Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C([O-])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31]2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-cyclohex-2-enyl-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.1 mmol) in DCM (4 mL), trifluoroacetic acid (0.4 mL) and water (20 μl) was stirred for 16 h at room temperature. Trifluoroacetic acid ((0.2 mL) was added and it was stirred for another 3 h. Saturated NaHCO3 solution was added and it was extracted with DCM. The extract was washed with brine, dried over MgSO4 and evaporated yielding crude 5-cyclohex-2-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg) which was used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([OH:19])[C:11]=23)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:34]4[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]4[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])[C:11]=23)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2ccnc3[nH]nc(O)c23)cc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
4-[2-(4-Hydroxyphenyl)ethyl]-1H-pyrazolo[3,4-b]-pyridin-3-ol (3.48 g) was stirred at 100° C. to be dissolved in N,N-dimethylformamide (55 mL). The solution was cooled to room temperature. To the solution were added potassium carbonate (3.77 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (9.48 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2-1/1-2/3) to give the title compound (2.26 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[O:6]=[C:7]1[C:16](=[O:17])[NH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:18](Cl)(=[O:20])=[O:19])[CH:13]=2)[NH:8]1.C(O)(=O)C>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:6])[C:16](=[O:17])[NH:15]2)(=[O:19])=[O:20]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: COCCN
Solvent: CC(=O)O
Solvent: O
Product: COCCNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Reaction time: 48 h
Yield: 63 %

Procedure:
To a solution of 7.51 g (0.1 mole) of 2-methoxyethylamine in 20 ml of water 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added in small portions, under stirring, and the mixture is stirred at room temperature for 16 hours. It is allowed to stand further for 2 days, and then 15 ml of acetic acid and 10 ml of water are added to it. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.80 g (63%) of 1,2,3,4-tetra-hydro-N-(2-methoxy-ethyl)-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 264-267° C.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11][NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[N:8]=[N:7]1)([CH3:4])[CH3:3].C(Cl)Cl.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>CCOC(C)=O>[C:34]([N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1)[CH2:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][Si:2]([CH3:3])([CH3:1])[CH3:4])[CH:10]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(CNCc2cn(C[Si](C)(C)C)nn2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)C(C)=O)cc1
Reaction time: 0.08 h

Procedure:
A solution of methyl 4-{[({1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)amino]methyl}benzoate (133 mg, 400 mmol), DCM (1.33 mL) and Et3N (167 uL, 1.2 mmol) were treated with acetyl chloride (42.7 uL, 0.600 mmol) and stirred for 5 min. The reaction was diluted with EtOAc and washed with 2M aq. HCl, water, brine, dried (MgSO4) and concentrated to afford the requisite compound as a clear, colorless residue. MS: cal'd 375 (MH+), exp 375 (MH+).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:28]=[CH:27][N:14]3[C:15](=[O:26])[C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:17][N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cnc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)cnc3c2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The ethyl (E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-2-propenoate (15 mg) obtained in (A) was dissolved in tetrahydrofuran (1 ml) and methanol (0.5 ml), added with a solution of 8 mg of lithium hydroxide dissolved in 0.5 ml of water, and stirred at room temperature for 3.5 hours, and the solvent was concentrated under reduced pressure. The residue was distributed between ether and water, and the aqueous layer was separated, made pH 3 with hydrochloric acid, extracted with ethyl acetate, and dried over sodium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>O.CO.C(O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[CH:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=Cc1cccc(Br)c1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(C=Cc1cccc(Br)c1)c1ccccc1
Yield: 75.6 %

Procedure:
Sodium hydroxide (12.00 g, 300 mmol) and acetophenone (24 g, 200 mmol) were dissolved in water (90 mL) and methanol (300 mL). 3-Bromobenzaldehyde (37 g, 200 mmol) dissolved in ethanol (50 mL) was added dropwise to the acetophenone solution. A slurry quickly formed, which was allowed to two additional hours. The slurry was filtered, was with water until the filtrate was neutral to pH paper, and dried at 80° C. for 12 hours. Light yellow crystals were obtained (43.4 g, 75.6% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH:9]([OH:16])[CH2:8][CH2:7]2.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][O:15][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:9]([OH:16])[CH2:8][CH2:7]2
Reactant: OCCCC1c2c(Br)cccc2CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCC1c2c(Br)cccc2CCC1O
Temperature: 25 °C
Yield: 107.1 %

