Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2ccc(-c3ccc(F)cc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 40.4 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 4-fluorobenzeneboronic acid (14 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (16.6 mg, 0.038 mmol, 40% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1H), 12.99 (br. s., 1H), 10.20 (t, J=5.56 Hz, 1H), 7.65-7.74 (m, 2H), 7.62 (d, J=8.08 Hz, 2H), 7.39 (d, J=8.34 Hz, 2H), 7.23-7.33 (m, 2H), 5.29 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.20 (sept, J=6.78 Hz, 1H), 1.22 (d, J=6.82 Hz, 6H). MS (ES+) m/e 440 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]#[N:18].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[CH3:16])=[CH:12][CH:13]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:22][N:23]([CH3:25])[CH3:24])#[N:18]
Reactant: CCOC(OCC)N(C)C
Reactant: CN(C)c1ccc(Nc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(Nc2ccc(N(C)C)cc2)c1C#N
Temperature: 30 °C

Procedure:
A suspension of 10 g (41.3 mmol) of 5-amino-4-cyano-3-(4-dimethylamino-phenylamino)-pyrazole [for preparation see: Arch.Pharm.(Weinheim) 326, 245 (1993)] in 8.75 ml (49.5 mmol) of N,N-dimethylformamide diethyl acetal (97%) and 200 ml of toluene is heated under reflux for 1 hour. The reaction mixture is then cooled to approx. 30° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 281-282° C. (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([O:29]C)=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([OH:29])=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCOC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of (S)-methyl 2-(1H-indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylate (110 mg, 0.27 mmol) in methanol (15 mL) and CHCl3 (5 mL) was added NaOH (32.4 mg, 0.81 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(1H-indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid as a yellow solid (81 mg, 76%).
Reaction SMILES: C([O:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:42])C1C=CC=CC=1.[H][H]>C(Cl)Cl.[Pd]>[OH:8][C:9]1[C:40]([CH3:41])=[CH:39][C:12]([CH2:13][C@@H:14]([CH2:18][C:19](=[O:38])[N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[CH3:42]
Reactant: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 2.41 g (4.23 mmol) (S)-2-(4-benzyloxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 300 mg 10% Pd/C in 50 mL DCM was hydrogenated at RT and 3447 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][Si:35]([CH3:40])([CH3:39])[CH2:36][CH2:37]O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:17]([C:18]([O:20][CH2:37][CH2:36][Si:35]([CH3:40])([CH3:39])[CH3:34])=[O:19])=[C:16]([F:21])[CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: C[Si](C)(C)CCO
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)OCC[Si](C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-(4,6-dimethoxypyrimidin-2-yl)oxy-2-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) were dissolved in 50 ml of tetrahydrofuran, and the mixture was refluxed under heating and stirring for one hour. After cooling the reaction solution, 2-(trimethylsilyl)ethanol (6.0 g) and potassium carbonate (1.5 g) were added thereto, and the mixture was refluxed under heating and stirring for one hour. The reaction solution was poured into ice water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was evaporated under reduced pressure. The residue thereby obtained was purified by silica gel column chromatography to obtain the above identified compound as a pale yellow oily substance (2.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[CH3:43])[NH2:39]>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:39][C:38]2[CH:40]=[CH:41][C:42]([CH3:43])=[C:36]([CH3:35])[CH:37]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(N)cc1C
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-3-nitro-benzoic acid (546 mg). EDCI (576 mg) and HOBt (405 mg) in DMF (8 mL) was added 3,4-dimethylaniline (363 mg) and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and exreacted with EtOAc. The organic phase was washed with water (2×) and was dried over sodium sulfate. The solvent was concentrated to approximately 10 mL and the resulting precipitate was filtered, washed with EtOAc and dried under reduced pressure to give 4-amino-N-(3,4-dimethyl-phenyl)-3-nitro-benzamide as a yellow solid, mp=192-195° C.; MS (m/z) 284 (M−1).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:36][C@H:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:46]([C:48]([OH:50])=O)[N:47]=3)[CH2:39][C@H:38]2[O:56][CH2:57][CH3:58])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]>CC(N(C)C)=O.ClCCl.C(OCC)(=O)C>[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:36][C@H:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][C:45]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:46]([C:48](=[O:50])[NH:3][CH2:1][CH3:2])[N:47]=3)[CH2:39][C@H:38]2[O:56][CH2:57][CH3:58])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]
Reactant: CCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCNC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1C(=O)OCC
Reaction time: 5 h
Yield: 81.3 %

