Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:14][C:10]1([CH3:15])[O:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12][O:11]1
Reactant: CC1(C)OCCC(c2cccc(Br)c2)O1
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OCCC(c2cccc(C(=O)O)c2)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A 1 g portion of 4-(3-bromophenyl)-2,2-dimethyl-1,3-dioxane was dissolved in 18 ml of THF solution and cooled to −78° C., and then 2.35 ml of hexane solution containing 1.57 M n-butyl lithium was added dropwise thereto spending 1 hour. After completion of the dropwise addition, this was further stirred for 30 minutes. After adding excess amount of carbon dioxide thereto at −78° C., the mixture was risen to room temperature. The reaction solution was mixed with ammonium chloride aqueous solution and extracted 10 times with chloroform-methanol (5:1), the organic layer was dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 550 mg (63%) of 3-(2,2-dimethyl-1,3-dioxan-4-yl)benzoic acid (Reference Example 15-1). FA: 237
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)=O.[C:21]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CC(O)=O>[C:21]1([CH:27]2[CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]4[O:12][C:11]5[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=5[CH2:9][CH2:8][C:7]=4[CH:20]=3)[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: NC(=O)c1ccc2c(c1)CCc1cc(C=O)ccc1O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)CCc1cc(CN3CCC(c4ccccc4)C3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde intermediate obtained in step 4, Example 1 (92 mg, 0.34 mmol) in THF/AcOH (6.5 mL/30 μL) add 3-phenylpyrrolidine (0.34 mmol). Stir the mixture at room temperature overnight. Add NaBH(OAc)3 (0.52 mmol) and stir at room temperature overnight. Eliminate the solvent and purify by ISCO chromatography (eluent: CHCl3/B 0-10%; B: EtOH/NH4OH 10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9])[CH3:18]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: CCOC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5′-Fluoro-2′-hydroxyacetophenone 2.0 g, ethyl iodoacetate 4.16 g and potassium carbonate 2.7 g were added to acetone 43 ml in a nitrogen atmosphere, and the mixture was stirred overnight under reflux with heating. After cooled to room temperature, the potassium carbonate was filtered off through Celite, and the filtrate was partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 3.07 g, 99% was obtained as a colorless oil.
Reaction SMILES: ClCCC1NC2C=CC=CC=2N=1.C(N)CN.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH2:31].[C:32]([NH:34][C:35](=[N:38][CH3:39])SC)#[N:33]>>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH:31][C:35]([NH:34][C:32]#[N:33])=[N:38][CH3:39]
Reactant: NCCNCCc1nc2ccccc2[nH]1
Reactant: CN=C(NC#N)SC
Agent: ClCCc1nc2ccccc2[nH]1
Solvent: NCCN
Product: CN=C(NC#N)NCCNCCc1nc2ccccc2[nH]1

Procedure:
Reacting 2-(2-chloroethyl)benzimidazole with ethylenediamine by the procedure of Example 34, then reacting the resulting N-[2-(2-benzimidazolyl)ethyl]-ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[CH:17]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:22][C:23](/[N:10]=[C:8]2\[S:9][C:5]3[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=3[N:7]\2[CH2:11][CH2:12][O:13][CH3:14])=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Reactant: O=C(Cl)CC1CCCC1
Agent: Br
Product: COCCn1/c(=N/C(=O)CC2CCCC2)sc2cc(F)ccc21

Procedure:
The product from Example 113A and cyclopentylacetyl chloride were processed as described for example 11 to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.54 (d, J=5.76 Hz, 2H) 7.65 (t, J=8.14 Hz, 1H) 7.75 (dd, J=8.81, 2.71 Hz, 1H) 7.83 (dd, J=7.97, 1.53 Hz, 2H) 7.97 (dd, J=8.14, 1.36 Hz, 1H) 8.41 (d, J=3.05 Hz, 1H); MS (ESI+) m/z 337 (M+H)+; Anal. Calculated for C17H21FN2O2S: C, 60.69; H, 6.29; N, 8.33. Found: C, 60.67; H, 6.41; N, 8.25.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: N#Cc1c(-c2ccccc2)cc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Yield: 86.1 %

