Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36][OH:37])([OH:35])[CH2:31][CH2:30]2)[C:9]=1[Br:38].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36][OH:37])([OH:35])[CH2:31][CH2:30]2)[C:9]=1[Br:38]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Yield: 39.3 %

Procedure:
4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol (385 mg, 0.510 mmol) was treated with a mixture of TFA/H2O (2/2 mL) at rt overnight. The reaction mixture was evaporated to dryness and purified by a reverse phase HPLC to afford 4-(7-amino-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol as a pale yellow solid (99 mg). HPLC-MS TR=3.27 min (isomer 1) and 3.32 min (isomer 2) (UV 254 nm, 10 min method); mass calculated for formula C24H24BrN5O2 493.1, observed LCMS m/z 494 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[C:14]([N:15]2[CH2:19][C@@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[F:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN1C(=O)N(c2cccnc2F)C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cccnc2F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.998 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-fluoro-3-iodopyridine (352 mg, 1.998 mmol) in 1,4-dioxane (20 ml) was added trans-N,N-dimethylcyclohexane-1,2-diamine (0.062 ml, 0.400 mmol), potassium phosphate (1272 mg, 5.99 mmol) and copper(I) iodide (38.0 mg, 0.200 mmol) and the reaction mixture was heated at reflux under argon overnight. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was partitioned between dichloromethane and water. The organic layer was separated and washed with water (˜50 ml) containing 0.880 ammonia solution (˜5 ml), then brine and passed through a hydrophobic frit and the organic layer was reduced under vacuum. The residue was purified by SP4 automated silica gel chromatography eluting with 10-80% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (405 mg, 67.3% yield). LC/MS [M+H]+=296. (ii) Trifluoroacetic acid (2 ml) was added to a solution of 1,1-dimethylethyl (4S)-1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (400 mg, 1.355 mmol) in dichloromethane (5 ml) and the solution was stirred at room temperature for 36 hours. The reaction mixture was reduced under vacuum and the residue was azeotroped with toluene and dried under heated vacuum to give 1-(2-fluoro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt (assume ˜1.35 mmol) which was used in the next step. LC/MS [M+H]+=240.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([NH:8][C:9]1[S:10][C:11]([Cl:20])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNc2nc(-c3ccccn3)cs2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Clc1sc(NCc2ccccc2)nc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-4-(pyridin-2-yl)thiazol-2-amine (60 mg, 0.23 mmol) in DMF (2 mL) was cooled to 0° C. and treated with N-chlorosuccinimide (33 mg, 0.25 mmol), and the reaction mixture was allowed to warm to room temperature. The solvent was evaporated, and the product was purified on reverse phase HPLC to produce N-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine. MS (Q1) 302.2 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2OCC(=O)O)CC1
Yield: 101 %

Procedure:
4-(2-Ethoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (21.4 g, 56.5 mmol) was set stirring in MeOH (150 mL). A solution of NaOH (4.5 g, 112.5 mmol) in water (150 mL) was added. After 3 h the mixture was acidified to pH 4 with 6 N HCl. MeOH was removed under reduced pressure and the aqueous layer extracted with EtOAc (2×150 mL). The organics were combined, dried (MgSO4) and evaporated to give 20 g (100%) of a brown solid. MS (electrospray): exact mass calculated for C18H26N2O5, 350.18. m/z found, 351.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: Sc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromothiophenol (10 g) in acetone (250 mL) was added potassium carbonate (14.6 g) and iodomethane (4.28 mL). The heterogenous mixture was refluxed for 4 hrs., cooled to room temperature, filtered, and concentrated under reduced pressure. Ether (200 mL) was added, and the mixture was filtered again and finally evaporated to dryness to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[NH2:3].O=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:4](=[O:7])[CH2:5][CH3:6])[N:3]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCC(=O)N(C)N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Yield: 48.4 %

Procedure:
A solution of N-methylpropionohydrazide (18.78 g, 183.9 mmol) and diethyl ketomalonate (56.1 mL, 368 mmol) in toluene (136 mL) was refluxed with a Dean-Stark trap for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10% EtOAc in hexanes) to afford 23 g (49%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Br:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Br:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Br:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Br:20]
Reactant: Nc1c(Br)cc(C(=CC(=O)O)c2ccc(F)cc2)cc1Br
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Br)cc(C(=CC(=O)N2CCOCC2)c2ccc(F)cc2)cc1Br

Procedure:
This compound was prepared from 4-amino-3,5-dibromo-β-(4'-fluorophenyl)-cinnamic acid (isomer ratio A:B=2.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C@@H:17]([NH:20][C:21]([C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]=3[CH:26]=[N:27][CH:28]=2)=[O:22])[CH2:18][CH3:19])[CH2:13][CH:12]1[C:39](=[O:41])[NH2:40])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:39]([CH:12]1[CH2:13][CH:14]([C@@H:17]([NH:20][C:21]([C:23]2[C:24]3[CH:31]=[N:30][N:29]([C:32]4[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=4)[C:25]=3[CH:26]=[N:27][CH:28]=2)=[O:22])[CH2:18][CH3:19])[CH2:15][CH2:16][NH:11]1)(=[O:41])[NH2:40]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCNC(C(N)=O)C1
Reaction time: 8 h

