Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17](=O)OC(C)(C)C)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:30][C:31]([F:49])([F:48])[C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[C@@H:45]3[N:41](S(=O)(=O)OC3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][CH2:17][C@@H:45]4[C@H:38]([C:35]5[CH:36]=[CH:37][C:32]([C:31]([F:30])([F:48])[F:49])=[CH:33][CH:34]=5)[CH2:39][CH2:40][NH:41]4)=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=S1(=O)OC[C@@H]2[C@H](c3ccc(C(F)(F)F)cc3)CCN21
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc([C@@H]2CCN[C@@H]2CNc2nnc(-c3ccc4cnccc4c3)s2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a stirred mixture of tert-butyl 5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate (99 mg, 0.30 mmol) and cesium carbonate (154 mg, 0.47 mmol) in DMF (1.0 mL) was added slowly a solution of (3aS,4S)-4-(4-(trifluoromethyl)phenyl)tetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (58 mg, 0.19 mmol) in DMF (1.0 mL) at 50° C. The mixture was stirred for 1 hour and then concentrated. The residue was dissolved in EtOH and acidified with 5 N HCl (˜pH 2). The mixture was heated at 120° C. for 20 minutes under microwave irradiation. The mixture was concentrated, and the residue was taken up in DCM (2 mL) and water (2 mL). The aqueous layer was made basic with 5 N NaOH and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (ISCO Combiflash system, eluting with a gradient of DCM to 10% MeOH in DCM) to provide 5-(isoquinolin-6-yl)-N-(((2S,3S)-3-(4-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl)-1,3,4-thiadiazol-2-amine as a pale yellow solid (8.8 mg, 10%). LCMS (M+H) 456.1 calc. for C23H21F3N5S 456.1. 1H NMR (400 MHz, CDCl3): δ ppm 2.14-2.29 (m, 1H), 2.48-2.54 (m, 2H), 3.72-3.81 (m, 1H), 3.82-3.92 (m, 1H), 4.04-4.23 (m, 1H), 4.54-4.67 (m, 1H), 7.48 (d, J=7.53 Hz, 2H), 7.70 (d, J=8.03 Hz, 2H), 7.78 (d, J=5.02 Hz, 2H), 7.86-8.02 (m, 1H), 8.30 (d, J=3.01 Hz, 1H), 8.42-8.54 (m, 2H), 9.24 (s, 1H). 2H obscured.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.OCCC1C=C(F)C=C([Cl:45])C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[Cl:45][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCc1cc(F)cc(Cl)c1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cc(F)cc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl)-3-chloro-5-fluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6](O)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]([CH3:23])[CH3:22].[ClH:31].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[NH2:1][C@H:2]([C:6]([NH:19][C@H:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:31]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)[C@H](N)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
37.7 g of Z-Val-OH, 31.4 g of H-Val-OBut.HCl and 19.75 g of HOBt are dissolved in 200 ml of dimethylformamide. 19.5 ml of N-ethylmorpholine are added to the solution, followed by 33 g of DCC at 0° C. The mixture is stirred for 1 hour at 0° C. and for 1 hour at room temperature, the precipitate is filtered off and the filtrate is concentrated in vacuo. The residue is partitioned between 200 ml of ethyl acetate and 200 ml of water. The ethyl acetate phase is then extracted by shaking with 150 ml of saturated NaHCO3 solution, 150 ml of K2SO2 /KHSO4 solution, 150 ml of saturated NaHCO3 solution and 150 ml of water and is dried over Na2SO4 and concentrated. The resulting oil (60 g) is dissolved in 300 ml of methanol and subjected to catalytic hydrogenation at pH 4.5 after adding methanolic hydrochloric acid and Pd-on-BaSO4. When the reaction is complete the catalyst is filtered off and filtrate is concentrated. The residue crystallizes from ether. Yield 40 g. Melting point 191°-194°, [α]D23 =-8.3° (c=1, in methanol).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][C@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:46][O:47][CH2:48]6)[CH2:41][C@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 107a (77 mg, 1.0 eq., 0.11 mmol), NaBH4 (21 mg, 5.0 eq., 0.55 mmol), and MeOH (10 mL). The mixture was stirred at room temperature for 1 h. It was then filtered and the filtrate was concentrated. The residue was purified by reverse-phase prep-HPLC to afford 107 (38 mg, 49%). MS: [M+H]+ 698.3. 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.81 (s, 1H), 7.56-7.54 (m, 2H), 7.40 (s, 1H), 7.31-7.27 (m, 2H), 7.11-7.10 (m, 1H), 6.81 (d, J=9.0 Hz, 1H), 4.71-4.62 (m, 4H), 4.35 (s, 2H), 3.73-3.70 (m, 4H), 3.53-3.46 (m, 2H), 3.08 (t, J=5.0 Hz, 2H), 2.56-2.46 (m, 3H), 2.22-2.18 (m, 1H), 1.43 (s, 9H), 0.98 (d, J=6.5 Hz, 3H).
