Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[C:28]([O:31][CH2:32][CH2:33][NH:34][C:35]([C@@H:37]1[CH2:42][O:41][CH2:40][CH2:39][NH:38]1)=[O:36])(=[O:30])[CH3:29]>>[C:28]([O:31][CH2:32][CH2:33][NH:34][C:35]([C@H:37]1[N:38]([CH2:20][C:13]2[NH:12][C:11]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Br:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:39][CH2:40][O:41][CH2:42]1)=[O:36])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(=O)OCCNC(=O)[C@@H]1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NCCOC(C)=O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 26.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with (S)-2-(morpholine-3-carboxamido)ethyl acetate hydrochloride (0.3 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](SC)=[N:14][N:15]=[C:3]12.[OH-:18].[K+]>>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](=[O:18])[NH:14][N:15]=[C:3]12
Reactant: CSc1nnc2n1C=Cc1ccccc1C2C
Reactant: [OH-]
Agent: [K+]
Product: CC1c2ccccc2C=Cn2c1n[nH]c2=O

Procedure:
11-Methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was treated with potassium hydroxide and the reaction mixture was treated as described. By this procedure was obtained 2,11-dihydro-11-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Pale brown needles (as recrystallized from ethanol), m.p. 119°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([N+:22]([O-])=O)[CH:15]=3)[N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[Cl-].[NH4+].C1C[O:30]CC1>CO.O.[Fe]>[NH2:22][C:16]1[CH:15]=[C:14]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]3[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]2)[CH:21]=[CH:20][C:17]=1[C:18]([NH2:19])=[O:30]
Reactant: CC(C)c1nn(-c2ccc(C#N)c([N+](=O)[O-])c2)c2nccc(Cl)c12
Reactant: C1CCOC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N)c2)c2nccc(Cl)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound (6b) (0.335 g) was dissolved in DMF (8.6 mL), and sodium hydride (0.097 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 4-fluoro-2-nitrobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 30 min. Water was added to the reaction solution, and the precipitate was collected by filtration and washed by sprinkling water to obtain 4-{4-chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.5 g, 85%). 4-{4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-nitrobenzonitrile (0.35 g) and ammonium chloride (0.35 g) were dissolved in a solvent mixture of THF (3 mL), methanol (3 mL), and water (3 mL). Iron (0.57 g) was added to the resulting solution, followed by stirring at 70° C. for 1 hr. Insoluble matters were filtered by celite, and the solvent was distilled away. The precipitate was washed with water and was collected by filtration to obtain compound (106a) (0.32 g, 95%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH2:23][CH3:24])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:26]([CH2:36][CH3:37])[C:27](=O)[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:26]([CH2:36][CH3:37])=[C:27]([C:28]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:29])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCCC)C2)oc1CC
Yield: 86.7 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-propoxypiperidin-4-yl)carbamate obtained in Example (113f) (0.80 g, 2.39 mmol), butyl 3-bromo-2-oxopentanoate obtained in Example (110a) (4 g, 15.9 mmol), sodium bicarbonate (0.7 g, 8.33 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 1.01 g of the title compound as a light brown oily substance (87%).
Reaction SMILES: [N+:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@H:19]([OH:22])[CH2:20][O:21][C@H:15]23)=[O:12])[CH2:7][CH2:6]1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][C:31]([O:22][C@H:19]2[C@H:16]3[O:17][CH2:18][C@@H:14]([O:13][C:11]([N:8]4[CH2:7][CH2:6][CH:5]([O:4][N+:1]([O-:3])=[O:2])[CH2:10][CH2:9]4)=[O:12])[C@H:15]3[O:21][CH2:20]2)=[O:32])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: O=C(O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O)N1CCC(O[N+](=O)[O-])CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-(nitrooxy)piperidine-1-carboxylate (0.47 g, 1.48 mmol) and Et3N (0.45 g, 4.44 mmol) in THF (25 mL) was added 4-Nitrophenyl chloroformate (0.30 g, 1.48 mmol) as solid. After stirring at rt over night, the mixture was concentrated. The residue was diluted with EtOAc and washed with NaH2PO4 5%. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column SNAP 50; 60% EtOAc in n-hexane), affording the title product as a white solid. 1H-NMR (300 MHz, CDCl3); δ 8.33-8.29 (2H, m), 7.45-7.40 (2H, m), 5.22-5.07 (3H, m), 4.88-4.80 (1H, m), 4.79-4.71 (1H, m), 4.20-3.71 (6H, m), 3.60-3.30 (2H, m), 2.12-1.98 (2H, m), 1.88-1.73 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccnc(C)c2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 8.50 (d, J=4.8 Hz, 1H) 7.67-7.25 (m, 5H) 7.20-6.85 (m, 4H) 2.52 (s, 3H) 2.45 (s, 3H). MS: (ES) m/z=429.0 (M++1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[C:13]([C:14]2[N:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[C:16]([C:23]([NH2:25])=[O:24])[CH:15]=2)=[CH:12][N:11]=[CH:10]1>C(#N)C.C(OCC)C>[Cl:1][C:15]1[C:16]([C:23]([NH2:25])=[O:24])=[C:17]2[N:22]([C:14]=1[C:13]1[S:9][CH:10]=[N:11][CH:12]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2
Reactant: NC(=O)c1cc(-c2cncs2)n2c1CCCC2
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOCC
