Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 40.8 %

Procedure:
To a solution of 15.0 g of 4-aminophenol dissolved in 300 ml of N,N-dimethylformamide, was added 28.5 g of anhydrous potassium carbonate. Subsequently, 46.0 g of 1-bromooctadecane was added thereto at 80° C., and the mixture was stirred for 3.5 hours at 80° C. Water was added to the reaction mixture, and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent: hexane—ethyl acetate—chloroform=5:1:1 to 1:1:1), followed by recrystallization from chloroform—methanol, to yield 20.28 g of 4-octadecyloxyaniline (melting point: 95-97° C.) (Reaction Scheme (58) described below).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]#[N:10])[CH:2]=1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9](=[N:12][OH:13])[NH2:10])[CH:2]=1
Reactant: N#CCCc1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(CCc1cccnc1)=NO
Yield: 61 %

Procedure:
20.1 g (0.15 mol) of 3-(3-pyridyl)propionitrile is dissolved in a mixture of 61 ml of ethanol, and 15 ml of water and 9.5 g (0.14 mol) of hydroxylamine hydrochloride and 21 g (0.15 mol) of K2CO3 are added. After 24 hours at reflux, the solvent is removed in a vacuum, and the residue is extracted twice with ethanol. The extracts are concentrated by evaporation and recrystallized in hot ethanol. 14.1 g (56%) of product is obtained. Melting point 119-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH2:25][OH:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1.CC(C)=O>C1COCC1.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:25]=[O:26])=[CH:11][C:12]3[N:16]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[N:14][C:13]=3[C:23]=2[F:24])=[C:4]([Cl:27])[CH:3]=1
Reactant: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(CO)cc21
Agent: O=[Mn]=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(2-methanesulfonyl-ethyl)-3H-benzoimidazol-5-yl]-methanol 10y (0.050, 0.105 mmol) is dissolved in 1:1 THF:acetone (2 mL) under N2 and MnO2 (0.046 g, 0.524 mmol) is added. The reaction mixture is stirred at room temperature for 16 hours, and then at 55° C. for 5 hours. Additional MnO2 (0.046 g, 0.524 mmol) is added and the reaction mixture stirred at 55° C. for 2 hours. The reaction mixture is concentrated to dryness and the residue dissolved in 10:1 methylene chloride:MeOH. The solution is filtered through a silica gel plug eluted with 10:1 methylene chloride:MeOH. The resulting filtrate is concentrated under reduced pressure to give 41 mg (82%) desired product as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:35])[CH:6]=1.Cl.ClC1C=CC=CC=1OC1CN([C@@H](CC2C=CC(Cl)=CC=2)C(NC2C=CN(C[C@@H](O)CO)N=2)=O)C(=O)C=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:35])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](Cc3ccccc3Cl)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Agent: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccc(Cl)cc1)N1CC(Oc2ccccc2Cl)=CC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccccc1Cl)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(4-chlorophenyl)-propionic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 188, 0.151 g, 0.259 mmol) in tetrahydrofuran (3 mL) was treated with 2N aqueous hydrochloric acid solution (3 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated to afford, (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(4-chlorophenyl)-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (0.110 g, 80%) as a white powder: HR-ES-MS m/z calculated for C25H24Cl2N4O5 [M+H]+ 531.1196, observed 531.1197; 1H NMR (300 MHz, DMSO-d6); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.19-3.30 (m, 4H), 3.74 (br. s., 1H), 3.80-3.91 (m, 1H), 4.07 (dd, J=13.6, 3.6 Hz, 1H), 4.25 (d, J=18.2 Hz, 1H), 4.39 (d, J=18.2 Hz, 1H), 4.65-4.71 (m, 1H), 4.72 (s, 1H), 4.93 (d, J=5.1 Hz, 1H), 5.18 (t, J=7.5 Hz, 1H), 6.43 (d, J=1.5 Hz, 1H), 7.18-7.30 (m, 2H), 7.30-7.47 (m, 5H), 7.53 (d, J=1.5 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: Br.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1cccs1
Reactant: CCOC(=O)CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2cccs2)Sc2ccccc21
Temperature: 10 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
With 100 ml of dimethylformamide is mixed 12.2 g of trans-3-amino-2-(2-thienyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide, and 2.7 g of 60% sodium hydride is added to the mixture under ice-cooling. The reaction temperature is gradually elevated to room temperature. The mixture is stirred for 2 hours. After the reaction mixture is cooled again to about 10° C., 5.7 g of ethyl bromoacetate is added dropwise. The reaction temperature is elevated to room temperature, and thereafter the mixture is stirred for one night and concentrated under reduced pressure. Ice water and ethyl acetate are poured to the residue to extract the organic substance. The ethyl acetate layer is washed with water, and dried. After the solvent is distilled off under reduced pressure, the obtained residue is purified by silica gel chromatography to give 8.0 g of ethyl trans-3-amino-4-oxo-2-(2-thienyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.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.[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([O:45][CH2:46][O:47][C:48](=[O:69])[C@@:49]([CH2:67][OH:68])([CH3:66])[CH2:50][C@H:51]([NH:65][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:57][CH:58]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
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: CC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 5 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid acetoxymethyl ester (47.8 mg, 124 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (3 mg; purity 95%). MS m/z [M+H]+ calc'd for C25H28N4O6, 481.20. found 481.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15]N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=O)[CH2:19][CH2:18]2.S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:10]2[NH:15][C:20]3[CH:21]4[CH2:24][CH2:25][N:17]([CH2:18][C:19]=3[C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH2:23][CH2:22]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1OCc1ccccc1
Reactant: O=C1CCN2CCC1CC2
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: c1ccc(COc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under nitrogen, (2-(benzyloxy)phenyl)hydrazine (214 mg, 1.0 mmol, International Publication No. WO2009001129) was mixed with the product of Example 1A (139 mg, 1.0 mmol) and sulfuric acid (0.2 mL, 3.76 mmol; J. T. Baker) in dry dioxane (10 mL). Then the mixture was heated to 80° C. and stirred for 16 hours in a sealed tube. The mixture was concentrated and basified with 1.0 M NaOH and then extracted with ethyl acetate (3×20 mL). The organic phase was concentrated and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.01-2.13 (m, 4 H), 3.01-3.13 (m, 3 H), 3.17-3.28 (m, 2 H), 4.22 (s, 2 H), 5.21 (s, 2 H), 6.66 (dd, J=7, 2 Hz, 1 H), 6.83-6.93 (m, 2 H), 7.28-7.41 (m, 3 H), 7.48-7.55 (m, 2 H); MS (DCI/NH3) m/z 319 (M+H)+.
Reaction SMILES: C([N:8]([CH2:13][CH:14]([OH:34])[C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[C:17]([CH:29]([O:32][CH3:33])[CH2:30][OH:31])[CH:16]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])C1C=CC=CC=1>[Pd].C(O)C>[C:9]([NH:8][CH2:13][CH:14]([OH:34])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:29]([O:32][CH3:33])[CH2:30][OH:31])[CH:16]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(CO)c1cc(C(O)CN(Cc2ccccc2)C(C)(C)C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(CO)c1cc(C(O)CNC(C)(C)C)ccc1O

