Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)(C)C.[OH-].[K+]>CO>[C:25]([C:21]1[CH:20]=[C:19]([C:18]#[CH:17])[CH:24]=[CH:23][CH:22]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cccc(C(C)(C)C)c1

Procedure:
Using the same general procedure as described for Compound 19), but using instead trimethylsilyl (3-tert-butyl)phenylethyne (Compound 25) and aqueous KOH in methanol, the title compound was synthesized as a colorless oil. PMR (CDCl3): & 1.29 (9H, s), 3.03 (1H, s), 7.22 (1H, t, J~7.5 Hz), 7.30 (1H, dt, J~7.5 Hz, 1.5 Hz), 7.36 (1H, dt, J~7.5 Hz, 1.5 Hz), 7.53 (1H, t, J~1.5 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[OH:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].[H-].[Na+].Cl>CN(C)C=O.O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH:22]=[C:21]([O:23][CH3:24])[C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])[CH2:2][O:27]/[N:28]=[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Reactant: COc1cc(CCl)cc(OC)c1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1cc(OC)c(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (585 mg) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115 mg) at 0° C. After stirring for 2 hours, the reaction mixture was poured into water, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave methyl E-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (970 mg, yield 65%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH2:16])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[NH:16][C:23]1=[O:24])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)CCNc1cc(C#N)ccc1N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCn1c(=O)[nH]c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-Amino-5-cyano-phenylamino)-propionic acid ethyl ester (0.65 g, 2.8 mmol) in CHCl3 (10 mL) was added CDI (0.68 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.6 g (83%) of the desired priduct as a brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1C=CC(S([N:31]=[N+:32]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([C:13](=[N+:31]=[N-:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: CCOC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of ethyl 3,5-bis(trifluoromethyl)phenylacetate (Step M, 26.0 g, 87 mmol) and 4-methylbenzenesulfonyl azide (Step L, 18.0 g, 91 mmol) in dry acetonitrile (150 mL) was added DBU (14.3 mL, 95 mmol) dropwise at −10° C. over 15 min with stirring. The mixture was stirred at −10° C. for a further 0.5 hr. The solvent was removed and the residue was partitioned between ether and water. The organic layer was washed with aqueous NaHCO3, brine, dried over Mg2SO4, and the solvent was removed. The residue was chromatographed (eluted with 9:1 hexane:ethyl acetate) to afforded a yellow solid. 1H-NMR (CDCl3): δ: 8.0 (2H, s), 7.68 (1H, s), 4.41 (2H, d, J=7.1 Hz), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[C:12]23[C@:28]([CH3:33])([CH2:29][CH2:30][C:31](=[O:32])[CH:11]12)[C@@H:27]1[C@H:15]([C@H:16]2[C@:24]([CH3:34])([CH2:25][CH2:26]1)[C@@H:19]([C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:13]3.[N-:35]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C:11]1[C:31](=[O:32])[CH2:30][CH2:29][C@@:28]2([CH3:33])[C:12]=1[CH:13]=[CH:14][C@@H:15]1[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:34])[C@H:16]1[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a vigorously stirred solution of (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one benzoate (1.0 g, 2.22 mmole) in dimethyl sulfoxide (35 mL), heated to 60° C., there was added sodium azide (2.7 g) and the concentrated sulfuric acid (0.2 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured onto cold water (250 mL). The resulting mixture was extracted with ether (300 mL) and the ether solution was washed with brine, dried over magnesium sulfate and filtrate and the filtrate was concentrated to give a yellow solid which was purified by chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one benzoate (0.8 g, 80.1%) melting at 163°-167° C. with decomposition. IR 3470, 3366, 1718, 1682 (m), 1656, 1608 (m), 1586 (m), 1567 (m), 1274, 1268, 718 cm-1 ; MS (CI) 448 (100%, M+1), 326 (35%, M+1 - PhCOOH); 1H NMR (CDCl3) δ 0.82 (3H, s, C18 -Me), 1.07 (s, C19 -Me), 1.15 (d, C22 -Me), 3.71 (2H, v br, NH2)4.07 (1H, dd, 1/2 C21 -CH2), 4.35 (1H, dd, 1/2 C21 -CH2), 5.98 (1H dd), 6.30 (1H dd), 7.35 (2H, t), 7.57 (1H, t), 8.04 (2H, dd).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:33]([O:32][C:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Yield: 70.1 %