Procedure:
A suspension of 24.9 gm (0.1 mol) of 2,6-dichloro-4-phenyl-3-cyano-pyridine in 400 ml of ethanol was slowly admixed with 17.4 gm (0.2 mol) of morpholine, and the resulting mixture was refluxed for about two hours. Even while refluxing, but primarily upon subsequent cooling (optionally on an ice water bath) of the reaction mixture, a colorless crystalline precipitate formed which was collected by suction filtration, very thoroughly washed with water and dried. 25.8 gm (86% of theory) of 2-chloro-6-morpholino-4-phenyl-3-cyanopyridine, m.p. 198°-200° C., were obtained.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:18]([NH2:21])[CH2:19][CH3:20].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([C:9]([NH:21][CH2:18][CH2:19][CH3:20])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a solution of 5-nitro-2-thiophenecarboxylic acid (967 mg, 5.59 mmol) in DMF (0.745 ml) and CH2Cl2 (4 ml) was added oxalyl chloride at 0° C. After stirring for 0.5 h at rt (room temperature), the solvent was evaporated below 30° C. to give yellow oil and solid. To a solution of n-propylamine (0.551 ml, 6.71 mmol) in Et3N (1.87 ml 13.4 mmol) and CH2Cl2 (25 ml) was added a solution of crude acid chloride in CH2Cl2 (10 ml) below 20° C. After stirring for 4 h at rt, the mixture was washed with water saturated NAHCO3 aqueous solution, water, brine, dried (Na2SO4), and concentrated to give brown solid, which was purified by column chromatography (silica gel 50 ,g CH2Cl2/MeOH=100/1-30/1) to afford 815 mg (68%) of white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:13]#[C:14][CH3:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O.[C:22](=O)(O)[O-].[Na+]>CO>[CH3:22][O:11][C:10](=[O:12])[CH2:9][C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:13]#[C:14][CH3:15]
Reactant: O=C([O-])O
Reactant: CC#C[C@H](CC(=O)O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC#C[C@H](CC(=O)OC)c1ccc(O)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 265 %

Procedure:
To a solution of (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (25 g) obtained in Step 2 in methanol (125 mL) was added concentrated sulfuric acid (1.25 mL), followed by stirring the mixture at 80° C. for 2.5 hours. After cooling down to room temperature, water (100 mL) and sodium bicarbonate (4.14 g) were added to the reaction mixture, followed by concentration of the mixture. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was distilled azeotropically with toluene to give (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (28.5 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17](Cl)=[O:18])[O:10][CH2:9][CH2:8]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:18])[O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C1CCCCC12OCCO2)N1CCOCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
Morpholine (0.22 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aqueous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (59 mg, 23%) as white solid. MS ISP (m/e): 256.3 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:25]1[C:24]([F:23])=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1F
Reactant: COc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)cc1
Product: COc1ccc(-c2nncc(-c3ccc(F)c(-c4ncccc4F)c3)n2)cc1
Yield: 38 %

