Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10 g, 40.77 mmol) in methylene chloride (56 mL) at 0° C. was added pyridine (30 mL), followed by dropwise addition of a solution of p-toluenesulfonyl chloride (9.4 g, 49.30 mmol) in methylene chloride. The reaction mixture was warmed to room temperature and then refluxed for 16 h. The reaction mixture was concentrated, re-dissolved in methylene chloride, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.4 g, 88.4% yield) as a light yellow sticky solid. The crude was used in the next step without further purification. MS calcd. for C18H26NO7S [(M+H)+] 400.0, obsd. 400.0.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CCOC(C)=O.CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:20](=[O:22])[NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 966.9 %

Procedure:
A reaction mixture of BOC-L-4-nitrophenylalanine (4.65 g, 1.5 mmol), tert-butylamine (2.19 g, 30 mmol), DMF (10 mL), HBTU (5.69 g, 15 mmol), and diisopropylethylamine (2.48 g, 22 mmol) was stirred for 2 hours. After the reaction was finished, the reaction mixture was added EtOAc (75 mL), and the EtOAc solution was washed with NaHCO3 (100 mL, 4 times), dried over NaHCO3, and concentrated to dryness. The crude reaction mixture was further purified by column chromatography (SiO2, EtOAc/hexane 1:1) to yield the title compound (5.3 g), mp=158-159° C.
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]1[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:14]1=[O:30])[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH2:18]([CH:17]1[CH2:16][N:15]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:14](=[O:30])[CH:13]1[CH2:12][N:9]([OH:8])[CH:10]=[O:11])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(C=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCCC1CN(Cc2ccc(O)cc2)C(=O)C1CN(O)C=O
Yield: 69.3 %

Procedure:
(+/−)-(3RS,4SR)-N-Benzyloxy-N-[4-butyl-1-(4-hydroxybenzyl)-2-oxopyrrolidin-3-ylmethyl]formamide (0.13 g, 0.32 mmol) was dissolved in methanol (5 mL) and stirred under a hydrogen balloon in the presence of palladium on activated carbon (30 mg) for 4 h. The reaction mixture was filtered, concentrated and the residue was purified by HPLC to afford the title compound as a white solid (0.071 g, 70%). MS(ES) m/e 321 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:3]([S:4]([CH3:7])(=[O:6])=[O:5])[C:8]1[CH:13]=[C:12]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-Ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (3.2 g, 12.2 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO at 50° C. for 5 hours. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. The product was purified by flash chromatography (ethyl acetate:petrol 1:1). Yield 2.6 g (48%) 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.33 Hz, 3 H), 1.39 (s, 9 H), 2.0 (br, 2 H), 2.99 (s, 3 H), 3.2 (br, 2 H), 3.54–3.75 (br, 8 H), 6.65 (br d, J=9.3 Hz, 1 H), 6.67 (d,j=2.93 Hz, 1 H), 8.1 (d, J=9.3 Hz, 1 H); MS (ESI+) for C19H30N4O6S m/z 442 (M+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16](=[O:21])[N:15](CC2C=CC(OC)=CC=2)[CH:14]=[CH:13]3)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>>[NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][C@H:5]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[CH3:20])[C:16](=[O:21])[NH:15][CH:14]=[CH:13]3)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CCC[C@@H](N)CC4)c(C)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CCC[C@@H](N)CC1
Temperature: 150 °C

Procedure:
130 mg (0.32 mmol) 6-(cis-4-amino-cycloheptyloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were dissolved in 730 mg (6.4 mmol) trifluoroacetic acid and the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with water and the solution was made alkaline. After extraction with dichloromethane, drying over magnesium sulfate and evaporation 24 mg of 6-(cis-4-amino-cycloheptyloxy)-7-methyl-2H-isoquinolin-1-one (47) were obtained. Rt=0.96 min (Method B). Detected mass: 287.3 (M+H+).
