Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.C(N1CCOCC1)C.CP(OP(CC)(C)=O)(CC)=O.[C:28](NCC(O)=O)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>CN(C=O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH3:7]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCP(C)(=O)OP(C)(=O)CC
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
At 0° C., 7.0 g (0.05 mol) of H-Gly-OC2H5.HCl, 15 ml of N-ethyl morpholine and 20 g of methylethylphosphinic acid anhydride were added successively to a solution of 10.5 g (0.05 mol) of carbobenzoxy-glycine in 20 ml DMF, while stirring and cooling thoroughly. The mixture was brought to room temperature, while stirring. After 16 hours of standing at room temperature the solvent was distilled off in vacuo, and the residue was dissolved in a mixture of 200 ml of ethyl acetate and 100 ml of a 5% potassium bisulfate solution. The ethyl acetate solution was washed twice with 100 ml each of saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:24]=[O:25].CO>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[C:18]([NH:22][C:24]([NH:23][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH:19]=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCOCCCCc1cccc(N)c1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1cccc(CCCCOCCCCCCOC(C)=O)c1
Reaction time: 0.5 h

Procedure:
6-[4-(3-Aminophenyl)butoxy]hexyl acetate (2.84 g) in CH2Cl2 (30 ml) was treated with ethyl isocyanatoacetate (1.2 ml). After 0.75 h the mixture was treated with MeOH (2 ml) and stirred for 0.5 h. The mixture was concentrated, purified on a 10 g silica Bond Elut cartridge eluting with Et2O-petroleum ether(1:1) and then with Et2O to give the title compound (3.33 g) ES+ve 437 (MH)+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:13]1[C:17]([NH2:18])=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]>C(Cl)Cl.CO.CCN(CC)CC>[CH2:10]([N:13]1[C:17]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:16][N:15]=[N:14]1)[CH2:11][CH3:12]
Reactant: CCCn1nnnc1N
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCCn1nnnc1NC(=O)c1ccccc1
Yield: 54 %

Procedure:
Employing 0.25 g (2.1 mmol) of benzoic acid and 0.26 g (2.1 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above for Compound F2 and elution with CH2Cl2/MeOH/Et3N (9.8:0.1:0.1) gave the product in 54% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O.Cl.CO>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[C:7]2/[O:8][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]/2=[O:9])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(/C=C2/Oc3cc(O)ccc3C2=O)cc1OC
Reaction time: 18 h
Yield: 41.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,4dimethoxybenzaldehyde 1.23 g were dissolved in acetic acid 20 ml, concentrated hydrochloric acid 1.1 ml was added, and the mixture was stirred for 18 hours, and methanol 15 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.82 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@@H:21]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].N1CCCC1.O>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:22][C@H:21]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@@H]1C(=O)OCc1ccccc1
Solvent: C1CCNC1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)OCc1ccccc1
Yield: 31.3 %

Procedure:
A solution of the product from step (b) (0.16g), pyrrolidine (0.16ml) and 3A molecular sieves (0.2g) in acetonitrile (3.2ml) was stirred at room temperature for 3.5 hours. The mixture was poured into water and extracted with ether, dried over magnesium sulphate and evaporated. The residue was flash chromatographed to give the sub-title product (0.05g) as a gum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1.[OH-].[Li+].Cl.O>CO>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:12][N:11]([C:13](=[O:16])[CH2:14][CH3:15])[CH2:10]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:26]2[CH:39]=[CH:38][C:29]3[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=3[CH:27]=2)[CH:19]=1
Reactant: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)OC)c3)c(C)c2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(=O)N1CC(Oc2cc(C)c(-c3cccc(COc4ccc5c(c4)OC[C@H]5CC(=O)O)c3)c(C)c2)C1
Reaction time: 3 h
Yield: 43.1 %

