Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:30](=[O:31])[NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: CCCCCN=C=O
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCNC(=O)OCC1(CO)CCOc2ccccc2C1=O

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (260 mg, 1.17 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.18 ml, 1.3 mmol) and n-pentyl isocyanate (332 μl, 2.57 mmol). The mixture was heated to reflux for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 210 mg (54%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[C:8](OP(OC3C=CC=CC=3)(OC3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@@H:5]12)[CH3:3].[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][CH2:52][N:51]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[CH2:50]1)=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:8]2[C@H:9]([CH3:10])[C@@H:5]3[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]3[C:7]=2[C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:53][CH2:52][N:51]([C:54]([O:56][CH2:57][CH:58]=[CH2:59])=[O:55])[CH2:50]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1CCC(C[C@@H]2C[C@H](S)CN2C(=O)OCC=C)C1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCN(C(=O)OCC=C)C3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 49.7 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-diphenoxyphosphoryloxy-1-carbapen-2-em-3-carboxylate (790 mg, 1.6 mmol), (2R,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)-4-mercaptopyrrolidine (560 mg, 1.6 mmol) and N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(N-allyloxycarbonylpyrrolidin-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (480 mg, yield: 50%).
Reaction SMILES: C[O:2][C:3](=[O:11])[CH2:4][CH:5](O)[CH2:6][CH2:7][CH2:8]Cl.CO[C:14](=O)[CH:15]=[CH:16][CH2:17]CCCl>>[C:3]([OH:2])(=[O:11])[CH:4]=[CH:5][CH2:6][CH2:7][CH:8]=[CH:14][CH:15]=[CH:16][CH3:17]
Reactant: COC(=O)C=CCCCCl
Reactant: COC(=O)CC(O)CCCCl
Product: CC=CC=CCCC=CC(=O)O

Procedure:
GC/MS (m/e); 166 (M+, 8%), 148 (2), 121 (2), 105 (2), 91 (4), 81 (100), 65 (5), 53 (18), 41 (16)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.[OH-].[K+]>[C:5]1([S:11][C:2](=[CH2:3])[CH2:1][OH:4])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CCO
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: C=C(CO)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
To a stirred solution of 36.0 g (0.64 mol) of propargyl alcohol and 0.12 g (1.8 mmol) of powdered potassium hydroxide, was added dropwise at 125° C. over 30 minutes, 60.0 g (0.54 mol) of thiophenol. The mixture was stirred for an additional 90 minutes, and allowed to cool to room temperature. The brown solution was diluted with 200 mL of ether, and extracted with three 100-mL portions of 2N sodium hydroxide, and two 100-mL portions of water. The organic phase was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. to give 90.4 g of a brown liquid, which, according to NMR analysis, contained 34% of the desired isomer. The mixture was fractionally distilled through a 0.8×20-cm column packed with glass helices to give 29.5 g of a colorless liquid, which by NMR analysis contained 67% of the desired isomer, bp 109°-116° C./1.2 Torr. This liquid was chromatographed on silica gel (100-200 mesh, 50 g/gram of compound) with 20% EtOAc/Skelly B as eluant, to give 16.4 g (18%) of the sulfide as a colorless liquid; IR (neat) cm-1 3360, 1610, 1580, 1470, 1430, 1040, 740, 690; 1H NMR (CDCl3) δ3.70 (t, 1H, OH), 4.10 (d, 2H, CH2), 5.2 (t, J=1 Hz, 1H, vinyl), 5.55 (t, J=1 Hz, 1H, vinyl), 7.15-7.55 (m, 5H, phenyl).
Reaction SMILES: BrC(C1C=CC=CC=1)CC.[Mg].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:22](O)([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CCOCC>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[CH:22]([CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH3:23]
Reactant: COc1ccc(OC)c(C(C)(O)CCCc2ccccc2)c1
Agent: CCC(Br)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: COc1ccc(OC)c(C(C)CCCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromopropylbenzene (51.7 g., 0.26 mole) in ether (225 ml.) is added dropwise over a one hour period to a refluxing mixture of magnesium (7.32 g.) in ether (78 ml.). The reaction mixture is refluxed for 30 minutes longer and then a solution of 2,5-dimethoxy-acetophenone (50 g.) in ether (60 ml.) is added dropwise and heated to reflux for 1.5 hours. The reaction is quenched by addition of saturated ammonium chloride (250 ml.) the ether layer is separated and the aqueous phase extracted with ether (3×200 ml.). The combined ether extracts are dried over magnesium sulfate and concentrated under vacuum to yield 80.3 g. (100%) of 2-(2'5'-dimethyloxyphenyl)-5-phenyl-2-pentanol as an oil. The oil (78.1 g., 0.26 mole), 21.7 g. of p-toluenesulfonic acid and 1250 ml. of phenol are combined and heated at reflux for one hour, while collecting the water (5.5 ml.) evolved in a Dean-Stark apparatus. The mixture is cooled to room temperature, washed with 200 ml. portions of water, saturated sodium bicarbonate and brine, then dried over magnesium sulfate. The filtered phenol layer yields 75.6 g. of 2-(2',5'-dimethoxyphenyl)-5-phenyl-2-pentene as an orange oil upon evaporation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@:8]([CH2:22][OH:23])([CH3:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C@:8]([CH2:22][OH:23])([CH3:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([NH2:18])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)c(N)c1
Reaction time: 2 h