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(4-methoxyphenyl)-[1,2,4]triazine (100 mg, 0.28 mmol) was coupled to 3-fluoro-2-tributylstannylpyridine (129 mg, 0.33 mmol) using the method described in Example 22 to give 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(4-methoxyphenyl)-[1,2,4]triazine as a pale yellow solid (40 mg): δH (400 MHz, CDCl3) 3.91 (3H, s), 7.04-7.08 (2H, m), 7.39-7.47 (2H, m), 7.56-7.61 (1H, m), 8.41-8.45 (1H, m), 8.54 (1H, dd, J 2.3, 6.7 Hz), 8.60-8.64 (3H, m), 9.57 (1H, s); m/z (ES+) 377.
Reaction SMILES: C([BH3-])#N.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(O)(=O)C.O=[CH:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:21]=[C:20]([C:34]#[N:35])[N:19]=1>C(#N)C>[N:4]1([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[N:21]=[C:20]([C:34]#[N:35])[N:19]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Solvent: CC#N
Solvent: CC(=O)O
Product: N#Cc1nc(CCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
To a suspension of macroporous cyanoborohydride (102 mg, 2.35 mmol/g) in acetonitrile (0.5 mL), was added piperidine (19 μL), acetic acid (0.1 mL), and a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (49 mg) in acetonitrile (0.5 mL). The mixture was heated in the microwave at 150° C. for 10 min, filtered in a fritted tube using a Vacmaster multi-filtration apparatus, and purified by preparative-HPLC. 4-(3-Piperidin-1-yl-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile was isolated as a clear gum (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Br:12][C:13]1[C:14]([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl.O1CCCC1.CO.[OH-].[Li+]>[Br:12][C:13]1[C:14]([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[N:26][CH:27]=2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1ccc(-c2cc3c(cc2Br)OCO3)cn1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Br)OCO3)cn1)c1c(F)cccc1F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (1.7 g, 9.4 mmol) was added to a stirred solution of 12 (1.5 g, 5.2 mmol), Hünig's base (2.7 mL, 2.0 g, 15.7 mmol), and DMAP (64 mg, 0.5 mmol) in dichloromethane (23 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (20 mL), methanol (10 mL) and 1.2 M lithium hydroxide solution (12 mL). The mixture was stirred and heated to 65° C. for 30 min then cooled to room temperature, quenched with brine (50 mL), and extracted with dichloromethane (3×100 mL). The combined extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 13 (1.64 g, 73%) as a solid: LRESIMS m/z 433.0 [M+H]+, calcd. for C19H12Br1F2N2O3 433.0.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][C:8]([C:11]#[CH:12])=[N:9][CH:10]=1)[CH3:2].[C:16]([O:22][CH2:23][N:24]=[N+:25]=[N-:26])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:16]([O:22][CH2:23][N:24]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:13][CH2:14][CH3:15])=[CH:10][N:9]=2)[N:26]=[N:25]1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C#Cc1ccc(C(OCC)OCC)cn1
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(OCC)c1ccc(-c2cn(COC(=O)C(C)(C)C)nn2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
In tert-butanol (10 mL) was dissolved 5-(diethoxymethyl)-2-ethynylpyridine (1.41 g, 6.87 mmol) obtained in Step 2. To the solution were added azidomethyl pivalate (1.08 g, 6.87 mmol), water (10 mL), copper (II) sulfate pentahydrate (86.0 mg, 0.343 mmol) and sodium ascorbate (408 mg, 0.343 mmol), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give (4-(5-(diethoxymethyl)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (2.27 g, 91% yield).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:13](=[O:14])[C@H:12]2[N:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[C:16](=[O:17])[C@@H:7]1[CH2:8][CH:9]=[CH:10][CH2:11]2.C(OCC)(=O)C>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1.CCCCCCC>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[N:15]1[C:16](=[O:17])[C@H:7]2[NH:6][C:13](=[O:14])[C@@H:12]1[CH2:11][CH:10]=[CH:9][CH2:8]2
Reactant: COc1ccc(CN2C(=O)[C@@H]3CC=CC[C@H]2C(=O)N3c2ccc3ccccc3c2)c(OC)c1
Agent: COc1ccc(CN2C(=O)[C@@H]3C/C=C\C[C@H]2C(=O)N3c2ccc3ccccc3c2)c(OC)c1
Agent: O=C1N[C@H]2C/C=C\C[C@@H]1N(c1ccc3ccccc3c1)C2=O
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: O=C1N[C@H]2CC=CC[C@@H]1N(c1ccc3ccccc3c1)C2=O