Procedure:
The crude (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 14d (45 mg, 0.09 mmol) was dissolved in 3 mL of methanol, followed by addition of 1M aqueous lithium hydroxide solution (0.5 mL, 0.50 mmol). The reaction solution was stirred for 3 hours. To the resulting solution, 1M hydrochloric acid was added dropwise to adjust the pH to 3, 3 mL of water were added, and then the solution was concentrated under reduced pressure and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (S)-2-(6-((2′,6′-dimethyl-4′-((1-propionylazetidin-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 14 (20 mg, yield 43.0%) as a yellow solid.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]1=2)=[N+:13]=[N-:14]
Reactant: BrC1CCCc2nccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCCc2nccnc21
Temperature: 60 °C
Yield: 96.9 %

Procedure:
5-bromo-5,6,7,8-tetrahydroquinoxaline (2.75 g, 12.9 mmol) and sodium azide (1.68 g, 25.8 mmol) were dissolved in DMF (50 mL) under nitrogen atmosphere and the reaction mixture was warmed to 60° C. for 2 days. The mixture was cooled to room temperature and poured over water (500 mL), and was extracted with CH2Cl2 (3×300 mL). The organic extracts were washed with brine (2×200 mL), dried and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using 1:1 EtOAc/hexanes to afford 2.19 g (97%) of 5-azido-5,6,7,8-tetrahydroquinoxaline as a yellow liquid: 1H NMR (CDCl3): δ 1.80-1.96 (m, 1H), 2.00-2.10 (m, 3H), 2.75-3.06 (m, 2H), 4.74 (t, 1H, J=6.5 Hz), 8.44 (d, 1H, J=3 Hz), 8.45 (d, 1H, J=3 Hz); 13C NMR (CDCl3): δ 18.6, 28.9, 31.7, 60.2, 142.6, 144.3, 150.3, 153.6.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[Cl:10].Br.[CH3:12][N:13]1[C:18]2[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.[OH:24]O>O.N.CC(C)=O>[Cl:10][C:4]1[CH:5]=[C:6]([OH:9])[CH:7]=[CH:8][C:3]=1[NH:2][C:21]1[C:20](=[O:23])[CH:19]=[C:18]([N:13]([CH2:14][CH2:15][OH:24])[CH3:12])[C:17](=[O:16])[CH:22]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: OO
Reactant: CN1CCOc2ccc(O)cc21
Agent: Br
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(C)=O
Product: CN(CCO)C1=CC(=O)C(Nc2ccc(O)cc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.90 g (0.005 mol) of 4-amino-3-chlorophenol hydrochloride in 8 ml of water and 2 ml of 20% aqueous ammonia is added a solution of 1.23 g (0.005 mol) of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 3 ml of water, 1 ml of 20% aqueous ammonia and 10 ml of acetone. 17 ml of 6% aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 6 hours 30 minutes. After 12 hours at 6° C., the precipitate formed is filtered off and dried. The product is purified on a column of silica (eluent: 100% dichloromethane and then dichloromethane/methanol up to 10% methanol). 0.01 g of 2-(2-chloro-4-hydroxyphenylamino)-5-[(2-hydroxyethyl)methylamino][1,4]benzoquinone (compound 4) is obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[S:34]([CH3:37])(=[O:36])=[O:35])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 40.3 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (140 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (330 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 4, the title compound (148 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(=[O:35])[N:25]([CH2:26][C:27](Cl)=[O:28])[C:24](=[O:30])[C:23]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]12>C(OCC)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:27](=[O:28])[CH2:26][N:25]2[C:24](=[O:30])[C:23]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:22]3[C:21]2=[O:35])[CH:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: CC1CC(=O)N(Cc2ccccc2)c2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O
Yield: 61 %

