Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:14]2[C:15]([I:24])=[CH:16][N:17]=[C:13]2[CH:12]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cc(-c3ccccc3)cc3nccn23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Ic1cnc2cc(-c3ccccc3)cc(OCc3ccccc3)n12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(benzyloxy)-7-phenylimidazo[1,2-a]pyridine (Compound 11-1) (60 mg, 0.20 mmol) in acetonitrile (4 mL) was added N-iodosuccinimide (59 mg, 0.26 mmol) at room temperature. The reaction was stirred at room temperature for 12 h, diluted with ethyl acetate, and washed with 1N aqueous sodium hydroxide. The organic layer was separated, and the aqueous layer was back extracted one time with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 5-(benzyloxy)-3-iodo-7-phenylimidazo[1,2-a]pyridine. 1H NMR (500 MHz, CDCl3) δ 7.55-7.59 (m, 4H), 7.54 (s, 1H), 7.36-7.47 (m, 7H), 6.34 (s, 1H), 5.34 (s, 2H). LRMS (ESI) calculated for C20H16IN2O [M+H]+, 427.0; found 426.9.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[NH:11][CH2:10][CH2:9]2)([CH3:5])[CH:3]=[O:4].[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[C:19]=1[CH:20]=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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].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>[Br:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N:11]2[CH2:10][CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:2]([CH3:1])([CH3:5])[CH:3]=[O:4])[CH:7]=3)[C:12]2=[O:16])[C:19]=1[CH:20]=[O:21]
Reactant: CC(C)(C=O)c1ccc2c(c1)CCNC2=O
Reactant: O=Cc1c(Br)cccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C=O)c1ccc2c(c1)CCN(c1cccc(Br)c1C=O)C2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 73.3 %

Procedure:
2-Methyl-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-propionaldehyde (224 mg, 1.03 mmol), 2,6-Dibromo-benzaldehyde (1.09 g, 4 eq), xanthphos (27 mg, 0.03 eq) and cesium carbonate (470 mg, 1.4 eq) were taken up in dioxane (2 mL) and argon was bubbled through the mixture for 10 minutes, before adding bis(dibenzylideneacetone)palladium (18 mg, 0.03 eq). The resulting mixture was placed under an argon atmosphere and heated to 100° C. with stirring for 2.5 hours by which time all of the starting material had been consumed by TLC and LC/MS analysis. After cooling to room temperature, ethyl acetate (175 mL) and water (50 mL) were added and the layers were partitioned and separated. The ethyl acetate layer was washed with brine (1×50 mL) and then dried over magnesium sulfate, filtered and concentrated to give the crude product. Purification on silica gel eluting with a gradient ranging from 5% ethyl acetate to 40% ethyl acetate in hexanes gave the title compound as a light yellow powder (302 mg). MS (ESI) 400.0 (M+H)+.
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](O)=[O:78])[CH:74]([CH3:76])[CH3:75])[O:49][C:48]1([CH3:81])[CH3:80])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CN(C)C=O>[C:40]([O:44][C:45]([N:47]1[C@@H:51]([CH2:52][C@@H:53]([CH:69]([CH3:71])[CH3:70])[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=2)[C@H:50]([CH2:72][C@H:73]([C:77](=[O:78])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:74]([CH3:75])[CH3:76])[O:49][C:48]1([CH3:80])[CH3:81])=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(N)C(N)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:35])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1c[nH]c2ccccc12

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 106 mg (0.661 mmol) of indole-3-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR86## is obtained (92 mg, 33%) as oil. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.61, FD-MS: M+ =505,507; IR: 3450, 3260, 1770, 1635 cm-1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCCCCCC.[Br:18][C:19]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1cc(OC)ccc1Br
Agent: CCCCCCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(O)ccc1Br
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Aluminum chloride (11.0 g) was added to toluene (80 mL) at room temperature. 1-Dodecanethiol (33.5 g) was added at 0° C., and the mixture was stirred for 30 min. A solution of ethyl 2-bromo-5-methoxybenzoate (5.36 g) in toluene (40 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water in an ice bath, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.66 g) as a pale-yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[CH:6][C:5]=1[OH:14]
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(O)c(N)c1
Yield: 81.5 %