Procedure:
Ester reduction, Method B: A solution of 35 g (69 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 380 ml toluene/60 ml THF was treated at −47° C. to −50° C. with 44 g (152 mmol) of a 70% solution of sodium dihydrido-bis(2-methoxy-ethoxo)aluminate in toluene (3.5 M Red-Al in toluene). After 3h at −50° C. and 1 h at −30° C. the solution was poured into water (1 l) with 40 g of citric acid and extracted with EtOAc (2×). The organic phase was dried over Na2SO4 and evaporated. Column chromatography on silica gel with hexane/EtOAc (7:3) gave 23.0 g (69%) (2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 476 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[OH:20].F[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[Cl:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:20][C:3]2[C:4]3[N:8]=[N:7][N:6]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=4)[C:5]=3[CH:18]=[CH:19][C:2]=2[Cl:1])[CH:29]=1)[C:25]#[N:26]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: COc1ccc(Cn2nnc3c(O)c(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)cc1
Temperature: 140 °C

Procedure:
A stirred suspension of 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-ol (0.050 g, 0.173 mmol), 3-fluoro-5-chloro-benzonitrile (0.081 g, 0.518 mmol) and cesium carbonate (0.068 g, 0.207 mmol) in NMP (1.5 mL) was heated at 140° C. for 72 hours. The reaction mixture was then quenched with aqueous ammonium chloride (25 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were concentrated under reduced pressure. The resulting residue was subjected to reverse phase chromatography (5-95% MeCN/H2O, 0.1% TFA). The product fractions were combined and extracted with dichloromethane (2×100 mL). The combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to yield the title product. 1H NMR (DMSO d6) δ 7.90-7.88 (m, 1H), 7.80 (s, 1H), 7.79-7.75 (m, 1H), 7.60-7.55 (m, 2H), 7.40-7.35 (d, J=6.9 Hz, 2H), 6.95-6.88 (m, 2H), 5.80 (s, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[Br:16]Br>COC.C(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: BrBr
Agent: COC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc(OC)c1OC
Reaction time: 1 h

Procedure:
A mixture of 3.0 g of 3,4,5-trimethoxyacetophenone in 70 ml of dimethyl ether and 30 ml of chloroform is cooled to 0° and then treated with a mixture containing 0.73 ml of bromine in 15 ml of chloroform in a dropwise manner. The reaction mixture is allowed to warm to 20°- 25° and stirred for 1 hr. The reaction mixture is partitioned between chloroform and water. The organic layer is separated, washed with dilute sodium bicarbonate, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (4.31 g) is recrystallized from ethanol/water. The solid is isolated and dried (18 hours, 0.01 mm, 40°) to give the title compound, mp 61°-62°; IR (mineral oil) 3010, 2995, 2952, 2926, 2868, 2855, 1695, 1687, 1586, 1505, 1466, 1455, 1428, 1417, 1389, 1335, 1255, 1229, 1190, 1151, 1128, 1004, 820, 636, and 602 cm-1 ; NMR (CDCl3, TMS) 7.24, 4.43 and 3.93δ; CMR (CDCl3) 190.2, 153.1, 149.9, 143.3, 128.9, 106.5, 60.9, 56.3 and 30.4δ; MS (m/z) M+ =288, other ions at m/z 259, 228, 195, 181, 167, 152, 137, 122, 109, 77, 66 and 53.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.CC[O-].[Na+].[NH2:17][CH:18]([CH2:22][C:23]1[C:24](=[O:33])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]([OH:21])=[O:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:17][CH:18]([CH2:22][C:23]2[C:24](=[O:33])[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([OH:21])=[O:20])=[O:8])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 9 %

