Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[CH2:16]([Sn](CCCC)(CCCC)C=CC)[CH2:17][CH2:18]C.[F-].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH:16]=[CH:17][CH3:18])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CC=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC=Cc1cc(C(=O)OC)c(N)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A solution of 0.5 g (1.8 mmol) of the above ester 0.9 g (2.7 mmol) of tributyl-propenyl-stannane, 0.18 g (0.18 mmol mmol) of (tetrakistriphenyl phosphine) palladium (0) in 25 mL of dioxane was degassed with nitrogen for 20 min then refluxed under nitrogen for 12 h. The reaction mixture was cooled, 20 mL of 2 M KF solution was added. The mixture was stirred for 20 min, extracted with ethyl acetate washed with water and brine. The residue was purified by column chromatography using 8:2 hexane and ethyl acetate to afford 0.35 g (77%) of the 2-amino-3-nitro-5-propenyl-benzoic acid methyl ester as a solid LCMS: 239 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]1[N:4]([CH:11]2[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]2)[CH2:3][CH2:2][S:17]1
Reactant: NCCCl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1C=CCCC1

Procedure:
Cyclohex-2-en-1-one was reduced according to Method B2b, Step 1 to afford cyclohex-2-en-1-ol. The alcohol was converted to the 3-bromo-1-cyclohexene according to Method B2b, Step 2. The halide was converted to N-(cyclohex-2-en-1-yl)-N-(2-hydroxyethyl)amine according to Method B2b, Step 3. The alcohol was reacted with SOCl2 according to Method B7a to afford N-(cyclohex-2-en-1-yl)-N-(2-chloroethyl)ammmonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to method C1a to afford 2-(2-methyl -4-nitrophenylimino)-3-(cyclohex-2-en-1-yl)-1,3-thiazolidine.
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH2:25])=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[C:27]=[O:28].O>CC(N(C)C)=O>[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH:25][C:27]([NH:26][C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[O:28])=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CN1CCN(c2ccc(N=C=O)cc2)CC1
Reactant: CC(C)(C)n1nc(N)c2cc(Sc3cc(F)cc(F)c3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(NC(=O)Nc3nn(C(C)(C)C)c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
0.048 g (1.19 mmol) of sodium hydride is added at 0° C. to 0.200 g (0.598 mmol) of 1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine dissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of 1-(4-isocyanatophenyl)-4-methylpiperazine is then added at 0° C. The mixture is left under stirring for 3 hours at room temperature. The reaction is treated by adding 20 ml of water drop by drop at 0° C. and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0.150 g (yield=45%) of 1-(1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea in the form of a light brown solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C([Li])CCC.[CH:18](N1CCOCC1)=[O:19].Cl>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:18]=[O:19]
Reactant: COc1ccc(F)c2c1OCC2
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of 665 mg of 4-fluoro-7-methoxy-2,3-dihydrobenzofuran and 740 mg of N,N,N′,N,N″-pentamethyldiethylenetriamine in 15 ml of THF there was added dropwise 1.66 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. The mixture was stirred at −74° C. for 1 hour, and then 500 μl of N-formylmorpholine was added. After further stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction mixture while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (321 mg) as an oil.
