Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][NH:20][S:21]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[C:28]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([N:20]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:35][CH:34]=2)(=[O:23])=[O:22])=[CH:33][CH:32]=1)([OH:30])=[O:29]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COc1ccc(CN(Cc2ccc(C(=O)O)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from methyl 4-(bromomethyl)benzoate and Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (example 5-10b). 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.65 (s, 3H), 4.24 (s, 2H), 4.33(s, 2H), 6.71 (d, 2H, J=8 Hz), 6.95 (d, 2H, J=8 Hz), 7.14 (d, 2H, J=8 Hz). 7.73 (d, 2H, J=8 Hz), 7.89(d, 2H, J=8 Hz), 8.06(d, 2H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][C:3]=1[C:17]([CH3:24])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.[C].[Rh]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16])[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C=C(C)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Agent: [Rh]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
To a solution of ethyl 3-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)buta-2-enoate (525 mg) in tetrahydrofuran (10.0 mL) was added 5% rhodium carbon (200 mg), followed by stirring at room temperature for 18 hours under hydrogen atmosphere. The reaction suspension was filtered through Celite, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 3-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)butanoate (282 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[N:3]2[CH2:10][CH2:9][CH:6](/[C:7]/1=[N:23]/[C:20]1[CH:21]=[N:22][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:18][CH:19]=1)[CH2:5][CH2:4]2
Reactant: Nc1ccc(-c2ccccc2)nc1
Reactant: CC1C(=O)C2CCN1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1/C(=N\c2ccc(-c3ccccc3)nc2)C2CCN1CC2

Procedure:
A solution of 2-methyl-1-aza-bicyclo[2.2.2]octan-3-one (1.33 g, 9.5 mmol), 6-phenyl-pyridin-3-ylamine (1.25 g, 7.3 mmol) and p-toluene sulfonic acid monohydrate (139 mg, 0.73 mmol) in toluene (40 ml) is heated under reflux for 18 hours using a Dean-Stark apparatus. The toluene is evaporated and the residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: EtOAc: CH3OH:NH4OH; 9:1:0.1) to afford [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine. A solution of LiAlH4 (1.03 ml, 1 M) in THF is added to a solution of [2-Methyl-1-aza-bicyclo[2.2.2]oct-(3Z)-ylidene]-(6-phenyl-pyridin-3-yl)-amine (300 mg, 1.02 mmol) in THF (10 ml). The resulting mixture is stirred at room temperature for 18 hours and then quenched with a saturated aqueous solution of sodium sulfate (1 ml). The solvents are removed by evaporation and the residue is redissolved in ethyl acetate and filtered. The filtrate is evaporated and purified by silica gel column chromatography (eluent: EtOAc: CH3OH: NH4OH; 8.5:1.5:0.1) to afford Rac.-trans-2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine. MS (ES+): m/e=294.4 (MH+); preparative enantiomer separation (column: Chiralpak AD-H 10 um; (4.6×250 mm), eluent: n-hexane : EtOH 50:50, flow: 1.0 ml/min, detector: UV 210 nm): peak 1: 6.29 min; peak 2: 20.16 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33].O>N1CCCCC1.C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH:23]=[C:31]3[S:27][C:28](=[O:33])[NH:29][C:30]3=[O:32])=[CH:25][CH:26]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1cc2c(cc1C(C)Oc1ccc(C=O)cc1)C(C)(C)CCC2(C)C
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc2c(cc1C(C)Oc1ccc(C=C3SC(=O)NC3=O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
A mixture of 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphtalene-2-yl)-ethoxy)-benzaldehyde (350 mg; 1.0 mmol), 2,4-thiazolidinedione (129 mg; 1.1 mmol), piperidine (1 drop) and acetic acid (1 drop) in toluene (10 ml) was refluxed for 3 hours using a water separator. Upon cooling to room temperature the product precipitated. Filtration gave the title compound in 325 mg (72%) yield.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][C:22]=1[O:29][CH3:30]>>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:23][C:22]=1[O:29][CH3:30]
Reactant: COc1cc(CN)ccc1O
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3ccc(O)c(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 4-hydroxy-3-methoxy-benzylamine to afford the title compound. MS: m/e=394 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[CH2:22][NH+:10]3[CH2:11][CH2:12][C:13]4[C:18]([C:9]3=[C:8]([CH3:24])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:25][CH3:26])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[I-].[C:28]([Mg]Br)([CH3:30])=[CH2:29].O1CCCC1>C(OCC)C>[C:28]([CH:22]1[N:10]2[CH2:11][CH2:12][C:13]3[C:18]([C:9]2=[C:8]([CH3:24])[C:7]2[CH:6]=[CH:5][C:4]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[C:23]1=2)=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=3)([CH3:30])=[CH2:29]
Reactant: C=C(C)[Mg]Br
Reactant: COc1ccc2c(c1OC)C[NH+]1CCc3cc4c(cc3C1=C2C)OCO4
