Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Br:2][CH:3]([CH2:13][C:14](Br)([Br:16])[Br:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl>C(O)C>[Br:2][CH:3]([CH:13]=[C:14]([Br:15])[Br:16])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Br)(Br)Br
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C)(C)C(Br)C=C(Br)Br
Reaction time: 2 h
Yield: 52 %

Procedure:
Two milliliters of an ethanolic solution containing 92 mg (4 mmoles) of sodium was added dropwise to a cold solution of 1.95 g (4 mmoles) of ethyl 4,6,6,6-tetrabromo-3,3-dimethylhexanoate in 10 ml of absolute ethanol. The cooled mixture was stirred for 2 hours, then poured into chilled 1N hydrochloric acid. The acidic mixture was extracted with diethyl ether, and the extract was washed successively with saturated aqueous sodium bicarbonate and sodium chloride. The washed extract was dried over magnesium sulfate and distilled to give 846 mg (52% yield) of ethyl 4,6,6-tribromo-3,3-dimethyl-5-hexenoate, b.p. 130°-133°/0.3 mm.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1>>[Cl-:12].[NH2:1][C:2]1[N:6]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:4]=2[N+:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1
Reactant: Cc1cccc2nc(N)[nH]c12
Reactant: ClCOc1cccc(Cl)c1
Product: Cc1cccc2c1[n+](COc1cccc(Cl)c1)c(N)n2COc1cccc(Cl)c1
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-4-methylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3-chlorophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1oc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (230 mg, 0.90 mmol) [prepared according to the procedure of Example 184], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (348 mg, 0.90 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (502 mg, 1.07 mmol) in chloroform (8.5 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 0.43 mmol, 48%): LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+]([O-])=O)=[CH:4][N:3]=1.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[NH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]1.[NH:3]1[CH2:11][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCOC1
Product: C1CCNCC1
Product: C1COCCN1

Procedure:
A solution of 2-chloro-5-nitropyridine (1.58 g, 10 mmol) and appropriate amine (20 mmol) in THF (60 mL) was heated for several hours at 60° C. The solvent was evaporated and water was then added to the reaction mixture. The product was isolated by filtration (piperidine, morpholine), or extracted from the water solution with ethyl acetate (1-methylpiperazine, 2-(2-hydroxyethylamino)ethanol)).
Reaction SMILES: [NH2:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:1][C:2]3([CH3:15])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.50 g of tert-butyl 4-amino-4-methylpiperidine-1-carboxylate, 0.38 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.13 mL of acetic acid were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 0.74 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes. The reaction mixture was added with 0.74 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes, and then the reaction mixture was stirred for 1 hour under reflux by heating. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.81 g of a light brown oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-methylpiperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH2:6][CH2:5]1)=[O:3].[CH3:17][O:18]C1C=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:17])[CH2:6][CH2:5]1)=[O:3]
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)Cl)CC1
Yield: 57 %

Procedure:
Compound 39A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(o-methoxyphenyl)piperazine (441 mg, 2.3 mmol); triphosgene (210 mg, 0.7 mmol); triethylamine (315 ml, 2.3 mmol); tetrahydrofuran (30 ml).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[C:19]3[C@@:9]4([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=5[NH:18]3)[CH2:10][CH2:11][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2.[H-].[Na+].[CH3:28]I.O>CN(C=O)C.CCOCC>[CH3:1][CH2:2][C:3]12[CH2:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[C:19]3[C:9]4([C:12]5[C:17]([N:18]3[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:10][CH2:11][N:7]([CH:8]14)[CH2:6][CH2:5][CH2:4]2
Reactant: CC[C@]12CCCN3CC[C@]4(C(=C(C(=O)OC)C1)Nc1ccccc14)[C@@H]32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCC12CCCN3CCC4(C(=C(C(=O)OC)C1)N(C)c1ccccc14)C32
Yield: 85 %

Procedure:
A solution of 34 mg (0.1 m mol) of ±vincadifformine in 1 ml of DMF was added at 20° C. to a mixture of 10 mg (0.2 m mol) of 50% NaH-mineral oil in 1 ml of DMF. After 20 min 20 μL (0.3 m mol) of methyl iodide was added to the brown solution. After 10 min 5 ml of water was added resulting in deposition of a gummy product. Decantation of the solvent, addition of ether, filtration of the ether solution through phase separating paper and concentration under vacuum gave 30 mg (85%) of minovine which showed no indolic NH singlet at δ 8.9 and the presence of the N-CH3 singlet at 3.24, integrating for 3 protons. A picrate was prepared with mp 194°-197° C., regeneration of the free base gave minovine, mp 119°-121° C., reported 120°-122° C.8MS (80eV) m/e (vel. intensity %): 124 (100), 168 (7), 228 (4) 267 (7), 352 (55) M+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13](F)[CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH2:16].[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29](O)=[O:30])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][C:29]([NH:16][CH:5]3[C:4]4[C:12](=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=4)[O:11][C:7]4([CH2:10][CH2:9][CH2:8]4)[CH2:6]3)=[O:30])=[CH:26][C:21]=2[O:20][CH:19]=[CH:18]1
Reactant: O=C(O)CCc1ccc2c(c1)OCCO2
Reactant: NC1CC2(CCC2)Oc2c(F)cc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc2c(c1)OC=CO2)NC1CC2(CCC2)Oc2ccc(F)cc21

