Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[O:15]1[C:19]([CH3:26])([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:16]1[CH2:17][OH:18]>O1CCCC1>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:16]([C:19]([CH3:26])([OH:15])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:17][OH:18])[CH2:7][CH2:8][CH3:9]
Reactant: CC(C)CCCC1(C)OC1CO
Reactant: CCCCNCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(CO)C(C)(O)CCCC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Under nitrogen atmosphere, 65 ml of n-butyllithium (1.6M in hexane) was added dropwise to a solution of 12.9 g of di-n-butylamine in 30 ml of tetrahydrofuran at -78° C. and after completion of addition, the mixture was stirred at 0° C. for 30 minutes. To this solution was added a solution of 8.6 g of 2,3-epoxy-3,7-dimethyl-1-octanol in 20 ml of tetrahydrofuran slowly in portions at 0° C. The mixture was then stirred at room temperature for 2 hours, after which it was poured into ice-water and extracted with diethyl ether. The extract was washed with water and after drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was further distilled under reduced pressure to give 12 g of 2-(dibutylamino)-3,7-dimethyl-1,3-octanediol [Compound (59)]. Yield 80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:22](I)([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[N:18][N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: c1ccc(COc2ccc(-c3nn[nH]n3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1nnc(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
5-(4-Benzyloxyphenyl)-2H-tetrazole (500 mg) was added to a suspension of sodium hydride (96 mg) in dimethylformamide (5 mL) under ice-cooling. The mixture was stirred at room temperature for 0.5 hour. After addition of isopropyl iodide (405 mg) thereto, the mixture was stirred at 60° C. for 2 hours under heating. The reaction mixture was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed with water and saturated brine, dried anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (571 mg).
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].[C:9]1([CH3:19])[C:10]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>C(Cl)(Cl)Cl>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:18][S:15]([C:10]1[C:9]([CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:17]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCCC(=O)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CCCC(=O)COS(=O)(=O)c1ccccc1C
Yield: 59.9 %

Procedure:
A 1.0 g quantity of 1-diazo-2-pentanone is dissolved in 50 ml of chloroform, and 2.2 g of o-toluene-sulfonic acid is slowly added to the solution. The same procedure as in Example 1 is thereafter repeated to afford 1.37 g of 2-oxopentyl-o-toluene sulfonate in the form of a transparent colorless oil (Compound 29). Yield 59.9%.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[CH:1]1([O:6][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CC=CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of cyclopent-3-enol (840 mg, 10.0 mmol) in CH2CT2 (25.0 mL) was added 2-hydroxyisoindolin-1,3-dione (1.96 g, 12.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (740 mg, 32%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57-2.87 (m, 4H) 5.12 (t, J=6.19 Hz, 1H) 5.75 (s, 2H) 7.74 (dd, J=5.68, 3.16 Hz, 2H) 7.79-7.87 (m, 2H). MS (ES) [M+H] calculated for C13H12NO3, 230.07. found 230.20.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([OH:29])=O)[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Cl.[CH3:31][O:32][NH2:33].CCN(CC)CC>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]([NH:33][O:32][CH3:31])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(CC)cc2)cc1
Reactant: CON
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2nc3ccc(C(=O)NOC)cc3nc2-c2ccc(CC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
A solution of 2,3-bis(4-ethylphenyl)quinoxaline-6-carboxylic acid (150 mg, 0.39 mmol, 1.00 equiv) in thionyl chloride (20 mL) was heated under reflux for 3 h in a oil bath. The resulting solution was concentrated under vacuum and diluted with 20 ml of CH2Cl2. The resulting solution was added to a solution of O-methyl-hydroxylamine hydrochloride (326 mg, 3.93 mmol, 10.00 equiv) and NEt3 (396 mg, 3.92 mmol, 10.00 equiv) in CH2Cl2 (20 mL) at 0° C. and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the crude product (100 mg) was purified by Prep-HPLC yielding 15 mg (7%) of 2,3-bis(4-ethylphenyl)-N-methoxyquinoxaline-6-carboxamide as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)[CH:16]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:36])[CH3:35])[C:29]=1[N:37]=[C:38]=[O:39])([CH3:27])[CH3:26].[ClH:40].Cl.C(OCC)(=O)C>>[ClH:40].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([CH3:35])[CH3:36])[C:29]=1[NH:37][C:38](=[O:39])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:16]=1)([CH3:26])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccnc(Cn2cc(CNc3ccc(C(C)C)cc3)cn2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccnc(Cn2cc(CN(C(=O)Nc3c(C(C)C)cccc3C(C)C)c3ccc(C(C)C)cc3)cn2)c1