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C1c2c(ccc(OC)c2OC)C(C)=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of 9,10-dimethoxy-13-methyl-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; iodide (300 mg, 0.63 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added a solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 18.8 mL, 9.4 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 8-isopropenyl-9,10-dimethoxy-13-methyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (90 mg, 36%). LC/MS m/e calcd for C24H23NO4 (M+H)+: 392.47, observed: 392.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 3 H) 2.13 (s, 3 H) 2.62-2.71 (m, 1 H) 2.72-2.79 (m, 1 H) 3.00-3.08 (m, 1 H) 3.13-3.21 (m, 1 H) 3.71 (s, 3 H) 3.80 (s, 3 H) 4.59 (s, 1 H) 4.77 (s, 1 H) 5.12 (s, 1 H) 6.03 (s, 2 H) 6.83 (s, 1 H) 6.93 (s, 2 H) 7.02 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[NH:10][C:11]1[N:16]=[C:15]([C:17]2[C:25]3[C:20](=[N:21][C:22]([NH:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:23][CH:24]=3)[NH:19][N:18]=2)[CH:14]=[CH:13][N:12]=1)(C)(C)C.Cl>CCO>[Cl:41][C:37]1[CH:36]=[C:35]([CH:9]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][C:22]([NH:26][CH2:27][CH2:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[N:23][CH:24]=4)[NH:19][N:18]=3)[CH:14]=[CH:13][N:12]=2)[CH2:8][NH2:7])[CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
(2-(3-Chloro-phenyl)-2-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.17 mmol) was dissolved in EtOH (4 mL), then HCl (4 mL) was added. The reaction mixture was stirred at room temperature for 10 hours. The solvent was removed under reduced pressure to afford the crude product which was purified by prep-HPLC to afford 1-(3-chloro-phenyl)-N1-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-yl}-ethane-1,2-diamine; hydrochloride. (Yield 24 mg, 23.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([CH3:28])([CH3:27])[NH2:26].[ClH:29]>C(#N)C>[ClH:29].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]([NH:26][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])([CH3:27])[CH3:28]
Reactant: COc1ccc2[nH]cc(CC(C)(C)N)c2c1
Reactant: Cc1ccccc1OCC1CO1
Agent: Cl
Solvent: CC#N
Product: COc1ccc2[nH]cc(CC(C)(C)NCC(O)COc3ccccc3C)c2c1

Procedure:
(2-Methylphenoxymethyl)oxirane, 4.1 g., (0.025 mole) and 5.4 g. (0.025 mole) of 5-methoxy-α,α-dimethyl-1H-indol-3-yl-ethaneamine were mixed and heated at 130° for 2 hrs. The mixture was allowed to cool, but while still warm was dissolved in 60 ml. of acetonitrile and acidified with ethanolic 5 N HCl to pH 2. Th product crystallized as the hydrochloride salt, yield 8.3 g.; recrystallized from isopropanol/methanol, yield 7.4 g., m.p. 201.0°-203.0°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]3[CH2:23][O:22]C4(CCCCC4)[O:20]3)[N:15]=2)=[N:11][CH:12]=1.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(OCC)(=O)C>[ClH:37].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([C@H:19]([OH:20])[CH2:23][OH:22])[N:15]=2)=[N:11][CH:12]=1
Reactant: COCCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCCSc1cnc(Nc2nc([C@H](O)CO)ns2)c(Oc2cccnc2C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
(S)-N-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (85 mg, 0.16 mmol) was dissolved in ethanol (5 ml) and 1M HCl (0.5 ml) was added. The mixture was heated to 70° C. and agitated 3 hours. Upon cooling, the reaction was diluted with ethyl acetate, basified with sodium carbonate solution and washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was dissolved in small amount of dichloromethane and treated with 1M HCl in ether. After evaporation, (S)-1-(5-(5-(3-methoxypropylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (65 mg, 90% yield) was obtained as white solid. Mass Spectrum (apci) m/z=450.1 (M+H−HCl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: OB(O)c1cccnc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3cccnc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 50 %

Procedure:
In a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (100 mg, 0.194 mmol) in dioxane (3 mL). Pyridine 3-boronic acid (23.822 mg, 0.194 mmol), and a 1N solution of potassium carbonate [(80.349 mg, 0.581 mmol) dissolved in 1.25 mL water] were added at room temperature, and the reaction mixture was purged with argon for 30 min. Then, Pd(triphenyl phosphine)4 (22.395 mg, 0.019 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15.911 mg, 0.039 mmol) were added and the reaction mixture was further degassed for another 10 min. The reaction mixture was heated at 80° C. for 4 h (monitored by LC-MS). The reaction mixture was filtered through a pad of cellite and the filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column (using amine bound silica gel) to get 9-benzyloxy-6-(4-chloro-2-pyridin-3-yl-benzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (389) (50 mg, 50.1%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=1)[NH:8][C:7]([C:21]([O:23]CC)=[O:22])=[CH:6]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([NH:12][S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH:11]=1)[NH:8][C:7]([C:21]([OH:23])=[O:22])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
To a mixed solution of ethyl 5-methoxy-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.34 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.20 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (300 mg, yield 96%) as pale-yellow crystals. melting point>240° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])[C:7]=1[CH3:8].Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=1[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])=[O:17]
