Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C[N:30](C)N.COS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:30])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CN(C)N
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: COc1ccc2c(Oc3ccc(C#N)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzaldehyde (8) (0.920 g, 2.5 mmol) in MeOH (25 mL) was added N,N-dimethylhydrazine (0.341 mL, 4.5 mmol). The resultant mixture was stirred at room temperature for 12 h under N2. Reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in CH3CN (25 mL) to which were added dimethylsulfate (0.378 mL, 3 mmol) and K2CO3 (0.415 g, 3 mmol) under N2. The reaction mixture was refluxed for 24 h. Reaction mixture was cooled at room temperature and poured into water (100 mL). Reaction mixture was extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The product was purified by column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to afford 0.560 g (62%) of the title compound (237) as an off-white solid. IR (film) 2958, 2225, 1602, 1501, 1235 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J=9.2 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J=6.4 Hz, 2H), 7.29-7.23 (m, 3H), 7.15 (d, J=2.4 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.09 (d, J=1.6 Hz, 1H), 7.08 and 7.05 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.64 (d, J=6.8 Hz, 2H), 3.94 (s, 3H), 2.25 (s, 3H). LCMS (ESI) m/z 366.11 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Br[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O>[CH:10]1([CH2:9][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: c1cn[nH]c1
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnn(CC2CCCCC2)c1
Reaction time: 0.08 h
Yield: 20.7 %