Procedure:
Z-(1S,6S)-7-(2,4-Dimethoxy-benzyl)-9-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (0.180, 0.406 mmol) was placed in a CEM microwave 10-mL pressure-rated tube and was dissolved in trifluoroacetic acid (4.25 mL) and thioanisol (0.05 mL). The reaction mixture was capped and heated in a CEM discover system laboratory microwave at 120° C. for 0.5 hours. The reaction mixture was poured into a 100 mL round bottom flask and Celite® (approximately 5 g) and ethyl acetate (20 mL) were added. The solvents were removed. The Celite®/reaction mixture was loaded into an Isco solid phase loading cartridge. Flash chromatography was carried out using an Isco Companion automated chromatography system, silica column (12 g), initially holding at 40% ethyl acetate in heptane for 8 column volumes, increasing the ethylacetate concentration to 100% over 3 column volumes, holding at 100% ethyl acetate for 20 more column volumes to yield a residue.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[S:19])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[O:8]=[C:2]1[C:3](=[O:5])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]#[N:10])=[CH:16][CH:15]=2)[C:18](=[S:19])[N:20]1[CH:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(NC(=S)Nc1ccc(C#N)cc1)C(C)(C)C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(C#N)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Ethyl chlorooxoacetate (5.60 mL, 50.0 mmol) was added to a stirring solution of the above thiourea (6.54 g, 25.0 mmol) in dichloromethane (170 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and filtration afforded 5.77 g (73%) of 4-[4,5-dioxo-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidin-1-yl]-benzonitrile as a yellow solid: mp 219.6–219.9° C.; 1H NMR (DMSO-d6): δ 8.03 (d, 2H), 7.60 (d, 2H), 4.82 (q, 1H), 1.47 (d, 3H), 1.00 (s, 9H); IR (KBr): 3505, 2970, 2230, 1765, 1600 cm−1; MS (m/z) 315 (M+).
Reaction SMILES: FC(F)(F)C(O)=[O:4].C(OC(N[C@@H:16]([C:25]([OH:27])=[O:26])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)(C)(C)C>ClCCl>[OH:4][C@H:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H](O)CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (40 mL) was added to a solution of N-tert-butoxycarbonyl-D-homophenylalanine (4.00 g) in dichloromethane (40 mL) at 0° C. After stirring at 0†° C. for 5 min and at room temperature for 40 min, the reaction mixture was evaporated in vacuo. The residue was dissolved in 10% sulfuric acid (80 mL), and the solution was warmed up to 60° C. After removing the bath, a solution of sodium nitrite (5.93 g) in water (5 mL) was added to the solution, and the solution was stirred at 60° C. for 7 hr. Then additional solution of sodium nitrite (1.98 g) in water (1.5 mL) was added, and the resulting solution was stirred at 60° C. for 2.5 hr. After cooling, urea (6.02 g) was added to the reaction mixture, and the whole was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate. The aqueous phase was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (2.51 g) as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.92-2.10 (m, 1H), 2.10-2.27 (m, 1H), 2.80 (t, J=7.8 Hz, 2H), 4.20-4.32 (m, 1H), 5.12 (br s, 2H), and 7.12-7.40 (m, 5H).
Reaction SMILES: [S:1]1[CH:5]=[C:4](C(C2CCN(C(OC(C)(C)C)=O)CC2)=O)[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.S1C=CC2C=CC=CC1=2.[Br:34]Br>C(Cl)(Cl)(Cl)Cl>[Br:34][C:4]1[C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[S:1][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2csc3ccccc23)CC1
Reactant: BrBr
Agent: c1ccc2sccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1csc2ccccc12
Yield: 48 %

Procedure:
4-[(Benzo[b]thiophene-3-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester ##STR13## Dissolve benzo[b]thiophene (23 g, 0.170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0.168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48%); bp 64°-72° C. @ 0.02 mm Hg.
Reaction SMILES: [CH:1](=[N:10][OH:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C>[OH:11][N:10]=[C:1]([Cl:19])/[CH:2]=[CH:3]\[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ON=CC=Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)/C=C\c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cinnamaldoxime (10 g, 68 mmol) in DMF (100 mL) at room temperature was added solid NCS (9.08 g, 68 mmol). The suspension was stirred at room temperature overnight. The reaction mixture was poured into ice-water, extracted with a mixture of ethyl acetate and hexanes (7:3, 3×), dried with Na2SO4, concentrated and dried in vacuum to give the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:37][N:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[N:19]2[C:20]([CH:21]=[N:22][C:17]([NH:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)=[N:18]2)=[CH:23][CH:24]=1)[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: CN(c1ccccc1-c1ccc2cnc(Nc3cccc(N4CCOCC4)c3)nn12)S(C)(=O)=O
Yield: 21.6 %

Procedure:
3-Morpholin-4-yl-phenylamine (122.3 mg, 0.6860 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (125.0 mg, 0.3430 mmol) and N,N-Diisopropylethylamine (0.1792 mL, 1.029 mmol) were dissolved in 1-Methoxy-2-propanol (1.25 mL, 12.8 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 35.51 mg of N-Methyl-N-{2-[2-(3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-methanesulfonamide as a lyophilized powder. (M+H)=479.1. 1H NMR (400 MHz, DMSO, d6) δ 9.26 (s, 1H), 8.97 (s, 1H), 7.73 (m, 1H), 7.66 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.02 (t, 1H, J=8.09 Hz), 6.93 (d, 1H, J=4.64 Hz), 6.87 (m, 2H), 6.45 (m, 1H), 3.57 (m, 4H), 3.08 (s, 3H), 2.71 (s, 3H), 2.67 (m, 4H).