Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2].[OH-:21].[K+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]([NH2:18])=[O:21])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cccc(F)c1

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (0.87 g, 3.0 mmol) and potassium hydroxide (0.34 g, 6.1 mmol) in ethanol (4 mL) was refluxed for 2 hours. The mixture was cooled, acidified with 1 N HCl, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to yield the crude product. LCMS calculated for C16H14ClFNO2 (M+H)+: m/z=306.1. found: 306.0.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:21][C:22]1[CH:30]=[CH:29][C:25](C(O)=O)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:25]1[CH:29]=[CH:30][C:22]([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=1)[CH3:4])#[N:2]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: CCCCCCCCOc1ccc(C(=O)N[C@@H](C)C#N)cc1
Yield: 29.9 %

Procedure:
General procedure D and E were used to deprotect 1.17 mmols of (S)-tert-butyl 1-cyanoethylcarbamate and couple the resulting amine to 1.17 mmols of 31. After standard purification techniques 0.35 mmols of the title product were recovered. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=8.9, 2H), 6.90 (d, J=8.8, 2H), 6.67 (s, 1H), 5.30-5.05 (m, 1H), 3.98 (t, J=6.6, 2H), 1.85-1.74 (m, 2H), 1.64 (d, J=7.2, 3H), 1.45 (s, 3H), 1.30 (d, J=19.1, 7H), 0.88 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 166.26, 162.49, 129.11, 124.52, 119.58, 114.40, 68.26, 36.25, 31.77, 29.30, 29.19, 29.07, 25.95, 22.63, 19.53, 14.08.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:35][CH2:36][C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:38]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3N)c(C3CCCCC3)c2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]c(-c3ccccc3NC(=O)CCl)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 5-(2-aminophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 9, sodium acetate (2.4 g, 29 mmol) and acetic acid (1.7 ml, 29 mmol) in tetrahydrofuran (70 ml) was added chloroacetyl chloride (2.3 ml, 29 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water (100 ml) was added to the obtained solid. The solid was collected by filtration, washed with diethyl ether (20 ml×2), and dried under reduced pressure to give methyl 5-[2-(2-chloroacetylamino)phenyl]-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (5 g, yield after 2 steps from Step 9: 58%).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.O=P(Cl)(Cl)[Cl:24].O>N1C=CC=CC=1>[Cl:24][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[N:5]=[CH:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Solvent: c1ccncc1
Solvent: O
Product: Fc1c(C#CCCCl)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a mixture of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (4.6 g, 16.0 mmol) in pyridine (50 mL), was added POCl3 (10.3 g, 67.3 mmol). The resulting solution was stirred at room temperature for 2 hours. Upon completion, the reaction solution was poured into water (250 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica gel column (0˜10% EtOAc in petroleum ether) affording the title compound (2.62 g). 1H NMR (300 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 5.87 (dd, 1H), 3.90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, 1H), 1.60-1.54 (m, 2H); LCMS: 307 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]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]([CH3:34])[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:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[CH3:34])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cc1cc(N2C(=O)CC[C@H]2CO)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 33.8 %

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one (153 mg) and (4-bromo-2-methylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 124 and by the reaction and treatment in the same manner as in Example 1, the title compound (183 mg) was obtained.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[CH2:6][CH:7]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[NH:12]C(=O)C)[N:8]=[C:2]12.[ClH:19]>CO.CC(O)C>[ClH:19].[ClH:19].[NH2:12][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:6][N:3]3[C:2]([S:1][CH2:5][CH2:4]3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1cccc(C2CN3CCSC3=N2)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Nc1cccc(C2CN3CCSC3=N2)c1
Reaction time: 8 h