Procedure:
A solution of 2-carbamoyl-4-((S)-1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid benzyl ester (340 mg, 0.61 mmol) in MeOH (10 mL) was added to a flask containing 10% palladium on carbon (52 mg, 0.05 mmol) under nitrogen and then the mixture was placed under 1 atmosphere of hydrogen. The reaction was monitored by HPLC-MS indicating 50% conversion. After stirring overnight, the mixture was filtered, and concentrated. The reaction was re-subjected to the above condition for an additional 5 hours at which time the mixture was filtered through diatomaceous earth, rinsed with MeOH, filtered and concentrated. The crude material was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 uM 30×150 mm column, eluted with 15-85% acetonitrile in water, with 0.1% TFA). Fractions containing the desired product were concentrated in vacuo, made basic with a few drops of saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 95 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a stirred solution of 100 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone dissolved in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate, and 100 mg of 3-(trifluoromethyl)benzeneboronic acid. Then the mixture was stirred at 95° C. for 24 hours. The reaction mixture was purified according to a procedure similar to Step 4 of Example 22 to yield 35 mg of 5-{4-(aminosulfonyl)phenyl}2,2-dimethyl-4-{3-(trifluoromethyl)phenyl}-3(2H)-furanone. mp: 129-130° C. NMR: δ1.59 (s, 6H), 4.93 (br, s, 2H), 7.48 (m, 2H), 7.59 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.93 (d, J=9.0 Hz, 2H). IR (cm−1): 3343, 3265, 1691, 1593, 1329, 1262.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[O:10])[S:6][CH:7]=1.CN.ClC1C=C(C=CC=1Cl)[CH2:26][NH:27]C(NC1SC=C(CNC)N=1)=O>>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][NH:27][CH3:26])[N:4]=1)=[O:10]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)cs1
Reactant: CNCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Agent: CN
Product: CNCc1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
Prepared by reaction of Intermediate 4 with methylamine, following the procedure described for Intermediate 3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]1[N:16]([CH3:41])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[N:20]=[C:19]([N:30]1[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]1[CH2:39][CH3:40])[N:18]=2>CN(C=O)C>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([CH2:14][N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]4=[O:10])[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)CC3=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.1 %

Procedure:
To a solution 4-isopropylpiperazin-2-one (56 mg, 0.35 mmol) in DMF (3 mL) at 0° C. was added sodium hydride (18 mg, 0.45 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 30 min before the addition of a solution of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (200 mg, 0.44 mmol) in DMF (2 mL). The resulting mixture was stirred at r.t. for 72 h, then partitioned between DCM and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient acetonitrile 30-70%) affording 711 as a white solid (22 mg, 15%). LCMS: RT 2.43 min, [M+H]+518.2. 1H NMR (DMSO, 400 MHz): δ 8.01-8.01 (1 H, m), 7.63-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.83 (2 H, s), 4.26 (4 H, brd s), 3.77 (4 H, t, J=4.61 Hz), 3.74 (3 H, s), 3.31 (2 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.15 (2 H, s), 2.69-2.68 (3 H, m), 1.33 (3 H, t, J=7.44 Hz), 0.98 (6 H, d, J=6.50 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH:21](O)([CH3:23])[CH3:22].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:22][CH:21]([O:19][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid (3.1 g, 0.0108 mole), isopropanol (50 ml), benzene (50 ml), and concentrated sulfuric acid (5 ml) was refluxed under a Dean-Stark trap for 24 hrs. The reaction mixture was concentrated and the residue partitioned between 5% potassium hydroxide solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous portion extracted with ethyl acetate (2×25 ml). The organic layers were combined and washed with 5% potassium hydroxide (25 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo to give 2.0 g (56%) of a solid, mp 118°-120° C. Recrystallization from isopropyl ether gave 1.7 g of off-white needles, mp 117.5°-119° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:23]C)[CH:10]=3)[C:5]2=[O:25])[CH2:3][CH2:2]1.[C-]#N.[Na+].Cl>CS(C)=O.O>[CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:23])[CH:10]=3)[C:5]2=[O:25])[CH2:2][CH2:3]1
Reactant: COc1ccc2c(=O)n(C3CC3)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c(-c2cccc(F)c2)c2cc(O)ccc2c(=O)n1C1CC1
Temperature: 160 °C