Reaction SMILES: C(OC([NH:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14]
Reactant: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Yield: 92.5 %

Procedure:
(R)-2-Benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide (80 mg) was dissolved in ethanol (10 mL), the solution was added with 5% palladium/carbon (4 mg), and catalytic hydrogenation was performed at room temperature under a hydrogen atmosphere. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound (43 mg, yield: 93%) as colorless crystals. Optical rotation [α]D24 was −35.9° (c 0.22, ethanol). Optical purity was more than 99.9% ee.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11](=[O:14])[CH2:12][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cyclohexylamine (45 g, 0.45 mol) in dichloromethane (100 mL) was slowly added bromo-acetic acid ethyl ester (15 g, 0.09 mol) in dichloromethane (150 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 1 h and then washed with water (3×200 mL). The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was purified with chromatography (DCM: MeOH=30:1) to give cyclohexylamino-acetic acid ethyl ester as an oil. MS: 186 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:22]([S:30][CH2:31][C@H:32]([CH3:36])[C:33](Cl)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O>[C:22]([S:30][CH2:31][C@@H:32]([CH3:36])[C:33]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Reactant: Cc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C2SC[C@@H](C(=O)O)N2C(=O)[C@H](C)CSC(=O)c2ccccc2)cc1

Procedure:
4.5 g of (4R)-2-(4-methylphenyl)-4-thiazolidinecarboxylic acid and 4.3 g of sodium carbonate are dissolved in 25 ml of water and 4.9 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and acidified with dilute hydrochloric acid. The produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give oil. The produced oil is purified by silica gel column chromatography to give the titled compound, yield 4.0 g (48%), mp. 131°-132° C. (ethyl acetatehexane), [α]D26 +117.6° (c=1.0, methanol).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=2)[CH:9]1[CH2:21][CH2:22][CH2:23][CH3:24])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>C(Cl)Cl>[CH2:21]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:18]([NH:58][C@@H:59]([CH2:73][C:74]3[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=3)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=3)=[O:20])[CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC1c2cc(C(=O)O)ccc2CCN1C(=O)OC(C)(C)C
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1NCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (205 mg, 0.61 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (4.0 mL) was added HBTU (233 mg, 0.61 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (250 mg, 0.61 mmol) in methylene chloride (4.0 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 95:5 chloroform/methanol) gave the desired amide product. The amide was then dissolved in dioxane (5.0 mL) to which was added hydrochloric acid (20 mL, 4.0 M dioxanes, 80 mmol) and the reaction mixture stirred overnight. The reaction mixture was then concentrated to dryness and purified by flash column chromatography (silica, 90:6:3:1 ethyl acetate/chloroform/methanol/ammonium hydroxide) to yield a colorless oil. The oil was partitioned between 3:1 chloroform/2-propanol, washed with water, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated to yield a white solid. The solid was dried under high vacuum at 45° C. in the presence of P2O5 to yield 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxamide(140 mg) characterized as a mixture of diastereomers: mp 121–124° C.; ESI MS m/z 550 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH2:28][CH3:29])=[CH:25][C:24]([C:30]([OH:32])=O)=[N:23]2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[NH2:71][C@H:72]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C@@H:73]([OH:77])[C:74]([OH:76])=[O:75]>>[OH:77][C@H:73]([C@H:72]([NH:71][C:30]([C:24]1[CH:25]=[C:26]([CH2:27][CH2:28][CH3:29])[N:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:16][CH:17]=2)[N:23]=1)=[O:32])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[C:74]([OH:76])=[O:75]
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@H](Cc2ccccc2)[C@@H](O)C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Reaction time: 0.02 h
Yield: 17.9 %

Procedure:
A solution of 1-((2′-(N-(methoxycarbonyl)sulfamoyl)biphenyl-4-yl)methyl)-5-propyl-1H-pyrazole-3-carboxylic acid (40.2 mg, 87.8 μmol), DIPEA (91.8 μL, 527 μmol) and HATU (33.4 mg, 87.8 μmol) in DMF (0.4 mL, 4 mmol) was stirred to pre-activate the acid. After 1 minute, (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (17.1 mg, 87.8 μmol) was added, and the mixture was stirred for 10 minutes. The reaction was quenched by adding 1 N HCl and extracted with DCM. The organic layer was added to AcOH (1 mL) and evaporated in vacuo. The material was then purified by preparative HPLC to yield the title compound (10 mg, 95% purity). MS m/z: [M+H]+ calcd for C32H34N4O8S, 635.21. found 635.20.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH2:10][C:9]2=O.Cl>O1CCCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[O:12][C:11]([CH3:19])([CH3:18])[CH:10]=[CH:9]2