Reaction SMILES: [C:1]([N:4]([CH3:39])[C:5]1[N:10]=[CH:9][C:8]([N:11]([CH3:31])[C:12](=[O:30])[C:13]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)([CH3:15])[CH3:14])=[C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH:6]=1)(=[O:3])[CH3:2].F[C:41](F)(F)[C:42]1C=C(C(C)(C)C(N(C)C2C(C3C=CC=CC=3C)=CC(NC(C3CC3)=O)=NC=2)=O)C=C(C(F)(F)F)C=1>>[F:24][C:22]([F:25])([F:23])[C:20]1[CH:21]=[C:16]([C:13]([CH3:15])([CH3:14])[C:12]([N:11]([CH3:31])[C:8]2[C:7]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[CH:6][C:5]([N:4]([CH3:39])[C:1]([CH:2]3[CH2:42][CH2:41]3)=[O:3])=[N:10][CH:9]=2)=[O:30])[CH:17]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: Cc1ccccc1-c1cc(NC(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)N(C)c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Product: Cc1ccccc1-c1cc(N(C)C(=O)C2CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a white foam in comparable yield according to the procedure described above for the preparation of N-[6-(acetyl-methyl-amino)-4-o-tolyl-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide using cyclopropanecarboxylic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-yl)-amide instead of N-(6-acetylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide. MS m/e (%): 600 (M+Na+, 22), 578 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32]CC2C=CC=CC=2)=[C:28]([O:40]CC2C=CC=CC=2)[CH:27]=1)[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1.[Pd]>[OH:40][C:28]1[CH:27]=[C:26]([CH2:25][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([O:12][C@H:13]([CH3:24])[CH2:14][O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[O:11])[CH:31]=[CH:30][C:29]=1[OH:32]
Reactant: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of (1R)-1-methyl-2-phenylcarbonyloxyethyl (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (2.6 g, 4.85 mmol) in 40 mL of tetrahydrofuran was added 200 mg of 10% Pd—C pre-mixed with 10 mL of methanol under a nitrogen atmosphere. The resulting mixture was stirred under hydrogen at room temperature for 2 hrs. After filtration and washing with methanol, the filtrate was concentrated and chromatography of the residue (silica gel, 30% ethyl acetate in hexane) afforded 1.87 g (100%) of (1R)-1-Methyl-2-phenylcarbonyloxyethyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate. MS (ESI) m/z 460.20 (M+H)+ and 458.17 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)#[N:11].[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])#[N:11]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNCc1cccc(C#N)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
To a stirred solution of glycine-ter-butyl ester (5 g, 0.038 mol) in toluene (100 mL). was added 3-cyanobenzaldehyde (5 g, 0.0381 mol) under N2 and refluxed at 140° C. for 2 h. After complete evaporation of the toluene, the reaction mass was cooled to RT and dissolved in dry methanol. Sodium borohydride (2.17 g, 0.0571 mol) was added in portions at 0° C. After 12 h, the reaction mass was evaporated under vacuum, washed with water (100 mL), extracted in DCM (100 mL), dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a yellow liquid (8.1 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 7.71-7.72 (m, 2H), 7.63-7.65 (m, 1H), 7.53-7.55 (m, 1H), 5.40-5.41 (m, 1H), 4.53-4.54 (m, 2H), 3.17 (s, 2H), 1.39 (s, 9H).
Reaction SMILES: FC1C(OC(=O)CCC[CH2:13][CH2:14][N:15]2C(=O)C=CC2=O)=C(F)C(F)=C(F)C=1F.[C:27](=O)([O:35][C:36]1[CH:41]=CC=CN=1)[O:28][C:29]1[CH:34]=CC=CN=1>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][CH:27]([O:28][CH2:29][CH3:34])[O:35][CH2:36][CH3:41]