Procedure:
Commercially available 4-t-butyl phenol (30 g, 0.2 mole) is dissolved in 200 ml ethyl acetate in a 500 ml round bottom flask fitted with a mechanical stirrer, and cooled to 0° C. The mixture is treated with nitric acid (13 ml, in 13 ml water) dropwise over 10 minutes and then a catalytic amount of NaNO2. After 45 minutes the reaction is washed with excess 1N HCl and the organic layer is dried over MgSO4 and stripped to yield 37 g of 2-nitro-4-t-butyl phenol. This nitrophenol (37 g, 0.19 mole) is dissolved in 100 ml ethyl acetate and placed into a parr bottle with a teaspoon of 10% Pd/C. The mixture is placed on a hydrogenator under 50 psi hydrogen with agitation for one hour. The catalyst is filtered off through celite, and the ethyl acetate is stripped off under vacuum. The material crystallizes with the addition of about 200 ml heptane to give 25.6 g of the corresponding amine (2-amino-4-t-butyl phenol).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[F:23])=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:19]=[CH:20][CH:21]=[N:22]3)=[CH:16][CH:15]=[CH:14][C:13]=2[F:23])=[O:11])=[N:26][CH:27]=1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CN
Reactant: Clc1ccc(Br)nc1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-n2nccn2)[C@@H]1CNc1ccc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 429 [M+1]+.
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1>S1(CCCC1)(=O)=O>[Cl:13][C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:1])=[N:7][CH:8]=1
Reactant: [F-]
Reactant: Fc1cc(Cl)cnc1Cl
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(Cl)cnc1F
Temperature: 140 °C
Reaction time: 35 h
Yield: 88 %

Procedure:
A suspension of 64.6 g (1.1 mol) of potassium fluoride and 11.25 g (0.075 mol) of cesium-fluoride in 240 ml of sulfolane (1,1-dioxo-tetrahydrothiophene) is heated to 140° C. By reducing the pressure 50 ml of sulfolane are distilled off. To the suspension a solution of 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine in 20 ml of sulfolane is added. The reaction-mixture is then stirred for 35 hours at a temperature of 140°, cooled and poured into ice/water. The organic material is extracted with ether. The ethereal layer is washed with water dried over magnesium sulfate, filtered and evaporated to yield 48.7 g of a colourless oil (88% of the theory) which boils at 65°-66° at 133 mbar.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[NH:22][CH2:21]1)[C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:10][N:9]=1.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1.C(N(C(C)C)C(C)C)C>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C@H:20]1[CH2:24][C@@H:23]([CH2:25][CH3:26])[N:22]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)[CH2:21]1)[C:8]1[N:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[CH:12][N:13]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1ccc(C(F)(F)F)cn1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
A mixture of [3,5-bis(trifluoromethyl)benzyl]-((3S,5R)-5-ethyl-pyrrolidin-3-yl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amine (45 mg, 0.09 mmol), 2-chloro-5-trifluoromethyl-pyridine (50 mg, 0.27 mmol) and iPr2EtN (45 uL 0.27 mmol) in THF (1.5 mL) is stirred at 120° C. under microwave irradiation. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: hexane/EtOAc) to give (3,5-Bis-trifluoromethyl-benzyl)-[(3S,5R)-5-ethyl-1-(5-trifluoromethyl-pyridin-2-yl)-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine as a colorless oil (38 mg, 66%). ESI-MS m/z: 643 [M+1]+, Retention time 2.45 min (condition A).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:21][C:22](O)=[O:23]>>[CH3:25][C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:19])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 1B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.16 (s, 1H), 8.30 (dd, J=7.8, 1.3 Hz, 1H), 8.01 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 7.97 (ddd, J=8.1, 6.9, 1.3 Hz, 1H), 7.89 (ddd, J=7.9, 7.0, 1.5 Hz, 1H), 7.43-7.45 (m, 2H), 7.29-7.34 (m, 2H), 7.15-7.22 (m, 1H), 3.78-3.84 (m, 4H), 3.05-3.08 (m, 4H), 2.57 (s, 2H), 1.46 (s, 6H); MS (APCI) M/Z 407 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2O.C(Cl)(=O)C([Cl:18])=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][N:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]#[N:13]
Reactant: N#Cc1cnc2cnc(F)cc2c1O
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cnc2cnc(F)cc2c1Cl
Temperature: 0 °C
Yield: 92 %