Procedure:
A mixture of the methyl ether 61 (3 g, 9 mmol) and NaCN (3.5 g, 72 mmol) in DMSO was heated at 160° C. for 3 h. The mixture was cooled, diluted with water, acidified with concentrated HCl and then extracted with EtOAc. The combined organic extracts were basified with 1N NaOH and washed with EtOAc. The aqueous layer was acidified with concentrated HCl and then extracted with EtOAc. Drying with Na2SO4 and concentration in vacuo gave a residue was purified by crystallization from EtOAc/hexanes.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:13])=[O:9].[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)[CH3:28].C(O)(=O)C>CO>[NH2:5][C:6]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH2:20][CH2:21]1)=[O:13])=[O:9]
Reactant: Nc1ccc(Cl)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: CCOc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(Cl)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
Sodium cyanoborohydride (140 mmol) in methanol (0.4 mL) was added to a mixture of 4-[{N -(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (0.10 mmol), 4-ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL), and methanol (1.6 mL). The reaction mixture was stirred at 60° C. for 14 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted using 2 N NH3 in CH3OH (6 mL) and concentrated. Preparative TLC (SiO2, AcOEt/CH3OH 5:1) afforded 4-[{N-(2-amino-5-chlorobenzoyl)glycyl}aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compound No. 1429) and 1-(4-ethoxybenzyl)-4-[{N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl}aminomethyl]piperidine (Compound No. 1433).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[O:12][C:11]([CH3:21])([CH3:20])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:19][C:15]1[CH:14]=[C:13]2[C:18]([CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[CH:4]=3)[CH2:10][C:11]([CH3:21])([CH3:20])[O:12]2)=[CH:17][CH:16]=1
Reactant: ClCC1CO1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC3CO3)cc2O1

Procedure:
Reaction of 4-(3-Trifluoromethylphenyl)-2,2-dimethyl-7-chromanol with epichlorohydrin, by an analogous method to that described in Example 1, gave 7-(2,3-epoxypropoxy)-4-(3-trifluoromethylphenyl)-2,2-dimethylchroman. Reaction of this epoxide with methylamine, by an analogous method to that described in Example 2 gave 4-(3-trifluoromethyl-phenyl-7-(2-hydroxy-3-methylaminopropoxy)-2,2-dimethylchroman, (benzoate salt, m.p. 145°-157°).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[OH:33])=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:13][CH3:14]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([C@:15]12[CH2:23][CH2:22][C@@H:21]3[C@@H:24]4[C:29]([CH2:30][CH2:31][C@H:20]3[C@@H:19]1[CH2:18][CH2:17][C@@H:16]2[O:33][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:28][C:27](=[O:32])[CH2:26][CH2:25]4)[CH2:13][CH3:14]
Reactant: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Temperature: 0 °C

Procedure:
Add 3-phenylpropionyl chloride (2.9 g.) in benzene (10 cc.) to 13β-propyl-17β-hydroxy-gon-4-en-3-one (2.5 g.) in pyridine at -10°. Pour the mixture into ice water and extract with benzene-ether. Wash, dry and evaporate the extracts to a gum and purify by chromatography upon Florex. Recrystallize from ethyl acetate-hexane to obtain the title compound, m.p. 104°-108°. Ultraviolet absorption peak at 240 mμ (ε16,000); infrared absorption peaks at 5.76, 6.00 μ.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCCNCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.44 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 109° C., (yield 0.645 gm, 89.3%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2([CH2:25][OH:26])[CH2:24][CH2:23]2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: NC1(CO)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OCC1(Nc2nc(Cl)nc3c2SCC3)CC1
Temperature: 160 °C

Procedure:
1.4 g (II) are placed in 10 ml dioxane, then 3.6 ml diisopropylethylamine are added followed by 1 g 1-aminocyclopropanmethanol (cf. 2.2). The reaction mixture is heated to 160° C. until there is no further reaction, then cooled and evaporated down. The residue is treated with cyclohexane/ethyl acetate (4:1) in the ultrasound bath, the solid is suction filtered and dried. 1.24 g (III-2) are obtained in the form of a solid. Analytical HPLC-MS (method A): RT=1.01 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[O:24]1CCC[CH2:25]1>>[F:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]2[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:25](=[O:24])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1F
Reactant: C1CCOC1
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-methylphenyl)amino]-1-piperidinecarboxylate (D28) (0.88 mmol, 284 mg) in tetrahydrofuran (30 mL) was treated with N,N′-carbonyldiimidazole (0.88 mmol, 141 mg, 1 eq) under argon at room temperature and was stirred at room temperature overnight. The reaction mixture was then concentrated under vacuum and the residue dissolved in THF (5 ml) and stirred for 3 h then heated at 45° C. for 45 min, then N,N′-carbonyldiimidazole (0.44 mmol, 70 mg, 0.5 eq) was added and allowed to react for 40 min. The mixture was concentrated, partitioned between 10% Na2CO3 aqueous solution and ethyl acetate. Organics were dried on MgSO4, concentrated and chromatographed (EtOAc/pet ether) to give the title compound (0.68 mmol, 239 mg, 77% yield). M−H=348.3.