Procedure:
To a solution of pyrazole (1.00 g, 14.7 mmol) in of dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 450 mg, 11 mmol). After 5 min, bromomethylcyclohexane (2.4 mL, 17 mmol) was added by syringe and the mixture was maintained overnight. The reaction mixture was quenched with methanol, diluted with water, and extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 500 mg (27%) of 1-cyclohexylmethyl-1H-pyrazole. To a solution of 1-cyclohexylmethyl-1H-pyrazole (490 mg, 3.00 mmol) in tetrahydrofuran (10 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (1.5 mL, 3.8 mmol). The reaction mixture was maintained at −78° C. for 1 h and was treated with dimethylformamide (1.0 mL, 13 mmol). The reaction mixture was allowed to warm to rt, maintained overnight, and was quenched with methanol. The reaction mixture was diluted with water and was extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (95/5 hexanes/ethyl acetate) to provide 390 mg (68%) of 2-cyclohexylmethyl-2H-pyrazole-3-carbaldehyde.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN(C)[CH:20]=[O:21].[Cl-].[Na+]>CCCCCC.C(OCC)C>[C:6]1([CH2:12][C:13]2[S:14][C:15]([CH:20]=[O:21])=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: c1ccc(Cc2cccs2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1ccc(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
Under a nitrogen atmosphere, 25.7 grams (0.40 mole) of n-butyllithium in 168 ml of hexane was added by syringe to 300 ml of diethyl ether. The stirred solution was cooled in an ice-water bath and 70.0 grams (0.40 mole) of 2-(phenylmethyl)thiophene in 100 ml of diethyl ether was added dropwise during a 0.75 hour period. Upon complete addition, the cooling bath was removed and the reaction mixture stirred for 1.5 hours, then transferred to a Morton flask using a nitrogen pressure differential and tubing connecting the reaction vessel with the Morton flask. A solution of 32.3 grams (0.44 mole) of dimethylformamide in 200 ml of diethyl ether was added dropwise. During the addition the reaction mixture was allowed to warm to reflux temperature, then was stirred for 4.5 hours while cooling to ambient temperature. Stirring was continued for an additional 16 hours. The reaction mixture was poured into 400 grams of ice, and solid sodium chloride was added to saturation. After an additional 0.25 hour stirring, the organic layer was separated and the aqueous layer was extracted with two portions of 400 ml each of diethyl ether. The extracts and the organic layer above were combined and washed, in succession, with one portion of 300 ml of a saturated aqueous solution of sodium chloride, one portion of 300 ml of aqueous 2 N hydrochloric acid, one portion of 300 ml of a saturated aqueous solution of sodium chloride, one portion of 300 ml of a saturated aqueous solution of sodium bicarbonate, and finally, one portion of 300 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a residual oil. The residual oil was distilled under reduced pressure using a Kugelrohr distilling system to give 70.2 grams of 5-(phenylmethyl)thiophene-2-carboxaldehyde; b.p. 105° C./0.25 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:56])([CH3:55])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:54])([C@@:17]4([CH3:53])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][C@@H:43]5[CH2:45][C@@H:41]([N:42]5C(OC(C)(C)C)=O)[CH2:40]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O.Cl.CCOCC>C(Cl)Cl.ClCCCl>[C@H:41]12[CH2:45][C@H:43]([NH:42]1)[CH2:44][N:39]([CH2:38][CH2:37][NH:36][C@:20]13[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:53])([CH2:18][CH2:19]3)[C@@:16]3([CH3:54])[C@@H:25]([C@:26]4([CH3:29])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:55])([CH3:56])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)=[CH:28][CH2:27]4)[CH2:24][CH2:23]1)[CH2:40]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H](C3)N4C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H](C3)N4)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of (1R,5S)-tert-butyl 3-(2-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)amino)ethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (123 mg, 0.160 mmol) in DCM (3 mL) was added TFA (0.5 mL, 6.49 mmol) and the mixture was stirred at rt for 1 h. The resulting brown reaction mixture was diluted with DCE (3 mL) and concentrated to a light brown foam. The material was dissolved in DCM (2 mL) and DCE (2 mL) and treated with 2N HCl in Et2O (0.5 mL, 1.0 mmol). The resulting slurry was concentrated and dried under vacuum to give the title compound (108.1 mg, 0.139 mmol, 87% yield) as light grey solid. LC/MS: m/e 668.5 (M+H)+, 2.28 min (method 3). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.89 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 5.27 (d, J=4.4 Hz, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 4.39 (d, J=5.4 Hz, 2H), 3.88 (s, 3H), 3.76 (br. s., 1H), 3.59 (br. s., 1H), 3.48 (q, J=7.1 Hz, 3H), 3.40-3.33 (m, 2H), 3.07-2.91 (m, 2H), 2.37 (d, J=10.3 Hz, 1H), 2.25-1.89 (m, 7H), 1.83 (d, J=12.0 Hz, 1H), 1.77 (br. s., 1H), 1.73-1.71 (m, 3H), 1.67 (br. s., 1H), 1.65-1.58 (m, 2H), 1.57-1.38 (m, 8H), 1.37-1.29 (m, 1H), 1.27-1.22 (m, 1H), 1.13 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.92 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6](C(NC)=O)[CH:5]=[N:4][C:3]=1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>CCN(CC)CC>[NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CNC(=O)n1cnc(C(=O)NC(C)(C)C)c1N
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1nc[nH]c1N
Temperature: 80 °C
Yield: 119.1 %

Procedure:
5-Amino-N4-(1,1-dimethylethyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide 6 (10.4 g, 0.041 mol, 93% pure), MeOH (100 mL) and Et3N (5 mL) were placed into a 250 mL, three-necked flask equipped with a nitrogen inlet, a gas outlet tube, reflux condenser, thermometer, magnetic stirrer bar, and maintained under a positive pressure of nitrogen. The mixture was heated at 80° C. (oil bath) for 3 hour with vigorous stirring (when HPLC analysis indicated that no more starting material was present), gradually cooled to room temperature, and concentrated under reduced pressure. The gummy residue was treated with a solution of t-BuOMe (10 mL), n-heptane (100 mL) and acetone (2 mL), and stirred at room temperature for 1 hour. The resulting precipitate was collected by vacuum filtration and dried (20 mm Hg, 20° C., 18 hours) to yield 8.9 g (theoretical yield is 7.37 g) of 5-amino-N-(1,1-dimethyl-ethyl)-1H-imidazole-4-carboxamide 17 as a tan solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[C:24]#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:17][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:26][C:23]=2[C:24]#[N:25])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(Br)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 93.5 %