Procedure:
In the same manner as in Example 62, reaction and treatment were conducted using (4-isopropylphenyl)({1-[(4-methyl-2-pyridyl)methyl]pyrazol-4-yl}methyl)amine (0.42 g) and 2,6-diisopropylphenyl isocyanate (0.42 mL) as starting materials. Further, the obtained oil compound was converted to hydrochloride with 4N hydrochloric acid-ethyl acetate to give N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-({1-[(4-methyl-2-pyridyl)methyl]pyrazol-4-yl}methyl)urea hydrochloride (0.33 g).
Reaction SMILES: OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3[CH2:32][O:33][CH2:34][CH2:35][Si](C)(C)C)C)C=CC=1.Cl.[OH:41][C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1>CO>[CH3:32][O:33][CH2:34][CH2:35][O:41][C:42]1[CH:43]=[C:44]([N:48]2[C:57](=[O:58])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[CH3:59])[N:50]=[C:49]2[CH:60]([NH:62][C:63]2[N:71]=[CH:70][N:69]=[C:68]3[C:64]=2[N:65]=[CH:66][NH:67]3)[CH3:61])[CH:45]=[CH:46][CH:47]=1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CO
Product: COCCOc1cccc(-n2c(C(C)Nc3ncnc4[nH]cnc34)nc3cccc(C)c3c2=O)c1

