Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[N:29][CH:30]=1)[CH3:24]>C(#N)C>[F:31][C:28]1[N:29]=[CH:30][C:25]([CH:23]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH3:24])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(Br)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 73 %

Procedure:
tert-Butyl piperazine-1-carboxylate (Aldrich, St. Louis, Mo.; 13.31 g, 71.5 mmol), potassium iodide (2.37 g, 14.29 mmol), and potassium carbonate (11.85 g, 86 mmol) were sequentially added to a solution of 5-(1-bromoethyl)-2-fluoropyridine (14.58 g, 71.5 mmol) in acetonitrile (300 mL) at 25° C., and the resulting mixture was heated at 80° C. for 1 h. The reaction mixture was then partially concentrated in vacuo (final volume: about 80 mL), diluted with EtOAc (600 mL), and sequentially washed with 4:1 water:brine (2×600 mL) and brine (600 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 100% EtOAc/Hexanes) furnished tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (16.9 g, 73% yield over (2 steps) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.8 Hz, 1H), 7.78 (td, J=8.1, 2.3 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.47 (q, J=6.7 Hz, 1H), 3.39 (t, J=4.8 Hz, 4H), 2.37-2.49 (m, 2H), 2.25-2.36 (m, 2H), 1.44 (s, 9H), 1.36 (d, J=6.7 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ −70.50 (dd, J=8.0, 2.3 Hz, 1 F). m/z (ESI, +ve) 310.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[CH:3]=1.[P:13](Cl)([Cl:16])([Cl:15])=[O:14].CCN(CC)CC>CCOCC>[P:13]([Cl:16])([Cl:15])([O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:10]([CH3:12])[CH3:11])=[O:14]
Reactant: Cc1cc(O)c(C(C)C)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(OP(=O)(Cl)Cl)c(C(C)C)cc1Cl

Procedure:
Following the procedure described for Example 1, Step 1, treatment of a solution (0.174 M) in Et2O of 4-chloro-2-isopropyl-5-methyl-phenol with phosphorus oxychloride (1.0 eq.) and Et3N (1.0 eq.) provided the title compound as a colorless oil. 31P NMR (300 MHz, CD3OD): δ 4.54.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C[N@@]1S(C1C=CC=C([C:34]([F:37])([F:36])[F:35])C=1)(=O)=O>>[F:35][C:34]([F:37])([F:36])[C:7]1[CH:6]=[C:5]([S:8]([NH:11][C@H:12]([CH2:14][C:15]#[C:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13])(=[O:9])=[O:10])[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)CC#C[Si](C)(C)C)cc1
Reactant: CC1C[N@@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CC1C[N@]1S(=O)(=O)c1cccc(C(F)(F)F)c1
Product: C[C@@H](CC#C[Si](C)(C)C)NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Proceeding as described for (51), but using (S)-2-methyl-1-(3-(trifluoromethyl)-benzenesulfonyl)aziridine afforded (S)-3-(trifluoromethyl)-N-(5-(trimethylsilyl)pent-4-yn-2-yl)benzenesulfonamide (52). MS (m/z): 364.1 (M+H) (Calc'd for C15H20F3NO2SSi: 363.47).
Reaction SMILES: [Cl-:1].[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[CH3:3]>C(Cl)(Cl)Cl>[CH2:2]([O:4][C:5](=[O:14])[CH:6]([Cl:1])[C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[CH3:3]
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulftiryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0°) solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J Org. Chem., 65:8402-8405 (2000).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O:17]O)(C)(C)C>ClCCl.O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:17])[CH2:7][C:8]2([CH3:12])[CH3:11]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CCc2ccc(Br)cc21
Agent: [Cr+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan 8g (4 g, 17.8 mmol) was dissolved in 40 mL of anhydrous dichloromethane, followed by addition of chromium oxide (280 mg, 1.8 mmol) and slowly dropwise addition of tert-butyl hydroperoxide (19 mL, 190 mmol). The reaction system was sealed and stirred overnight at room temperature after the reaction solution was crimson and the generated gas was released. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of water and extracted with dichloromethane (100 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-bromo-3,3-dimethyl-indan-1-one 19a (3.5 g, 82.3%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[NH:9])[NH:5][N+:6]([O-:8])=[O:7])[CH3:2].[Cl-].[Na+].Cl.CN.[C:15](=O)([O-])O.[Na+].Cl>O>[CH2:1]([O:3][C:4](=[N:5][N+:6]([O-:8])=[O:7])[NH:9][CH3:15])[CH3:2]
Reactant: CCOC(=N)N[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CCOC(=N[N+](=O)[O-])NC
Reaction time: 15 h
Yield: 70 %

