Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1I.[C:23]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][S:28]1(=[O:34])=[O:33])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C.CN(C=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[C:29]1[S:28](=[O:33])(=[O:34])[N:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:31](=[O:32])[CH:30]=1
Reactant: COC(=O)[C@H](Cc1ccc(I)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)N1C(=O)C=CS1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 52.2 %

Procedure:
Methyl (2S)-3-(3-bromo-4-iodophenyl)-2-[(tert-butoxycarbonyl)amino]-propanoate (2.35 g, 4.85 mmol), 2-tert-butylisothiazol-3(2H)-one 1,1-dioxide (1.61 g, 8.49 mmol), palladium acetate (218 mg, 0.971 mmol), tetra-N-butylammonium chloride (1.35 g, 4.85 mmol), and then triethylamine (2.03 mL, 14.6 mmol) were dissolved in DMF (40.0 mL, 0.516 mmol). The solution was degassed and then stirred with heating at 70° C. under nitrogen for 120 minutes. LCMS indicated an absence of starting material. The solution was diluted with ethyl acetate (150 mL) and washed with water (150 mL) and aqueous hydrochloric acid solution (1.0 N, 150 mL). The organic phase was filtered through celite with ethyl acetate washing. The organic solution was dried over sodium sulfate, concentrated in vacuo, and then purified by silica gel chromatography (slow gradient, 10–25% ethyl acetate/hexanes) to afford product as a yellow solid (1.38 g, 52%). 1H NMR (500 MHz, CD3OD): δ 7.80 (d, J=8.2 Hz, 1H), 7.55 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 6.89 (s, 1H), 5.08–5.05 (m, 1H), 4.62–4.59 (m, 1H), 3.76 (s, 3H), 3.23–3.20 (m, 1H), 3.06–3.02 (m, 1H), 1.79 (s, 9H), 1.43 (s, 9H). LCMS found for C22H29BrN2O7SNa (M+Na)+: m/z=567.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:32][CH:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C1CCN(C2CNC2)CC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCCCC4)C3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-(azetidin-3-yl)piperidine were reacted to give 386. LCMS m/z: 502.3 (MH+)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH2:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O.[C:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>O1CCCC1.CCCCCC>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CCC=C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Temperature: 25 °C

Procedure:
In a 300 ml three-necked flask equipped with a magnetic stirrer and three-way cock was thoroughly purged with nitrogen, 4.75 g of 3-tert-butyl-cyclopentadiene (38.9 mmol) was dissolved in 100 ml of dehydrated tetrahydrofuran in a nitrogen atmosphere. To the solution, 26 ml of n-butyl lithium/hexane solution (1.58M: 41.1 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 21 ml of hexamethyl phosphoramide (121 mmol) dried with molecular sieves 4A was added in the ice bath and further stirred at room temperature for 1 hr. To the solution, a solution prepared by dissolving 10.2 g of benzophenone (56.0 mmol) to 30 ml of dehydrated tetrahydrofuran was gradually added dropwise in an ice bath and stirred at room temperature 1 day. To the resulting reaction mixture, 100 ml of a hydrochloric acid aqueous solution (5%) was added. Thereafter, hexane was added to the mixed solution to separate an organic phase. The organic phase was washed with water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give dark-brown oil. The oil was purified with a column chromatography using 400 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (15.4 mmol) as an orange solid (yield: 40%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][C:15](=[O:18])[CH2:16]2)[CH2:12][C@H:11]1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][CH:15]([OH:18])[CH2:16]2)[CH2:12][C@H:11]1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of (3aR,4S,5R,6aS) -4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-one (22) (96.7 g, 261 mmol) in toluene (600 ml) was cooled to −75° C. 1.5M-diisobutyl aluminum hydride (261 ml, 392 mmol) was added thereto drop wise and the mixture was stirred at −78° C. for approximately 2 hours. After adding methanol (69.0 ml, 1703 mmol) drop wise to the solution, the solution was warmed to room temperature. Saturated aqueous potassium sodium tartrate (800 ml) and diethyl ether (400 ml) were added thereto and the mixture was stirred for one hour, let to stand and then separated into two layers. The aqueous layer was extracted twice with diethyl ether (400 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (800 ml) and then dried with anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give (3aR,4S,5R,6aS)-4-(t-butyldimethylsilyloxymethyl)-5-(2-tetrahydropyranyloxy)hexahydrocyclopenta[b]furan-2-ol (23) (97.8 g, quantitatively) as a slightly yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[CH:19][N:18]=[C:17]([NH2:23])[C:16]=2[N:15]=[C:14]1[CH2:24][O:25][CH2:26][CH3:27]>>[NH2:23][C:17]1[C:16]2[N:15]=[C:14]([CH2:24][O:25][CH2:26][CH3:27])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:21]=2[C:20]([CH3:22])=[CH:19][N:18]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(=O)(=O)N(C)C