Procedure:
An argon purged solution of [(R)-1-Hydroxymethyl-3-(4-hydroxy-3-nitro-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (3.02 g, 8.87 mmol) in ethanol (40 ml) was treated with 10% Pd on activated charcoal (0.5 g). Argon was replaced by hydrogen and the reaction was allowed to proceed under atmospheric pressure for 2 hours. The reaction suspension was filtered and the filtrate evaporated to dryness in vacuum. Silica gel chromatography (eluent: DCM/methanol 20/1 to 10/1) followed by crystallization from diethyl ether provided the title compound as colorless crystals. mp 122.1/123.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]=1>O1CCCC1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:31]([C:30]4[CH:29]=[N:28][C:27]([Cl:26])=[CH:35][CH:34]=4)=[O:32])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a suspension of 8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (31.2 mg, 0.118 mmol) in tetrahydrofuran (0.5 mL) were added triethylamine (19.8 μL, 0.142 mmol) and 6-chloronicotinoyl chloride (25.0 mg, 0.142 mmol). The reaction mixture was stirred at room temperature for 4 hrs. The mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from n-hexane to give the title compound as a colorless powder (27.1 mg, 0.0672 mmol, 57%).
Reaction SMILES: Cl[C:2]1[N:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:18]=[C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[CH:23]=2)[CH:20]=[N:21][C:2]=1[C:34]1[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2Cl)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2-c2cnn(C)c2)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)nicotinamide (1-3, 50.0 mg, 0.122 mmol)) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.3 mg, 0.122 mmol) in dioxanes (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (7.03 mg, 6.08 μmol) and 2 N aqueous sodium bicarbonate solution (0.304 mL, 0.608 mmol). Under microwave heating the deoxygenated mixture was held at 160° C. for 1 h. The reaction mixture was filtered and concentrated to dryness. A solid residue was triturated with ethyl acetate (4 mL), collected by filtration, washed with water (10 mL) and air dried to afford N-(3,4-dimethoxybenzyl)-5-(3,5-dimethylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)nicotinamide (1-4). 1H NMR (300 MHz, DMSO) δ 9.09 (t, 1H, J=5.8 Hz), 8.87 (d, 1H, J=1.8 Hz), 7.92 (d, 1H, J=1.8 Hz), 7.82 (d, 1H, J=9.8 Hz), 7.39 (s, 2H), 7.06 (s, 1H), 6.92 (m, 3H), 4.29 (d, 2H, J=5.3 Hz), 3.74 (m, 6H), 3.32 (s, 3H), 2.35 (s, 3H). HRMS m/z (M+H) 457.2242 found, 457.2234 required.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][CH3:15]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[N:16][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][C:2]=1[NH:10][CH2:3][CH2:2][CH3:9])([O-:12])=[O:11]
Reactant: CCCN
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: CCCN=Cc1ccc(NCCC)c([N+](=O)[O-])c1

Procedure:
(a-1) A solution of 40 parts of 4-chloro-3-nitrobenzaldehyde and 338 parts of 1-propanamine was stirred and refluxed for 1.50 hour. The reaction mixture was evaporqted, yielding 53.7 parts of 2-nitro-N-propyl-4-[(propylimino)methyl]benzenamine as a residue (int. 1).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH:25]=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:20][CH:19]=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][CH2:14][CH2:15][CH3:16].[H][H]>O1CCCC1>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:32][CH:33]=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][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC=CC(=O)OCC)cc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCC(=O)OCC)cc1