Product: NC(=O)c1c(Cl)c(-c2cncs2)n2c1CCCC2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Chlorosuccinimide is added in 0.05 g portions to a solution of 0.1 g of 3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide in 10 cm3 of acetonitrile at 65° C. After 2 hours a precipitate is seen to form. The mixture is allowed to cool to approximately 20° C., the solid is filtered off and washed with two times 0.5 cm3 of acetonitrile. The operation was repeated another two times on 0.1 g of 3-(4-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide. The solids obtained in the three tests were combined and chromatographed on a column of 1.8 cm diameter containing 40 g of silica (0.063-0.220). Elution is carried out with a 95/5 mixture of dichloromethane and methanol, 2-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C., to give a white solid which is taken up in ethyl ether and then filtered off and dried in air. 0.12 g of 2-chloro-3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid which melts at 227° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([C:17]3[N:21]([CH3:22])[N:20]=[C:19]([CH3:23])[CH:18]=3)=[CH:16][C:9]=2[CH2:8][CH2:7]1)[CH3:5].[CH3:24][N:25]1[C:29]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][NH:27][C:26]1=[S:41].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][N:21]1[C:17]([C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][S:41][C:26]4[N:25]([CH3:24])[C:29]([C:30]5[CH:39]=[CH:38][CH:37]=[C:36]6[C:31]=5[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]6)=[N:28][N:27]=4)[CH2:7][CH2:8][C:9]=3[CH:16]=2)=[CH:18][C:19]([CH3:23])=[N:20]1
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCCl)CC3)n(C)n1
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3nnc(SCCC(C)N4CCc5ccc(-c6cc(C)nn6C)cc5CC4)n3C)cccc2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
To a stirred solution of 3-(3-chloro-1-methylpropyl)-7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.10 g) (intermediate 10) and 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.093 g) (intermediate 7) in dimethylformamide (2 ml), at room temperature, sodium iodide (0.040 g) and anhydrous potassium carbonate were subsequently added. Then the reaction mixture was warmed to 70° C. and stirring continued for 3 h after which time the mixture was allowed to reach room temperature and the solvent evaporated under reduced pressure. The residue was treated with water (10 ml), extracted with ethyl acetate (20 ml). The organic phase was dried with sodium sulphate and after evaporation the crude product was purified by chromatography on silica gel with 100-95% dichloromethane-methanol elution to give 7-(1,3-dimethyl-1H-pyrazol-5-yl)-3-(1-methyl-3-{[4-methyl-5-(2-methyl-5-quinolinyl)-4H-1,2,4-triazol-3-yl]thio}propyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.040 g) as a pale yellow solid. This product was dissolved in dichloromethane (2 ml), and hydrochloridric acid was added dropwise (0.072 ml, 1M/ether), at room temperature. Following solvent evaporation gave the title compound (0.042 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:94])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])[CH2:83][C@H:82]3[CH3:93])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:90])([CH3:91])[CH3:89])[CH2:83][C@H:82]5[CH3:93])=[CH:79][CH:80]=4)=[O:94])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (1 mL) was added HATU (6.4 mg, 0.017 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (12.0 mg, 0.014 mmol; Preparation 32) was added followed by DIPEA (12.3 μL, 0.07 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (9 mg, 56% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O8 939.37. found 939.8.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:27])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1.Cl>C1COCC1>[CH3:9][C:10]1([CH3:27])[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccccc1

Procedure:
To a stirred solution of phenylmagnesium bromide [from bromobenzene and magnesium in dry tetrahydrofuran] was added 2,2-dimethyl-7-(2-dimethylaminoethoxy)-chroman-4-one in dry THF and the resulting solution was boiled under reflux for 2 weeks. The cooled reaction mixture was decomposed with 2.5 N hydrochloric acid and the organic layer separated and dried (magnesium sulphate). Removal of the solvent gave a yellow oil which was chromatographed on silica in 3% ether - 97% light petroleum (b.p. 60°-80°) gave the title compound as a colourless oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the hydrochloride salt, m.p. 186.5°-187.5°. An analogous procedure yielded 7-(2-N-benzyl-N-methyl-aminoethoxy)-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromene as a colourless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1>C(O)(=O)C.[C].[Pd]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][CH2:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=c1[nH]ccn1-c1ccc(-n2cnnn2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCN1c1ccc(-n2cnnn2)cc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1-[4-(1H-1-Tetrazolyl)phenyl]-2(1H,3H)-imidazolone (5.0 g) was dissolved in acetic acid (500 ml) and 10% palladium-carbon (50% wet, 5.0 g) was added. The resulting mixture was stirred at 40° C. for 4 hours under a hydrogen atmosphere. The catalyst was filtered and washed with acetic acid. The filtrate and the washings were combined and distilled off under reduced pressure. The residue was crystallized from ethanol to give 1-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidi-none (4.1 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Nc1cc(Br)ccc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Br)cc1NC(C)C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a suspension of 4-bromo-2-(isopropylamino)benzoic acid (448 mg) and potassium carbonate (480 mg) in N,N-dimethylformamide (9 ml) was added methyl iodide (162 μl) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added water (20 ml) and extracted with mixed solvent (hexane/ethyl acetate=1/1). The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 4-bromo-2-(isopropylamino)benzoate (443 mg).
