Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1)[CH2:2][CH3:3].[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2/[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7](=[O:10])[S:8]/2)[CH2:18][CH2:17]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a solution of 4-(propylamino)-1,3-thiazol-2(5H)-one (450 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.06 g) in 2-propanol (10 mL) was added piperidinium acetate (413 mg). The reaction mixture was stirred at 75° C. for 4 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with diisopropyl ether to give the title compound (350 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1.O>[OH:4][CH2:3][C:2]([NH:1][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])([CH3:6])[CH3:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
Part A: To a solution of 4.47 g (50 mmol) of 2-amino-2-methyl-1-propanol in 20 mL of THF and 5 mL of water, was added 10 mL (72 mmol) of triethylamine. After cooling in an ice bath, 9.0 g (44 mmol) of 4-methoxybenzenesulfonyl chloride was slowly added over 10 minutes. After stirring at room temperature for 12 hours, the reaction was concentrated, ethyl acetate and water were added, the organic layer was separated and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated to afford 9.1 g of the desired N-(2-hydroxy-1,1-dimethylethyl)-4-methoxybenzenesulfonamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CCOC(C)=O.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>[C:25]([O:24][C:22]([NH:21][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[CH:35]=2)=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 95 °C
Reaction time: 19 h
Yield: 48.1 %

Procedure:
A suspension of give (R)-benzyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (2.00 g, 4.46 mmol), 3-chlorophenylboronic acid (1.046 g, 6.69 mmol), Pd(PPh3)4 (0.515 g, 0.446 mmol) and Na2CO3aq (4.46 ml, 8.92 mmol) in Toluene (30 ml) is allowed to stir under nitrogen at 95° C. for 19 hr. The reaction mixture is cooled to ambient temperature, and diluted with brine and EtOAc. The products are extracted twice with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by flash column chromatography on 90 g silica gel (eluent: heptane/EtOAc=100:0 to 65:35) to give (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (1.03 g); HPLC retention time=1.74 minutes (condition B); MS (ES+)=380.2 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 2.52 (A of ABX, Jab=15.9 Hz, Jax=5.8 Hz, 1H) 2.58 (B of ABX, Jab=15.9 Hz, Jbx=5.6 Hz, 1H) 2.81-2.98 (m, 2H) 4.19 (br s, 1H) 5.07 (br d, 1H) 5.12 (A of AB, J=12.3 Hz, 1H) 5.17 (A of AB, J=12.3 Hz, 1H) 7.20-7.22 (m, 2H) 7.28-7.39 (m, 7H) 7.42-7.47 (m, 3H) 7.53-7.54 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:19]([CH3:21])[CH3:20])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:19]([CH3:21])[CH3:20])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1oc(-c2ccc(F)cc2)nc1CC(=O)O
Yield: 83 %