Procedure:
Using the method of Examples 115-135, dimethylsulfamoyl chloride was reacted with 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 385.2029.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23](=[O:25])[CH3:24])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Product: CC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(2-Aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) was dissolved in acetic anhydride (10 ml) and the solution was stirred at room temperature for 3 hours. The precipitate that forms after 75 min was filtered off and washed with water to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21](O)[CH3:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([O:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:22]
Reactant: C[C@H](O)c1ccccc1Cl
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1O
Product: COC(=O)c1sc([N+](=O)[O-])cc1O[C@H](C)c1ccccc1Cl

Procedure:
Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate Example 1, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([CH2:24][CH3:25])=[N:15][N:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18][C:17]=23)=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:24]([C:14]1[C:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=2)=[C:17]2[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]2[N:15]=1)[CH3:25]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCC(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(OCCO)cc1
Reaction time: 3 h

Procedure:
[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenoxy]-acetic acid methyl ester (9) (1.2 g, 3.40 mmol) was dissolved in 36 ml of THF. LiAlH4 (1.867 ml, 3.73 mmol) was added slowly to the reaction mixture and stirring was continued for 3 h at rt. The mixture was quenched with water and washed twice with CH2 Cl2. The aqueous layer was acidified with 1N HCl to pH3 and three times extracted with CH2 Cl2. The combined organic layers were washed with water and NaCl-solution, dried over Na2 SO4 and evaporated. The product was purified by chromatography (silica gel, chexane/ethylacetate).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(N=Cc1cccc2ccccc12)c1ccccc1

Procedure:
3.1 g of 1-naphthaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 1-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.1 g (59.6%) of light yellow needle-like crystals which melt at 92.5°-94.9° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:17][C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:17][C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:12][O:11][CH3:10])=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(-c2ccc(CC(=O)OC)cc2Cl)cc1
Reaction time: 3 h

Procedure:
Diisopropylethylamine (936 μl, 5.37 mmol) and chloromethyl methyl ether (303 μl, 4.02 mmol) were successively added to a solution of methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (650 mg, 2.68 mmol) obtained in Example (23-3) in methylene chloride (10 ml) under ice-cooling, and the mixture was stirred for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude methyl [2-chloro-4′-(methoxymethoxy)-1,1′-biphenyl-4-yl]acetate. According to a method similar to Example (104-1), Example (12-4), Example (40-2), Example (33-5) and Example (17-4), from the compound obtained in the above, the title compound was obtained as a colorless powder (260 mg, six-step total yield: 18%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C@@H](C3C=CC=CC=3)C)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@@H:13]2[C@@H:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1CC2CCN(C(=O)OC(C)(C)C)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Temperature: 50 °C
Reaction time: 16.5 h

Procedure:
To the minor isomer product of Example 3E (2.4 g, 7.5 mmol) in 30 mL CH3OH was added 0.58 g of 20% Pd(OH)2/C (wet). This mixture was shaken under 60 psi of H2 for 16.5 h at 50° C. The mixture was filtered, concentrated to proved the title compound, suitable for use without further purification. MS (DCl/NH3) m/z 213 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=O)[CH2:9][CH2:8]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:14][OH:15])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=O)CC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1C(=NO)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a suspension of 7-methoxyindanone (5.0 g, 31 mmol) and hydroxylamine hydrochloride (12.9 g, 185 mmol) in 100 mL ethanol was added the solution of sodium acetate (11.4 g, 139 mmol) in 35 mL water at room temperature. The reaction mixture was heated at reflux for 4 h, then stirred at room temperature for 18 h. The suspension was filtered, the white solid was washed with water, ethanol and diethyl ether to give the title compound (5.4 g, 31 mmol, 98%). ESMS m/z 178 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(C)(C)C.C(Br)(Br)(Br)[Br:41]>CCCCCC>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: BrCCCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
7.0 g of 5-hydroxypentyl benzyl ether and 10.6 g of triphenylphosphine were added to 50 ml of methyl tert-butyl ether and then cooled to 0° C. Further, 13.2 g of carbon tetrabromide was added and the mixture was stirred at room temperature for 3 hours. Thereafter, 100 ml of hexane was added and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of 5-bromopentyl benzyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].[CH3:14][N:15]([CH3:17])[NH2:16]>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:17])[NH:16][C:12]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:13]
Reactant: CN(C)N
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)NN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 300 mL of toluene containing 50 g of 2-methoxycarbonylphenyl isocyanate at 0° C. under a nitrogen atmosphere was added dropwise 21.44 mL of 1,1-dimethylhydrazine. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was then cooled to approximately 0° C., filtered, and the solid was rinsed with hexane to give 61.5 g of the title compound of Step A as a white solid.
Reaction SMILES: C[Si](C)(C(C)(C)C(C)C)[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C@H:11]([O:29][C:30](=[O:40])[C@@H:31]([NH:33]C(OCC=C)=O)[CH3:32])[O:10][C:9](=[O:41])[C:8]=2[C:7]([CH3:42])=[C:6]([O:43][CH3:44])[CH:5]=1.[F-].[NH4+].[ClH:54]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:54].[OH:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][CH2:12][C@H:11]([O:29][C:30](=[O:40])[C@@H:31]([NH2:33])[CH3:32])[O:10][C:9](=[O:41])[C:8]=2[C:7]([CH3:42])=[C:6]([O:43][CH3:44])[CH:5]=1
Reactant: C=CCOC(=O)N[C@@H](C)C(=O)O[C@H]1CCCC(=S)N[C@H](c2nc(C)no2)CSCc2c(O[Si](C)(C)C(C)(C)C(C)C)cc(OC)c(C)c2C(=O)O1
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)O[C@@H](OC(=O)[C@H](C)N)CCCC(=S)N[C@H](c1nc(C)no1)CSC2