Procedure:
Into a 100-ml, 4-necked flask equipped with a stirrer were introduced 1.5 g (11.3 mmole) of O-ethyl-N-nitroisourea, 8 g of water, 2 g of sodium chloride and 2 g (29.6 mmole) of methylamine hydrochloride, and the resulting material was maintained at 15 degree centigrade. Thereafter, 0.1 g of sodium hydrogen carbonate was added to the mixture and the mixture was stirred at 30 degree centigrade for 15 hours. Then, while stirring the reaction mixture, 0.1 g of concentrated hydrochloric acid and 200 ml of water were added to the mixture to give a homogenious aqueous solution of O-ethyl-N-methyl-N′-nitroisourea, which was analyzed by HPLC. In the aqueous solution, 1.2 g of O-ethyl-N-methyl-N′-nitroisourea was contained, and the reaction yield was 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([I:12])[CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:16][C:5]1[C:4]2[C:9](=[C:10]([I:12])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2c(I)cc(Cl)cc12
Solvent: CN(C)C=O
Product: Clc1cc(I)c2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
To around bottom flask was added 6-chloro-8-iodo-3H-quinazolin-4-one (1000 mg, 3.3 mmol); and thionyl chloride (50 mL). DMF (0.1 mL) was then added, and the reaction was stirred at reflux for 2 h. The reaction was cooled to room temperature, then concentrated via rotovap. The product was then azeotroped 2× with DCM, then dried under vacuum yielding 4,6-dichloro-8-iodo-quinazoline, carried immediately to the next step. 1H NMR (400 MHz, DMSO) δ 9.24-9.20 (s, 1H), 8.77-8.73 (d, J=2.2 Hz, 1H), 8.36-8.31 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[Cl:28][C:29]1[C:30]([C:36]#[N:37])=[N:31][CH:32]=[C:33](Cl)[N:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:33]2[CH:32]=[N:31][C:30]([C:36]#[N:37])=[C:29]([Cl:28])[N:34]=2)=[CH:17][CH:18]=1)(=[O:10])=[O:11]
Reactant: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)OC1(C)C
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Temperature: 100 °C

Procedure:
2,3-Dichloro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzenesulfonamide (5.78 g) was added to a reaction vessel containing a magnetic stirring bar together with 3,5-dichloro-pyrazine-2-carbonitrile (2.35 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (Pd(dppf)2Cl2) (791 mg) and cesium carbonate (13.2 g), followed by 100 ml dioxane and 10 ml water, and the mixture heated to 100° C. under stirring. After 3 h the reaction mixture was cooled to RT and quenched with a saturated aqueous sodium bicarbonate solution (100 ml) and extracted with EtOAc (3×200 ml). The combined aqueous phases were dried over sodium sulfate, filtered and evaporated to afford the crude product as a brown oil. Purification by flash chromatography on silica gel using a mixture of EtOAc and heptane as the eluent afforded 2,3-dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-benzenesulfonamide as a light brown foam after evaporation of the solvents under reduced pressure. Yield: 4.32 g (73%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[O:27]=[C:28]1[N:32]([C@@H:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][C@H:34]2[F:46])[C:31](=[O:47])[CH2:30][S:29]1>>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:30]3/[C:31](=[O:47])[N:32]([C@@H:33]4[CH2:38][CH2:37][NH:36][CH2:35][C@H:34]4[F:46])[C:28](=[O:27])[S:29]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](F)C1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) and 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-fluoropiperidine-1-carboxylate (from Example 273) following General Procedure F.
Reaction SMILES: C(OC1C=CC(C(CCCC2C=CC=C(OC3C=CC=CC=3)C=2)C(F)(F)F)=CC=1)C.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:49]=2)[CH2:46][CH3:47])[C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=1)[CH3:32]>C(O)C.[Pd]>[CH2:31]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH:40]([CH:45]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([O:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:49]=2)[CH2:46][CH3:47])[C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=1)[CH3:32]
Reactant: CCOc1ccc(C(=C(CC)c2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: [Pd]
Agent: CCOc1ccc(C(CCCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Solvent: CCO
Product: CCOc1ccc(C(C(CC)c2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 79.6 %

