Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH3:17])[CH2:15][N:14]([CH2:23][C:24]2[CH:33]=[C:32]3[C:27]([C:28]([Cl:34])=[CH:29][CH:30]=[N:31]3)=[CH:26][CH:25]=2)[C:13](=[O:18])[C@@H:12]1[CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2cc(CBr)ccc12
Reactant: C[C@@H]1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 83 %

Procedure:
(2S, 6R)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (750 mg, 2.86 mmol) is dissolved in 20 mL of THF and 2 mL of DMF. Sodium hydride (60%, 142.6 mg, 6.20 mmol) is added at 0° C., and the reaction is left to stir at room temperature for thirty minutes at which time the 7-bromomethyl-4-chloro-quinoline (952 mg, 3.72 mmol) is added. The reaction is complete after stirring for four hours. Ethyl acetate (200 mL) is added to the mixture, and the reaction is quenched with 3 mL of H2O. The two layers are separated, and ethyl acetate (2×30 mL) is used to extract and dried over magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (60% EtOAc/Hexane) to give (2S,6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.04 g, 83%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N=C=N.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: Nc1ccccc1C(=O)O
Reactant: NC1CCCCC1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)NC1CCCCC1
Temperature: 40 °C

Procedure:
To a dry reaction vial was added cyclohexylamine (40 uμmol, 1.0 eq) and PS-carbodiimide resin (72 μmol, 1.8 eq). The solution of 2-amino-benzoic acid (44 μmol, 1.1 eq), diisopropyl ethyl amine (10 μLl) and HOBt (44 μmol, 1.1 eq) in THF (500 μL) was added to the above vial. The reaction mixture was heated at 40° C. for 6 h on a shaker. The resin was removed by filtration and washed with 10% MeOH/CH2Cl2. The solvent was removed in vacuo and the residue was applied to solid phase extraction cartridge (basic silica, 200 mg) and eluted with 50% EtOAc/CH2Cl2. After removal of the solvents, the crude 2-amino-N-cyclohexyl-benzamide was obtained and used for the following reaction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:35][O:36]C(=O)[C@@H](N1CC2C(=CC(C3C=CC(NC(NC4C=CC(OC)=CC=4)=O)=CC=3)=CC=2)C1=O)C(C)C>>[CH3:35][O:36][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)cc2C1=O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 86 %