Procedure:
The benzyl alcohol (0.7 g., 1.5 mmol) in 150 ml. of ethanol is hydrogenated over 0.7 g. of 10% palladium-on-carbon at 50 psi for 25 minutes. The catalyst is filtered and the filtrate evaporated to give α-(t-butylaminomethyl)-4-hydroxy-3-(2-hydroxy-1-methoxyethyl)-benzyl alcohol; fumarate m.p. 230° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C1C=C[C:37]2N(O)N=[N:40][C:38]=2C=1.C(Cl)CCl.Cl.C(N)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:40][CH2:38][CH3:37])=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:32])([F:31])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCNC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (394 mg, 0.74 mmol), HOBT (199 mg, 1.47 mmol), EDC (211 mg, 1.47 mmol), ethylamine hydrochloride (119 mg, 1.47 mmol) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexane) to yield the title compound (100 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([C:11]1[N:12](COC)[CH:13]=[CH:14][N:15]=1)[OH:10].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([C:11]1[NH:15][CH:14]=[CH:13][N:12]=1)[OH:10]
Reactant: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ccc(F)cc1)(c1ncc[nH]1)c1ccc(Cl)cc1Cl

Procedure:
A solution of 12 g (0.031 mol) of α-(2,4-dichlorophenyl)-α-(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol, 150 ml. of glacial acetic acid, 15 ml. of concentrated hydrochloric acid and 15 ml. of water was refluxed for 5 hours. The dark brown solution was concentrated and water was added to the residue. The mixture was then made alkaline by addition of ammonia and extracted with diethyl ether. The organic phase was separated off, decolorized with active charcoal, dried over sodium sulphate and the ether was distilled off. The solid residue was twice crystallised from acetone, rewashed with petroleum ether (boiling range 60°-80° C.) and once crystallised from isopropyl alcohol. α-(2,4-Dichlorophenyl)-α-(p-fluorophenyl)imidazole-2-methanol was obtained. Melting point 193.5°-194° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([N:11]1[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12]1=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 3 h
Yield: 89.2 %