Procedure:
This Example illustrates the preparation of 2-(4-ethoxyphenyl)-5-(3-phenoxyphenyl)-1,1,1-trifluoropentane. A mixture of E and Z isomers of 2-(4-ethoxyphenyl)-3-(3-phenoxyphenyl)-1,1,1-trifluoropent-2-ene (0.4 g) in ethanol (20 cm3) in the presence of a hydrogenation catalyst (10% palladium on charcoal, 50 mg) was stirred under an atmosphere of hydrogen at a pressure of 2 atmospheres for 1 hour, then 4 atmospheres for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate concentrated by removal of the ethanol by evaporation under reduced pressure. The residue was dissolved in chloroform, and the solution washed with water twice, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by column chromatography using a short silica gel column eluted with 2:25 mixture by volume of ethyl acetate and hexane to yield 2-(4-ethoxyphenyl)-3-(3-phenoxyphenyl)-1,1,1-trifluoropentane (0.32 g) as a colourless oil.
Reaction SMILES: [F:1]C1C=C(C(OC)=O)C2C3C(=O)CNCC=3NC=2C=1.C1(C(Cl)=O)CC1.[CH:26]1([C:29]([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[CH:26]1([C:29]([N:31]2[CH2:43][C:42]3[NH:41][C:40]4[CH:39]=[C:38]([F:1])[CH:37]=[C:36]5[C:44](=[O:47])[NH:45][N:46]=[C:33]([C:34]=3[C:35]=45)[CH2:32]2)=[O:30])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CNC3
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Agent: O=C(Cl)C1CC1
Product: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cc(F)cc1c4c32

Procedure:
Compound 49 was prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and cyclopropanecarbonyl chloride according to the procedures similar to those for Compound 47. 1H NMR (DMSO-d6) δ 9.64 (s, 1H), 6.80-7.08 (m, 2H), 4.95 (s, 1H), 4.74 (s, 1H), 4.40 (s, 1H), 4.20 (s, 1H), 2.03-2.07 (m, 1H), and 0.75 (s, 4H). MS (ESI) m/e [M+1]+ 313.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[C:5]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)C>[C].[Pd].O1CCCC1>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][O:2][CH3:1])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]2
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2n1COC
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(N)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-nitro-1H-indole-2-carboxylate (2.35 g), 10% palladium-carbon (0.24 g), ethanol (4 ml) and tetrahydrofuran (10 ml) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.92 g, yield 91%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=O>>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: Cc1ccccc1C(=O)CBr
Product: COC(=S)c1cc(-c2nc(-c3ccccc3C)cs2)c(C)s1
Yield: 55.5 %

