Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Br.[CH3:13][NH:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][N:14]([CH3:15])[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: CNC
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 3-methyl-4-nitrobenzyl bromide (1.0 g, 4.3 mmol), anhydrous dimethylamine (0.34 mL, 5.1 mmol) and potassium carbonate (1.5 g, 0.011 mol) in N,N-dimethylformamide (4.5 mL) was stirred at 70° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford N,N-dimethyl-1-(3-methyl-4-nitrophenyl)methanamine as oil (0.80 g, y. 95%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si](OCC)(OCC)(OCC)OCC.[CH:26]([C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:30]=1[NH2:31])([CH3:28])[CH3:27].OS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:31]/[C:30]2[C:32]([CH:36]([CH3:37])[CH3:38])=[CH:33][CH:34]=[CH:35][C:29]=2[CH:26]([CH3:28])[CH3:27])/[CH3:10])[C:3]=1[OH:12]
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCO[Si](OCC)(OCC)OCC
Agent: O=S(=O)(O)O
Product: C/C(=N\c1c(C(C)C)cccc1C(C)C)c1cc(C)cc(Br)c1O
Temperature: 170 °C
Reaction time: 5 h
Yield: 81.8 %

Procedure:
In a 50 mL Claisens flask under argon atmosphere, a mixture of 10.6 g (46.3 mmol) of 29, 20.2 g (97.2 mmol) of Si(OEt)4, and 9.03 g (50.9 mmol) of 2,6-diisopropylaniline was heated to 170° C., and then 0.37 mL of 96% H2SO4 was added. This mixture was stirred for 5 hr, and the formed ethanol was slowly distilled off. Later, 300 mL of cold water was added, and the product was extracted with 2×100 mL of diethyl ether. The combined extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-63 um, eluent: hexanes and then hexanes-diethyl ether, 100:1, vol.). The isolated product was additionally washed with 3×30 mL hexanes and dried in vacuum. This procedure gave 14.7 g (82%) of yellowish solid.
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]([O:19]CC)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][O:34][C:35]2[CH:36]=[C:37]([NH2:40])[NH:38][N:39]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:32][O:31][C:29]1[CH:28]=[C:27]([CH2:33][O:34][C:35]2[CH:36]=[C:37]([NH:40][C:17]([C:15]3[S:16][C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11][CH2:10]4)=[CH:13][CH:14]=3)=[O:19])[NH:38][N:39]=2)[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C)CC2)s1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32127.9 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of ethyl 5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate (0.254 g, 1 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.286 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at room temperature for 18 h and then heated at 65° C. for 6 h. Ethyl acetate (5 mL) was added to the reaction mixture followed by a solution of potassium sodium tartrate (5 mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was added and the mixture was filtered through celite. The filtrate was transferred to a separating funnel and the aqueous layer removed. The ethyl acetate layer was washed with saturated brine and then dried over magnesium sulphate. After filtration the solvent was evaporated to give the crude product as a yellow solid. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0. 147 g, 32.1%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]C)=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH2:6][C:5]2([CH2:19][CH2:18][CH2:17]2)[CH2:4]1)[CH3:2].B(Br)(Br)Br.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:15])=[C:10]([CH3:14])[C:11]=2[CH3:13])[CH2:6][C:5]2([CH2:17][CH2:18][CH2:19]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CC2(CCC2)Cc2cc(OC)c(C)c(C)c21
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCN1CC2(CCC2)Cc2cc(O)c(C)c(C)c21
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 1′-ethyl-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (100 mg) in 2 mL chloroform cooled in ice bath (10° C.) was added BBr3 (2 mL, 1 M). After 4 hours, ice was added to quench the reaction. After separation of the two layers, dichloromethane was used to extract the aqueous phase. The combined organic phases were then washed with brine, dried and evaporated to give a crude oil which was then passed through a column (EtOAc: Hexane; 2-16%) to give 1′-ethyl-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-6′-ol (35.9 mg). 1H-NMR (300 MHz, CDCl3): δ=6.37 (s, 1H), 3.04 (s, 2H), 2.95-2.65 (q, 2H), 2.74 (s, 2H), 2.12 (s, 3H), 2.1 (s, 3H), 2.05-1.85 (m, 4H), 1.84-1.64 (m, 2H), 1.3-1.1 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=152.88, 143.52, 133.97, 130.4, 126.13, 116.74, 62.54, 55.07, 44.81, 42.13, 36.29, 19.77, 19.31, 16.6, and 15.79 ppm. MS: (m/z): 246.2 (M+H+)
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:35][C:30]2C=[CH:32][CH:33]=[CH:34][C:29]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:35]2[CH2:32][CH2:33][CH2:34][CH2:29][CH2:30]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Reaction time: 0.17 h