Procedure:
The compound of example 26 was prepared analogous to compound of example 8 by hydrolysis of compound of example 27.
Reaction SMILES: C(SC1N=C(SCCC)C2N=NN([C@@H:14]3[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:25]([O:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:15]3[O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)C=2N=1)CC.[CH2:51]([S:54][C:55]1[N:56]=[C:57]([S:97][CH2:98][CH2:99][CH3:100])[C:58]2[C:59](=[N:61][N:62]([C@@H]3O[C@H](COC(=O)C4C=CC=CC=4)[C@@H](OC(=O)C4C=CC=CC=4)[C@H]3OC(=O)C3C=CC=CC=3)[N:63]=2)[N:60]=1)[CH2:52][CH3:53]>>[CH2:51]([S:54][C:55]1[N:56]=[C:57]([S:97][CH2:98][CH2:99][CH3:100])[C:58]2[N:63]([C@@H:14]3[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C@@H:25]([O:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:15]3[O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:62]=[N:61][C:59]=2[N:60]=1)[CH2:52][CH3:53]
Reactant: CCCSc1nc(SCCC)c2nnn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c2n1
Reactant: CCCSc1nc(SCCC)c2nn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)nc2n1
Product: CCCSc1nc(SCCC)c2c(nnn2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
Hydrogen bromide gas was bubbled into an ice-cooled solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2.02 g) in dichloromethane (15 ml) for 15 min. The reaction was stirred at 0° for 1 hour then at room temperature for 15 min. The solution was concentrated and the residue azeotroped with dichloromethane (3×50 ml). Sodium hydride (60%, 0.19 g) was added to a stirred suspension of the product of step b) (1.08 g) in acetonitrile (29 ml). After stirring at room temperature for 15 min the bromo sugar described above, in acetonitrile (10 ml), was added and stirring continued for 24 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was dried and concentrated. Chromatography (SiO2, dichloromethane:diethylether, 39:1, as eluant) gave a mixture of 5,7-bis(propylthio)-3-(2,3,5-tri-O-benzoyl-β-D-ribo-furanosyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine [MS (FAB): 714 (M+H+), 105 (100%)] and 5,7-bis(propylthio)-2-(2,3,5-tri-O-benzoyl-β-D-ribo-furanosyl)-2H-1,2,3-triazolo[4,5-d]pyrimidine [MS (FAB): 714 (M+H+), 105 (100%)] (1.9 g). Further elution gave 5,7-bis(propylthio)-1-(2,3,5-tri-O-benzoyl-β-D-ribo-furanosyl)-1H-1,2,3-triazolo[4,5-d]pyrimidine as a colourless foam (0.46 g).
Reaction SMILES: [I:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3C(OC(C)(C)C)=O)=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[I:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][NH:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H]1C[C@@H](c2nc3cc(I)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN[C@H](c2nc3cc(I)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a stirring solution of tert-butyl (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (3.70 g, 8.659 mmol) in dichloromethane (34 mL) is added TFA (17.22 mL, 223.5 mmol) and stirred at rt for 1 h. The reaction mixture is concentrated, azeotroped 2× with toluene and dried in vacuo. The residue is diluted with dichloromethane (200 mL), washed 2× with saturated sodium bicarbonate and brine and then dried over sodium sulfate. The organic is evaporated to give 5-iodo-2-[(2S,4S)-4-methylpyrrolidin-2-yl]-1H-benzimidazole (2.32 g, 82%).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([OH:16])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)CNc1ncc(C=O)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnc(NCC(=O)N[C@@H](Cc2ccccc2)C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of material from Example 10 (27 mg, 0.07 mmol) in CH2Cl2 (6 mL) is added trifluoroacetic acid (2.5 mL, 32.4 mmol). The resulting solution is stirred at room temperature for 1 h, then evaporated to dryness over 18 h to give the title compound as a TFA salt that is used crude, and in its entirety in the next step. LC/MS (Condition A): ret. T=2.45 min, (M+1-H)+ 334.08.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11].C(Br)C.[Mg].[C:19]([O:24][CH2:25][CH3:26])(=[O:23])[C:20]([O-])=[O:21]>O.C1COCC1>[CH2:13]([O:12][CH:10]([O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20](=[O:21])[C:19]([O:24][CH2:25][CH3:26])=[O:23])[CH3:11])[CH3:14]
Reactant: CCOC(C)OCc1ccccc1Br
Reactant: CCOC(=O)C(=O)[O-]
Agent: [Mg]
Solvent: CCBr
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1ccccc1COC(C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (3.11 g, 0.012 mol) and dry THF (10 ml) was added dropwise at 50° to 60° C. over 25 minutes to a solution prepared by adding dry THF (2 ml) and ethyl bromide (0.2 ml) to magnesium (0.44 g, 0.018 mol) in a stream of nitrogen. After completion of the addition, the mixture was stirred at 50° to 60° C. for 1 hour and cooled to room temperature. After cooling, the mixture was added dropwise to a mixed solution of ethyl oxalate (2.63 g, 0.018 mol) and dry THF (30 ml) at below -50° C. over 15 minutes. Then, the mixture was stirred at -50° to -60° C. for 1 hour. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate (2.30 g, Yield: 68.4%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(O)cc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(C)cc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-5-methylphenol (J. Org. Chem. 1996, 61, 6814): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.8 Hz), 8.15 (1H, d, J=2.6 Hz), 8.01 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.12 (1H, m), 6.97 (1H, m), 6.85 (1H, m), 5.36 (1H, m), 3.91 (3H, s), 2.38 (3H, s), 1.59 (3H, d, J=7.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:10]([NH:12][CH:13]1[C:30](=[O:31])[N:15]2[CH:16]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C:17]([CH3:21])([CH3:20])[S:18](=[O:19])[C@H:14]12)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:38]N1C(=O)CCC1=O>>[CH3:20][C:17](=[CH2:21])[CH:16]([N:15]1[C:30](=[O:31])[CH:13]([NH:12][C:10](=[O:11])[CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:14]1[S:18]([Cl:38])=[O:19])[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(C)S(=O)[C@H]12)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1S(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 2.85 g. (5 mmol) of 2,2,2-trichloroethyl 6-(α-t-butyloxycarbonylaminophenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide in 175 ml. of toluene was dried azeotropically by distillation of about 50 ml. of toluene from the mixture. To the dried solution was added 0.685 g. (5.5 mmol.) of N-chlorosuccinimide. The resulting mixture was refluxed for 70 minutes. The mixture was allowed to cool to room temperature and then was filtered and evaporated in vacuo to dryness to provide the title product (contaminated with succinimide).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C(COc1ccc(Br)nn1)N1CCCCC1
Reactant: OB(O)c1ccc(F)cc1
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: COCCOC
Product: O=C(COc1ccc(-c2ccc(F)cc2)nn1)N1CCCCC1