Procedure:
Ethylamine (2.0 M solution in THF) (0.60 mL, 1.20 mmol), WSC hydrochloride (345 mg, 1.80 mmol) and 1-hydroxybenzotriazole (8 1 mg, 0.60 mmol) were added to a mixed solution of cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (300 mg, 0.60 mmol) in DMA/dichloromethane (6 mL/6 mL) at room temperature, followed by stirring for five hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with a 1 N aqueous hydrochloric acid solution and 5% saline. The organic layer was dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain 257 mg of the title compound as a white solid (81%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)C1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Agent: [Pt]
Solvent: CC#N
Product: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CCCCC1
Yield: 89.7 %

Procedure:
A suspension of 5% platinum on carbon (1.2 g) and ethyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanecarboxylate (11.7 g, 32.7 mmol) in acetonitrile (100 mL) was placed under hydrogen pressure (3 atm, 2.1×105 Pa) on a Parr apparatus for five hours and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide 9.60 g of ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexanecarboxylate as an orange oil that solidified upon standing.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH2+]1CCCCC1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][C:15]#[C:16][CH3:17].C(O)(=O)CC(O)=O.O>CS(C)=O.N1CCCCC1.C(O)(=O)C.CCOCC>[C:1]([OH:4])(=[O:3])[CH2:2]/[CH:17]=[CH:16]/[CH2:15][CH2:14][C:13]#[C:12][CH3:11]
Reactant: CC(=O)[O-]
Reactant: CC#CCCCC=O
Agent: C1CC[NH2+]CC1
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(=O)O
Product: CC#CCC/C=C/CC(=O)O
Yield: 44 %

Procedure:
At room temp., a piperidinium acetate solution, freshly prepared by mixing piperidine (35.0 μL, 0.354 mmol) and acetic acid (19.0 μL, 0.332 mmol) in dimethyl sulfoxide (1.00 mL), was injected into a stirred solution of the prepared hept-5-ynal (1.50 g, 13.6 mmol) and malonic acid (2.83 g, 27.2 mmol) in dimethyl sulfoxide (50 mL). After refluxing the reaction mixture for 4 h, water (10 mL) and ether (20 mL) were added at room temp., and the layers were separated. The aqueous layer was extracted with ether (3×25 mL), and the combined organic extracts were washed with water (25 mL), dried (Na2SO4), and concentrated under reduced pressure. Kugelrohr distillation at 149° C./14 mbar furnished (3E)-non-3-en-7-ynoic acid (902 mg, 44%) as colorless crystals (mp 43-45° C.).
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:12][C:13](=O)[CH2:14][CH2:15][CH:16]=[CH2:17])C1C=CC=CC=1.C1([SiH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC1C(B(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.C(OC(N1[C@@H](CCC=C)CC[C@H]1C(OCC1C=CC=CC=1)=O)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.C1COCC1>[C:23]([O:22][C:20]([N:19]1[C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C@@H:13]1[CH2:14][CH2:15][CH:16]=[CH2:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CCCC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C=CCC[C@H]1CC[C@@H](C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: [Al+3]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCC[C@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-5-oxo-non-8-enoic acid benzyl ester in DCM (5 mL) was added at −78° C. to a solution of triphenylsilane (496 mg, 1.90 mmol) and tris(pentafluorophenyl)borane (55 mg, 0.11 mmol) in DCM (5 mL), then after 30 min the cooling bath was removed and the reaction mixture was allowed to reach room temperature over 2 h. After cooling to −78° C. a solution of triphenylsilane (496 mg, 1.90 mmol) and tris(pentafluorophenyl)borane (55 mg, 0.11 mmol) in DCM (5 mL) was added to the reaction mixture, then after 30 min the cooling bath was removed. The reaction mixture was stirred at room temperature for 72 h, then treated with Et3N (1 mL), then after 20 min partitioned between sat. aq. ammonium chloride solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc3:1) afforded an inseparable mixture of (2S,5S)-5-but-3-enyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester and unspecified reagents. This mixture was dissolved in THF (2.5 mL) and added dropwise at 0° C. to a suspension of lithium aluminum hydride (65 mg, 1.71 mmol) in THF (2.5 mL), then after 20 min excess reagent was destroyed by addition of water (2 mL), EtOAc and 2 M aq. sodium hydroxide solution (1 mL). The reaction mixture was filtered through diatomaceous earth, the filtrate was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane/EtOAc 3:1) afforded the title compound (179 mg, 82%). Colourless oil, MS: 256.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[C@H:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][O:21][C:19]=4[CH:20]=3)[CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:4]=[C:3](F)[CH:2]=1.[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>CC(O)C>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[CH2:8]1[C@@H:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C@H:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][O:21][C:19]=3[CH:20]=2)[CH2:11][NH:10][CH2:9]1
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Temperature: 18 °C