Procedure:
The title compound was prepared from Intermediate 6 (200 mg, 0.963 mmol) and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid (187 mg, 0.963 mmol) in presence of EDCI.HCl (276 mg, 1.441 mmol), HOBt (221 mg, 1.441 mmol) and triethylamine (403 μl, 2.891 mmol) in dichloromethane (10 ml) as described in Example 1 to give 16 mg of the product as a white solid; IR (KBr) 3307, 2951, 1869, 1643, 1508, 1257, 1071, 817 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 1.13-1.23 (m, 1H), 1.66-1.78 (m, 3H), 2.04-2.13 (m, 3H), 2.18-2.27 (m, 2H), 2.42-2.49 (m, 1H), 2.72-2.79 (m, 2H), 4.17 (s, 4H), 5.01 (br s, 1H), 6.54 (d, J=11.1 Hz, 1H), 6.38-6.74 (m, 4H), 6.93 (t, J=8.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H); ESI-MS (m/z) 396.66 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH2:32][C:33]([CH3:36])([OH:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][CH2:32][C:33]([OH:35])([CH3:36])[CH3:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Reactant: CC(C)(O)CN
Product: Cc1cc(F)ccc1-c1nc(NCC(C)(C)O)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 79.3 %

Procedure:
Following the general procedure outlined in Example 225, the product of Example 121 (120 mg, 0.28 mmol) and 1-amino-2-methyl-2-propanol (76 mg, 0.85 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, afforded the desired product 96 mg (79%). LC-MS: 433.4 (MH+, m/z), 1.87 (Rt, min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
In a 3-neck 1 L round-bottom flask fitted with a condenser, nitrogen inlet, and 2 stoppers was added 2,6-dibromopyridine (15.3 g, 64.58 mmol), phenylboronic acid (7.87 g, 64.58 mmol), and potassium carbonate (17:85 g, 129.16 mmol) in 228 mL of dimethoxyethane and 150 mL of water. Nitrogen was bubbled directly into the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) was added (1.85 g, 1.60 mmol) and the reaction mixture was heated to reflux. The reaction was complete after 3 h of heating. It was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 2% ethyl acetate/hexanes followed by vacuum distillation using a Kugelrohr collecting product at 150° C. 5.2 g of product was obtained (34%)
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Br.[CH3:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][N:10]=[C:9]1[NH2:19].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:7][N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][N:10]=[C:9]1[NH:19][C:2]([O:4][CH3:5])=[O:3]
Reactant: COC(=O)Cl
Reactant: CN1C(N)=NCC1c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)NC1=NCC(c2ccccc2)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This example illustrates another process embodiment of the invention wherein an alkyl chloroformate is used as one of the reagents. In the example, 0.8 g. of methyl chloroformate is added over a five minute period to a stirring mixture of 2 g. 1-methyl-2-amino-5-phenyl-2-imidazoline hydrobromide, 1.4 g. sodium bicarbonate, and 20 ml. acetone held at 0° C. After addition is complete, the mixture is allowed to warm to room temperature and then stirred for 16 hours at room temperature. The mixture is distilled to a low volume and 50 ml. of water is then added. The mixture is filtered and the precipitate collected and washed with water and then dried affording 1-methyl-4,5-dihydro-5-phenyl-2-methoxycarbonylaminoimidazole which is then further purified by recrystallization from chloroform.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCc1ccccc1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)NCCCc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 3-phenylpropylamine to give N-(3-phenylpropyl)-7-methoxybenzofuran-2-carboxamide (Compound 239a). Successively, it was formylated to give N-(3-phenylpropyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 239b), then compound 239b was reacted with cyclobutylamine to give compound 239 as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:30]=[O:31]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
N,N-dimethylformamide (1.68 ml) was added dropwise slowly with phosphorus oxychloride (0.9 ml, 9.65 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.31 g, 8.77 mmol) in 10.5 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (5 ml) and stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (550 mg, 17.5%) as a red oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].[O:40]1[CH2:52][CH:41]1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>C(O)(C)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[C:7]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([NH:30][CH2:52][CH:41]([OH:40])[CH2:42][O:43][C:44]3[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=3[C:46]#[N:47])([CH3:29])[CH3:28])=[CH:21][CH:20]=2)=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)N)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(OCC(C)(C)NCC(O)COc3ccccc3C#N)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.4 g (10 mmol) of 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{2-[p-(2-amino-2-methylpropoxy)-phenoxy]-ethyl}-ester 5-methyl ester and 2.3 g (13 mmol) of 2-(2,3-epoxypropoxy)-benzonitrile in 30 ml of isopropanol is heated under reflux for 18 hours. After working up and chromatography analogously to Example 1, 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-pyridine-3,5-dicarboxylic acid 3-{{{2-{{p-{2-[3-(o-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropoxy}-phenoxy}}-ethyl}}}-ester 5-methyl ester is obtained in the form of an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=O)[O:18]C(C)(C)C)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17](=[O:18])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:24][CH:25]=2)=[O:10])=[CH:4][C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[NH2:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:4]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC(=O)c2ccccn2)cc1