Procedure:
A solution of 1.00 g. (0.0038 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)acetanilide (Example 8) in 17 ml. of 6N hydrochloric acid is heated at reflux for 2.5 hours and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aqueous sodium hydoxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g. of an oil, i.e., m-aminotetramisole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution and crystallization of the residue from 2-propanol gives 0.91 g. (81%) of cream colored solid, melting point 198°-201°C., dec.
Reaction SMILES: [H-].[Li+].[F:3][C:4]([F:17])([F:16])[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6].[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[O:24][C:23]=1[CH3:30])=[O:21].CC(OC)(C)C>C1COCC1>[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH2:28][C:5]([OH:6])([C:7]2[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[C:4]([F:3])([F:16])[F:17])[O:24][C:23]=1[CH3:30])=[O:21]
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cc(C(C)=O)oc1C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)c1cc(C(=O)CC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)oc1C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
LiH (1.76 g) is added to a solution of 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (35.33 g) and 5-acetyl-2-methyl-furan-3-carboxylic acid methyl ester (20 g) in THF (300 ml). After 1 hour 30 at 60° C. MTBE is added (450 ml) and the reaction mixture is poured onto water (750 ml) at 0° C. The organic phase is washed with water and a saturated aqueous solution of NaCl dried over MgSO4 and concentrated in vacuo to yield 62.3 g of 2-methyl-5-[4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trichloro-phenyl)-butyryl]-furan-3-carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLC/MS): 459 (MH+).
Reaction SMILES: [S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18]OS(C)(=O)=O)[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C(OCC)(=O)C>[S:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][N:26]=[N+:27]=[N-:28])[O:15][C:14]3=[O:24])=[CH:9][C:8]=2[F:25])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCSCC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid (5R)-3-[4-(3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (8 g, 19.7 mmol) and sodium azide (4 g, 61.5 mmol) were heated in N,N-dimethylformamide (75 ml) at 80° C. for 2 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with potassium phosphate buffer (pH 7) and with water and dried over sodium sulfate. After evaporation of the solvent the title product was obtained as a brown oil (˜7 g, crude).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:58])([CH3:57])[C:48]([N:50]1[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]1)=[O:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]4)=[O:49])([CH3:58])[CH3:57])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CCN(C(=O)C(C)(C)N)CC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)C(=O)N2CCN(C)CC2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 1-(2-amino-2-methylpropionyl)-4-methylpiperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methylpropionamide, respectively.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH2:14]1[O:16][CH2:15]1>>[CH3:13][O:12][C:11]1[C:2]([CH2:14][CH2:15][OH:16])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C1CO1
Reactant: COc1cc2ccccc2cc1Br
Product: COc1cc2ccccc2cc1CCO

Procedure:
The title compound was synthesized as described above from 2-bromo-3-methoxynaphthalene and ethylene oxide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH2:11])[CH2:8][N:7]1[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:5])[CH3:2].[OH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27](O)=[O:28]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:27]([C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[OH:16])=[O:28])[CH2:8][N:7]1[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: CCOC(=O)[C@@H]1C[C@H](N)CN1CC(C)C
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC(C)C

Procedure:
(2S,4S)-4-[(1-Hydroxy-naphthalene-2-carbonyl)-amino]-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-amino-1-isobutyl-pyrrolidine-2-carboxylic acid ethyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C22H29N2O4 [(M+H)+] 385.0, obsd. 385.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[O:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2occc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2ccoc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 49 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [CH3:1][O-].[Na+].[Na].[C:5]([C:9]1[O:13][N:12]=[C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[CH3:1][N:14]([C:11]1[CH:10]=[C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])[O:13][N:12]=1)[C:15](=[O:18])[O:16][CH3:17]
Reactant: C[O-]
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)N(C)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
To the sodium methoxide obtained by mixing sodium (1.57 g) with anhydrous methanol (45 ml), methyl N-(5-t-butyl-3-isoxazolyl)carbamate (12.88 g) is added. The resultant mixture is stirred at room temperature for 10 minutes, and the methanol is evaporated under reduced pressure. The residue is mixed with anhydrous benzene (100 ml) and dimethyl sulfate (8.61 g). The resultant mixture is stirred for 1 hour and refluxed for 1 hour. After cooling, the precipitate is filtered off. The organic layer is washed with an aqueous saturated solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and the solvent is evaporated. The residue is distilled to give methyl N-methyl-N-(5-t-butyl-3-isoxazolyl)carbamate (11.45 g) as a distillate boiling at 84.0° to 87.0° C./0.55 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:3]=1[N:4]=[C:5]([O:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:12][C:5]1[CH:6]=[C:7]([OH:9])[C:15]2[C:3](=[C:2]([F:1])[C:18]([F:19])=[C:17]([F:20])[CH:16]=2)[N:4]=1)[CH3:14]
Reactant: CCOC(=O)CC(=Nc1ccc(F)c(F)c1F)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOc1cc(O)c2cc(F)c(F)c(F)c2n1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A solution of 2,3,4-trifluoro-N-[1-ethoxy-2-(ethoxycarbonyl)ethylidene]aniline (122 g) in phenyl ether (120 cc) is introduced dropwise in the course of 25 minutes and with stirring into phenyl ether (600 cc) at a temperature in the region of 250° C. while the ethanol formed is removed by distillation. After stirring for 15 minutes at the same temperature, the solution is cooled to approximately 20° C. and treated with n-hexane (750 cc). The precipitate formed is drained and washed with n-hexane (3×200 cc). 2-Ethoxy-6,7,8-trifluoro-4-hydroxyquinoline (69.5 g) is obtained in the form of a beige solid, m.p. 171° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[N:13]=O.[S:15]([O-:18])([OH:17])=[O:16].[Na+].S(=O)(O)[O-].Cl>O>[OH:1][C:2]1[CH:11]=[C:10]([S:15]([OH:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH2:13]
Reactant: O=S([O-])O
Reactant: O=Nc1c(O)ccc2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(O)cc(S(=O)(=O)O)c2ccc(O)cc12

