Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[F:23][C:22]([F:24])([F:25])[CH:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[C:18]1[CH:19]=[CH:20][C:15]([NH:13][C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=[CH:11][N:10]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC(c1ccc(Nc2nccc(-c3ccccc3)n2)cc1)C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 4-phenylpyrimidin-2-amine (70 mg, 0.4 mmol), tert-butyl 1-(4-bromophenyl)-2,2,2-trifluoroethylcarbamate (160 mg, 0.45 mmol), Xantphos (20 mg, 0.03 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), Cs2CO3 (160 mg, 0.5 mmol) and DME (1.0 mL) was placed in a sealed tube and heated up to 100° C. in a microwave (Biotage, Model: Initiator) for 30 min. The reaction mixture was filtered through a pad of Celite, washed with ethyl acetate, and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel (ethyl acetate/hexanes) to give tert-butyl 2,2,2-trifluoro-1-(4-(4-phenylpyrimidin-2-ylamino)phenyl)ethylcarbamate. 1H NMR (CDCl3, 400 MHz) δ 8.41 (dd, 1H), 8.01-7.98 (m, 2H), 7.70 (d, 2H), 7.46-7.42 (m, 3H), 7.28 (d, 2H), 7.12 (d, 1H). MS (ESI) 445 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
Amine preparation: To a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (250 mg), in dry THF (15 mL), was added carbon tetrabromide (769 mg), and triphenyl phosphine (609 mg). The reaction mixture was stirred at room temperature for 24 h, and then the solvents were evaporated in vacuo to give a residue which was purified by flash chromatography to give 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (279 mg), as a colourless oil. To a solution of 4-bromomethyl-piperidine-1-carboxylic acid tent-butyl ester (240 mg), in dry DMF (5.0 mL), was added imidazole (129 mg). The reaction mixture was heated in a sealed reaction vial at 100° C. for 24 h, then cooled and the contents evaporated onto flash silica for purification. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: C(C([NH:7][C:8]1[C:13]([S:14][CH3:15])=[C:12]([CH3:16])[CH:11]=[CH:10][N:9]=1)=O)(C)(C)C>Cl.O>[NH2:7][C:8]1[C:13]([S:14][CH3:15])=[C:12]([CH3:16])[CH:11]=[CH:10][N:9]=1
Reactant: CSc1c(C)ccnc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: O
Product: CSc1c(C)ccnc1N
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 2-tert-butylcarbonylamino-3-methylthio-4-picoline (Step B, 260 mg) in 2 N HCl (5 mL) was heated at reflux for 10 hrs. after cooling to room temperature, the mixture was diluted with water and the aqueous layer was washed with ether. The combined organic layers were discarded and the aqueous layer was neutralized to pH=7 with saturated sodium carbonate. The aqueous layer then was extracted with ether, dried over sodium sulfate, and concentrated in vacuo to afford the title compound (150 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]1[NH:28][CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH2:32][C@H:24]12>>[CH2:23]1[N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27][CH2:26][N:25]2[CH2:29][CH2:30][CH2:31][CH2:32][C@H:24]12
Reactant: C1CCN2CCNC[C@H]2C1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN2CCCC[C@@H]2C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH:16]2[C:18](=[O:21])[C:19](=[O:20])[CH:13]1[CH:14]=[C:15]2[Br:22])=[O:11].B(F)(F)F.[CH3:27]COCC>ClCCl>[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH:16]2[C:15]([Br:22])=[CH:14][CH:13]1[C:19](=[O:20])[CH2:27][C:18]2=[O:21])=[O:11]
Reactant: CCOCC
Reactant: COC(=O)C1CC2C(=O)C(=O)C1C=C2Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)C1CC2C(=O)CC(=O)C1C=C2Br
Temperature: 20 °C
Reaction time: 4 h