Reactant: O=C(CCCCCN1C(=O)C=CC1=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: CCOC(CCN)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 924 mg (3 mmol) of 6-maleimidocaproic acid pentafluorophenyl ester 1 (see Example 11) dissolved in dry methylene chloride (30 ml) was added 10 g (1 mmol) of alpha-amino-omega-carboxy-PEG (2) (MW 10,000, n=226) and 4-dimethylpyridine (402 mg, 3 mmol) dissolved in 50 ml of dry methylene chloride. The reaction mixture was stirred at room temperature for 2 h and the product precipitated in ether (100 ml). After cooling to 4° C. the crude amide of formula 3 was collected by filtration and precipitated twice from methylene chloride by addition of ether to give 9 g of compound 3 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=[CH:14][CH2:15][OH:16].O[C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1>>[CH3:30][C:23]([O:22][C:21]1[CH:20]=[CH:19][C:18]([O:16][CH2:15][CH:14]=[CH:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:32][CH:31]=1)([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: Cc1oc(-c2ccccc2)nc1C=CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC=Cc2nc(-c3ccccc3)oc2C)cc1

Procedure:
Synthesized from 3-(5-methyl-2-phenyloxazol-4-yl)-prop-2-en-1-ol and ethyl 2-(4-hydroxyphenoxy)-2-methylpropanoate (American Home Products, U.S. Pat. No. 3,795,691) via an analogous procedure to that reported for Example 2, Step A: 1H NMR (300 MHz, CDCl3) δ 7.95-7.99 (m, 2H), 7.36-7.43 (m, 3H), 6.80 (s, 4H), 6.61 (dt, 1H), 6.49 (d, 1H), 4.62 (d, 2H), 4.18 (q, 2H), 2.37 (s, 3H), 1.49 (s, 6H), 1.23 (t, 3H); MS (EI): 422 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].I[CH3:18]>CN(C)C=O>[CH3:18][N:1]1[C:9]2[C:8](=[O:10])[N:7]3[CH2:11][CH2:12][CH2:13][CH2:14][C:6]3=[N:5][C:4]=2[N:3]=[CH:2]1
Reactant: CI
Reactant: O=c1c2[nH]cnc2nc2n1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2nc3n(c(=O)c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60% sodium hydride was added to the suspension at 0° C. After 30 minutes, 0.433 ml (6.95 mmol) of iodomethane was added and the mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by filtration and recrystallized from isopropanoldiisopropyl ether to afford 0.700 g (54.3%) of Compound 25 as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH2:24][CH3:25])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[CH:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[NH2:22][C:17]1[N:18]=[C:19]([NH:21][C:31]2[CH:32]=[CH:33][C:28]([CH:26]=[O:27])=[CH:29][CH:30]=2)[CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[O:23][CH2:24][CH3:25])[CH:16]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCOc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Yield: 22 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-ethoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-formyl-phenylboronic acid provided the title compound (22% yield). 1H NMR (acetone-d6) δ1.36 (t, 3H, J=6.9 Hz, CH3), 4.11 (q, 2H, J=7.0 Hz, CH2), 5.51 (bs, 2H, NH2), 6.33 (d, 1H, J=1.1 Hz, Ar), 6.44 (d, 1H, J=1.0 Hz, Ar), 7.12 (d, 1H, J=8.5 Hz, Ar), 7.31-7.37 (m, 2H, Ar), 7.78 (d, 2H, J=8.8 Hz, Ar), 7.88-7.97 (m, 2H, Ar), 8.57 (s, 1H, NH), 9.84 (s, 1H, CH).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=[O:12])=[N:7][CH:8]=1.[CH3:16][CH:17](CC1C=CC(CO)=CC=1)C(O)=O>>[CH2:16]([CH:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][N:7]=1)[C:11]([OH:13])=[O:12])[CH3:17]
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Reactant: CCOC(=O)/C=C/c1ccc(CO)cn1
Product: CCC(Cc1ccc(CO)cn1)C(=O)O

Procedure:
The title compound was prepared from Intermediate E by the same methodology used to make Intermediate B.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:25]=[C:26]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:34]=2)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cccc(OCc3ccccc3)c2)n1
Product: c1ccc(COc2cccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)c2)cc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 48, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(3-benzyloxyphenyl)-4-chloromethyloxazole to give 2-(3-benzyloxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 112-113° C.