Reaction SMILES: C(CC[N:5]1[C:9](=[O:10])[CH2:8][C:7]2([CH2:15][CH2:14][C:13]([CH2:19][CH2:20][CH3:21])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)[C:6]1=[O:22])#N.CNCCCN.O>C1(C)C=CC=CC=1>[CH2:19]([C:13]1([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:7]2([C:6](=[O:22])[NH:5][C:9](=[O:10])[CH2:8]2)[CH2:11][CH2:12]1)[CH2:20][CH3:21]
Reactant: CCCC1(CCC)CCC2(CC1)CC(=O)N(CCC#N)C2=O
Agent: CNCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1(CCC)CCC2(CC1)CC(=O)NC2=O
Temperature: 25 °C

Procedure:
To a solution of toluene and 4,4 dipropylcyclohexane 1 carboxy 1 acetic acid anhydride (1 equivalent) was added 3 methylaminopropylamine (1.05 equivalents). The reaction mixture was heated at reflux using a Dean Stark trap. Following collection of water (1 equivalent), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:7])P(Cl)(Cl)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13](O)=[O:14]>COCCOC>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([N:2]([CH3:7])[CH3:1])=[O:14]
Reactant: CN(C)P(=O)(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: COCCOC
Product: COc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 54.3 %

Procedure:
N,N-Dimethylphosphoramidodichloridate (1.8 mL, 15.22 mmol) was added to a solution of 3-methoxy-4-nitrobenzoic acid (300 mg, 1.52 mmol) in anhydrous 1,2-dimethoxyethane (15 mL) and the resulting mixture was heated at reflux for 110 hours ca. The reaction mixture was then cooled and poured into ice-water (50 mL); the resulting mixture was extracted with diethyl ether (50 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic extracts were concentrated under reduced pressure; the residue was dissolved in dichloromethane and washed with water (30 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The tan liquid residue was purified by flash chromatography (DCM/MeOH, 98/2) to give 185 mg of 3-methoxy-N,N-dimethyl-4-nitro-benzamide as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:21][NH2:22].CN1CCCC1=O>O>[C:14]1([CH2:13][CH2:12][C:6]2[CH:5]=[CH:4][N:3]=[C:2]3[NH:21][N:22]=[C:8]([OH:9])[C:7]=23)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(CCc2ccccc2)ccnc1Br
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-bromo-3-methoxycarbonyl-4-(2-phenylethyl)pyridine (1.42 g), hydrazine monohydrate (0.65 mL) and N-methylpyrrolidone (10 mL) was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.74 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Sn](C)(C)C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].O>C1C=CC=CC=1>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: COCC(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc([Sn](C)(C)C)c2C1
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)COC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
Bis-triphenylphosphine palladium dichloride (120 mg) was added to a solution of 2-dipropylamino-8-trimethylstannyl-1,2,3,4-tetrahydronaphthalene (500 mg, 1.27 mmol) in benzene (20 ml). Methoxyacetyl chloride (1.5 ml; 1.77 g; 16.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and then heated to reflux for 5 hr. The reaction mixture was poured into water and extracted with methylene chloride. The extract was dried (MgSO4) and concentrated to give 800 mg of crude product. Purification by chromatography using 1:10 methanol: methylene chloride as solvent gave 380 mg of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccnc1
Product: O=C(c1cccnc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-pyridin-3-yl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 6.93 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.58-7.61 (m, 3 H), 7.67 (d, J=8.8 Hz, 2H), 8.03-8.05 (m, 1H), 8.74 (d, J=1.6 Hz, 1H), 8.79 & 8.80 (dd, J=6.0 Hz, 1.6 Hz, 1H), 9.73 (s, 1H). MS: M/z 456.9 (M++1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([CH2:29][C:30](O)=[O:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1cccc2ccccc12)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(naphthalen-1-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.87-8.04 (m, 5H), 7.49-7.62 (m, 4H), 4.15 (s, 2H), 3.78-3.85 (m, 4H), 3.07-3.12 (m, 4H); MS (ESI−) M/Z 413 (M−H)−.