Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]([CH2:21][CH2:22][OH:23])([CH2:19][OH:20])[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(Cl)(Cl)Cl>[CH3:36][S:37]([O:20][CH2:19][C:17]1([CH2:21][CH2:22][O:23][S:37]([CH3:36])(=[O:39])=[O:38])[O:16][N:15]=[C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]3[CH:26]=[N:25][N:24]([CH2:27][CH3:28])[C:10]3=[N:11][CH:12]=2)[CH2:18]1)(=[O:39])=[O:38]
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CCO)C3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CCOS(C)(=O)=O)(COS(C)(=O)=O)C3)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl}ethanol (150 mg, 0.00038 mole) (example 11) was taken in a mixture of dichloromethane and chloroform (10 ml: 10 ml). At 0° C., triethylamine (0.153 g, 0.001513 mole) and methane sulphonyl chloride (0.173 g, 0.001513 mole) were added. The reaction mixture was stirred at 0° C. for about 2 h. The mixture was diluted with dichloromethane and washed with sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[N:14]=[N:15][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[C:11]=2[C:10](=[O:26])[CH2:9]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Yield: 10.6 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (2.0 g), 2-bromo-4′-chloroacetophenone (1.6 g), anhydrous potassium carbonate (1.8 g) and ethanol (50 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography. The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.2 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=O)[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>CCO.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH2:18][CH2:17][C:16](=[N:21][OH:22])[CH:15]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C=C(c2ccc(Sc3ccc(F)cc3)o2)CC1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-[5-(4-fluorophenylthio)-2-furyl]-2-cyclopentenone (5.9 g; 21.5 mM) in EtOH-pyridine (50 ml-12 ml) was added hydroxylamine hydrochloride (2.24 g; 32.3 mM) at room temperature. After stirring overnight, solvent was removed. To the residue was added 0.5N aqueous HCl (80 ml), and the whole was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with water (70 ml), brine (70 ml), dried over MgSO4, and concentrated in vacuo to give 6 g (yield 97%) of crude subtitle compound as a brown oil, which was used without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11]([CH2:18][OH:19])([CH2:13]CC(O)=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+].C[OH:25]>>[CH2:1]([C:8]1[CH2:12][C:11]([CH2:13][OH:25])([CH2:18][OH:19])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCC1(CO)CC(Cc2ccccc2)=NO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Product: OCC1(CO)CC(Cc2ccccc2)=NO1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 1 l flask, equipped with thermometer and mechanical stirrer, in a nitrogen atmosphere are added: 71.55 g (0.272 mol) of raw 3-benzyl-5-hydroxymethyl-5-carboxyethyl isoxazoline deriving from Example 3 and 553 ml of methanol. The solution is cooled to −10° C. and in the time period of 1 h are added: 10.29 g (0.272 mol) of NaBH4 granules (10–40 mesh). Once the addition is completed the temperature is increased up to room temperature and the solution is allowed to stir for 1 h 30′. Then are added 250 ml of a saturated ammonium chloride solution maintaining the temperature at approx. 20° C. The solvent is evaporated under vacuum (24 mbar at 25° C.). The residue is taken up with 150 ml of methylene chloride and the residue formed after evaporation is dissolved in a minimum quantity of water. The two phases obtained are separated and the aqueous one is retroextracted three times, each time with a volume of 100 ml, with methylene chloride. The organic phases are collected and dried with sodium sulphate. It is filtered and, after evaporation of the solvent, 59.85 g of a raw orange oil product are obtained. The raw product is crystallized in 150 ml of ethyl acetate and 140 ml of hexane. 39.91 g of 3-benzyl-5,5-bis(hydroxymethyl)isoxazoline as a pale yellow solid are obtained. Another 4.16 g of product are recovered from the mother liquors.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:14]1[N:15]=[C:16]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[C:34](=[O:35])[NH:33][CH2:32][CH2:31][N:30]3[CH2:36][CH3:37])=[CH:25][CH:24]=2)[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[F:38][C:39]1[C:44]([NH:45][C:46]([C:48]2[S:52][C:51]3[CH2:53][CH2:54][CH2:55][CH2:56][C:50]=3[CH:49]=2)=[O:47])=[C:43]([CH3:57])[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=1>O>[CH2:36]([N:30]1[CH2:31][CH2:32][NH:33][C:34](=[O:35])[CH:29]1[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:16]2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=[C:14]([C:42]3[C:43]([CH3:57])=[C:44]([NH:45][C:46]([C:48]4[S:52][C:51]5[CH2:53][CH2:54][CH2:55][CH2:56][C:50]=5[CH:49]=4)=[O:47])[C:39]([F:38])=[CH:40][CH:41]=3)[N:15]=2)=[CH:24][CH:25]=1)[CH3:37]