Procedure:
75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Pd].CO>[CH:1]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)C2CCCC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(S(=O)(=O)C2CCCC2)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Intermediate 2 (13.1 g) was dissolved in acetic acid (150 ml) and hydrogenated over palladium on activated carbon (1.6 g) with stirring overnight. The mixture was filtered through Celite filter aid, and the filtrate was evaporated to give a yellow/green oil. The oil was taken up in methanol and an insoluble precipitate filtered off; the filtrate was evaporated in vacuo to give a yellow solid. Trituration with ether and filtration gave the title compound as a pale yellow solid (8.1 g).
Reaction SMILES: ClCCCCS(NCC(OC)C[O:13][C:14](=O)[NH:15][CH2:16]CCCCCCCCCCCCCCCCC)(=O)=O.[CH2:37]([S:53][CH2:54][CH:55]([OH:77])[CH2:56]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].C(SCC(OC)C[NH:98][S:99]([CH2:102][CH2:103][CH2:104][I:105])(=[O:101])=[O:100])CCCCCCCCCCCCCCC>>[CH2:37]([S:53][CH2:54][CH:55]([O:77][C:14](=[O:13])[NH:15][CH3:16])[CH2:56][NH:98][S:99]([CH2:102][CH2:103][CH2:104][I:105])(=[O:100])=[O:101])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC(=O)NC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-methylcarbamoyloxypropan III c1 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in the Table 8.
Reaction SMILES: Br.C1(C)C=C(C)C=C(C)C=1S([N:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH3:27])[CH3:14])(=O)=O.C1(O)C=CC=CC=1.C(Cl)[Cl:61]>>[ClH:61].[ClH:61].[ClH:61].[CH3:27][NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:13][CH3:14]
Reactant: ClCCl
Reactant: Cc1cc(C)c(S(=O)(=O)N(C)CCCCCN(CCCCCN(C)S(=O)(=O)c2c(C)cc(C)cc2C)S(=O)(=O)c2c(C)cc(C)cc2C)c(C)c1
Agent: Br
Solvent: Oc1ccccc1
Product: CNCCCCCNCCCCCNC
Product: Cl
Yield: 76 %

Procedure:
HBr (30% in HOAc, 30 mL), 55 (1.48 g, 1.94 mmol), and phenol (5.2 g, 55 mmol) in CH2Cl2 (30 mL) were reacted, and product was isolated by the method of 2 to produce 480 mg (76%) of 25 as needles: NMR (D2O) δ 1.4-1.5 (quintet, 4 H), 1.7-1.8 (quintet, 8 H), 2.7 (s, 6 H), 3.05 (t, 8 H, J=7). Anal. (C12H32Cl3N3) C, H, N.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][C:12](=[O:14])[CH3:13])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[CH3:15]I.[H-].[Na+]>CS(C)=O>[C:1]([C:3]1[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: CI
Reactant: CSc1ncc(C#N)c(NC(C)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(C#N)c(N(C)C(C)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide (562 mg, 2.70 mmol) and methyl iodide (1.7 mL, 27.0 mmol) in anhydrous DMSO (14 mL) was added NaH (60% wt. dispersion in mineral oil, 130 mg, 3.23 mmol) at 0° C. The reaction mixture was stirred at RT for 16 h and was then quenched by adding water (50 mL). The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >33% EtOAc/hexane in 5 min.) to afford 431 mg (72% yield) of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-N-methyl-acetamide as an off-white solid. MS=223 [M+1]+.