8, 252.8 (M−1).
Reaction SMILES: N[C:2]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:3]=1[CH2:4][NH:5][C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][CH:14]=2)[N:9]=1)=[O:7].N1C2C(=CN=CC=2)C=[CH:25][C:24]=1C(O)=O.O.ON1C2C=CC=CC=2N=N1.NC1C=CC=C(F)C=1CN>CN(C=O)C>[C:19]1([C@@H:18]2[CH2:3][C@H:4]2[NH:5][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[N:13][CH:14]=3)[N:9]=2)=[O:7])[CH:20]=[CH:21][CH:2]=[CH:25][CH:24]=1
Reactant: Nc1cccc(F)c1CNC(=O)c1ccc2cnccc2n1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: NCc1c(N)cccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Compound #16 N-(2-amino-6-fluorobenzyl)-2-[1,6]naphthyridinecarboxamide To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino-6-fluorobenzylamine (60.0 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (80.0 mg, 94%): m.p. 165 (dec.).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C(C(O)=O)=[CH:9]1.CN(C=O)C>C(Cl)Cl>[CH3:9][N:8]1[C:16]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:7]1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Oxalyl chloride (5.0 mL, 57.3 mmol) was added under nitrogen to a solution of 1-methylindole-3-carboxylic acid (2.00 g, 11.4 mmol) in 150 mL of methylene chloride at room temperature. A catalytic amount of DMF (10 μL) was added and the reaction stirred at room temperature for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure. To remove any residual oxalyl chloride the residue was taken up in benzene and then concentrated under reduced pressure to give 1-methyl-1H-indole-3-carbonyl chloride (2.21 g, 99%) as a yellow solid that was used in the next step without additional purification
Reaction SMILES: Cl[CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[CH3:23][NH2:24]>CC(O)C>[CH3:23][NH:24][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Nc1ccccc1CC(Cl)c1ccccc1
Reactant: CN
Solvent: CC(C)O
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-[2-(2-chloro-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (1.0 g, 3.17 mol) was reacted with monomethyl amine (7 g of 40% aqueous solution) in 2-propanol (3 g). The mixture was heated to 80° C. and stirred for 1 hour. Formation of product was indicated by TLC (silica gel/70 ethyl acetate/30 methanol).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.C1COCC1.CO.O[Li].O>O.Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([OH:31])=[O:30])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: COC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer A (2.0 mg, 5 μmol) in water (0.25 mL), THF (0.25 mL) and methanol (0.5 mL) was added LiOH.H2O (10 mg, 0.23 mmol). The mixture was stirred overnight at rt. The mixture was diluted with 5% aq HCl (10 mL) and extracted with EtOAc (2×40 mL). The combined organic extracts were dried over Na2SO4 and concentrated to leave crude 2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid isomer A (3 mg, quant) as an oil. 1H NMR (CDCl3) δ=2.49 (m, 1H), 2.63 (m, 1H), 3.00 (m, 1H), 3.1 (1H), 3.65 (1H), 3.92 (1H), 4.02 (2H); LC-MS (3 min) tR=1.90 min, m/z=423.
Reaction SMILES: C1C=CC=CC=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[O:14])S[CH:12]=1.[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=[O:27])=CC=1>CCOCC.O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]2[O:14][CH2:15][CH2:16][O:17]2)[O:27][CH:12]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: Brc1coc(C2OCCO2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A benzene (58 mL) solution of 4-bromo-2-thiophene carboxaldehyde (10.14 g 57.95 mmol), ethylene glycol (9.70 mL, 173.85 mmol) and p-toluenesulfonic acid monohydrate (1.10 g, 5.79 mmol) was refluxed with azeotropic removal of H2O for 6 h and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and the organics were washed with sat'd NaHCO3, brine and then dried (MgSO4), filtered and concentrated. Chromatography on silica gel using 95:5 Hexanes:EtOAc eluted the product to provide the title compound upon concentration as a yellow oil (12.69 g 100% yield): 1H NMR (CDCl3, 400 MHz) δ 7.45 (s, 1H), 6.52 (s, 1H), 5.92 (s, 1H), 4.17–4.00 (m, 4H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:51]=[CH:50][C:22]([O:23][CH2:24][C@@H:25]([OH:49])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]([C:45]([CH3:47])=[CH2:46])[C:37]3=[O:48])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:49][C@H:25]([CH2:24][O:23][C:22]1[CH:50]=[CH:51][C:19]([OH:18])=[CH:20][CH:21]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:40]3=[N:41][CH:42]=[CH:43][CH:44]=[C:39]3[N:38]([C:45]([CH3:47])=[CH2:46])[C:37]2=[O:48])=[CH:32][CH:31]=1
Reactant: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc3)cc2)c2ncccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=C(C)n1c(=O)n(-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)c2ncccc21
Yield: 86 %

Procedure:
3-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)phenyl]-1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.19 g, 0.272 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.108 g, 0.234 mmol).
Reaction SMILES: C([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)#N.C(=O)([O-])[O-].[K+].[K+].CN(C)S(Cl)(=O)=O>C(#N)C>[N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][CH:3]=1
Reactant: N#Cc1nc2ccccc2[nH]1
Agent: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2[nH]cnc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
2.83 Grams of a 2-cyanobenzimidazole compound compound (i)]of the formula (II) in which X is H and Z is OCF2CFHO was dissolved in 50 ml of acetonitrile. 3.8 Grams of potassium carbonate was added thereto. The resulting mixture was heated under reflux for 15 minutes. Thereafter, 2.6 g of dimethylsulfamoyl chloride was added to the refluxed mixture. Refluxing was continued for additional 40 minutes with heating. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. A residue was obtained by removing the solvent from the dried layer by distillation. Column chromatographying the residue on silica gel with toluene as an eluent gave 1.53 g of a benzimidazole derivative present compound (1)] of the formula (I) in which X is H, Z is OCF2CFHO, R is CN and Q is N(CH3)2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17](N)=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1.[OH-:23].[Na+].O.Cl>CCCCCC.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:23])=[O:18])=[CH:15][C:9]=3[C:8](=[O:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc(Cl)ccc1S2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(Cl)ccc1S2
Temperature: 0 °C
Yield: 47.4 %

Procedure:
A mixture of 0.4 g of 2-(8-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 6.0 g of sodium hydroxide, 50 ml of water and 60 ml of methanol was refluxed for 3 hours. The solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was crystallized from benzene--n-hexane to give 190 mg (yield: 47%) of 2-(8-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a powder having a melting point of 195°-196° C.