Reactant: CCN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2c(s1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1CCNC(=O)C1c1ccc(Nc2nc(-c3ccc(F)c(NC(=O)c4cc5c(s4)CCCC5)c3C)cn(C)c2=O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (13 mL), water (3 mL) and sodium carbonate (417 mg, 3.93 mmol). After bubbling nitrogen through the resulting mixture for 15 min, 34 (150 mg, 0.370 mmol), N-(6-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5,6,7-tetrahydro benzo[b]thiophene-2-carboxamide. (192 mg, 0.460 mmol and tetrakis(triphenyl phosphine)palladium(0) (75 mg, 0.065 mmol) were added, and the reaction mixture then heated at reflux for 5 h. After this time, the reaction mixture was cooled to room temperature, filtered and the filter cake washed with diethyl ether (10 mL). The resulting solid was dissolved in methylene chloride/methanol (10:1), absorbed onto silica gel and purified by flash chromatography to afford 35 in 41% yield (93 mg) as a yellow solid: mp 179-180° C.; 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 7.79 (d, 2H, J=8.5 Hz), 7.39 (m, 3H), 7.33 (m, 1H), 7.22 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.68 (s, 1H), 5.80 (d, 1H, J=3.5 Hz), 3.99 (s, 1H), 3.65 (s, 3H), 3.64 (m, 1H), 3.36 (m, 1H), 3.11 (m, 1H), 2.82 (t, 2H, J=6.0 Hz), 2.66 (t, 2H, J=6.0 Hz), 2.59 (m, 2H), 2.36 (s, 3H), 2.27 (m, 1H), 1.85 (m, 4H), 0.99 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 615.3 (M+H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([NH2:24])=[N:18][C:19]=3[Cl:23])[C:11](=[CH2:25])[C@@H:10]1[CH2:26][O:27][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:23][C:19]1[N:18]=[C:17]([NH2:24])[N:16]=[C:15]2[C:20]=1[N:21]=[CH:22][N:14]2[C@H:12]1[CH2:13][C@H:9]([OH:8])[C@@H:10]([CH2:26][OH:27])[C:11]1=[CH2:25]
Reactant: C=C1[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1n1cnc2c(Cl)nc(N)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1[C@H](CO)[C@@H](O)C[C@@H]1n1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
200 mg (0.38 mmol) Compound 24 was dissolved in 10 ml THF, to which 720 mg TBAF (tetrabutylammonium fluoride) (6 mmol) was added. The mixture was stirred at room temperature for 1 hour. TLC showed the dot of starting material disappeared. THF was evaporated off under reduced pressure. 40 ml EtOAc was added to the residue. The mixture was successively washed with 20 ml water and saturated NaCl solution, dried with anhydrous Na2SO4, and filtered. The filtrate was evaporated to dryness under reduced pressure, to afford 52 mg (47%) of title compound as light yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:7])[C:3]([O:5]C)=[O:4].[OH-].[K+].O>O1CCOCC1>[CH3:7][C:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)c1cccs1
Temperature: 0 °C
Yield: 97.7 %

Procedure:
A solution containing 17.5 g of methyl 2-methyl-2-(2-thienyl)propionate [prepared as described in step (i) above], 12.6 g of potassium hydroxide, 72 ml of water, and 168 ml of 1,4-dioxane was heated under reflux for 2 hours. At the end of this time, it was diluted with ice-water, and extracted twice with diethyl ether. The aqueous layer was adjusted to a weakly acidic pH, extracted three times with diethyl ether, washed with water and with a saturated aqueous solution of sodium chloride, in that order, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure to give 15.8 g of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:18][C:17]1[C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:34][CH2:35][N:30]([CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:31][CH2:32]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Product: O=C(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)N1CCN(Cc2ccccc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-benzyl-piperazine, yield 94%. White crystals; m.p. 111–113° C. (resolidifies) and 114–115° C.; HPLC-MS m/z=492 (M+H).
