Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:45])[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(N1CCNCC1)N1CCOCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with morpholin-4-yl-piperazin-1-yl-methanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O4 [(M+H)+] 721.3031, observed 721.3031.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][O:7][CH2:8][CH2:9]Cl.[OH-].[Na+]>O>[CH3:6][O:7][CH2:8][CH2:9][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: COCCCl
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOC

Procedure:
A mixed solution prepared by mixing together 100 ml of diethylamine (Kanto Chemical Co., Inc.) and 85 ml of 2-methoxyethyl chloride (Kanto Chemical) was placed in an autoclave and reacted at 120° C. for 12 hours. The internal pressure during the reaction was 0.283 MPa (2.9 kgf/cm2). This yielded a mixture of deposited crystals and reaction solution to which was added, following the 12 hours of reaction, 200 ml of an aqueous solution prepared by dissolving 40 g of sodium hydroxide (Katayama Chemical Inc.) in 200 ml of water. Each of the two divided organic phases that formed as a result was separated off with a separatory funnel and subjected twice to extraction with 250 ml of tetrahydrofuran (Wako Pure Chemical Industries, Ltd.). The separated organic phases were then combined and washed with a saturated saline solution, following which potassium carbonate (Wako Pure Chemical Industries) was added to remove water and vacuum filtration was carried out. The solvent in the resulting organic phase was distilled off in a rotary evaporator, after which the residue was subjected to normal-pressure distillation, yielding 21 g of 2-methoxyethyldiethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[C@H:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg, 4.95 mmol) and the mixture was stirred for 30 min. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (40 g) with ethyl acetate/heptane 4:1 to give 760 mg of (2S)-2-([N-methyl-N{(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylic acid tert-butylester. The obtained product was taken up in 50% trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was liophilized to give 720 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7].C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:2][S:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][C:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[N:25][CH:24]=2)[N:19]=1)=[O:30]
Reactant: CSc1ccccc1CN
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1ccccc1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
To a stirring mixture of 2-methylsulfanylbenzylamine hydrochloride (81.7 mg, 0.431) in anhydrous DMF (1.0 mL) was added triethylamine (60.0 μL, 0.431 mmol). After 5 minutes, 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol) were added sequentially. The resulting mixture was allowed to stir at room temperature overnight. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a light brown solid (88.2 mg, 99%): m.p. 102-103° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[NH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>C1COCC1.CCOC(C)=O>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([Cl:20])=[CH:18][C:10]3[N:11]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C

Procedure:
To a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (5.37 g, 14.0 mmol) in THF (70 mL) was added DIPEA (3.67 mL, 21.0 mmol) followed by SEMCl (3.7 mL, 21.0 mmol). The reaction was maintained for 5 h at ambient temperature. Then the reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, followed by brine. The organic phase was dried over Na2SO4, filtered, and concentrated. Chromatography of the resulting residue over silica eluting with 5-25% EtOAc/hexanes afforded the desired product as a white solid. LC-MS: calculated for C14H20ClN2O3SSi 485.97, observed m/e 428.83 (M+H)+ (Rt 2.30 min).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(O[CH:23](OCC)[CH2:24][O:25][C:26]1[CH:27]=[C:28]([F:33])[C:29](F)=[N:30][CH:31]=1)C.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:33][C:28]1[C:29]([O:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][N:10]=[C:9]3[NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[N:30][CH:31]=[C:26]([O:25][CH2:24][CH2:23][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:27]=1
Reactant: CCOC(COc1cnc(F)c(F)c1)OCC
Reactant: C1CCNC1
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCCN5CCCC5)cc4F)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazoline-6-ol, 5-(2,2-diethoxyethoxy)-2,3-difluoropyridine and pyrrolidine, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (27 mg) was obtained as a pale yellow solid.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH:31]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)[CH2:32]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC(n2cncn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 130 %