Procedure:
4.2 ml of trimethylsilyl-diazomethane are added dropwise at a temperature of −10° C. to a solution of 1.91 g (7 mmol) of 5-bromo-7,8-dioxo-bicyclo[2.2.2]oct-5-ene-2-carboxylic acid methyl ester in 20 ml of dichloromethane and 0.089 ml (0.7 mmol) of boron trifluoride etherate. The cooling is removed and the reaction mixture is stirred for 4 hours at a temperature of 20° C. The reaction solution is then extracted with water, the organic phase is dried over sodium sulfate and concentrated by evaporation using a rotary evaporator, and the residue is purified by silica gel chromatography. An isomer of 8-bromo-2,4-dioxo-bicyclo[3.2.2]non-8-ene-6-carboxylic acid methyl ester is obtained.
Reaction SMILES: ClC1C=CC(CC2C(=O)OC(C)(C)OC2=O)=CC=1.ClC1C=CC(CC(C(O)=O)C(O)=O)=CC=1.[F:34][C:35]1[CH:51]=[CH:50][C:38]([CH2:39][CH:40]2[C:45](=[O:46])[O:44]C(C)(C)[O:42][C:41]2=[O:49])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:39][CH:40]([C:41]([OH:49])=[O:42])[C:45]([OH:46])=[O:44])=[CH:50][CH:51]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(F)cc2)C(=O)O1
Agent: CC1(C)OC(=O)C(Cc2ccc(Cl)cc2)C(=O)O1
Agent: O=C(O)C(Cc1ccc(Cl)cc1)C(=O)O
Product: O=C(O)C(Cc1ccc(F)cc1)C(=O)O

Procedure:
The title compound was prepared by substituting 5-(4-chlorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 3: step a) with 5-(4-fluorobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 4: step a) then following the procedure described for the preparation of 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b).
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11]>O.C1COCC1>[Cl:4][C:5]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCOc1ccc(OC)cc1Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
A solution of LiOH.H2O (0.67 g; 16 mmol) in water (20 mL) was added to a solution of ethyl 3-(2-chloro-4-methoxyphenoxy)propionate (1.90 g; 7.3 mmol; from step (i) above) in THF (10 mL). The reaction mixture was stirred at RT overnight, THF was evaporated and the water phase was washed with ether. The resultant solution was acidified with HCl (2M) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated yielding 0.90 g (54%) of the sub-title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)[CH2:22][CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH2:22][CH2:23][OH:24])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(NCCC2CCCCC2)cc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(Cc1ccc(NCCC2CCCCC2)cc1)OCCCO

Procedure:
A mixture of 2.25 g. of methyl 4-(2-cyclohexylethylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 4-(2-cyclohexylethylamino)phenylacetate.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[C:21]([F:24])([F:23])[F:22])[N:8]=1)=[O:5].P(Br)(Br)[Br:31]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Br:31][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:28][CH:27]=[CH:26][C:25]=3[F:29])=[N:8]2)=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:15]=1
Reactant: O=C(Nc1ccn(Cc2ccc(CO)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2ccc(CBr)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,6-difluoro-N-(1-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 44) (0.119 g, 0.289 mmol) in DCM (6.5 ml) in an ice-water bath under nitrogen was added phosphorus tribromide (0.027 ml, 0.289 mmol, Aldrich). The cloudy mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate aqueous (15 ml) and ice (15 ml). The biphasic mixture was diluted with DCM (25 ml). The phases were separated and the aqueous phase washed with DCM (20 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound a colourless gum (98 mg). LCMS: (System 4) MH+=475.9, tRET=3.06 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[N:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc2nc(-c3ccc(C(=O)O)cc3Cl)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Yield: 17.4 %