Procedure:
160 mg (0.647 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-2′-methyl acetophenone (0.711 mmol, 152 mg) in a manner similar to Example 22, step (a) to afford 124 mg (53% yield) of methyl 4-[4-(2-methylphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: CCCBr
Reactant: Fc1ccc(N2CCNCC2)cc1C(F)(F)F
Product: CCCN1CCN(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(4-fluoro-3-trifluoromethyl-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 238° C. (HCl); MS m/z (rel. intensity, 70 eV) 290 (M+, 17), 261 (70), 190 (34), 70 (bp), 56 (44).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:21])[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=1.[NH2:22][C:23]([NH2:25])=[S:24].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O1CCCC1.O>[NH2:25][C:23]1[S:24][C:13]([C:12](=[O:21])[C:8]2[CH:9]=[CH:10][CH:11]=[N:6][CH:7]=2)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:22]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)CC(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(N)sc1C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
A solution of sulfuryl chloride (2.84 g) in methylene chloride (5 ml) was dropwise added to a solution of ethyl 4-(3-pyridyl)-2,4-dioxo-butyrate (4.42 g) in methylene chloride (40 ml) at 18° C. to 30° C. After being stirred at ambient temperature for one hour, the mixture was added to a solution of thiourea (4.56 g) in a mixture of tetrahydrofuran (50 ml) and water (10 ml). The resulting mixture was adjusted to pH 7.5 with 20% aqueous potassium carbonate and stirred for one hour, and then the solvent was removed in vacuo. To the residue was added a mixture of water and ethyl acetate, and the mixture is acidified to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 9.0 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give ethyl 2-amino-5-nicotinoyl-4-thiazolecarboxylate (0.9 g). mp 221° C. (dec.)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1(O)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:23]1([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: OC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid (2.53 g, 7.6 mmol) in DCM (50 ml) at 0° C. was added cyclopentanol (1.39 ml, 15.3 ml), EDC (1.61 g, 8.4 mmol) and DMAP (0.093 g, 0.76 mmol). The reaction mixture was stirred for 16 hours at room temperature before evaporation under reduced pressure. The crude residue was dissolved in ethyl acetate (100 ml) and washed with 1M HCl, 1M Na2CO3 and brine. The organic layer was then dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by column chromatography using ethyl acetate/heptane (1:4) to give 2.24 g, 73% yield of title compound. LCMS purity 100%, m/z 402.5 [M++H], 1H NMR (300 MHz, CDCl3), δ: 5.20 (1H, d, J=6.3 Hz), 5.15 (1H, m), 4.20 (1H, m), 3.6 (2H, m), 2.00 (1H, m), 1.95-1.55 (9H, bm), 1.40 (9H,s), 0.85 (9H,s), 0.10 (6H,s).
Reaction SMILES: Cl.C[O:3][C:4]1[C:5]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1.[BrH:19]>>[BrH:19].[OH:3][C:4]1[C:5]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCNCC2
Agent: Br
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1O)CCNCC2

Procedure:
8-Methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3benzazepine hydrochloride (1.5 g, 0.005 m) was dissolved in 48% hydrobromic acid (15 ml), refluxed for 2 hours and concentrated in vacuo. The residue was triturated with acetone and then recrystallized from methanol to give 8-hydroxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 315°-320° (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Yield: 78.2 %

Procedure:
A solution of tert-butyl 7-nitro-3,4-dihydroisoquinoline-2(1H)-carboxylate (9.4 g, 34 mmol) in ethanol (150 mL) was treated with 10% palladium on carbon (0.5 g), and the resulting mixture was hydrogenated on a Parr shaker at an initial pressure of 40 psi for 30 minutes. The catalyst was removed by filtration through a glass microfibre filter, and the filtrate was concentrated. The residue was purified by chromatography on silica gel, eluting with 75/25 to 70/30 hexanes/ethyl acetate, to afford tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate as a yellow oil (6.6 g, 79% yield).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([NH:17]C(=O)OCC1C=CC=CC=1)[CH:12]=3)(=[O:3])[NH2:2]>O1CCCC1.CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]3[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]=3[NH:10]2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Yield: 90.1 %

Procedure:
A mixture of benzyl 1-carbamoyl-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indol-7-ylcarbamate (210 mg, 0.416 mmol) and 10% Pd/C (45 mg, 0.042 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was stirred under H2, provided with a H2 balloon, at rt for 1 hr. The catalyst was removed by suction filtration through CELITE®. The filtrate was concentrated under vacuum. The residue was diluted with CH2Cl2 (100 mL), washed with brine (30 mL), and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product, 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (132 mg, 0.375 mmol, 90% yield), as a tan solid. LCMS (M+H)+=321.10.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Br:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[Br:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 27 h
Yield: 0.1 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.62 g, 4.16 mol) in methanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (8.7 mL, 8.74 mol). The reaction mixture was stirred at 25° C. for 27 h. The reaction mixture was concentrated in vacuo to remove methanol. The resulting aqueous residue was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (1×400 mL). The organic layer was washed with water (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.39 g, 89%) as a white solid which was used without further purification: mp 149–150° C.; FAB-HRMS m/e calcd for C15H19BrO4S (M+H)+ 375.0266, found 375.0274.