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Reactant: CN(C)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Nc2ccccc2C(=O)OCC(=O)N(C)C)c1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of mefenamic acid (2.41 g, 0.01 mole), 2-chloro-N,N-dimethylacetamide (1.6 g, 0.013 mole), triethylamine (1.6 ml, 0.011 mole) and sodium iodide (0.15 g, 0.001 mole) in N,N-dimethylformamide (10 ml) was stirred at 90° C. for 2 h. Water (50 ml) was added and the mixture allowed to stand at 4° C. for 5 h. The title compound was isolated by filtration, washed with water and recrystallized from ethanol-water (3.0 g, 92%). Mp 85°-86° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])=[CH2:17])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CS(O)(=O)=O>ClCCl>[CH3:17][C:16]1([CH3:18])[CH2:15][C:9]2[C:8](=[CH:13][CH:12]=[C:11]([F:14])[CH:10]=2)[NH:7]1
Reactant: C=C(C)Cc1cc(F)ccc1NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2cc(F)ccc2N1
Temperature: 170 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
A sample of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester (1.10 g, 4.14 mmol) was treated with anisole (5 mL), dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred for 4 hours. The solvent was removed and the reaction was transferred to a microwave reaction vial using methanesulfonic acid (3 mL). The reaction was heated to 170° C. for 10 minutes. The reaction was cooled to room temperature and quenched into excess stirring 1 M NaOH. The aqueous phase was extracted twice with ethyl acetate and the combined organics were dried over MgSO4 and filtered. The resulting oil was purified on silica gel using a gradient of 0-70% t-butyl ethyl ether and hexane to afford 450 mg (66% yield) of 2,2-dimethyl-5-fluoroindoline; 1H NMR (CDCl3, 400 MHz) δ 1.08 (s, 6H), 2.58 (s, 2H), 6.24 (dd, 1H, J1=4.4, J2=8.4), 6.43-6.48 (m, 1H), 6.53-6.56 (m, 1H); HPLC-MS calcd. for C10H12FN (M+H+) 166.1, found 166.4.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.ClS([N:12]=[C:13]=[O:14])(=O)=O>ClCCl>[CH3:1][C:2]12[NH:12][C:13](=[O:14])[CH:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1=CCCCC1
Solvent: ClCCl
Product: CC12CCCCC1C(=O)N2
Temperature: -10 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Following the procedure of Spurr et al, J. Am. Chem. Soc., 1983, 105, 4735, a solution of 1-methyl-1-cyclohexene (1 g, 10.4 mmol) in dichloromethane (30 mL) was cooled to −20° C. and chlorosulfonylisocyanate (1.08 mL, 12.5 mmol) was added drop wise. The reaction was warmed to −10° C. over 3 h, then warmed to room temperature and stirred for 1 h. The reaction mixture was then concentrated, and taken up in ether (15 mL) and dimethylethyleneglycol (5 mL) to homogenize. To the reaction mixture was added 25% Na2SO3 (25 mL), followed by 10% sodium hydroxide solution to keep the pH between 7-8. The reaction was stirred overnight, taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated to afford racemic (1S,6R)-6-methyl-7-azabicyclo[4.2.0]octan-8-one (0.95 g, 66%). MS: 140.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2=[CH:37][CH:38]=[CH:39][NH:40][C:35]2=[CH:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)C1=CC=CNC1=CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48-2.63 (m, 2H), 2.74-3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20 (d, 2H), 7.22-7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[BrH:25]>C1COCC1>[Br:25][CH2:10][C:9](=[O:13])[C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Reactant: Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (S)-[3-diazo-1-(4-nitrobenzyl)-2-oxo-propyl]-carbamic acid tert-butyl ester, 6, (0.350 g, 1.04 mmol) in THF (5 mL) is added dropwise 48% aq. HBr (0.14 mL, 1.25 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours then the reaction is quenched at 0° C. with sat. Na2CO3. The mixture is extracted with EtOAc (3×25 mL) and the combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated to obtain 0.400 g of the product which is used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.20 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 5.06 (d, J=7.8 Hz, 1H), 4.80 (q, J=6.3 Hz, 1H), 4.04 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.CC(C)([O-])C.[K+].[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36]Br)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH2:36][N:9]2[C:8](=[O:12])[CH2:7][C:6]3[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH:11]=[CH:10]2)[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC1CCCN(Cc2ccccc2)C1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccccc3)C1)C=C2
Reaction time: 0.75 h

Procedure:
17.54 g (0.08 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are suspended in 150 ml of dimethylsulphoxide and 8.98 g (0.08 mol) of potassium tert.butoxide are added with stirring. After 45 minutes, 21.45 g (0.08 mol) of N-benzyl-3-(bromomethyl)-piperidine dissolved in 50 ml of dimethylsulphoxide are added dropwize to the resulting solution with stirring. After 2 hours the mixture is poured onto ice water. The aqueous phase is extracted three times, each time with 150 ml of ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and purified over 800 g of aluminium oxide (neutral, activity II-III) with methylene chloride and then with increasing amounts of ethanol (up to 3%). Yield: 14.3 g (44% of theory), Rf value: 0.35 (aluminium oxide neutral, eluant: 1% ethanol in methylene chloride).