Procedure:
To a suspension of 3-chloro-4-(6-methoxyquinolin-2-yl)benzoic acid (150 mg, 0.479 mmol) in anhydrous CH2Cl2 (5 mL) was added AlCl3 (320 mg, 2.40 mmol). The reaction mixture was refluxed overnight. The mixture was quenched with saturated NH4Cl (10 mL) and the aqueous layer was extracted with CH2Cl2/MeOH (v/v=10:1, 30 mL×3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive) to give 3-chloro-4-(6-hydroxyquinolin-2-yl)benzoic acid (25 mg, yield 18%). 1H NMR (DMSO, 400 MHz): δ 10.20 (brs, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.10-8.00 (m, 2H), 7.95 (d, J=9.2 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.38 (dd, J=6.4, 2.8 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), MS (ESI): m/z 299.9 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:16]3[CH2:18][CH2:17]3)[CH:9]=[C:10]([C:11]([O:13]CC)=[O:12])[C:5]=2[CH:4]=[N:3]1.[OH-].[Na+]>C(O)C>[NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:16]3[CH2:17][CH2:18]3)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nn1ncc2c(C(=O)O)cc(C3CC3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.406 mmol) in ethanol (10 mL) was added sodium hydroxide (1 ml, 0.406 mmol), and the mixture stirred at room temperature for 2 h. The solvent was removed in vacuo, and the residue diluted with EtOAc (30 mL) and water (20 mL). The reaction mixture was acidified to pH 3 with citric acid. The phases were separated and the aq. phase extracted with EtOAc (4×20 mL). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 0.075 g (84%). LCMS E-S (M+H)=219.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.13 (m, 4 H), 2.27-2.45 (m, 1 H), 6.36 (s, 2 H), 7.60 (s, 1 H), 8.06 (s, 1 H), 13.81 (br. s., 1 H).
Reaction SMILES: C1(N2CCC([NH:9][C:10]([C:12]3[S:13][C:14]([S:20][C:21]4[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=4[Cl:28])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)=[O:11])C2)CC1.Cl.[N:30]1([C:39](=[NH:41])[NH2:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38]C=2N=N1>>[C:39]([N:30]1[CH2:34][CH2:35][CH:36]([NH:9][C:10]([C:12]2[S:13][C:14]([S:20][C:21]3[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=3[Cl:27])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)=[O:11])[CH2:37][CH2:38]1)(=[NH:41])[NH2:40]
Reactant: N=C(N)n1nnc2ccccc21
Reactant: O=C(NC1CCN(C2CC2)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: Cl
Product: N=C(N)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 236 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.43 mmol) from example 198 and 1H-benzo[d][1,2,3]triazole-1-carboximidamide HCl salt (0.17 g, 0.85 mmol) from example 236 step A. The titled product was afforded as a solid (15 mg, 7% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.72 (1H, m), 8.47 (1H, s), 7.37 (4H, m), 3.98 (1H, m), 3.83 (2H, m), 3.17 (2H, m), 1.86 (2H, m), 1.44 (2H, m). MS m/z: 475.11, 477.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[F:30][C:31]1([F:36])[CH2:34][CH:33]([OH:35])[CH2:32]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:33]2[CH2:34][C:31]([F:36])([F:30])[CH2:32]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:6]=2[N:7]=1
Reactant: OC1CC(F)(F)C1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(F)(F)C4)c23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A solution of 4-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 3,3-difluorocyclobutan-1-ol (1.1 equiv), and sodium tert-butoxide (1.2 equiv) in 1,4-dioxane (0.22 M) were combined in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed, and the mixture was stirred at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and purified using silica gel chromatography (0-50% ethyl acetate in hexane) to afford the title product (64.1% yield) as a clear oil. MS (ESI) m/z 523.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:19]C(=O)OCC4C=CC=CC=4)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1
Agent: [Pd]
Product: COc1cccc(-c2cccc3c2OC(CN)C3)c1
Yield: 61.7 %

Procedure:
Treatment of (−)-benzyl {[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (1.38 g, 3.54 mmol) with palladium on carbon (0.138 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.558 g (62%) of (−)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−32.14 (c 10.0 in methanol); mp 156-158° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.03; H, 6.22; N, 4.7.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][N:23]1[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
2-chloro-5-nitrobenzaldehyde (1.03 g, 5.39 mmol) was dissolved in dichloromethane (20 mL), and added with tert-butyl-piperazine-1-carboxylate (1 g, 5.39 mmol). The reaction solution was cooled to 0° C., and slowly added with NaBH(OAc)3 (1.6 g, 7.55 mmol), followed by stirring for 3 hours at room temperature. The reaction mixture was added with water, and subjected to extraction with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography (ethyl acetate:hexane=1:7 (v/v)) to obtain the title compound (1.9 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[C:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:25])[F:26])/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH3:23])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 100 °C
Yield: 45 %