Procedure:
(S)-2-Allyloxycarbonylamino-propionic acid (4R,10S)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-10-yl ester was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon addition of 3N hydrochloric acid in diethyl ether, a precipitate formed which was collected to yield (S)-2-amino-propionic acid (4R,10S)-16-hydroxy-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-10-yl ester hydrochloride as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30].C[O-].[Na+]>CO.C(Cl)Cl>[NH2:30][C:29]1[N:31]=[CH:17][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]3[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=3[C:6]=2[N:28]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 8 h

Procedure:
A stirred suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047 mol) of guanidine carbonate in 250 ml of methanol was treated at room temperature, under argon, with 5.1 g (0.094 mol) of sodium methylate in one portion. Methylene chloride (150 ml) was added after 10 min and stirring was continued. The same quantities of sodium methylate and guanidine carbonate were added two more times at 2 hr intervals and stirring was continued overnight. After diluting with 250 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization of the residue from ethanol gave light tan crystals: mp 209°-210° C. Recrystallization of a sample from methylene chloride/ethyl acetate gave off-white prisms: mp 210°-211° C.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:19][CH:18]3[N:20]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:14](C[C:16](=[O:34])[CH2:17]3)[CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C(OCC)=O>C1COCC1.[NH4+].[Cl-]>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:13][CH:14]3[N:20]([S:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)(=[O:23])=[O:22])[CH:18]([CH2:17][C:16](=[O:34])[C:1]3=[CH:2][OH:3])[CH2:19]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC[O-]
Reactant: O=C1CC2CC(c3cccc(Br)c3)CC(C1)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC=O
Product: O=C1CC2CC(c3cccc(Br)c3)CC(C1=CO)N2S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21% NaOEt (6 ml, 16.1 mmol) was added to a solution of 7-(3-Bromophenyl)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one (90) (2.28 g, 4.54 mmol) and ethyl formate (6 ml, 74.5 mmol) in THF (20 ml). The solution was placed into a preheated oil bath at 60° C. After stirring for 30 min, the solution was cooled to ambient temperature, diluted with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford 7-(3-bromophenyl)-2-(hydroxymethylene)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one. Hydrazine monohydrate (3 ml) was added to a solution of 7-(3-bromophenyl)-2-(hydroxymethylene)-9-(4-(trifluoromethyl)phenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one and glacial acetic acid (1 ml) in EtOH (20 ml). After stirring for 18 h, the solution was concentrated to afford compound 92.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=4)[CH:20]=3)[CH2:14][CH2:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:49]2[CH:56]=[CH:55][C:52]([CH2:53][Cl:54])=[CH:51][CH:50]=2)[CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:69].Cl>>[ClH:54].[ClH:69].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=4)[CH:20]=3)[CH2:16][CH2:17]2)[CH2:53][C:52]2[CH:55]=[CH:56][C:49]([C:41]3[CH:42]=[C:43]([O:47][CH3:48])[C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=3)=[CH:50][CH:51]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(OC)cc(N(Cc2ccc(-c3cc(OC)c(OC)c(OC)c3)cc2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)c1

Procedure:
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave yellow powder of the title compound.