Procedure:
A mixture of (S)-methyl 6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 0.167 mmol), 5-chloro-2-fluorobenzonitrile (0.065 g, 0.416 mmol), and cesium carbonate (0.136 g, 0.416 mmol) in DMF (2.0 mL) was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature and water was added. The mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-methyl 6-bromo-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.068 g, 94%) as an off-white solid. MS (ESI, pos. ion) m/z 435, 437 [M+H]+.
Reaction SMILES: [NH2:1][C:2](N)=[NH:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:33]=[C:32]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:40][CH3:41])[CH:30]=4)[CH:25]=3)[CH:21]=[CH:20][N:19]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:33]=[C:32]([N:34]4[CH2:39][CH2:38][N:37]([C:2](=[NH:1])[NH2:3])[CH2:36][CH2:35]4)[C:31]4[C:26]([CH:25]=3)=[CH:27][CH:28]=[C:29]([O:40][CH3:41])[CH:30]=4)[CH:21]=[CH:20][N:19]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: N=C(N)N
Reactant: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCNCC3)c2c1
Product: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCN(C(=N)N)CC3)c2c1

Procedure:
4-[3-(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4-yl)-7-methoxy-1-naphthyl]piperazine-1-carboximidamide was synthesized according to General Procedure A: guanidine formation except N-[2-(3,4-dimethoxyphenyl)ethyl]-4-(6-methoxy-4-piperazin-1-yl-2-naphthyl)pyrimidin-2-amine (0.020 g, 0.035 mmol) was used. The reaction mixture was triturated with ether (10 mL) to obtain 4-[3-(2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}pyrimidin-4-yl)-7-methoxy-1-naphthyl]piperazine-1-carboximidamide 203 as a of yellow solid (0.010 g). LC/MS (m/z): 543 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=1.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[C:14]([NH:18][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: CCc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: CCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
In 5 ml of DMF, 330 mg (1.4 mol) of 2,4-dichloro-7-etylthieno[3,2-d]pyrimidine was dissolved, and then 228 mg (3.1 mmol) of t-butylamine was added dropwise thereto under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further 1 hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 312 mg (yield: 81.7%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]([CH3:24])[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>>[C:27]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]([CH3:24])[CH2:16]3)[CH2:11][CH2:10]2)=[CH:25][CH:26]=1)(=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)Cl
Reactant: CC1CN(C2CCN(CCc3ccc(CN)cc3)CC2)c2ccccc21
Product: CCC(=O)NCc1ccc(CCN2CCC(N3CC(C)c4ccccc43)CC2)cc1

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]-3-methylindoline (0.1 g) and propionyl chloride (0.028 ml) were treated as in Example 36 to give the title compound (0.122 g) as a pale yellow oil (yield: quantitative).
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH:9]1([CH2:12][NH:7][C:2]2[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccccc1N
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccccc1NCC1CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a solution of benzene-1,2-diamine (1.62 g, 15.0 mmol) and cyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in MeOH (15 mL) at 0° C. was added NaCNBH3 (2.07 g, 33.0 mmol) and acetic acid (0.2 mL). The ice bath was removed and the resulting mixture was stirred at room temperature over night. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-cyclopropylmethyl-benzene-1,2-diamine (836 mg, 34%). MS 163 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=O)[CH:7]=[CH:6]2.P(Br)(Br)([Br:18])=O.O>ClC1C=CC=CC=1>[Br:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cc2ccc(=O)[nH]c2cc1OC
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Br)c2cc1OC
Temperature: 150 °C
Reaction time: 6 h
Yield: 41.6 %