Procedure:
A solution of 8-bromo-1,2,3,4-tetrahydro-1-(3-hydroxypropyl)-2-hydroxynaphthalene (B-3, 29.15 g, 0.10 mol) and imidazole (17.02 g, 0.25 mol) in dimethylformamide (70 mls) was cooled in ice, and t-butyldimethylsilyl chloride (17.3 g, 0.115 mol) was added with stirring. The mixture was allowed to warm to room temperature slowly. After stirring for a total of 18 hours, crushed ice (30 mls) was added, and the mixture was stirred at ambient temperature for 0.5 hour. The mixture was diluted with water (300 mls) and extracted twice with 1:1 diethylether/hexane. The extracts were washed twice with water and once with brine. The solution was dried (MgSO4), and the solvent was removed under vacuum to leave the title compound as an oil (B-4, 42.78 g, 100%). NMR (CDCl3, TMS)δ0.083, 0.099 (twos,6H,Si-CH3), 0.91 (s,9H,Si-tBu), 1.50-1.60(m, 1H), 1.8-2.0(m,5H), 2.8-3.0(m,2H), 3.19 (d,J=4.3 Hz, 1H), 3.48(m,5 lines, 1H), 3.65-3.85 (m,2H), 4.0-4.13 (m,1H), 6.86(t,J=7.6 Hz, 1H), 6.93 (br. d,J=7.6 Hz, 1H), 7.30 (br. d,J=7.5 Hz,1H). IR (Major peaks)3411, 3057, 1592, 1559, 1472, 1463, 1438, 1256, 1100, 1067, 835, 774. CI Mass spec. m+at m/z 399,401.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S:10]([CH2:15][C:16](O)=[O:17])[CH2:11][C:12]([OH:14])=[O:13].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:16](=[O:17])[CH2:15][S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(O)CSCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)CSCC(=O)O)cc1
Yield: 15.3 %

Procedure:
A solution of 4-aminobenzonitrile (500 mg, 4.23 mmol), 2,2′-thiodiacetic acid (3.18 g, 21.2 mmol), WSC (4.87 g, 25.4 mmol), DMAP (258 mg, 0.21 mmol) and DIEA (5.47 g, 42.3 mmol) in THF (200 mL) was stirred at room temperature for 60 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)thio)acetic acid (162 mg, 15.3%) as a pale-yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[C:6]=2[CH:24]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:19]1[N:18]=[C:17]([N:7]2[C:6]3[CH:24]=[C:2]([C:34]#[C:33][C:31]([C:28]4[CH:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: Nc1nccc(-n2c(OC3CCOCC3)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1cc(C)on1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OC4CCOCC4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A mixture of 4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.27 mmol, 70%), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) was stirred under nitrogen atmosphere for 5 hr at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to give 30 mg (24%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid. 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.28-7.07 (m, 1H), 7.08 (s, 2H), 6.99 (d, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 5.39-5.35 (m, 1H), 3.88-3.82 (m, 2H), 3.06-3.55 (m, 2H), 2.51 (s, 3H), 2.24-2.16 (m, 2H), 1.88-1.82 (m, 5H); LC-MS: m/z=+461 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[O:12]([CH2:19][CH:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.CCCCCC.CCOCC.CCCCCC>[O:12]([CH2:19][CH:20]([OH:21])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=CCOc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)C#CC(O)COc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
To 7.2 g of trimethylsilylacetylene dissolved in 110 ml of THF and cooled to -20° C. was added 46.2 ml of 1.55M n-butyl lithium in hexane. The mixture was allowed to come to room temperature for 15 minutes, recooled to -20° C., and treated dropwise with 5.3 g of phenoxyacetaldehyde (II) in THF. After the addition was complete, the reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was then poured into a mixture of ether:hexane (1:1) over 0.5N HCl and shaken. The organic layer was separated, washed 3 times with H2O, dried (Na2SO4), and evaporated to dryness. The residue was chromatographed on a column of silica gel that was eluted with 30% ethyl acetate in hexane to yield 3.8 g of 1-phenoxy-4-trimethylsilylbut-3-yn-2-ol (III).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccno2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccno2)c1