Reaction SMILES: C(OC([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7]1)=O)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17]([CH:9]1[CH:8]2[N:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]([CH2:13][CH2:6][CH2:7]2)[CH2:11][CH2:10]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C1CC2CCCC(C1)N2
Reactant: CCOC(=O)CBr
Solvent: CCO
Product: CCOC(=O)CN1C2CCCC1C(C(=O)OCC)CC2
Yield: 100 %

Procedure:
To a 250 mL round-bottomed flask equipped with a condenser and nitrogen inlet were added 5.59 g (28.36 mmol) ethyl-9-azabicyclo[3.3.1]nonane-3-carboxylate, 142 mL ethanol, and 9.47 g (56.72 mmol) ethyl bromoacetate. The reaction was refluxed 3 days, cooled, and evaporated. The residue was partitioned between methylene chloride and aqueous sodium hydroxide, and the organic layer was dried over sodium sulfate and evaporated. The residue was filtered through silica gel using ethyl acetate to afford an oil, 4,835 g (100% yield crude), as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])(=[O:10])[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CS(=O)Nc1ccc(Br)cc1
Product: CS(=O)(=Nc1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and pyrrolidine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.99 min; Mass spectrum (ESI+): m/z=303, 305 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][CH:3]=1.Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.Cl.O1CCOCC1>C(O)(C)C>[S:17]1[CH:18]=[CH:19][N:20]=[C:16]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:13][CH:14]=1
Reactant: Brc1nccs1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nccs2)cc1
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a suspension of tert-butyl 4-aminobenzoate (1.93 g, 10 mmol) and 2-bromothiazole (1.2 g, 7.3 mmol) in isopropanol (60 mL) was added 4 N HCl solution in 1,4-dioxane (0.5 mL, 2 mmol). The mixture was refluxed at 100° C. for 50 h, and then allowed to cool to room temperature. The mixture was concentrated to one third of the initial volume. The resulting precipitate was isolated by filtration to yield the first crop of the title compound as a brown solid (915 mg). The mother liquor was dried in vacuo. The obtained residue was dissolved in ethyl acetate (50 mL), washed with water (2×15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was triturated with isopropanol (8 mL) to yield the second crop of the title compound (341 mg) (total 1.25 g, 78% yield). HPLC/MS (Method D): retention time=0.57 min, [M+H]+=221.3.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]2[C:14](=O)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:4]2=[C:3]1[C:22]#[N:23].[OH-].[K+].CC(C)([OH:29])C.C(O)(=O)C>O>[C:8]1([C:6]2[NH:7][CH2:2][C:3]([C:22]([NH2:23])=[O:29])=[C:4]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[CH2:14][C:5]=23)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)O
Reactant: N#Cc1c2c(c(-c3ccccc3)[nH]c1=O)C(=O)c1ccccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)C1=C2C(=C(c3ccccc3)NC1)Cc1ccccc12

Procedure:
A mixture of 1 part of 3,9-dihydro-3,9-dioxo-1-phenyl-2H-indeno[2,1-c]pyridine-4-carbonitrile, 5 parts of potassium hydroxide, and 39 parts of 1,1-dimethylethanol is heated at the boiling point under reflux for 16 hours. The resultant mixture is diluted with 1000 parts of water, followed by sufficient acetic acid to neutralize the base present. The precipitate which forms is filtered off; consecutively washed with water, methanol, and 1,1'-oxybisethane; and dried in vacuo. The resultant yellow solid is crystallized from aqueous N,N-dimethylformamide to afford 3,9-dihydro-1-phenyl-2H-indeno[2,1-c]pyridine-4-carboxamide melting above 300°. The product has the formula ##STR19##
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][C:15](ON1C(=O)CCC1=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([O:14][C:15]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCBr
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: ClCCl
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
TEA (6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3×), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35]Cl)=[CH:28][CH:27]=1)[CH3:23].[BrH:38]>[I-].[K+].C(O)(=O)C>[BrH:38].[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)=[CH:28][CH:27]=1)[CH3:23]
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: Br
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(OCCCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 20 %

Procedure:
Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]piperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted using potassium iodide as catalyst to give the free base which was reacted with hydrogen bromide in glacial acetic acid. The oil was stripped to dryness and the solid obtained was recrystallized from isopropyl alcohol-diethyl ether to give the white salt in 20% yield, m.p. 142°-144° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[C:25]([Cl:31])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:10]2[CH2:11][CH2:12][N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3][CH2:4]3)[C:9]2=[O:13])=[C:25]([Cl:31])[CH:24]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (Preparation 24) (20 mg, 0.11 mmol) in 3 mL dry THF, add 0.165 mL of 2M LDA (1.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of 4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, brine, dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford 10.5 mg of the title compound: mass spectrum (m/z): 389 (M+1).