Procedure:
858 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(1-1,2,4-triazolyl)-1-azetidinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were suspended in 1.7 ml of anisole, and 8.4 ml of trifluoroacetic acid and 0.27 ml of trifluoromethanesulfonic acid were added to the resulting suspension, whilst ice-cooling, after which the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was washed with hexane to remove anisole. The mixture was then mixed with diethyl ether to wash the mixture further. The resulting compound was mixed with 100 ml of ethyl acetate and with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The organic layer was then dried over anhydrous magnesium sulfate, and the residue was filtered and concentrated by evaporation under reduced pressure, to give 873 mg of the title compound, as a white powder.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:4]1=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:14]=1
Reactant: Clc1ccc2c(c1)OCc1ccccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
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: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccccc4COc4cc(Cl)ccc43)cc2[nH]1
Yield: 70.1 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3-chloro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 40 mg, 0.124 mmol) (prepared essentially as described in Preparation 55), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (31 mg, 0.118 mmol), Na2CO3 (2M in water, 148 □L, 0.295 mmol), dioxane (1 mL), and Pd(PPh3)4 (7 mg, 0.006 mmol). Purify the crude product on silica gel (12 g) eluting with 2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 31 mg (69%) of the title compound as a white solid. HPLC (ISO80-10) t=2.85min, 99%; MS [ES] 373 (M−H); 1H-NMR (DMSO-d6) 10.57 (s, 1H), 10.47 (s, 1H), 7.56 (dd, 2H, J=7.8, 6.1 Hz), 7.35 (t, 1H, J=7.5 Hz), 7.24 (t, 1H, J=7.7 Hz), 6.98 (m, 3H), 6.82 (d, 1H, J=4.4 Hz), 6.69 (m, 2H), 6.57 (s, 1H), 5.89-4.79 (br d, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:22]>CO>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:22])[N:11]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Reactant: N
Solvent: CO
Product: COc1ccc(N(C)c2nc(N)nc3ccccc23)cn1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10 mg, 0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to example 10 (3 mg, 30%). 1H NMR (CDCl3): 8.04 (dd, J=2.9, 0.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7 Hz, 1H), 6.92 (brd, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H), 3.96 (s, 3H), 3.54 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]1[O:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1)C1C=CC=CC=1.C[Si](I)(C)C.N#N.CO>C(#N)C.O>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]1[O:22][C:23]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[N:24][N:25]=1
Reactant: Cc1cccc(-c2nnc(-c3nc4ccc(C)cn4c(=O)c3OCc3ccccc3)o2)c1
Agent: C[Si](C)(C)I
Agent: N#N
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2nnc(-c3nc4ccc(C)cn4c(=O)c3O)o2)c1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of the product from Example 8.4 (20 mg, 0.047 mmol) in acetonitrile (5 mL), was added trimethylsilyl iodide (54 uL, 0.38 mmol) dropwise under N2 at room temperature. After 2 h, methanol (5 mL) was added and the solution was stirred for 10 min. Water (10 mL) was added and the reaction extracted with dichloromethane. The organic phase was washed with aqueous sodium bisulfite solution, dried (Na2SO4) and concentrated in vacuo to afford the desired compound (88.6%).
Reaction SMILES: [CH2:1]([C:3]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[CH:4]=1)[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=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.O>[CH2:1]([C:3]1[C:12]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[CH:29][CH:30]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[CH:4]=1)[CH3:2]
Reactant: Cn1ccc(-c2ccc(CBr)cc2)n1
Reactant: CCc1cc(O)c(C(=O)OC)cc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1cc(O)c(C(=O)OC)cc1Cc1ccc(-c2ccn(C)n2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of methyl 4-ethyl-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.41 g), 3-(4-(bromomethyl)phenyl)-1-methyl-1H-pyrazole (0.44 g), sodium carbonate (0.28 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g), DME (15.0 mL) and water (5.0 mL) was stirred overnight at 90° C. under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH:23]([F:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1.Cl[C:32]([O:34][CH3:35])=[O:33].[Cl-].[NH4+]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([C:23]([F:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:32]([O:34][CH3:35])=[O:33])[N:18]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(OC)nc(C(F)c2ccccc2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(F)(c1ccccc1)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexane, 1.7 ml) was added to diisopropylamine (0.59 ml) under nitrogen in dry tetrahydrofuran (15 ml) at -78° C. This solution was stirred for 30 minutes, then a solution of the product of stage (a) above (1.0 g) in tetrahydrofuran (10 ml) was added over 20 minutes. Methyl chloroformate (0.4 g) in dry tetrahydrofuran (10 ml) was added over 15 minutes at -78° C., and the reaction mixture was allowed to warm slowly to room temperature, after which it was added to aqueous ammonium chloride solution. The mixture was extracted with ether, the extracts being washed with water, dried over magnesium sulfate, and evaporated to dryness to give 1.08 g of the desired product, identical to that of Method A above.