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([O:42]CC)=O)[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]>>[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([NH:7][CH3:6])=[O:42])[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)c(F)c1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)c(F)c1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(3,4-difluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 12).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl:12][S:13](O)(=[O:15])=[O:14].C(Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl.CCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: O=S(=O)(O)Cl
Reactant: CC#CCOc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of 0.146 g (1.0 mmol) of the but-2-ynyloxy-benzene in 0.3 mL of dichloromethane in an acetone/ice bath under N2 was dropwise added a solution of 0.073 mL (1.1 mmol) of chlorosulfonic acid in 0.3 mL of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 h. To the reaction was then dropwise added 0.113 mL (1.3 mmol) of oxalyl chloride, followed by 0.015 mL DMF. The reaction was heated to reflux for 2 h and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 0.130 g (53%) of the desired product as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 13 g of N-[4-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 250 ml of tetrahydrofuran is added dropwise with stirring under argon 59.14 ml of 1 molar lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature for 0.5 hours and refluxed for 5 hours. Ethyl acetate is added dropwise followed by water. The mixture is filtered and the cake washed with ether. The filtrate is evaporated to a residue which is purified by chromatography on silica gel with 2:1 chloroform:hexane to give the desired product.
Reaction SMILES: [C:1]([P:5]([CH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][CH:12]=1)[C:6](C)([CH3:8])[CH3:7])(C)([CH3:3])[CH3:2].[BH4-].[Na+]>CC(O)C>[CH:1]([P:5]([CH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)P(Cc1cccc(-c2ccccn2)n1)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)P(Cc1cccc(-c2ccccn2)n1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a suspension of complex 5 (77 mg, 0.1 mmol) in 2-propanol (10 ml) was added a fine powder of NaBH4 (9.5 mg, 0.25 mmol). The mixture was stirred at room temperature for 12 hrs and then filtered. The resulting yellow solid was washed with 2-propanol (3×1.5 mL) and then dissolved in benzene (10 mL) and the solution was filtered. The yellow filtrate was evaporated to dryness under vacuum, yielding complex 6′ as a yellow solid which was dried under vacuum overnight to give 61 mg (85% yield). 31P{1H} NMR (C6D6): 61.6 (d, JPP=29.2 Hz), 67.9 (t, JPP=29.2 Hz). 1H NMR (C6D6): −14.0 (q, 1H, JPH=28.0 Hz, Ru—H), −0.84 (br s, 4H, BH4), 0.91 (q, 6H, JPH=JHH=8.0 Hz, P(CH(CH3)2)2), 0.87 (m, 12H, JPH=JHH=8.0 Hz, P(CH(CH3)2)2), 1.18 (q, JPH=JHH=8.0 Hz, 6H, P(CH(CH3)2)2), 1.44 (m, 2H, P(CH(CH3)2)2), 1.77 (m, 2H, P(CH(CH3)2)2), 2.85 (dt, 2H, JHH=16.0 Hz, JPH=4.0 Hz, −CHHP), 3.92 (dt, 2H, JHH=16.0 Hz, JPH=4.0 Hz, —CHHP), 6.56 (d, 2H, JHH=8.0 Hz, pyridine-H3, 5), 6.79 (t, 1H, JHH=8.0 Hz, pyridine-H4), 7.01 (d, 3H, JHH=8.0 Hz, P(C6H5)3), 7.12 (t, 6H, JHH=8.0 Hz, P(C6H5)3), 8.18 (t, 6H, JHH=8.0 Hz, P(C6H5)3). 13C{1H} NMR (C6D6): 18.0 (s, P(CH(CH3)2)2), 18.5 (s, P(CH(CH3)2)2), 19.6 (s, P(CH(CH3)2)2), 20.8 (s, P(CH(CH3)2)2), 25.6 (t, JPC=8.0 Hz, P(CH(CH3)2)2), 26.4 (t, JPC=11.6 Hz, CH2P), 39.2 (t, JPC=6.0 Hz, P(CH(CH3)2)2), 118.4 (t, JPC=2.5 Hz, Py-C3,5), 127.1 (d, JPC=9.0 Hz, m-C6H5—P), 128.8 (s, p-C6H5—P), 134.2 (s, Py-C4), 135.7 (d, JPC=10.1 Hz, o-C6H5—P), 142.0 (d, JPC=36.2 Hz, ipso-C6H5—P), 163.7 (t, JPC=4.5 Hz, py-C2,6).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:3](=[O:2])[C:4]2[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC2CC2)cn1
Yield: 84 %

Procedure:
As described for example 168, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (90 mg, 0.26 mmol) was converted using cyclopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (81 mg, 84%) which was obtained as an off white solid. MS: m/e=367.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]1[C:15]([O:17]CC)=[O:16].[Li+].[OH-].O.C1COCC1>CO>[C:11]([O:10][C:8]([N:6]1[CH2:7][C@@H:3]([C:2]([F:21])([F:1])[F:20])[C@H:4]([C:15]([OH:17])=[O:16])[CH2:5]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](C(F)(F)F)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of trans-1-tert-butyl 3-ethyl 4-(trifluoromethyl)pyrrolidine-1,3-dicarboxylate (61.2 g, 0.19 mol), LiOH (39.9 g, 0.95 mol) in a mixed solvent of water (300 mL), THF (300 mL) and MeOH (150 mL) was stirred at rt overnight. The reaction mixture was concentrated in vacuum, then acidified with 1N HCl to pH=1, and extracted with EtOAc (three×300 mL). The combined organics were dried over Na2SO4 and concentrated to give the title compound (47 g, 87% yield) as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:2]1[C:3](=[O:9])[CH:4]2[CH2:7][CH2:8][CH:1]1[CH2:6][CH2:5]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C2CCC(CC2)N1Cc1ccccc1
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
Compound 2-azabicyclo[2.2.2]octan-3-one (1.1 g, 8.8 mmol) in THF (10 ml) was added to a stirred suspension of sodium hydride (0.42 g, 10.6 mmol, 60%) in THF (10 ml) at 0° C. and stirred for 15 min. Benzyl bromide (1.05 ml, 8.80 mmol) was added to the reaction mixture at 0° C. and stirred for 4 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude compound. The crude compound was triturated with n-pentane to afford 900 mg (47.6%) of 2-benzyl-2-aza-bicyclo[2.2.2]octan-3-one as solid.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.Cl[C:17]1C=CC=C(C)N=1>>[CH3:17][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)=[N:7][CH:2]=1
Reactant: Cc1cccc(Cl)n1
Reactant: Cc1cccc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1ccc(N2C[C@@H]3CCNC[C@@H]32)nc1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 40, substituting 2-chloro-5-methylpyridine for 2-chloro-6-methylpyridine in step A. MS (ESI) mass calcd. for C12H17N3, 203.2; m/z found, 204.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7])(O)=[O:2].[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:7])=[O:2])=[CH:33][CH:32]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)O)c2ccc(Cl)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)Nc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 84.3 %

Procedure:
Methyl 4-[3-[N-(3-carboxypropionyl)-N-(4-chlorophenyl)amino]propoxy]benzoate (1.6 g), p-chloroaniline (0.54 g), DCC (0.87 g) and 4-dimethylaminopyridine (47 mg) were dissolved in methylene chloride (40 ml), and the mixture was stirred at room temperature for 52 hours, and concentrated under reduced pressure. The residue was dissolved in a small amount of DMF, and filtered. To this filtrate were added water and ethyl acetate and it was separated into layers. The organic layer was washed with water 3 times and concentrated under reduced pressure. The oily product thus obtained was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/methanol [30:1 (v/v)], and then concentrated under reduced pressure. The residue was crushed in aqueous methanol and collected by filtration to give the subject product (1.70 g). mp. 128°-130° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([I:11])[CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[I:11][C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:8]=1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(I)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (280 mg, 0.8 mmol) was added to a mixture of methanol (4 mL) and 2M aqueous NaOH (2 mL). The mixture was stirred for 48 hours at room temperature, then neutralized by addition of 1M aqueous HCl. Solvent was removed under reduced pressure and the mixture was coevaporated twice with toluene to give crude 5-iodo-4′-methyl-biphenyl-3-carboxylic acid, which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:12][CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=1
Reactant: Clc1ccc2cccc(NCc3cccnc3)c2n1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: c1cncc(CNc2cccc3ccc(-c4cccnc4)nc23)c1
Yield: 75.4 %

Procedure:
A mixture of 2-chloro-N-(pyridin-3-ylmethyl)quinolin-8-amine (160 mg, 0.59 mmol), 3-pyridylboronic acid (111 mg, 0.9 mmol), PdCl2(dppf).CH2Cl2 complex (53 mg, 0.06 mmol), K2CO3 (248 mg, 1.8 mmol) and dioxane/H2O (5:1, 6 ml) was stirred at 80° C. for 3 h under N2. The reaction was filtered, concentrated and purified by prepTLC (4:1 pentane/ethyl acetate) to give 2-(pyridin-3-yl)-N-(pyridin-3-ylmethyl)quinolin-8-amine as a yellow solid (139 mg, yield 75%). MS (ESI) calcd for C20H16N4 (m/z): 312.14. found: 313 [M+1].