Procedure:
To a stirred solution of (E)-ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added 11 N HCl (30 mL), and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform (CHCl3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure, and the crude compound was washed with n-hexane to afford the title compound as a white solid (0.7 g, 50%): mp 142-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H), 7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d, J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387.05 ([M−H]−); IR (thin film) 3448, 1701, 1109, 777 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:22][C:23]([O:25]CC)=[O:24])[N:15]=3)[N:11]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]([CH2:48][C:49]([O:51]CC)=[O:50])[CH2:42][C:43]([O:45]CC)=[O:44])[N:35]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>[OH-].[K+].CCO>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][N:41]([CH2:42][C:43]([OH:45])=[O:44])[CH2:48][C:49]([OH:51])=[O:50])[N:35]=3)[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:22][C:23]([OH:25])=[O:24])[CH2:28][C:29]([OH:31])=[O:30])[N:15]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1cccc(-c2cc(-c3cccc(N)c3)cc(-c3cccc(CN(CC(=O)OCC)CC(=O)OCC)n3)n2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(-c2cc(-c3cccc(CN(CC(=O)O)CC(=O)O)n3)nc(-c3cccc(CN(CC(=O)O)CC(=O)O)n3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The corresponding tetraester, 10c (0.10 g, 0.17 mmol) was dissolved in 5 ml 0.5M KOH-EtOH solution. After 2 hours stirring at room temperature, the ethanol was evaporated to dryness and water was added. The mixture was stirred at room temperature for 30 min whereafter the product was precipitated with 2M hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.CO[C:15]1C(OC)=C[C:18]2[NH:19][C:20](CCCNC)=N[C:17]=2[CH:16]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: CNCCCc1nc2cc(C(=O)OC)ccc2[nH]1

Procedure:
Prepared from 3,4-diamino-benzoic acid methyl ester (Eur. J. Med. Chem. 2004, 39(3), 291-298) in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:17][CH:16]=1>[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[O:17][CH:16]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[CH:19]=1
Reactant: Brc1coc(-c2ccccn2)c1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1coc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-bromo-5-(2-pyridyl)-furan with 2 equivalents of copper (I) iodide. The title compound (90 mg) was obtained as a pale yellow solid, m/z 342 (MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1.Cl.[C:36]([O:40][C:41](=[O:45])[CH2:42][CH2:43][NH2:44])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:44][CH2:43][CH2:42][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:45])=[O:32])=[CH:33][CH:34]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Solid HATU (4.5 g, 11.9 mmol) was added to a DMF solution (5 mL) of 4-bromobenzoic acid (2.0 g, 9.9 mmol), i-Pr2Net (5.3 mL, 14.0 mmol), and β-alanine tert-butyl ester hydrochloride (1.8 g, 9.9 mmol) and the resulting mixture was stirred at room temperature. After 3 days the resulting mixture was concentrated, diluted with EtOAc, washed with water, 1N KHSO4, water, saturated aqueous NaHCO3, and brine. The organic layer was dried (Na2SO4), concentrated to yield the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]([CH3:31])([CH2:18][N:19]1[N:23]=[C:22]2[C:24]([Cl:30])=[CH:25][C:26]([Cl:29])=[C:27]([Cl:28])[C:21]2=[N:20]1)[C:16]#[N:17]>C1COCC1>[C:16]([C:15]([NH:14][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)([CH3:31])[CH2:18][N:19]1[N:23]=[C:22]2[C:24]([Cl:30])=[CH:25][C:26]([Cl:29])=[C:27]([Cl:28])[C:21]2=[N:20]1)#[N:17]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-trifluoromethylbenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=476, RT=0.72 min.