Procedure:
In the second reaction stage, the 2,7-dihydroxy-1-nitrosonaphthalene (I) which is generally still moist with water and which reacts in the tautomeric oxime form (Ia), is first suspended, according to Boninger, Chem. Ber. 27, 3050 (1894), in commercially-available 37% aqueous sodium hydrogen sulfite solution and stirred at about 20°-25° C. until it is completely dissolved. The bisulfite addition compound (IIa) thus formed is not isolated, but the brown reaction solution is acidified with hydrochloric acid and heated to about 25°-60° C. 2,7-Dihydroxy-1-aminonaphthalene-4-sulfonic acid (II) is formed by reduction of the nitroso group and aromatization of the cycloaliphatic ring system. The aminonaphtholsulfonic acid (II) is isolated by filtering off the resulting light-gray crystals with suction, washing these on a suction filter first with water and then with methanol and, if desired, drying them. The reaction product thus prepared is used without further purification, if appropriate still moist, for the next reaction stage. The yield of reaction product II is about 90-95% of theory. ##STR6##
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[C:31](=[O:32])[N:30]2[CH:25]1[S:26][CH2:27][C:28]([CH3:36])=[C:29]2[C:33]([OH:35])=[O:34])=[O:22])([CH3:19])([CH3:18])[CH3:17].N[C@H](C(O)=O)[C@@H](C)O>C(#N)C>[CH:7]([O:35][C:33]([C:29]1[N:30]2[CH:25]([S:26][CH2:27][C:28]=1[CH3:36])[CH:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:31]2=[O:32])=[O:34])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Solvent: CC#N
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 22 °C
Reaction time: 16 h
Yield: 66.3 %

Procedure:
A solution of diphenyldiazomethane (116.5 g) in acetonitrile (800 cc) is added dropwise, in the course of 45 minutes, at a temperature of between 25° and 30° C., to a solution of 7-tert.-butyoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (188.6 g) in acetonitrile (2,100 cc). Thr reaction mixture is stirred for 16 hours at 22° C. and is then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is redissolved in ethyl acetate (2 liters) and the solution is washed with 2 N hydrochloric acid (700 cc) and then with a saturated aqueous sodium bicarbonate solution (70 cc) and a saturated aqueous sodium chloride solution (700 cc). The solution is dried over sodium sulphate, treated with decolorising charcoal, filtered, and then concentrated to dryness under reduced pressure (20 mm Hg) at 40° C. The residue is dissolved in boiling ethyl acetate (600 cc). Cyclohexane (1 liter) is added, and the mixture is heated to the reflux temperature and then allowed to cool. The crystals which have appeared are filtered off, washed with diethyl ether (3×250 cc) and then dried. 2-Benzhydryloxycarbonyl-7-tert.-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (191 g) is obtained in the form of white crystals (m.p.=179° C.). On concentrating the mother liquor to 500 cc, a second fraction of product (32.6 g, m.p.=178° C.) is obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:4].O=[CH:25][CH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]([CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33][CH3:34])=[O:32])[CH2:11][CH2:12]1)[C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:4]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1cccc(CCC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cccc(CCCN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (100 mg, 0.306 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 3-(3-oxopropyl)benzoate (70.7 mg, 0.368 mmol) and sodium triacetoxyborohydride (104 mg, 0.490 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was then quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes then 0 to 15% MeOH/EtOAc) to give 98 mg of product as pale yellow solid. MS: (M+H)+=503.1. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.32-1.53 (m, 3H), 1.57-1.69 (m, 1H), 1.75-1.90 (m, 2H), 1.91-2.08 (m, 4H), 2.26-2.56 (m, 3H), 2.65-2.88 (m, 4H), 3.13-3.29 (m, 2H), 3.45-3.65 (m, 2H), 3.89-3.95 (m, 3H), 7.05-7.36 (m, 5H), 7.39-7.57 (m, 2H), 7.83-8.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C[O:21][C:22](=[O:33])[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:23]([CH3:24])[C:22]([OH:33])=[O:21])=[CH:30][CH:29]=1
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Reactant: Cc1cnc2c(Cl)cccc2c1-c1cccc(O)c1
Product: Cc1cnc2c(Cl)cccc2c1-c1cccc(OCc2ccc([C@H](C)C(=O)O)cc2)c1

Procedure:
This compound was prepared according to the procedure of example 41, substituting 3-(8-chloro-3-methyl-quinolin-4-yl)-phenol and 2-(4-bromomethyl-phenyl)-propionic acid methyl ester. Purification by supercritical fluid chromatography (MeOH/CO2). Electronic circular dichroism CD λmax=−4 mdeg @ 225 nm (EtOH). MS (ESI) m/z 432.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:25]=[CH:26][CH:27]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CCOc1cccc(S)c1
Product: CCOc1cccc(SC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield (1.29 g, yellow oil) from tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.60 g, 5.73 mmol) and 3-ethoxybenzenethiol (1.06 g, 6.87 mmol) by the similar manner in Step-1 of Intermediate-4.