Procedure:
A round bottomed flask was charged with a solution of paroxetine base (23.5 g) in toluene (50 ml), obtained directly from the base hydrolysis of the N-phenoxycarbonyl intermediate. The toluene was removed in vacuo to produce an oily residue. To this residue was added propan-2-ol (50 ml) and the mixture was warmed to ensure total dissolution of the paroxetine. The temperature of the solution was cooled to 18° C. and methanesulfonic acid (6.86 g) was added, then the solvents were removed at reduced pressure and replaced with fresh propan-2-ol (110 ml). The solution was heated to reflux temperature, cooled to 18° C., and seeded with crystalline paroxetine methanesulfonate. Crystallisation was induced with vigorous stirring and insonation, and the product collected by filtration, and dried over phosphorus pentoxide in a vacuum desiccator to produce paroxetine methanesulfonate as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].O.ClCCl>ClCCl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][CH2:17][C@@H:13]1[CH2:12][O:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][C:5]2[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of Example 18 (step 4) (0.8 g, 2.63 mmol) in dichloromethane (7.6 mL) was added triethylamine (0.78 mL, 5.60 mmol) and methyl 4-bromobutyrate (0.35 mL, 3.04 mmol). The resulting solution was stirred at 30° C. overnight. The reaction mixture was poured into water/dichloromethane (50 mL/50 mL). The crude residue was extracted into dichloromethane. The organic portion was washed with water (50 mL), washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.60 g, 57%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27]CC)=[O:26].[CH:30](/B(O)O)=[CH:31]\[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(COC)OC.[Li+].[OH-]>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.C(O)C>[C:15]1([O:14][CH2:13][CH2:12][CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:3]2[C:25]([OH:27])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1c(/C=C/c2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), (E)-styrylboronic acid (39 mg), and bis(triphenylphosphine)palladium(II) dichloride (8 mg) in 7:3:3 dimethoxyethane:ethanol:1N aqueous LiOH (2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes The mixture was quenched with 1NHCl and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15 (d, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 7.21 (m 1H), 6.87 (d, 1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccccc1O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccccc1CC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of the alcohol from Step A (218 mg, 0.82 mmol), tetradecyl bromide (170 μL, 0.9 mmol) and CSCO3 (532 mg, 1.63 mmol) in DMF (8 mL) was stirred for 16 hs at room temperature under argon. The mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an oil. Purification by chromatography (SiO2, 20% EtOAc in hexanes) gave the title compound as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[S:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].IC.[CH2:25](O)C>CN(C)C=O>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:25])=[N:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: Cc1ccnc2c1NC(=S)c1cccnc1N2C1CC1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a warm (40° C.) solution of 1.0 g (3.54 mmol) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione in 25 mL of dry dimethylformamide under argon was added 200 mg (4.43 mmol) of a 60% sodium hydride on mineral oil dispersion. The suspension was heated at 60° for 30 min., cooled to 40° C., and 0.3 mL (4.43 mmol) of iodomethane was added in one portion. After stirring the mixture for 1 hr at room temperature, ethanol was added dropwise until bubbling ceased. The mixture was then poured over 200 mL of water, and the product was extracted with 2×200 mL of ethyl ether. The combined organics were washed with 300 mL of water, dried (Na2SO4), and concentrated. The resulting reddish solid was flash chromatographed over silica gel (eluted with 83% methylene chloride/ethyl acetate) to give a yellow solid. Recrystallization from ethyl ether/petroleum ether gave 350 mg of the title compound, m.p. 173°-177° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[CH:33][CH:32]=1>O1CCOCC1>[F:25][C:22]([F:23])([F:24])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:38]([NH:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:39])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)([OH:30])[C:26]([F:29])([F:27])[F:28]
Reactant: Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 100 °C

Procedure:
Reaction 2: A mixture of 2-(4-((4-(4-aminophenyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.925 mmol, 400 mg) and phenyl pyridin-4-ylcarbamate (1.388 mmol, 297 mg) in dioxane was heated in a reactivial at 100° C. (heating block temperature) for 48 hours.