Procedure:
To 10 g of 6-fluoro-4-hydroxy-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere in 150 mL of methylene chloride was added 24 mL of oxalyl chloride followed by 0.4 mL of N,N-dimethyl formamide. After two hours at reflux, an additional 5 mL of oxalyl chloride and 0.3 mL of N,N-dimethyl formamide was added. After an additional hour at reflux, the reaction was poured into ice-water and solid potassium carbonate was added carefully to a pH of about 8. The chloroform layer was washed with brine, dried with sodium sulfate, and stripped to give a crude product. This material was further purified by passing it through a plug of silica gel with chloroform and recrystallizing from a mixture of chloroform and hexanes to give 10 g (92%) of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 150-155° C.; mass spectrum (m/e): M+H2O-Cl 190.0.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:28]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:29])[CH2:26][CH2:25]1
Reactant: O=C=NC1CC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)NC3CC3)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 17 mg (0.20 mmol, 1.0 eq.) of cyclopropyl isocyanate were reacted according to General Method 4. Yield: 63 mg (80% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[Cl:21][CH2:22]I.C(=O)=O.CC(C)=O.C[Li]>CCOCC.C1COCC1>[Cl:21][CH2:22][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=2)[CH2:13][CH2:12]1)=[O:16]
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Reactant: ClCI
Agent: O=C=O
Agent: [Li]C
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C(=O)CCl)CC2)ccc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A dry 3-neck, 250-mL round bottom flask was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (3.0 g, 10.07 mmol), anhydrous THF (50.4 mL) and chloroiodomethane (0.878 mL, 12.09 mmol). The flask was fitted with a rubber septum and pressure-equalized dropping funnel topped with an inert gas inlet and placed under a nitrogen atmosphere. The mixture was cooled to −78° C. (CO2/acetone bath). Methyllithium (7.56 mL of a 1.6 M solution in Et2O, 12.09 mmol) was added dropwise to the mixture from the dropping funnel over 10 min. The mixture was stirred at −78° C. for 1 h and then quenched with saturated NH4Cl (10 mL) and warmed to RT. The mixture was adjusted to a pH=6 and extracted with Et2O (3×75 mL). The extract was washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using an 80 g silica gel cartridge and gradient elution from 20:1 Hex/EtOAc to 2:1 Hex/EtOAc. The fractions containing the product were pooled and concentrated on a rotary evaporator to give 2-chloro-1-(1-(4-chloro-3-methoxyphenyl)piperidin-4-yl)ethanone (1.3 g, 4.30 mmol, 43% yield) as a pale orange solid. LC/MS [M+H]+=302. 1H-NMR (400 MHz, CDCl3) δ ppm 7.19 (1 H, d, J=8.57 Hz), 6.50 (1 H, s), 6.44 (1 H, s), 4.18 (2 H, s), 3.87 (3 H, s), 3.62-3.71 (2 H, m), 2.75-2.86 (3 H, m), 1.97 (2 H, s), 1.84 (2 H, s).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[C:35]([OH:37])=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH:27]3[C:35]([OH:37])=[O:36])=[O:24])[CH:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)C1Cc2ccccc2N1C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
107 mg (0.31 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 65.0 mg (0.40 mmol) 2,3-dihydro-1H-indole-2-carboxylic acid, 107.0 mg (0.33 mmol) TBTU and 100 μL (0.71 mmol) triethylamine in 10 mL DMF were stirred overnight at RT. The mixture was evaporated down i. vac. and the residue was dissolved in 5 mL DMF. The purification was carried out by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:18][CH:17]=1)#[N:12].[OH-].[Na+]>O1CCCC1.C(OCC)C.O>[NH2:12][CH2:11][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:20][CH:21]=1
Reactant: N#CCCCc1ccc(CCCC#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCCc1ccc(CCCCN)cc1
Reaction time: 0.17 h
Yield: 101.5 %