Procedure:
Compound 126 (300 mgs, 0.54 mmol) was treated with toluene 4-sulfonic acid 2-methoxy ethyl ester at 50 C for 42 hrs using the procedure described above for compound 127. The generated intermediate was then treated with 4N HCl in MeOH, using the procedure described for compound 121 (step D). m/z=487 (M+H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[C:22]3[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[S:19][C:18]=3[C:17]([OH:27])=[C:16]([C:28]3[C:33]4[S:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[C:32]=4[CH:31]=[CH:30][CH:29]=3)[CH:15]=2)=[CH:3][CH:2]=1.[CH2:41]1C[O:44][CH2:43][CH2:42]1.C(N(CC)CC)C.C(Cl)(=O)C=C>O.C(OCC)(=O)C>[C:43]([O:27][C:17]1[C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[C:22]=2[C:14]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:15][C:16]=1[C:28]1[C:33]2[S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:44])[CH:42]=[CH2:41]
Reactant: Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)c2c1sc1ccccc12
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)c2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1.6 g of the thus obtained 1,3-bis(4-dibenzothiophenyl)-4-hydroxydibenzothiophene is placed in a round bottom flask; 35 mL of THF is added to form a transparent solution; after ice cooling the flask, 0.47 g of triethylamine is added; 0.38 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 15 mL of water is added; the mixture is vigorously stirred; and 30 mL of ethyl acetate and 15 mL of saturated salt water are then added, thereby separating an aqueous solution. An organic phase is washed with saturated salt water and dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and a major product is separated by a silica gel column (eluate: hexane/dichloromethane mixture), thereby obtaining the foregoing brown solid. This is washed with a mixed solvent of 20 mL of dichloromethane and 60 mL of hexane and then dried to obtain 1.1 g (yield: 63%) of the foregoing pale brown solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.90 (dd=1.2 & 10.4 Hz, 1H), 6.16 (dd=10.4 & 17.2 Hz, 1H), 6.47 (dd=1.2 & 17.2 Hz, 1H), 6.89 (d=7.6 Hz, 1H), 6.98 (dt=1.2 & 7.6 Hz, 1H), 7.30 to 7.35 (m, 1H), 7.40 to 7.58 (m, 6H), 7.62 to 7.68 (m, 2H), 7.73 to 7.84 (m, 4H), 8.12 to 8.18 (m, 2H), 8.25 (dd=0.8 & 7.6 Hz, 1H), 8.31 (dd=1.2 & 7.6 Hz, 1H)
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:30][C:13]4=[C:14]([NH2:29])[N:15]=[CH:16][C:17]([C:18]5[CH:19]=[N:20][N:21]([CH:23]6[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]6)[CH:22]=5)=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:40]([N:44]=[C:45]=[O:46])[CH:41]([CH3:43])[CH3:42]>CN(C=O)C>[CH2:40]([NH:44][C:45]([N:26]1[CH2:25][CH2:24][CH:23]([N:21]2[CH:22]=[C:18]([C:17]3[CH:16]=[N:15][C:14]([NH2:29])=[C:13]4[O:30][C:10]([C:6]5[C:5]6[S:1][N:2]=[CH:3][C:4]=6[CH:9]=[CH:8][CH:7]=5)=[CH:11][C:12]=34)[CH:19]=[N:20]2)[CH2:28][CH2:27]1)=[O:46])[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)CN=C=O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnsc34)oc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnsc56)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzo[d]isothiazol-7-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (20.8 mg, 0.05 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.05 mL, 6.5 mmol) and isobutyl isocyanate (0.06 mmol). The resulting solution stirred at room temperature overnight. The mixture was concentrated and then purified by MDP to afford the title compound as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 9.51 (s, 1H), 9.12 (d, J=1.5 Hz, 1H), 8.84 (d, J=7.3 Hz, 1H), 8.72 (d, J=7.3 Hz, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 4.53 (m, 1H), 3.03 (m, 4H), 2.18 (m, 2H), 2.06 (m, 4H), 1.83 (m, 1H), 1.76 (d, J=5.8 Hz, 6H); MS (ESI): MS (ESI): 516.64 [M+H]+; HPLC tR=0.86 min (HPLC: Analytical—2 min).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:14](=[O:25])[N:13]2[CH2:26][CH2:27][CH3:28])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl.CCOCC.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[C:14](=[O:25])[N:13]2[CH2:26][CH2:27][CH3:28])=[CH:5][CH:4]=1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A solution of 4-[3-(4-methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one (1.22 g, assume 3.21 mmol) was dissolved in dry CH2Cl2 (25 mL), cooled to 0° C. and then treated dropwise with BBr3 (2.41 g, 9.63 mmol). The reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with Et2O and water, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 1:1 hexanes:EtOAc to afford 0.687 g (68%) 4-[3-(4-hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one. MS (ES+) Calc'd for C23H31N2O2 (M+1) 367. Found m/z 367 (100%). 1H NMR.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[CH:3]1.[CH2:9](O)[CH2:10][CH2:11][OH:12].O>C1(C)C=CC=CC=1.C(Cl)Cl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[O:8]1[CH2:9][CH2:10][CH2:11][O:12][CH:7]1[C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1
Reactant: Cn1cncc1C=O
Reactant: OCCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1cncc1C1OCCCO1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a solution of 1-methyl-1H-imidazole-5-carbaldehyde (2.9 g, 26.3 mmol) in toluene (20 mL) was added propane-1,3-diol (4.01 g, 52.7 mmol) and CSA (0.306 g, 1.317 mmol) and the reaction mixture was heated to reflux with azeotropic removal of the evolved water for 24 hours. The reaction mixture was cooled to RT, diluted with DCM and washed with NaHCO3 solution. It was then dried over Na2SO4, filtered and concentrated. Purification by column chromatography (80% EtOAc in Hexane to EtOAc) afforded 38 (2.53 g, 57% yield) as a yellow oil which solidified on standing to a yellow solid. MS (m/z): 169.2 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16]>O>[S:12]1[C:13]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[N:11]1
Reactant: NN
Reactant: COC(=O)c1cccc2nnsc12
Solvent: O
Product: NNC(=O)c1cccc2nnsc12
Reaction time: 6 h
Yield: 90.7 %

Procedure:
9.7 g of 7-methoxycarbonylbenzo-1,2,3-thiadiazole are reacted for 19 hours with 4.8 g of hydrazine hydrate in 30 ml of water at 50° C. and then for a further 6 hours at 80°-90° C. The suspension is cooled slightly, filtered while hot and washed with water to give 8.8 g of white crystals having a melting point of 270°-272° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.3 %

Procedure:
5-Cyano-2-benzofurancarboxylic acid (830 mg, 4.43 mmol) and ethyl 4-aminophenoxyacetate (910 mg, 4.66 mmol) were dissolved in N,N-dimethylformamide (40 ml), and 1-hydroxy-1H-benzotriazole (630 mg, 4.66 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (893 mg, 4.66 mmol) were added. The mixture was stirred at room temperature for 13 hours. Water (100 ml) was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water to give 1.49 g of ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate as a colorless solid (92%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)(O)[CH2:5][CH2:4]1)[CH3:2].Cl>C(O)C>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2cccc3[nH]ccc23)CC1
Agent: Cl
Solvent: CCO
Product: CCN1CC=C(c2cccc3[nH]ccc23)CC1
Yield: 69.1 %