Reaction SMILES: N1CCCCC1.[CH:7]1([CH2:13][C@H:14]([NH:22][C:23](=[O:43])[C@@H:24]([NH:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:34])[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C@@H:15]([OH:21])[C@H:16]([CH:18]2[CH2:20][CH2:19]2)[OH:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:44]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](O)=[O:47]>C(Cl)Cl>[C:55]([O:54][C:52]([N:44]1[CH2:51][CH2:50][CH2:49][C@@H:45]1[C:46](=[O:47])[NH:34][C@H:33]([C:32](=[O:42])[NH:31][C@H:24]([C:23](=[O:43])[NH:22][C@@H:14]([CH2:13][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C@@H:15]([OH:21])[C@H:16]([CH:18]1[CH2:19][CH2:20]1)[OH:17])[CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 19, by condensing (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide with Fmoc-Phe-OH there was obtained 9H-fluoren-9-ylmethyl [(S)-α-[[(S)-1-[[(1S,2R, 3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate which, by reaction with piperidine in methylene chloride, was converted into (S)-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-α-[(3-phenyl-L-alanyl)amino]imidazole-4-propionamide. Further condensation with Boc-D-Pro-OH, analogously to Example 19, yielded (R)-2-[[(S)-α-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamoyl]-1-pyrrolidinecarboxylic acid tert-butyl ester as an amorphous solid, MS: 709 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:50][CH2:51][CH:52]4[CH2:54][CH2:53]4)=[C:29]([NH:32][C:33](=[O:49])[CH:34]=[CH:35][CH2:36][N:37]([CH2:43][C:44]([O:46]CC)=[O:45])[CH2:38][C:39](O)([CH3:41])[CH3:40])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20].C(OCC)(=O)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:50][CH2:51][CH:52]4[CH2:54][CH2:53]4)=[C:29]([NH:32][C:33](=[O:49])[CH:34]=[CH:35][CH2:36][N:37]4[CH2:43][C:44](=[O:46])[O:45][C:39]([CH3:41])([CH3:40])[CH2:38]4)[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CN(CC=CC(=O)Nc2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3cc2OCC2CC2)CC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
15 mg of p-toluenesulphonic acid monohydrate are added to 150 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methyl-propyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline in 2.5 ml of acetonitrile. The solution formed is stirred first for three hours at ambient temperature, then refluxed for a further two hours until the reaction is complete. For working up, the reaction mixture is combined with 30 ml of ethyl acetate. The organic phase is separated off, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The oily yellow residue is stirred with diethylether, whereupon a light yellow solid crystallises out, which is filtered off and dried. Yield: 85 mg (61% of theory), Melting point: 140-142° C. Mass spectrum (ESI+): m/z=554, 556 [M+H]+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@H:71]([CH2:75][CH:76]1[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1)[C:72]([OH:74])=[O:73])=[O:69].[BH4-].[Na+]>CN(C=O)C>[CH:76]1([CH2:75][C@@H:71]([NH:70][C:68](=[O:69])[CH2:67][NH:66][C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([C@@H:14]3[C@@H:13]([S:12][CH2:11][CH:10]([C:7]4[CH:8]=[CH:9][C:4]5[CH2:3][CH2:2][O:1][C:5]=5[CH:6]=4)[OH:36])[C:16](=[O:17])[N:15]3[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:35][CH:34]=2)[C:72]([OH:74])=[O:73])[CH2:77][CH2:78][CH2:79][CH2:80][CH2:81]1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of {4-[(2R,3R)-3-[2-(2,3-dihydro-benzofuran-6-yl)-2-oxo-ethylsulfanyl]-1-(4-fluoro-phenyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetic acid (33 mg, 0.065 mmol) in DMF (3 mL) at RT was added N-methylmorpholine (22 μl, 0.198 mmol) and TBTU (22 mg, 0.069 mmol). The mixture was stirred for 30 min before (R)-2-(2-amino-acetylamino)-3-cyclohexyl-propionic acid (15 mg, 0.066 mmol) was added. After 2 h 30 min, the reaction was quenched by the addition of water (1 mL) The mixture was diluted with MeOH (1 mL) and then added NaBH4 (35 mg, 0.925 mmol). After 15 min, the reaction was quenched by the addition of 1M HCl (3 mL) and the resulting solution was purified by preparative HPLC using a gradient of 0-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:44](=[O:46])=[O:45]>C1COCC1>[Br:15][C:13]1[CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]([F:16])=[C:11]([CH:12]=1)[C:44]([OH:46])=[O:45]