Procedure:
6,7-Dimethoxyquinolone (0.79 g) was dissolved in chlorobenzene (7 ml) to prepare a solution. Phosphorus oxybromide (3.34 g) was added to the solution, and the mixture was stirred at 150° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give 4-bromo-6,7-dimethoxyquinoline (429 mg, yield 42%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[CH:9]([CH:12]=O)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].[OH-].[Na+]>COCCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:30]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=4)[N:29]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(C=O)CC2
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O=[N+]([O-])O
Product: Cc1nc2c(s1)-c1nc(Nc3cccc([N+](=O)[O-])c3)ncc1CC2
Yield: 5.3 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazole-6-carbaldehyde (200 mg, 1 mmol), meta-nitro-phenyl guanidine nitrate (248 mg, 1), NaOH (41 mg, 1 mmol) and 2-methoxyethanol (2 mL) was heated under reflux for 16 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title compound as a yellow solid (18 mg, 5%): mp 227-228° C. Anal. RP-HPLC: tR 21.9 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 10.00 (s, 1H, NH), 8.89 (t, 1H, J 2.3, Ph-H), 8.30 (s, 1H, Py-H), 7.92 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.66 (ddd, 1H, J 8.3, 2.3, 0.7, Ph-H), 7.44 (t, 1H, J 8.3, Ph-H), 2.90 (m, 4H, CH2—CH2), 2.66 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 169.16, 159.27, 158.42, 156.05, 155.39, 148.04, 142.02, 129.57, 127.56, 124.22, 117.13, 115.16, 111.91, 24.56, 23.06, 19.48. MS (ESI−): m/z 337.94 (M−H)+.
Reaction SMILES: [CH3:1][C@@H:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH3:1][C@@H:2]([NH:6][CH2:7][C:8]1[S:12][C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=2)[NH:22][CH:21]=[C:20]3[CH:29]2[CH2:30][CH2:31][N:32]([S:35]([CH2:38][CH3:39])(=[O:36])=[O:37])[CH2:33][CH2:34]2)=[CH:10][CH:9]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)[C@@H](C)NCc1ccc(B(O)O)s1
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: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN[C@H](C)C(C)C)s4)cc23)CC1
Yield: 30 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)C.[C:49]12([CH2:59][C:60](Cl)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2>>[C:49]12([CH2:59][C:60]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=3)=[O:61])[CH2:58][CH:53]3[CH2:54][CH:55]([CH2:57][CH:51]([CH2:52]3)[CH2:50]1)[CH2:56]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Product: CC(C)c1ccc(C(=O)CC23CC4CC(CC(C4)C2)C3)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with adamantaneacetyl chloride; 1HNMR(CDCl3):1.21 (d, 12H), 1.6-2.0 (m, 15H), 2.15 (s, 2H), 3.4 (m, 2H), 7.15-7.25 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18](=O)[CH2:19][CH2:20][C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:17]=[C:18]([CH2:19][CH2:20][C:21]#[C:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: C[Si](C)(C)C#CCCC(=O)CBr
Product: C[Si](C)(C)C#CCCc1cn2cccc(OCc3ccccc3)c2n1

Procedure:
The title compound was prepared in accordance within the general method of Example 223(D), from 3-(benzyloxy)pyridin-2-amine (274 mg, 1.37 mmol) and 1-bromo-6-(trimethylsilyl)hex-5-yn-2-one (compound 223(C), 750 mg, 3.0 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH: from 98/2 to 95/5 as eluent) to afford 331 mg of 8-(benzyloxy)-2-(4-(trimethylsilyl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 69%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)=[O:3].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:14]=[CH:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)C=Cc1ccc(NC(C)=O)cc1
Yield: 10.4 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.35 g (25 mmols) of 4-bromoacetanilide and 2.99 ml (27.5 mmols) of ethyl acrylate. After a reaction time of 12 hours at 130° C. and working up as described in Example 1, recrystallisation of the crude product from toluene gives 0.60 g (2.6 mmols) of ethyl 4-(N-acetylamino)-cinnamate as pale yellow crystals of melting point 133° C.; yield 10% of theory (conversion figure 1000; Pd content 0.01 mol %). Analysis for C13H15NO3 (molecular weight 233): calculated C 66.92; H 6.48; N 6.01; O 20.59, found C 66.52; H 6.38; N 6.07; O 20.59.