Procedure:
95 mg (0.326 mmol) of 2-(6-bromo-pyridazin-3-yloxy)-(1-piperidin-1-yl)-ethanone, 46.7 mg (0.334 mmol) 4-fluoro-phenylboronic acid, 11 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium and 0.5 ml of a 1 M aqueous sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried and evaporated, and the product was purified by RP18 chromatography. Yield: 73 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([CH3:8])[CH3:7])=[O:4].[OH:9][C:10]1[CH:21]=[CH:20][C:13]2[NH:14]C(=O)[O:16][C:17](=O)[C:12]=2[CH:11]=1>C(#N)C.ClCCl>[NH2:14][C:13]1[CH:20]=[CH:21][C:10]([OH:9])=[CH:11][C:12]=1[C:17]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([CH3:8])[CH3:7])=[O:16]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CC(C)NC(=O)CN
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (4.77 g, 41.1 mmol) in acetonitrile (50 mL) was added 6-hydroxy-1H-benzo[d][1,3]oxazine-2,4-dione (6.13 g, 34.2 mmol). The mixture was stirred for 16 h at room temperature during which time a very thick precipitate formed. The mixture was diluted with dichloromethane (100 mL) and the solid collected by filtration and washed with dichloromethane (2×20 mL) to afford 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE II.1) (6.75 g, 32.0 mmol, 78%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:20]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(OC(F)(F)F)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 4-(trifluoromethoxy)-benzaldehyde (776 uL, 4.38 mmol) in methylene chloride (30 mL) was added cis-2,6-dimethyl piperazine (1.0 g, 8.77 mmol). After 1 hour sodium triacetoxy borohydride (2.45 g, 8.77 mmol) was added to the mixture. The solution was stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate and extracted with 1N HCl (2×50 mL). The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4) and concentrated to provide cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine (1.01 g, 80%). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, 2H), 7.23 (d, 2H), 3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H), 1.69 (t, 2H), 1.05 (d, 6H); LCMS 289.5 (M+I)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:25]([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3ccccc23)CC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(Cc4ccccc4)C3)nc3ccccc23)CC1
Yield: 62.5 %

Procedure:
A mixture of t-butyl 4-(2-chloroquinazolin-4-yl)piperazine-1-carboxylate (30 g) synthesized in the same manner as in Example 1, (S)-1-benzyl-3-aminopyrrolidine (15 g), triethylamine (8.7 g), and isopropyl alcohol (43 mL) was heated to reflux for 40 h. The reaction mixture was concentrated under reduced pressure, then water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous magnesium sulfate, concentrated, and then purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=4:1) to obtain t-butyl 4-(2-((S)-1-benzylpyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (26 g).
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>>[CH2:14]1[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]3[S:1][C:2]4[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=4[CH:4]=3)=[CH:8][C:9]=2[O:15]1
Reactant: OC(c1ccc2c(c1)OCO2)c1cc2ccccc2s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2sc(Cc3ccc4c(c3)OCO4)cc2c1