Procedure:
7-t-Butoxycarbonylamino-4-oxo-7-methyl-5-azaspiro[2.4]heptane (42.63 g) was suspended in dimethylformamide (850 mL) under a nitrogen gas atmosphere, and the suspension was cooled with ice. To the suspension, 60% sodium hydride (6.93 g) was added, and the mixture was returned to room temperature. Subsequently, benzyl bromide (22.64 mL) was added to the reaction mixture, followed by stirring. After three hours, insoluble material was removed through filtration, and water was added to the filtrate. Ethyl acetate was further added thereto for extraction. The organic layer obtained through extraction was dried with sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure, to thereby yield an oily residue. The residue was subjected to silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product as pale yellow oil (51.0 g, yield: 89.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14]O)([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][N:45]3[C:41](=[O:51])[C:42]4[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:44]3=[O:46])([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CO)[C@@H]1c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2(CN2C(=O)c3ccccc3C2=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To racemic Intermediate 19, one enantiomer being (1S,2S,5S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol), was added anhydrous THF (5 mL), triphenylphosphine (0.43 g, 1.6 mmol), phthalimide (0.30 g, 2.1 mmol), and diethylazodicarboxylate (0.22 mL, 1.7 mmol). The reaction was allowed to stir at room temperature for 16 hours. The solvent was removed at reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and methylene chloride, the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. The material was purified by chromatography on silica by elution with a gradient of 5 to 20% EtOAc/Hexanes to give the title compound as an white solid (0.56 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:29](I)[CH2:30][CH3:31].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:29][CH2:30][CH3:31])[CH:21]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CCCI
Reactant: Cn1c(=O)cc(-c2cccc(O)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Yield: 100 %

Procedure:
A mixture of interm. (7-h) (9.5 g), propyl iodide (5.9 ml) and K2CO3 (10.1 g) was stirred and refluxed for 4 hours. Water was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 10.4 g (100%) of 6-(4-chlorobenzoyl)-1-methyl-4-(3-propoxyphenyl)-2(1H)-quinolinone (interm. 7-i).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])[CH2:2][CH3:3].[CH3:12][C:13]([CH3:15])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]2[O:8][C:13]([CH3:15])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using a mixture of 7.61 g (50 mM) of 4-n-propylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 15 ml of benzene. 5-n-Propyl-2,2-dimethyl-1,3-benzodioxol was obtained in the yield of 9.13 g (47 mM) as colorless transparent liquid having a boiling point of 82°-87° C./3 mmHg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]3[N:25]=[N:26][N:27]=[C:18]3[C:17]=2[N:16]=[C:15]1[CH2:28][CH3:29])(=[O:7])=[O:6]>CN(C=O)C>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]3[N:25]=[N:26][N:27]=[C:18]3[C:17]=2[N:16]=[C:15]1[CH2:28][CH3:29]
Reactant: CCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCCNS(=O)(=O)CCCCl
Solvent: CN(C)C=O
Product: CCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCCN1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, 1,8-diazabicyclo[5.4.0]undecene-7 (4.2 mL, 28 mmol) was added to a solution of 3-chloro-N-{2-[2-(8-ethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridin-7-yl)ethoxy]ethyl}propane-1-sulfonamide (2.50 g, 5.63 mmol) in DMF (50 mL), and the reaction was stirred overnight at room temperature. The solution was concentrated to about 25 mL under reduced pressure, and water (300 mL) was added. A white precipitate formed, which was isolated by filtration and recrystallized from acetonitrile (20 mL) to provide 1.95 g of 7-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-8-ethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine as white crystals, m. p. 176–178° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13]C(O)=C[C:10]=1[C:16]1[CH:17]=[N:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH:29]=3)[C:24]([S:39]([CH3:41])=[O:40])=[CH:23]2)=[N:20][CH:21]=1>N1C=CC=CC=1.O>[C:5]([O:4][C:1]1[CH:13]=[CH:14][C:9]([F:8])=[C:10]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:32])[CH:29]=4)[C:24]([S:39]([CH3:41])=[O:40])=[CH:23]3)=[N:20][CH:21]=2)[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CS(=O)c1cn(-c2ncc(-c3cc(O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.18 mL, 1.9 mmol) was added at 0° C. to 264a) (0.45 g, 0.94 mmol) in pyridine (2.0 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with cold water and extracted with dichloromethane/methanol (9:1; 3×30 mL). The organic layers were washed with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (20 mL), dried over sodium sulfate and evaporated. The remnant was purified by flash column chromatography [silica; dichloromethane with 1.5% methanol]. Yield: 0.09 g (38% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:31]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccccc1Cl

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 2-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(OC([NH:23][C@H:24]([C:32](O)=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.P(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:23][C@@H:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)=[O:33]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)aniline (0.20 g, 0.87 mmol), N-(tert-butoxycarbonyl)-L-phenylalanine (254.8 mg, 0.96 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and toluene (4 mL) was stirred at 80° C. for 1.5 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by isopropyl ether/n-hexane to give the title compound (333.7 mg, 92.9%) as an yellow white powder.