Procedure:
106 mg of 5-(3-methylphenyl)isoxazole, 119 mg of N-bromosuccinimide and 2 mg of benzoyl peroxide were dissolved in 10 ml of carbon tetrachloride, and the solution was refluxed for 3 hours with stirring. After cooling, the precipitate was separated by filtration, and concentrated under reduced pressure to give 5-(3-bromomethylphenyl)isoxazole as a pale yellow oily product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([F:32])[CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: Fc1cccc(CBr)c1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccc(F)c3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 25, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide, prepared as described in EXAMPLE 43, part A, and 3-fluorobenzyl bromide. The crude product is purified by column chromatography eluting with gradient of 40% EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as a white foam.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:43]=[CH:42][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:25][C:24]=3[O:40][CH3:41])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH2:69][CH:70]2[CH2:72][O:71]2)=[CH:64][CH:63]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:41][O:40][C:24]1[CH:25]=[C:26]([O:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:72][C@H:70]([OH:71])[CH2:69][O:68][C:65]3[CH:66]=[CH:67][C:62]([OH:61])=[CH:63][CH:64]=3)=[CH:43][CH:42]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: COc1cc(OCCCOc2ccccc2)ccc1CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 39.6 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[2-methoxy-4-(3-phenoxypropoxy)phenethyl]-1-piperidinecarboxamide formate (0.426 g, 0.718 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.29 g, 0.718 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.27 g, 0.284 mmol).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:11][C:12]1[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:14]([CH3:17])=[CH:15][N:16]=1)[CH3:10].C(OCC)(=O)C>CC#N.O.C(=O)([O-])[O-].[Na+].[Na+]>[Br:8][C:15]1[N:16]=[C:12]([O:11][CH2:9][CH3:10])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[C:14]=1[CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ncc(C)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOc1nc(Br)c(C)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of NBS (5.16 g, 29 mmol) in MeCN (60 mL) was added to a stirred solution of 2-ethoxy-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-imidazole (7.92 g, 29 mmol) in MeCN (115 mL) at such a rate that the internal temperature of the mixture did not exceed 25° C. (a RT cooling bath was used). After 0.5 h the mixture was diluted with water (50 mL) and saturated sodium carbonate (aq) (50 mL). Ethyl acetate (50 mL) was added. The mixture was stirred vigorously then the phases were separated. The organic phase was washed with saturated brine (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was taken into dichloromethane and filtered through a 25 g Si II SPE cartridge. The cartridge was washed with DCM and 10% EtOAc in DCM.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[NH3:10].O>C1(C)C=CC=CC=1>[C:5](=[O:6])([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])[NH2:10]
Reactant: N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)OCC(Cl)(Cl)Cl

Procedure:
Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein.
Reaction SMILES: CNC(C1C=C2C(=CC=1OCC)CN=C2N)=[O:4].Br[CH2:19][C:20]([C:22]1[CH:23]=[C:24]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH:25]=[C:26]([S:28]([F:33])([F:32])([F:31])([F:30])[F:29])[CH:27]=1)=[O:21]>>[F:37][C:36]([F:39])([F:38])[C:35]([OH:40])=[O:4].[NH2:34][C:24]1[CH:23]=[C:22]([C:20](=[O:21])[CH3:19])[CH:27]=[C:26]([S:28]([F:33])([F:29])([F:30])([F:31])[F:32])[CH:25]=1
Reactant: CCOc1cc2c(cc1C(=O)NC)C(N)=NC2
Reactant: O=C(CBr)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Product: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Product: O=C(O)C(F)(F)F
Yield: 72.1 %

Procedure:
N-Methyl-3-amino-6-ethoxy-1H-isoindole-5-carboxamide (30 mg, purchased from Chembiotek) was reacted with N-[3-(2-bromoacetyl)-5-pentafluorosulfanylphenyl]-2,2,2-trifluoroacetamide (50 mg) analogously to example 3b). 31 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:30]([O-:32])=[O:31])=[C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH2:27]C)=[O:25])[C:16]3=[O:29])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].S(=O)(=O)(O)O.CO>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:30]([O-:32])=[O:31])=[C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[N:17]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:16]3=[O:29])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:33]([F:35])([F:34])[F:36]
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-{5-[(2-chloro-α,α,α-trifluoro -p-tolyl)oxy]-2-nitrophenyl}tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (16.0 g, 0.030 mol) and sulfuric acid (1.60 mL, 0.030 mol) in methanol (240 mL, 5.92 mol) is refluxed overnight, treated with sulfuric acid (0.40 mL), refluxed for 90 minutes, treated with sulfuric acid (0.80 mL), refluxed for 90 minutes, treated with sulfuric acid (0.80 mL), refluxed for 1 hour, treated with sulfuric acid (0.80 mL), refluxed for 90 minutes, stirred at room temperature overnight, partially concentrated in vacuo and diluted with ether. The organic mixture is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a white solid, mp 166°-167° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:4]1[CH:3]=[C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:7]=[CH:6][N:5]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccccc1-c1ccnc(Cl)c1
Yield: 52.5 %

Procedure:
To a solution of 4-bromo-2-chloro-pyridine (1.0 g, 5.2 mmol) in DME/water 10:1 (15 mL) was added (2-methoxyphenyl)boronic acid (0.79 g, 5.2 mmol), Pd(PPh3)2Cl2 (240 mg, 0.34 mmol), and K2CO3 (1.8 g, 13.0 mmol). The mixture was heated with reflux for 6 hours. It was diluted with DCM, washed three times with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM/MeOH 100:0 to 90:10) to give the title compound A1 (0.6 g, 52%). MS (ES) C12H10ClNO requires: 219. found: 220 (M+H)+.