Procedure:
2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene was prepared by the method of Example 47B using α-(2-benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol (6.2 mmoles, 1.8 g), triethylsilane (6.8 mmoles, 1.1 ml) CH2Cl2 (50 ml) and TFA (12.4 mmoles, 0.95 ml). Recrystallization from hexanes provided 1.2 g (73%) of a light orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([S:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[CH:14]1([S:11]([C:8]([C:6]2[CH:5]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[N:3]=[C:2]([C:34]3[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=3)[N:7]=2)([CH3:10])[CH3:9])(=[O:13])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (200 mg, 0.28 mmol) was added to 2-chloro-4-(2-cyclopentylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidine (1.66 g, 4.28 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.406 g, 6.42 mmol) and sodium carbonate (10 mL, 20.00 mmol) in a mixture of ethanol (5 mL), DMF (10 mL), water (7 mL) and DME (25 mL) at RT. The resulting mixture was degassed then stirred at 95° C. for 18 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate (200 mL) then washed with water (2×150 mL), and brine (150 mL). The organic layer was dried (Na2SO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 60% ethyl acetate in isohexane, and the residue obtained was triturated with a mixture of diethyl ether and isohexane to give the desired material as a pale pink solid (1.52 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])[CH3:4].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>O1CCCC1>[CH2:3]([N:5]([CH3:10])[C:6]([N:8]([CH3:9])[C:18]([NH:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19])=[O:7])[CH3:4]
Reactant: CCN(C)C(=O)NC
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C)C(=O)N(C)C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
In 300 ml of anhydrous tetrahydrofuran, 2.9 g (0.06 mole) of sodium hydride (50% in oil) was added thereto. The mixture was cooled below 10° C. and 7.0 g (0.06 mole) of 1-ethyl-1,3-dimethylurea was added to the mixture under stirring. The reaction was then continued at a room temperature for 15 hours. Next the reaction mixture was cooled below 0° C. and 7.1 g (0.06 mole) of phenyl isocyanate was added dropwise with stirring. The reaction was continued at about 0° C. for 3 hours, then the solvent was removed by distillation under reduced pressure to obtain a residue. Ice-water was added to the residue and 1 N-hydrochloric acid was added to make the mixture acidic, then extracted with chloroform. The extracted liquor was dried with anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure to obtain a residue. The residue was recrystallized from ethanol-petroleum ether to obtain 7.2 g (yield, 51%) of 1-ethyl-1,3-dimethyl-5-phenylbiuret having a melting point of 88.5°-90.5° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1B(O)O.C([O-])(O)=O.[Na+].[K+].[Br-]>C1(C)C=CC=CC=1.CCO.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>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[C:12]([F:11])=[CH:17][CH:16]=[CH:15][C:14]=2[F:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1c(F)cccc1F
Reactant: N#Cc1ccc(Br)cc1Cl
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: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(-c2c(F)cccc2F)cc1Cl
Reaction time: 5 h

Procedure:
In an oven-dried flask purged with argon, a solution of 4-bromo-2-chlorobenzonitrile (268 mg, 1.238 mmol), 2,6-difluorophenylboronic acid (293 mg, 1.857 mmol), Pd(PPh3)4 (143 mg, 0.124 mmol) in toluene (10 mL) and EtOH (10 mL), and saturated solution of NaHCO3 in water (1 mL) were refluxed while sterring for 5 h. The reaction mixture was poured into water and extracted 3 times with CH2Cl2. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude compound was then purified by flash cromatography (diethyl ether-hexanes) to provide EM-4977 (45 mg, 15%) as a white solid. IR (KBr): 3072, 2237, 1626, 1602, 1578, 1468, 1386, 1231, 1058, 996, 888, 844, 783, 730, 693, 622, 516 cm−1. 1H RMN (400 MHz, acetone d6) δ 7.23 (t, J=8 Hz, 2H), 7.60 (m, 1H), 7.73 (ddd, J=1.3, 1.4 & 8 Hz, 1H), 7.88 (d, J=1.3 Hz, 1H), 8.07 (d, J=8 Hz, 1H) ppm. 13C RMN (75 MHz, CDCl3) δ 112.06 (d, J=25 Hz), 112.14, 112.85, 115.83, 129.15, 130.80 (t, J=11 Hz), 131.73, 133.63, 135.40, 136.70, 159.63 (dd, J=7 & 250 Hz) ppm. GC/NCI/MS (m/e); 249 (M−, 100).