Procedure:
A solution of 4 g. (8.7 m moles) 2-(ethoxycarbonyl)vinyl 4-(hexadecylamino)benzoate and 400 mg. 10% Pd(C) in 100 ml. tetrahydrofuran is hydrogenated at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetonitrile to yield 2-(ethoxycarbonyl)ethyl 4-(hexadecylamino)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH2:48].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[CH2:46][CH2:47][NH:48][C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[CH:10]=[C:9]3[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)=[O:19]
Reactant: NCCc1ccc(Cl)cc1Br
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Br)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 1.32 g; 3.52 mmol), 1-hydroxybenzotriazole hydrate (0.59 g; 3.85 mmol) and 2-(2-bromo-4-chlorophenyl)ethanamine (Preparation 5; 0.904 g; 3.85 mmol) in dry dimethylformamide (10 mL) was added 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.806 g; 4.02 mmol) at ambient temperature. After stirring at ambient temperature for 5 hours, the solution was diluted with 100 mL of water, stirred for 10 minutes longer and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage 40M), eluting with hexane and ethyl acetate to provide ethyl 7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as a white solid (1.21 g). MS (apci, pos) m/z=594.
Reaction SMILES: [C:1]([C:5]1[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[C:11]([CH3:27])=[CH:10][C:9]=2[C:8]([CH3:29])([CH3:28])[CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30](=O)[CH3:31]>>[CH2:30]([N:15]([C:12]1[C:11]([CH3:27])=[CH:10][C:9]2[C:8]([CH3:28])([CH3:29])[CH2:7][CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]=2[CH:13]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:31]
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CC=C3C(C)(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)(C)CC=C3C(C)(C)C)cc1
Yield: 77.3 %

Procedure:
Following General Procedure D, ethyl 4-[(8-tert-butyl-3,5,5-trimethyl-5,6-dihydronaphthalen-2yl)amino]benzoate (Compound 18, 0.14 g, 0.37 mmol) was reacted with acetaldehyde (0.40 mL, 7.4 mmol) to give 0.12 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[C:5]2=[C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]2=[C:5]2[C:4]3[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]2=1
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Solvent: O
Product: Fc1ccc2[nH]c3c4[nH]c5ccc(F)cc5c4c4c5cc(F)ccc5[nH]c4c3c2c1
Yield: 64.7 %

Procedure:
15 ml of acetone was poured into a 200 ml three-neck flask, and 1.35 g of 5-fluoroindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 33.6 g of cupric chloride anhydrate and 13.5 g of water in 55 ml of acetone and then agitating the resultant mixture for 5 minutes. Then the prepared oxidant solution was dripped into the 5-fluoroindole solution over 2 hours, and the resultant mixture was agitated for 5 hours at the temperature of 40° C. Color of the reaction solution changed from white to dark blue with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction solution was suction-filtered with a Perforated funnel, and the filtrate was washed with acetone and then methanol, and was dried to obtain 0.86 g of 2,9,14-trifluoro-6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole (5-fluoroindole trimer) (yield: 64%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and to be 0.88 S/cm. The result of elemental analysis was: <C8.00H3.95N1.10Cl0.10>3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]=[C:10]=[O:11])[N:3]=1.[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH2:26])(=[O:25])=[O:24])(=[O:14])[CH3:13]>C(#N)C>[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:10]([NH:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)=[O:11])(=[O:24])=[O:25])(=[O:14])[CH3:13]
Reactant: CC(=O)OCc1ccccc1S(N)(=O)=O
Reactant: O=C=Nc1nc(Cl)nc(Cl)n1
Solvent: CC#N
Product: CC(=O)OCc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 4,6-dichloro-1,3,5-triazin-2-yl isocyanate (0.87 g, 4.5 mmol) in acetonitrile (9 ml) was treated with 2-(acetoxymethyl)benzenesulfonamide (1.04 g, 4.5 mmol) and stirred for 16 hours. Volatiles were removed under vacuum to give a residue whose 'H NMR showed δ(CD3)2CO, 8.05-7.80 (m, 1H), 7.65-7.27 (m, 3H), 6.45 (brd s, 1H), 5.50 (s, 2H), 2.10 (s, 3H), consistent with the assigned structure.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][N:13]([C:15]1[CH:31]=[CH:30][C:18]([CH:19](O)[C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:17][CH:16]=1)[CH3:14].COC.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([CH:19]([C:18]2[CH:30]=[CH:31][C:15]([N:13]([CH3:14])[CH3:12])=[CH:16][CH:17]=2)[O:1][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[CH:25][CH:24]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: O=C(CO)Nc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)c1ccc(C(OCC(=O)Nc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of alpha-hydroxyacetanilide (3.62 g, 0.024 mole), 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (6.81 g, 0.024 mole) 50 ml of tetrahydrofuran, 153 ml of n-hexane, and one drop of methanesulfonic acid was refluxed for 11 hours, during which time an additional 300 ml of solvent was added. The blue-green solution was decolorized with 4 drops of tetramethylguanidine and the reaction mixture was filtered hot and the filtrate chilled. Yellow-green crystals formed, which were recrystallized from 30 ml petroleum ether/15 ml acetone to give a white solid, mp 118°-128° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([NH:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])[NH:8][C:7]=12>C(O)C>[CH:14]1([NH:13][C:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(NC1CCCC1)c1cc2ccnc(Cl)c2[nH]1
Solvent: CCO
Product: O=C(NC1CCCC1)c1cc2ccncc2[nH]1
Yield: 43 %