Reaction SMILES: [F:1][C@H:2]1[C@@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)[C@H](F)C1
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (cis)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (Peak 1 of Example 94, Step 3D; 0.288 g, 1.14 mmol) was treated with 1.0 M KOtBu in THF (1.10 mL, 1.10 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added as a solid, followed by the addition of DMF (3.3 mL), and the resultant mixture was stirred at ambient temperature for 40 hours. The crude reaction mixture was chromatographed on SiO2 eluting with a gradient of (2% NH4OH in isopropanol)/methylene chloride. The desired product was isolated as a pale yellow solid (196 mg). MS APCI (+) m/z 498.2 (M+1) detected.
Reaction SMILES: C([Li:5])CCC.[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCCCCC.CCOCC>[C:13]1([N-:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[Li+:5]
Reactant: [Li]CCCC
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li+]
Product: c1ccc([N-]c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml Schlenk equipped with a 250 ml pressure equalizing dropping funnel is added 250 ml of diethyl ether which is chilled to -78° C. in an acetone/dry ice bath. To this is added n-butyl lithium, 0.10 mole of a 2.90 molar solution in hexane, followed by the addition of 16.923 g (0.10 mole) of diphenylamine dissolved in ether, 50 ml. The flask contents are stirred magnetically and maintained at -78° C. during the addition of diphenylamine which requires 0.5 hour. The contents are warmed to room temperature for 2 hours.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[CH:16]=[O:17])(=[O:3])[CH3:2].[BH4-].[Na+].O>C(Cl)Cl.CO>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:6][C:5]=1[CH2:16][OH:17])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C=O)[nH]c(-c2ccncc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1c(CO)[nH]c(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a stirred solution of 3-acetyl-2-formyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (84 mg, 0.37 mmol) in CH2Cl2 (2 mL) and methanol (2 mL) was added sodium borohydride (14 mg, 0.37 mmol) at 0° C. and stirred for 30 minutes at room temperature. The mixture was poured into water (15 mL) and extracted with ethyl acetate-ethanol (10:1, 20 mL×3). The combined organic layers were washed with brine, dried over MgSO4, and evaporated in vactio. Recrystallization from ethyl acetate provided the title compound (20 mg, 24% yield) as a solid.
Reaction SMILES: ClC1[C:7]([C:8](OCC)=[O:9])=C(C)N=C2N(CC)C=NC=12.[CH2:19]([N:23]1[C:27]2=[N:28][C:29]([CH3:38])=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31](Cl)=[C:26]2[N:25]=[CH:24]1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:23]1[C:27]2=[N:28][C:29]([CH3:38])=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:31]([O:9][CH2:8][CH3:7])=[C:26]2[N:25]=[CH:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Product: CCCCn1cnc2c(OCC)c(C(=O)OCC)c(C)nc21
Yield: 81 %

Procedure:
By replacing 7-chloro-3-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 1 e with 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, 3-butyl-7-ethoxy-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is obtained. Yield 81%, b.p. 200°-210°/0.01. An equivalent of aqueous sodium hydroxide is added to an ethanol solution of the ethyl ester and refluxed for 1 hour. The reaction mixture is then taken to dryness, the residue is suspended in water and HCl to pH 4 is added. The precipitated solid is filtered off to obtain the free carboxylic acid. The sodium salt is obtained by dissolving this product in one equivalent of aqueous sodium hydroxide and freeze drying.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:31]([NH2:33])=[O:32])[C:18]2[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:17]([C:31]([NH2:33])=[O:32])[C:18]2[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH2:14][CH2:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=CC(=O)OCC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CCC(=O)OCC)cc1

Procedure:
An amount of 0.60 gm (1.34 m mol) of ethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate was hydrogenated in 10 ml of ethanol on 0.20 gm of 10% palladium/charcoal at ambient temperature under 5 bar of hydrogen. The mixture was filtered and concentrated by evaporation in vacuo.