Procedure:
2.0 g of ethyl 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetate, 15 ml of methanol, 5 ml of water and 0.8 g of potassium hydroxide are treated in the same manner as described in Example 8. 1.5 g of 2-[2-(4-fluorophenyl)-5-isopropyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH3:12])[CH:5]=O.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH2:31].C(OC)(OC)OC.[BH4-].[Na+].[Cl-].[NH4+:42]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:31]([CH2:14][C:13]2[NH:42][CH:9]=[CH:10][N:11]=2)[CH2:30][C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]([CH3:12])[CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20]
Reactant: [NH4+]
Reactant: CCCN(CCC)CCCCN(C)Cc1ccc(C=O)cc1Cl
Reactant: Cn1ccnc1CN
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound (124.0 mg) obtained in Example 77-5 was dissolved in methanol (1.5 ml). The reaction solution was added with the compound (45.2 mg) obtained in Example 14-7 and trimethyl orthoformate (0.2 ml) and the whole was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and added with sodium borohydride (27.8 mg) and the whole was stirred at room temperature for 10 minutes. The reaction solution was added with a saturated aqueous ammonium chloride solution and the whole was stirred at room temperature for 20 minutes. The reaction solution was added with distilled water and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the resultant was concentrated under reduced pressure and the resultant residue was dissolved in methanol (2 ml). The reaction solution was added with 2-imidazole carboxaldehyde (53.9 mg) and sodium cyanoborohydride (59.3 mg) and solution was adjusted to pH 5 with acetic acid. The whole was stirred at room temperature for 15 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After the drying agent was filtrated out, the resultant was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (42.3 mg) of the subject compound as a pale-pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[C:12](O)(=O)[CH2:13][OH:14].Cl.O.C>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:12]([CH2:13][OH:14])[NH:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)CO
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(CO)[nH]c2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
1,2-Diamino-4-nitrobenzene (5.00 g, 0.0326 mol), glycolic acid (3.72 g, 0.0490 mol), 4.00 M hydrogen chloride in water (13.1 mL, 0.0522 mol), water (13.1 mL, 0.725 mol), and activated charcoal (100 mg) were refluxed overnight. The reaction was cooled to room temperature, filtered and neutralized with aqueous ammonia. The product was filtered and dried in a vacuum desiccator overnight to obtain (6-nitro-1H-benzoimidazol-2-yl)-methanol as a brown solid (6.29 g, 100%). m.p.=157-162° C.; LCMS (m/e) 194 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 10.24 (bs, 1H), 8.39 (d, 1H, J=1.9 Hz), 8.09 (dd, 1H, J=1.9 and 8.8 Hz), 7.66 (d, 1H, J=8.8 Hz), 5.93 (bs, 1H), 4.77 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH:4]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:11][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](O[N:37]2N=[N:44][C:39]3C=CC=C[C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C>CN(C=O)C>[C:38]([CH2:39][NH:44][C:5](=[O:7])[CH:4]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:11][CH:12]=1)[CH2:3][CH:2]([CH3:1])[CH3:19])#[N:37]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)CC(C(=O)O)c1csc(-c2ccccc2)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)NCC#N)c1csc(-c2ccccc2)n1
Reaction time: 3 h
Yield: 76.7 %

Procedure:
A solution comprised of 4-methyl-2-(2-phenylthiazol-4-yl)pentanoic acid (150 mg, 0.6 mmol), prepared as in Example 5, in DMF (5.0 mL) was treated with PyBOP (300 mg, 0.7 mmol), aminoacetonitrile hydrochloride (100 mg, 1 mmol) and triethylamine (250 μL, 1.5 mmol). The mixture was stirred for 3 hours and then partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with 1 M saturated sodium bicarbonate solution, 1 M hydrochloric acid solution and water, dried (MgSO4) and concentrated. Product was purified from the residue by flash column on silica gel (60° A) with 40% ethyl acetate in hexane to provide N-cyanomethyl-4-methyl-2-(2-phenylthiazol-4-yl)pentanamide (120 mg, 0.46 mmol). Rf 0.30. 1H NMR (DMSO-d6): 1.01 (m, 6H), 1.31-1.59 (m, 3H), 3.91 (m, 1H), 4.14 (s, 2H), 7.44 (m, 4H), 7.81 (m, 2H), 8.61 (s, 1H). LCMS: 312.2.0 (M+H+).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:29])[CH2:27][CH3:28].C(N(C(C)C)CC)(C)C>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CCC(=O)Nc1ccc(Cl)cc1CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(=O)Nc1ccc(Cl)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 6.2 %

Procedure:
(Step 3) A solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.88 g), N-[2-(aminomethyl)-4-chlorophenyl]propanamide hydrochloride obtained in Step 2 (1.99 g) and diisopropylethylamine (4.1 ml) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was further purified by HPLC. The obtained residue was extracted with ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol, and 4N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration, and recrystallized from ethanol and ethyl acetate to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:33](Cl)(Cl)([Cl:35])[Cl:34]>C(#N)C>[Cl:34][C:33]([Cl:35])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccc(Cl)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)C(=C(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
A solution of 29.9 g (0.15 mol) of the keto ester of Example 2 in 300 ml of acetonitrile were treated with 117.9 g of PPh3 (0.45 mol), and 69.3 g (0.45 mol) of carbon tetrachloride were then added dropwise. After the reaction solution had remained at approximately 56° C. for 4 hours, it was concentrated; the residue obtained was chromatographed over silica gel with cyclohexane/MtBE (3:1). This gave 39.2 g of the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:16])[CH3:15])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
At −78° C. a 2.5 M solution of n-butyl lithium (18.6 mL, 46.4 mmol, 1.1 equiv) was added dropwise to 2,6-dibromopyridine (1) (10.0 g, 42.2 mmol, 1.0 equiv) in THF (780 mL). The solution was then stirred for 20 min at which point acetophenone (5.06 g, 44.3 mmol, 1.0 equiv) was added. The reaction was allowed to stir an additional 0.5 hr at −78° C., at this time the cooling bath was removed and the reaction allowed to warm room temperature. The reaction was stirred at room temperature for 1 hr and quenched with saturated sodium bicarbonate (250 mL). The layers were separated and the aqueous layer extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate and absorbed onto silica gel (30 g) by concentration under reduced pressure. This material was then purifies on a silica gel column (300 g) by eluting with heptanes (1 L), ethyl acetate (2%) in heptanes (2 L), ethyl acetate (5%) in heptanes (2 L) and finally ethyl acetate (10%) in heptanes (1 L). The desired product was isolated pure in 40% yield (4.7 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[N:13]=[C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)[NH:15][C:9]=2[CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C.O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[CH2:7][CH2:8][C:9]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)[NH:13][C:10]=2[CH2:11][CH2:12]1
Reactant: COCC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCN1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 53.9 %