Procedure:
N-Cyclopentyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (20 mg, 43%) was prepared as an off-white solid following the procedure described for Example 27 using 7-chloro-N-cyclopentyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and ethanol as a solvent: mp 220-224° C.; 1H NMR (300 MHz, CD3OD) δ1.22-2.18 (8H, m), 4.28-4.42 (1H, m), 7.27 (1H, s), 7-82 (1H, d, J=5.8 Hz), 8.15 (1H, d, J=5.8 Hz), 8.85 (1H, s); ESI MS m/z 230 [C13H15N3O+H]+; HPLC (Method A) >99% (AUC), tR=12.1 min.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[C:23]([O:25]CC)=[CH2:24])=[CH:7][C:6]=1[F:28])(=O)C.Cl>CO>[C:23]([C:10]1[C:11](=[O:22])[CH2:12][CH2:13][C:14]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]=1[C:8]1[C:16](=[CH:17][C:5]([NH2:4])=[C:6]([F:28])[CH:7]=1)[CH2:15]2)(=[O:25])[CH3:24]
Reactant: C=C(OCC)C1=C2c3cc(F)c(NC(C)=O)cc3CC2(CCCC)CCC1=O
Agent: Cl
Solvent: CO
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1cc(F)c(N)cc1C2
Temperature: 80 °C
Yield: 93.9 %

Procedure:
A solution of 7-(acetylamino)-9a-butyl-4-(1-ethoxyvinyl)-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (205 mg, 0.53 mmol) in methanol (7.5 mL) was treated with aqueous 6N HCl (7.5 mL). The resulting mixture was placed under a N2 atmosphere and stirred with heating in an oil bath at 80° C. for 50 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc and aqueous 5% NaHCO3. The organic solution was washed with water and brine, dried over MgSO4, filtered, and evaporated under vacuum to afford 4-acetyl-7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (157 mg, 93%) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:15][C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]([NH2:14])=[O:13]
Reactant: [Br-]
Reactant: COc1ccc2cc(C(N)=O)[nH]c2c1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: COc1ccc2c(Br)c(C(N)=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 70.4 %

Procedure:
A solution of 540 mg (2.84 mmol) of 6-methoxy-1H-indole-2-carboxamide in 8 ml of pyridine is cooled to 0° C. and a solution of 908 mg (2.84 mmol) of pyridinium tribromide in 6 ml of pyridine is added thereto, dropwise. The reaction medium is stirred at 0° C. for 30 minutes and at ambient temperature for 19 h. 20 ml of ice-cold water is added to the reaction medium. The latter is then stirred at ambient temperature for 1 h and then filtered over sintered glass, to give 538 mg of 3-bromo-6-methoxy-1H-indole-2-carboxamide in the form of a white solid.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12](=[S:31])[NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27](=[O:30])[CH2:28][CH3:29])[N:20]=2)[N:18]=1)(=O)C1C=CC=CC=1>O.CO>[C:27]([NH:26][CH2:25][C:21]1[N:20]=[C:19]([C:17]2[N:18]=[C:14]([NH:13][C:12]([NH2:11])=[S:31])[S:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(=O)NCc1cccc(-c2csc(NC(N)=S)n2)n1
Temperature: 60 °C
Yield: 117.7 %

Procedure:
A solution of sodium hydroxide (3.7 g) in water (30 ml) was added to a suspension of 2-(3-benzoylthioureido)-4-(6-propionylaminomethylpyridin-2-yl)thiazole (16.5 g) in methanol (300 ml) at room temperature. The mixture was heated at 60° C. for 4.5 hours. The solvent was removed under reduced pressure. The residue was dissolved in water (200 ml). The mixture was neutralized with 6N hydrochloric acid. The resulting precipitate was collected by filtration to afford 4-(6-propionylaminomethylpyridin-2-yl)-2-thioureidothiazole (14.67 g).