Procedure:
To a suspension of 4.0 g of 4-iodobenzoic acid (16.13 mmol) in 40 ml of CH2Cl2 there are added 3.65 ml of diisopropylethylamine (20.97 mmol) and then, after 10 minutes, 5.18 g of TBTU (16.13 mmol). After stirring for 10 minutes more, 1.60 ml of piperidine (16.13 mmol) are added and the reaction mixture is stirred overnight at ambient temperature. The reaction mixture is washed 3 times with water and then once with saturated NaCl. After drying (MgSO4) and evaporation under reduced pressure, the residue is chromatographed on silica (CH2Cl2/acetone 9/1) to yield the title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH3:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>CCCCCCC.O>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O
Product: CCCCCOc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 105.6 %

Procedure:
p-Hydroxyacetophenone (40.0 g), n-pentyl bromide (48.8 g) and dimethylformamide (200 ml) were charged in 1-liter three-necked flask, and disintegrated potassium carbonate (48.7 g) was added thereto with stirring. The mixture was heated, and the reaction was carried out for 3 hours at the inner temperature of 65 to 70° C. After completion of the reaction, the mixture was cooled, water (360 ml) and n-heptane (360 ml) were added thereto and, after the mixture was stirred, it was separated to collect a n-heptane layer. The n-heptane layer was washed with 0.5N aqueous solution (200 ml) of sodium hydroxide twice and, finally, washed with a saturated saline solution (200 ml). The n-heptane solution was concentrated in vacuo to give p-pentyloxyacetophenone (64.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61]C(=O)C)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 63 °C
Yield: 85.1 %

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (483 mg) was suspended in dry methanol (3 mL). To this solution was added 4N HCl in dioxane. The mixture was heated at 63° C. for 3-4 hours. Upon complete conversion, the mixture was concentrated to dryness. The solid was re dissolved in DCM 10 mL and was washed with Na2CO3 to a pH of 8. The organic layer was washed with water, brine, dried (anhydrous Na2SO4) and concentrated to get a white solid. The solid was purified by column chromatography (silica, DCM-EtOAc, 90/1-60/40) to get the desired product as a white solid (393 mg). LCMS (m/z) 926.
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(C[C@H](C)O)CC2
Yield: 46 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as an off-white foam (55 mg, 46%). MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 110H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N:17]1[C:21]([CH3:22])=[CH:20][C:19]([NH2:23])=[N:18]1>>[CH3:16][N:17]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:18]1
Reactant: Cc1cc(N)nn1C
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3cc(C)n(C)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1,5-dimethyl-1H-pyrazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=36%). MS ISP (m/e): 293.2 (100) [(M+H)+].
Reaction SMILES: [N:1]1([C@@H:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(OCC)C>Cl>[N:1]1([C@@H:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)C[C@H](c1ccccc1)n1cnc2ccccc21
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C[C@H](c1ccccc1)n1cnc2ccccc21