Procedure:
Using the procedure of Example 17, 2 g of the product of Example 19, 34 ml of ethanol and 66 ml of N hydrochloric acid were reacted to obtain 1.28 g of 4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 151° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O=CCCc1ccccc1Cl
Reactant: COC(=O)/C=C/C(=O)C1CCCCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(C2CCCCC2)OC(=O)[C@H]1Cc1ccccc1
Yield: 76 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-cyclohexylbut-2-enoate using 0.5 mol % 1 as the catalyst in 76% yield as a single diasteromer (white solid). [α]D20 (c 1.06, CHCl3)=+178.6; mp=87-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.32-7.25 (m, 3H), 7.15-7.13 (m, 2H), 4.98 (d, 1H, J=6.9 Hz), 3.73 (s, 3H), 3.47 (dd, 1H, J=14.3, 4.8 Hz), 3.06 (t. 1H, J=6.3 hz), 2.86-2.81 (m, 1H), 2.67 (dd, 1H, J=14.3, 10.1 Hz), 2.06-2.03 (m, 1H), 1.88-1.83 (m, 5H), 1.28-1.13 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 171.4, 169.6, 170.3, 138.3, 129.1, 128.9, 127.0, 96.2, 52.6, 43.0, 41.0, 40.0, 33.4, 30.2, 30.0, 26.1, 26.0, 25.9; IR (thin film) ν 3086, 3027, 2929, 2854, 1773, 1737, 1452, 1436, 1155, 1056 cm−1; HRMS (ESI) calcd for C20H24O4 [M+Na]+ 351.1566, found 351.1574; 86% ee (3S,4S)-isomer as determined by HPLC(OD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=8.5 min, tr (3R,4R)=7.7 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[CH:20]=[C:21]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])[CH:22]=[CH:23][CH:24]=2)[CH:13]=1.[N:30]([Sn](CCCC)(CCCC)CCCC)=[N+:31]=[N-:32]>FC(F)(F)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:29])([C:26]3[N:30]=[N:31][NH:32][N:27]=3)[CH3:28])[CH:20]=2)[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C#N)c2)n1
Solvent: FC(F)(F)c1ccccc1
Product: Cc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)c3nn[nH]n3)c2)n1
Temperature: 180 °C

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionitrile [50 mg, 0.11 mmol, Intermediate (67)] in α,α,α-trifluorotoluene (2 mL) is added azidotributyltin (0.251 mL, 0.88 mmol) and heated in microwave oven at 180° C. for 1.5 hours. Reaction mixture is concentrated and purified via silica gel chromatography eluting with 20 to 100% EtOAc in heptane to give [2-(2,4-dichloro-phenyl)-ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)-ethyl]-phenyl}-pyrimidin-4-yl)-amine as a solid, which is treated with 1M hydrogen chloride in ether affording [2-(2,4-dichloro-phenyl)-ethyl]-(2-methyl-6-{3-[1-methyl-1-(2H-tetrazol-5-yl)-ethyl]-phenyl}-pyrimidin-4-yl)-amine hydrochloride [47 mg, 80%, Example 47] as a solid. LC/MS: RT=2.47 minutes, MS: 484 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □8.64 (1H, br s), 7.3-7.8 (7H, m), 6.56 (1H, s), 3.98 (3H, s), 3.64 (2H, m), 3 (2H, m), 1.8 (6H, s). IC50=0.4 nM
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:20]([C:29]([O:31][CH2:32][CH2:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:30])=[C:19]([CH3:47])[NH:18][C:17]=2[CH3:48])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C([O-])=O>ClCCl>[C:41]1([CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:33][CH2:32][O:31][C:29](=[O:30])[C:20]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)=[C:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[C:17]([CH3:48])=[N:18][C:19]=2[CH3:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCNCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
233 mg (0.350 mol) of 4-(4-(3-chlorophenyl)-5-(3,3-diphenylpropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl) piperazine-1-carboxylic acid-t-butyl ester was dissolved in 10 ml of dichloromethane. 5 ml of trifluoroacetate was added and stirred at room temperature for 2.5 hours. After concentration under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.