Procedure:
0.09 g 2-Methoxy-1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone in 5 ml tetrahydrofurane were reacted with 0.2 ml lithiumaluminium hydride solution (1 M in tetrahydrofurane) over night at room temperature. 5 ml ethylacetate was added followed by 5 ml water at 0–5° C. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol 96:4 yielded 0.047 g (53%) 6-(2-methoxy-ethyl)-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine as yellow solid; MS (ISP): m/e=444 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>C(O)C.N1CCCCC1>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]#[N:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1ccccn1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C#N)c2ccccn2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4-dimethoxybenzaldehyde in 75 ml absolute ethanol are added 1.56 g (13.3 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 6 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 4:1. The yellow solid is recrystallized from acetone-hexane to give 2-(2-pyridyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 112°-14 114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C)C=O.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichloromethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted with water and extracted into ethyl acetate and concentrated to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC.O>CN(C)C=O>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][CH2:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:11]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Dimethylamine (2.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 8.9 g (83% yield) of N,N-dimethyl-3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[F:25].[Br:26]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:26][C:18]1[C:17]([F:25])=[C:16]([Cl:15])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)c(F)c1Br
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a cooled (−78° C.) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise n-BuLi (132 mL, 2.3 eq, 2.5 M). The mixture was stirred at −30° C. for 30 min. Again the reaction mixture was cooled to −78° C., and a solution of 4-chloro-3-fluorobenzoic acid (25 g, 143 mmol) in THF was added over 1 h. The reaction was stirred at −78° C. overnight. The next day a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added and the reaction was stirred at −78° C. for further 2 h and then rt for 4 h. The reaction mixture was quenched with H2O, organic layer was separated and aqueous layer washed with Et2O. Aqueous layer acidified with 1.5 N HCl and extracted in EtOAc (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford Intermediate 12A (30 g, 83.3%). MS (ESI) m/z: 252.6 (M−H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=[O:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>C1COCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:3][C:2]=1[CH:31]([OH:32])[C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:21]=[CH:22][CH:23]=[N:24]2
Reactant: O=Cc1ccc2nccnc2c1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(F)c(C(O)c2ccc3nccnc3c2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of N-(3-bromo-4-fluorophenyl)pivalamide (9.48 g, 34.6 mmol, 1.2 eq.) in THF (100 mL) cooled at −78° C. was added n-BuLi (27.6 mL, 69 mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at −78° C. for 1 h, then was added a solution of quinoxaline-6-carbaldehyde (4.5 g, 28.8 mmol, 1.0 eq.) in THF (200 mL) dropwise. The mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (100 mL ×3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford N-(4-fluoro-3-(hydroxy(quinoxalin-6-yl)methyl)phenyl)pivalamide as a yellow foam (5.16 g, 50.7%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4]1.O=S(Cl)[Cl:12].[CH3:14][CH2:15]O>>[ClH:12].[NH2:2][C@H:3]1[CH2:6][C@H:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])[CH2:4]1
Reactant: N[C@H]1C[C@H](C(=O)O)C1
Reactant: CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CCOC(=O)[C@H]1C[C@H](N)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of trans-3-aminocyclobutanecarboxylic acid hydrochloride (1.0 g, 6.5 mmol) in 20 mL of EtOH was added 10 mL of SOCl2 dropwise at 0° C. The resulting mixture was heated with stirring at 100° C. for 16 hours. And then, the solvent was evaporated to afford the residue which was used in the next step directly.