Procedure:
A solution of tert-butyl (3R)-3-(1H-benzimidazol-1-yl)-3-phenylpropanoate (92 mg, 285 μmol) in hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 48 hours. The solution was then evaporated in vacuo to give a gum. Trituration of this residue with diethyl ether afforded the title compound, [LCMS (Method B, Mobile Phase I) RT=3.45 min, MH+ 267].
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][C:11](=[O:16])[CH2:10][CH2:9]2)(=[O:4])[CH3:3].[C:17]1([C:26]2[CH:31]=[CH:30]C=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:20](C(Cl)=O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[O:16]=[C:11]1[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:5][C:2]([C:3]3[CH:28]=[CH:27][C:26]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:31][CH:30]=3)=[O:4])[CH:15]=[CH:14][C:13]=2[CH2:12]1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(=O)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
Concentrated hydrochloric acid (1.5 ml) was added to 6-acetamido-2-tetralone (20 mg. 0.098 mmol) obtained in Reference Example 71, which was stirred at 100° C. for 1 hour, and the solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. [1,1′-Biphenyl]-4-carbonyl chloride (21.3 mg, 0.098 mmol) was added to a dimethylformamide solution (0.5 ml) of the obtained oily substance and triethylamine (0.014 ml, 0.098 mmol) under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with 1N hydrochloric acid, aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (10 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br.Br[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].[H-].[Na+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCBr
Reactant: O=[N+]([O-])c1cccc(-c2ncc[nH]2)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCn1ccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At rt and under N2, to a solution of 2-(3-nitrophenyl)-1H-imidazole (0.189 g, 1.00 mmol) and (2-bromoethyl)dimethylamine hydrobromide (0.280 g, 1.20 mmol) in anhydrous DMF (5 mL) was added NaH (60% in mineral oil, 160 mg, 4.0 mmol) in two portions with caution. The mixture was stirred at rt for 15 h. Water (0.3 mL) was added cautiously to quench the reaction. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=2.24 (s, 6H), 2.69 (t, J=7.2 Hz, 2H), 4.13 (d, J=6.8 Hz, 2H), 7.17 (d, J=1.2 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 8.04(dt, J=0.8, 8.0 Hz, 1H), 8.28 (dq, J=1.2, 8.4 Hz, 1H), 8.56 (t, J=1.6 Hz, 1H). MS (ES+): m/z 261.17 [MH+]. HPLC: tR=0.46 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[O:19]COC)[OH:12])=[CH:7][CH:6]=1)=[O:4].[ClH:23]>CO>[ClH:23].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[OH:19])[OH:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: COCOc1cnccc1C(O)c1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C(O)c2ccncc2O)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
Next, a mixture of (4-methoxycarbonylphenyl)-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.06 g, 6.79 mmol), methanol (35 mL) and concentrated hydrochloric acid (4.4 mL) was heated under reflux for 20 minutes. After cooling to room temperature, the reaction mixture was concentrated. Methanol and ethyl acetate were added to the residue and the resulting precipitate was filtered to give (4-methoxycarbonylphenyl)-(3-hydroxypyridin-4-yl)-methanol hydrochloride (1.87 g, 81%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7][NH2:8])=[O:6].[C:22](=S)=[S:23].[OH-].[K+].Cl>CCO.CCOC(C)=O.O>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[CH3:21])=[C:4]([C:5]2[O:6][C:22]([SH:23])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NN)ccc(F)c1F
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(I)ccc1Nc1c(-c2nnc(S)o2)ccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide (170 mg, 0.42 mmol) was suspended in 7 mL of absolute EtOH and cooled to 0° C. Carbon disulfide (74 mg, 0.97 mmol) was added followed by 24 mg (0.42 mmol) of powdered KOH. The reaction was stirred for 1 h at 0° C., 1 h at rt, and refluxed for 3 h to afford a homogeneous reaction. The reaction was cooled to rt. at which point a ppt formed. Water was added and the reaction diluted with 5 mL of EtOAc. 1N HCl was added to acidify the aqueous layer (pH=2). The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated to obtain 96 mg (51%) of 5-[3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[1,3,4]oxadiazole-2-thiol as a yellow powder. M.p.=231.8-232.8° C. 1H NMR (400 MHz, CDCl3) δ7.62 (m, 2H), 7.47 (s, 1H), 7.30 (complex m, 2H), 6.44 (dd, J=8.0, 4.5 Hz, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:28]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][N:22]=2)=[O:29])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1cnccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2cnccn2)cc1
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydrofuran-3-yl)pent-1-en-3-one (523 mg) in ethanol (8.5 mL) were added pyrazine-2-carbaldehyde (220 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (50.5 mg) and triethylamine (102 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (100 mg, yield 14%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].N[C@@H:14](CCC)C(O)=O.C(N)(C)C>>[NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:14])[C@H:3]([OH:10])[C:4]([NH:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CCC[C@H](N)C(=O)O
Solvent: CC(C)N
Product: CCC[C@H](N)[C@H](O)C(=O)NC(C)C

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using (S)-2-aminopentanoic acid in the first step (step B1), and isopropylamine in the seventh step (step B7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Oc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-2-fluoronitrobenzene (3.0 g, 17.0 mmol) in DMF (8.7 mL), 4-fluorophenol (2.0 g, 17.9 mmol) and potassium carbonate (2.46 g, 17.9 mmol) were successively added, and the mixture was stirred at 70° C. for 2 hours. After the reaction, the mixture was cooled to room temperature and ethyl acetate was added to the mixture. After the organic phase was washed with water (30 mL), 1N sodium hydroxide (aq., 30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give 4-chloro-2-(4-fluorophenoxy)-1-nitrobenzene as a crude product. The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[S:29][C:30]2[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][C:31]=2[N:32]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:35]5[CH:34]=[CH:33][C:31]6[N:32]=[C:28]([CH3:27])[S:29][C:30]=6[CH:36]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1nc2ccc(B(O)O)cc2s1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6nc(C)sc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzothiazol-6-boronic acid (prepared from 2-methyl-benzothiazole-6-ylboronic acid pinacol ester using NaIO4 and NH4O2CCH3 in acetone and water) following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.74 min; Mass spectrum (ESI+): m/z=506 [m+H]+.