Procedure:
To a solution of 2.01 g lithium aluminium hydride in 24 ml of tetrahydrofuran was added dropwise a solution of 7.04 g aluminium chloride in 36 ml of ethyl ether at a room temperature for 10 minutes, and after stirring for 10 minutes, a solution of 5.09 g 1,4-bis(3-cyanopropyl)benzene in 48 ml of tetrahydrofuran was added dropwise over 30 minutes, and the mixture was stirred for 5 hours. To the reaction mixture were successively added 2.0 ml of water, 15% sodium hydroxide aqueous solution and a solution of 6.34 g of sodium hydroxide in 6 ml of water. The mixture was stirred for 30 minutes, filtered to remove impurity and washed with tetrahydrofuran. The washed filtrate was concentrated under a reduced pressure, codistilled twice with tetrahydrofuran and twice with chloroform, and dried under a reduced pressure to obtain 5.36 g of 1,4-bis(4-aminobutyl)benzene as yellow liquid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[I:11][C:10]1[C:3]2[C:2]([NH:22][CH:20]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH3:21])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: Clc1ncnc2scc(I)c12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)Nc2ncnc3scc(I)c23)cc1
Yield: 50.1 %

Procedure:
A mixture of 4-chloro-5-iodothieno[2,3-d]pyrimidine (100 mg, 0.34 mmol) and 1-(4-methoxyphenyl)ethylamine (69 mg, 0.37 mmol) and triethylamine (87 μL, 0.9 mmol) in DMF (2.0 mL) was allowed to react for 15 hours at 25° C., then 3 hours at 50° C. The reaction mixture was filtered through a cotton plug and purified by HPLC (Gilson system; Phenomenex column: Luna 5μ C18(2), 150×21.20 mm, 5μ micro) with water/acetonitrile gradient. Appropriate fractions were pooled to provide 70 mg of tan solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8]1[O:11][CH:9]1[CH3:10]>C(O)(C)C>[OH:11][CH:9]([CH3:8])[CH2:10][S:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH:9]([OH:11])[CH3:10])=[N:5][N:6]=1
Reactant: CC1CO1
Reactant: Sc1nnc(S)s1
Solvent: CC(C)O
Product: CC(O)CSc1nnc(SCC(C)O)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole(276.21 grams, 1.84 moles) and isopropanol (400 ml) were charged into a reaction flask. Propylene oxide(222.8 grams, 3.84 moles) was added at a rate sufficient to maintain reflux condition. The mixture was refluxed for 15 minutes. The solvent was stripped off by using a rotary evaporator at approximately 20 mm Hg and 100° C. The product is characterized by infrared absorption bands at 3350, 2900, 1680, 1450, 1380, 1250, 1120, 1040, 930, 740, and 705 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([CH:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34](Cl)=[O:35])[CH3:32].O>C(Cl)Cl.C(OCC)(=O)C>[CH2:31]([CH:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1)=[O:35])[CH3:32]
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)c(OC)c1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCC(CC)C(=O)Nc1ccc2ccn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A stirred solution of methyl ester (B) (0.5 g) in methylene chloride (16 ml) was cooled to 0° C. and treated with triethylamine (0.34 ml) followed by 2-ethylhexanoyl chloride (0.31 ml). The resulting solution was stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and poured into cold water. The organic layer was washed sequentially with 10% v/v hydrochloric acid, water, and brine; dried (MgSO4) and evaporated. The residue was purified by flash chromatography on a 4×18 cm silica gel column using 35:65 v/v ethyl acetate:hexane as the eluent to give methyl 4-[6-(2-ethylhexanamido)indol-1-ylmethyl]-3-methoxybenzoate (C) (0.7 g; 99%) as a white solid; partial NMR: 0.9(t, 6H, 2CH3), 1.5(m, 9H).