Reactant: O=C=O
Reactant: Fc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reaction time: 0.75 h
Yield: 40 %

Procedure:
Add dropwise a solution of dibenzyl-(5-bromo-2-fluorophenyl)-amine (4.00 g, 10.8 mmol) in THF (12 mL) to a solution of lithium diisopropylamide, freshly prepared by adding n-butyllithium (1.6 M in hexanes, 7.09 mL, 11.3 mmol) to diisopropylamine (1.74 mL, 12.4 mmol) in THF (25 mL) at −78° C. Stir the resulting yellow solution at −78 C for 45 min. Pour into a dry ice slurry containing about 100 g in dry THF (40 mL). Stir the solution until it reaches room temperature. Concentrate the solution and dissolve the residue in 10% aqueous potassium hydroxide solution (40 mL) and extract with diethyl ether (70 mL). Acidify the aqueous layer to about pH=3 with concentrated HCl. Extract the aqueous layer with diethyl ether (2×200 mL). Combine the organic layers and wash with water (150 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (1.81 g, 40%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([C:30]#[N:31])=[CH:27][CH:28]=3)[C:23]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([Cl:42])[CH:35]=3)=[N:22][N:21]=2)[CH2:16][CH2:15]1.[C:43]1(=[O:53])[NH:47][C:46](=[O:48])[C:45]2=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:42][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[O:40][CH3:41])[CH2:33][NH:32][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:47]3[C:46](=[O:48])[C:45]4=[CH:49][CH:50]=[CH:51][CH:52]=[C:44]4[C:43]3=[O:53])[CH2:15][CH2:16]2)=[N:21][N:22]=1
Reactant: COc1ccc(CNc2nnc(N3CCC(O)CC3)c3ccc(C#N)cc23)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nnc(N3CCC(N4C(=O)c5ccccc5C4=O)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 4 °C
Reaction time: 24 h
Yield: 88.5 %

Procedure:
Then, 30 ml solution of 3.48 g diethyl azodicarboxylate in tetrahydrofuran was added to 100 ml solution of 4.2 g 1-(4-hydroxypiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine, 2.94 g phthalimide, and 5.24 g triphenylphosphine in tetrahydrofuran over 30 min under ice-cooling, and then it was stirred at 4° C. for 24 hr. The reaction solution was evaporated, water and ethyl acetate were added thereto, and then the insoluble matters were removed by filtration. The organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography to give 4.85 g of 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-phthalimidopiperidino)phthalazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.ClCCl.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[F:23]
Reactant: Fc1ccccc1CBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1Cc1ccccc1F
Temperature: 100 °C
Yield: 77.9 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 100 mg, 0.33 mmol), tetrabutylammonium iodide (85 mg, 0.23 mmol) and 2-fluoro-benzyl bromide (164 μL, 1.3 mmol) in dimethylformamide (2 mL) was heated at 100° C. overnight. Dichloromethane (50 mL) and a mixture of water (13 mL) and brine (6 mL) were added. The organic layer was washed with 10% aqueous sodium thiosulfate (20 μL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 50-60% ethyl acetate/petroleum ether, to give (4S,7R)-2-(2,4-difluoro-phenyl)-1-(2-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (106 mg, 78%) as a pale solid. ES(+)-MS (M+H) 413.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:51])([F:50])[C:17]1[CH:18]=[C:19]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:21].[CH3:52][N:53]1[CH:57]=[C:56]([CH:58]=O)[CH:55]=[N:54]1>ClCCl>[F:51][C:16]([F:15])([F:50])[C:17]1[CH:18]=[C:19]([CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=1)[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:58][C:56]2[CH:55]=[N:54][N:53]([CH3:52])[CH:57]=2)[CH2:24][C@H:23]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)=[O:21]