Procedure:
The titled compound was synthesized from 1-benzyl-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one and phthalimidoacetyl chloride in substantially the same manner as in Working Example 46. Yield 61%. m.p. 248°-250° C. (diethyl ether).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>N1CCCCC1.C(O)C>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: Cc1c(Cl)ccc2c1CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)c(C)c21
Yield: 55 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (91 g), 91 mg 5-chloro-4-methyl-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 90° C. for 4 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 95 mg of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13]>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: NCCCC(=O)O
Reactant: CCO
Product: CCOC(=O)CCCN
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanol (500 mL) was cooled to 0° C., and thionyl chloride (85 mL, 1.2 mol) was added dropwise with stirring. The reaction was stirred for one hour at 0° C., and solid 4-aminobutyric acid (100 g, 0.97 mol) was then added. After ten minutes of stirring, the reaction was allowed to warm to ambient temperature and stirred for two hours. The reaction was then allowed to stand at ambient temperature overnight. The ethanol was removed under reduced pressure, and the solid residue was dissolved in ethyl acetate. After one hour, the solution was cooled to 0° C., and a precipitate formed. The precipitate was isolated by filtration and washed with diethyl ether (300 mL) to provide 126.6 g of ethyl 4-aminobutyrate hydrochloride as a white solid. A precipitate formed in the filtrate and was isolated by filtration to provide 19.1 g of ethyl 4-aminobutyrate hydrochloride as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].Cl[C:23]1[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=2[N:24]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:23]4[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]5[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=5[N:24]=4)=[CH:15][CH:14]=3)[C:5]=12
Reactant: CC(=O)Cn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (1.13 g) obtained in Example 9, step C) in DMF (10 ml) was added sodium hydride (60% in oil, 0.200 g) at room temperature by small portions. After stirring for 10 min, a solution of 1-(2-chloro-1H-benzimidazol-1-yl)propan-2-one (1.25 g) in DMF (5 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from methanol to give the title compound (0.371 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
To a solution of methyl 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (694.5 mg, 1.50 mmol) in tetrahydrofuran (4.0 mL) was added lithium tetrahydroborate (35.7 mg, 1.641 mmol) at 0° C. The reaction mixture was stirred at room temperature for 17 hrs. The starting material wasn't consumed completely. To the reaction mixture was added lithium tetrahydroborate (35.7 mg, 1.641 mmol) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The solvent was removed by concentration. The precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (144.0 mg, 0.381 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(Cl)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(Cl)cc2)n1

Procedure:
98.4 mg (78.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-chlorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (80.1 mg, 0.275 mmol), 1-(2-fluorophenyl)piperazine (65 mL, 0.413 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH2:35][CH2:36][CH2:37][OH:38]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@H:22]2[C:27](=[O:28])[NH:35][CH2:36][CH2:37][OH:38])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: NCCO
Reactant: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)NCCO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 55.9 %

Procedure:
(3S)-4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with 2-aminoethanol (72 mg, 1.2 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.3 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][NH2:76])[CH:70]=1>C(Cl)Cl>[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][NH:76][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])[CH:70]=1
Reactant: COC(=O)c1cccc(CN)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 177 mg, 0.46 mmol) was added followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and 3-aminomethyl-benzoic acid methyl ester hydrochloride salt (Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 118 mg.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[C:7]([NH2:12])[C:6]4[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=4[C:4]=3[CH:3]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccc(C(C)(C)C)cc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 4-tert-butylbenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 8-(4-tert-butylphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. >250° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:12][C:13]1[CH:18]=[N:17][C:16]([OH:19])=[CH:15][N:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](OS(C)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:19][C:16]2[CH:15]=[N:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Oc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc(Br)cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 96.7 %

Procedure:
Cesium carbonate (372 mg) was added to a DMF solution (2 ml) of 2-bromo-5-hydroxypyrazine (100 mg) and 1-t-butoxycarbonyl-4-(methanesulfonyloxy)piperidine (192 mg), and stirred at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate=1:11) to obtain the entitled compound (198 mg).
Reaction SMILES: N=C=N.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=S.CS(Cl)(=O)=O.C(N(CC)CC)C>>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[N:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:16]=1[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2F)c1O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: N=C=N
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2F)c1O[Si](C)(C)C(C)(C)C
Yield: 104.8 %

Procedure:
Following the general procedure for carbodiimide formation outlined in example 12, N-(2-fluorophenyl)-N′-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]thiourea (357 mg, 0.69 mmol), methanesulfonyl chloride (0.12 mL, 1.38 mmol) and triethylamine (0.2 mL, 1.38 mmol) were reacted to form the desired product (350 mg, crude). 1H NMR (CDCl3) δ 0.38 (s, 6H), 1.05 (s, 9H), 1.72 (m, 4H), 2.87 (s, 6H), 7.06 (d, 1H), 7.19 (m, 3H), 7.28 (d, 1H), 7.31 (d, 1H).