Reactant: COc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)OC(C)(C)C=C2
Yield: 92 %

Procedure:
In a mixture of 75 ml of tetrahydrofurane and 25 ml of ethanol 4.7 g (20 millimoles) of 6,7-dimethoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 1.5 g (40 millimoles) of sodium tetrahydro borate are added in small portions. The reaction mixture is heated to boiling for an hour, cooled to 15° C., whereupon 50 ml of 4N hydrochloric acid are added and the mixture is stirred at a temperature not exceeding 20° C. for 3 30 minutes. The two-phase layer is separated, the aqueous phase is extracted twice with 40 ml of petrol-ether (30°-40° C.) each, the organic phases are collected, washed twice with 25 ml of 5% sodium hydroxide solution and twice with 40 ml water each, dried over sodium sulfate and evaporated. The residue is crystallized from 80% methanol. Thus 4.0 g of the desired compound are obtained, yield 92%. Mp.: 46°-47° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>Br>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCCN2CCN2CCOCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1ccc(C2CCCN2CCN2CCOCC2)cc1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
1-[2-(4-Morpholinyl)ethyl]-2-(4-methoxyphenyl)pyrrolidine (3.75 g) was dissolved in 48% hydrobromic acid (35 ml) and warmed at 110° C. for 5 hrs. The reaction mixture was cooled, neutralized with saturated sodium bicarbonate solution and extracted into dichloromethane (6 times). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography. The appropriate fractions were collected and concentrated to afford 2.36 g (66.0%) of product. The analytical sample was recrystallized from ether/petroleum ether and had mp 107°-108° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][C@@H:20]1[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:21]1[CH2:22][C@@H:20]1[CH2:19][O:17][C:13]1[CH:12]=[C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc(-c2cccc3cccnc23)c1
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OC[C@H]2CO2)cc(-c2cccc3cccnc23)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A mixture of 3-(quinolin-8-yl)phenol (221 mg, 1 mmol) and (S)-2-(chloromethyl)oxirane (114.6 mg, 1.2 mmol) in CH3CN (10 mL) was added K2CO3 (690 mg, 5 mmol). The reaction mixture was stirred at 80° C. for 4 h. The solid was removed by filtration and the filtrate was concentrated to yield a crude (R)-8-(3-(oxiran-2-ylmethoxy)phenyl)quinoline which was used in the next step without further purification. (210 mg, Yield 75%). LCMS (m/z): 278.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2>C1(C)C(C)=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:32][C:29]1[CH:30]=[CH:31][C:22]([N:21]=[CH:11][C@@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])=[C:23]2[C:28]=1[NH:27][C:26](=[O:33])[CH:25]=[CH:24]2
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 300 mg (1.01 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 180 mg (1.01 mmol) of 5-amino-8-fluoroquinolone and 0.48 ml of titanium tetraisopropoxide in 9 ml of xylene are reacted to give 8-fluoro-5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one. 80 mg of imine purified by column chromatography (silica gel, hexane; CH2Cl2/i-PrOH 0-5%) are cyclized, in the same way as in Example 1, at −40° C. using 1.7 ml (1.5 mmol) of 1 M boron tribromide solution to give the desired product and the ether-cleaved Example 8.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH2:3][CH2:2]1.[H-].[Na+].F[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([CH3:25])[C:16]=1[N+:26]([O-:28])=[O:27].C(OCC)(=O)C>CN(C)C=O.O>[CH3:25][C:17]1[C:16]([N+:26]([O-:28])=[O:27])=[C:15]([N:11]2[CH:10]=[CH:9][N:8]=[C:7]2[CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1C
Reactant: c1c[nH]c(C2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccnc2C2CCOCC2)c([N+](=O)[O-])c1C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To a mixed liquid of 1.70 g of 2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole and 20.0 mL of N,N-dimethylformamide was added slowly 450 mg of 60% sodium hydride portionwise under ice-cooling, followed by stirring at the same temperature for 10 minutes and then stirring at room temperature for 30 minutes. After ice-cooling again, a mixed liquid of 2.00 g of methyl 4-fluoro-2-methyl-3-nitrobenzoate in 10.0 mL of N,N-dimethylformamide was added thereto, followed by stirring at the same temperature for 10 minutes and then stirring at room temperature overnight. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.13 g of methyl 2-methyl-3-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzoate as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41N4O2Cl2 [(M+H)+] 607.2601, observed 607.2603.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCc1ccncc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3ccncc3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-(2-aminoethyl)pyridine (0.012 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-(pyridin-4-yl)ethyl)aminomethyl]indol-2-yl)isoindolinone.