Reactant: COCCOCOc1cc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCOCOc1cc(C[C@@H]2CN(Cc3cnn(C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Sodium triacetoxyborohydride (0.3 g) was added in portions to a mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-piperazine (0.5 g) and 1-methyl-1H-pyrazole-4-carboxaldehyde (0.12 g) in dichloromethane (10 ml) and the whole was stirred at room temperature for 1 hour. The mixture was washed with sodium hydrogen carbonate aqueous solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The fractions containing the objective compound were collected and evaporated in vacuo to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[3-[(2-methoxyethoxy)methoxy]-4-methylbenzyl]-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine (0.54 g) as an oil.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC>[Br:11][CH:3]([C:2](=[O:1])[CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCC(C)=O
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)CC(Br)C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a solution of ethyl 4-oxopentanoate (4.92 mL, 34.7 mmol) in Et2O (180 mL) at about 0° C. was added bromine (1.8 mL, 34.7 mmol) in Et2O (10 mL) and the reaction was stirred for about 3 h. To the reaction mixture was added saturated aqueous sodium thiosulfate (50 mL) and stirred for about 10 min. The reaction was warmed to ambient temperature. The organic layer was separated and the aqueous layer was back extracted with Et2O (30 mL). The combined organic layers were washed with water (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:20) to afford ethyl 3-bromo-4-oxopentanoate (3.29 g, 14.6 mmol, 43%). 1H NMR (CDCl3) δ 4.67-4.33 (m, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.29-3.22 (m, 1H), 2.90-2.86 (m, 1H), 2.42 (s, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cc1cccc(O)c1Cl
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@H](C)Oc1cccc(C)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 2-chloro-3-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:5]2[CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)c1cn2c(cc(OC)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2nc(C(=O)O)cn2c2ccccc12

Procedure:
250 mg of ethyl 5-methoxyimidazo-[1,2-a]-quinoline-2-carboxylate in 20 ml of ethanol and 10 ml of water was hydrolyzed with 2 ml of N sodium hydroxide solution and was then acidified with 2.2 ml of N hydrochloric acid as in Example 36 to obtain 5-methoxyimidazo-[1,2-a]-quinoline-2-carboxylic acid as colorless needles melting at 244°-247° C. The I.R. spectrum indicated that the compound existed entirely in the zwitterionic form.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[C:3]=1[N+:10]([O-])=O.C(N(CC)CC)C.[O:20]=[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[NH:22]1>CO.[Pd]>[NH2:10][C:3]1[C:2]([N:29]2[CH2:28][CH2:27][CH:26]([N:25]3[C:24]4[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=4[NH:22][C:21]3=[O:20])[CH2:31][CH2:30]2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][CH3:9]
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CNc1ncnc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a suspension of 6-chloro-N-methyl-5-nitropyrimidin-4-amine (550 mg, 2.92 mmol) in methanol (11 mL) was added triethylamine (0.55 mL, 3.94 mmol) and 4-(2-keto-1-benzimidazolinyl)piperidine (638 mg, 2.94 mmol). The mixture was stirred at ambient temperature for 1 h and then 10 wt % Pd on C (wet) was added and the mixture was stirred under hydrogen for 1 h. The mixture was diluted with methanol and was filtered through Celite. The filtrate was concentrated and the resulting solid was triturated with a solution of 50% aqueous methanol. The methanol was removed in vacuo and the aqueous slurry was filtered and dried to afford 1-{1-[5-amino-6-(methylamino)pyrimidin-4-yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (842 mg, 2.48 mmol, 85% yield) as a peach colored solid. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 7.82 (s, 1H), 7.43-7.36 (m, 1H), 7.01-6.94 (m, 3H), 6.29 (q, 1H), 4.31 (tt, 1H), 4.20 (s, 2H), 3.50 (br d, 2H), 2.85 (d, 3H), 2.74 (t, 2H), 2.54 (qd, 2H), 1.68 (dd, 2H). MS (EI) for C17H21N7O: 340 (MH+).