Procedure:
In 100 ml of ethanol, 1.66 g of ethyl p-chlorobenzate, 0.5 g of sodium ethylate and 2.09 g of 2-amino-3-(2-quinolon-3-yl)propionic acid were added and the whole mixture was placed in an autoclave. The reaction was carried out under 110 atmospheric pressure at 140°-150° C. for 6 hours. After completion of the reaction, the reaction mixture was cooled and concentrated under a reduced pressure. The residue was dissolved in 200 ml of chloroform, washed with 1%-potassium carbonate aqueous solution, a diluted hydrochloric acid and water in this order, then the chloroform layer was dried with sodium sulfate. The solvent was removed by distillation, the residue was recrystallized from ethanol-water to obtain 300 mg of 2-(4-chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid in the form of white powdery product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH:26]12[NH:37][CH:33]([CH2:34][O:35][CH2:36]1)[CH2:32][C:31]1[C:27]2=[CH:28][O:29][N:30]=1>>[CH3:18][O:17][C:15]([C:14]1[C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]=1[CH2:19][N:37]1[CH:33]2[CH2:34][O:35][CH2:36][CH:26]1[C:27]1[C:31]([CH2:32]2)=[N:30][O:29][CH:28]=1)=[O:16]
Reactant: c1onc2c1C1COCC(C2)N1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Product: COC(=O)C1=C(CN2C3COCC2c2conc2C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1a in Scheme 3 by using methyl (4R)-4-(2-chloro-4-fluoro-phenyl)-6-(bromomethyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (200 mg) and 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (100 mg). 15 mg of the title compound was isolated as yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:9]=[CH:8][C:6]=2[CH:7]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CC#N>[N:31]1([CH2:2][C:3]2[O:4][C:5]3[CH:11]=[C:10]([O:12][C:13]4[S:14][C:15]5[C:16]([N:21]=4)=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: ClCc1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc2nc(Oc3ccc4cc(CN5CCOCC5)oc4c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
To a solution 2-(2-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (110 mg, 0.3 mmol) in MeCN (3 mL) was added DIEA (209 μL, 0.155 mg, 0.8 mmol) followed by morpholine (27 μL, 27 mg, 0.3 mmol) and stirred (rt, 12 h). The reaction mixture was partitioned between DCM (15 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with saturated NH4Cl (10 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to provide the title compound as colorless crystals (41 mg, 37%). MS (ESI): mass calcd. for C19H17N3O3S, 367.1; m/z found, 368.1.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.01 (dd, J=7.9, 1.7, 1H), 7.59-7.51 (m, 2H), 7.28-7.25 (m, 1H), 7.20 (dd, J=8.0, 4.8, 1H), 6.65 (s, 1H), 3.75 (dd, J=15.5, 10.8, 4H), 3.70 (s, 2H), 2.62-2.49 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH3:14].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(OCC)C>[CH:22]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]([CH3:14])[CH3:12])[C:20]=1[O:21][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])([CH3:24])[CH3:23]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of phthalic anhydride (0.84 g, 5.6 mmol) and propofol (1 g, 5.6 mmol) was added triethylamine (0.65 g, 6.4 mmol) and a catalytic amount of DMAP. The reaction mixture was brought to 90° C., stirred for 14 h, cooled to room temperature and diluted with ethyl ether (100 mL). The organic layer was washed with 10% aqueous citric acid solution (2×50 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was sufficiently pure to be carried to the subsequent step.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][OH:7])(=[O:24])=[O:25]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: OCCNC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCO)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To 2-(cyclopropylamino)ethanol (2 eq.) was added triethylamine (2.5 eq.) and the mixture was cooled to 0° C. To this cold reaction mixture was added 2-chloro-6-methylbenzene sulfonyl chloride (1 eq.) and the mixture was stirred at 25° C. for 2 h. It was diluted with dichloromethane and the organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was purified by column chromatography (10% ethyl acetate in hexane). Yield: 50%
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(Oc2ccccc2)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol (300 mg, 0.89 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (169 mg, 0.89 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (256 mg, 1.33 mmol) and 1-hydroxy-1H-benzotriazole (136 mg, 0.89 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (148 mg, 33%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:36][CH2:37][N:38]([CH2:14][CH2:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:39][CH2:40]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(-c2cc(C(=O)CC3CCNCC3)c3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)CC3CCN(CCc4ccccc4)CC3)c3ccccc3n2)cc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
3.45 g of potassium carbonate and 1.39 g of 2-phenylethyl bromide are added to a solution of 1.72 g of 1-[2-(4-methyl-phenyl)-4-quinolyl]-2-(4-piperidyl)-ethanone, prepared as indicated in Example 8, in 25 ml of dimethylformamide. The suspension, well stirred, is heated for 5 hours at 60° C., then poured into 1 liter of ice-water. The oil which separates is decanted, washed with water, then 100 ml of ether and 100 ml of a 1N aqueous solution of hydrochloric acid are added. The precipitate formed is filtered, washed with water and then with acetone. 2 g of 1[2-(4-methyl-phenyl)-4-quinolyl]-2-[1-(2-phenyl-ethyl)-4-piperidyl]-ethanone are obtained in the form of dihydrochloride melting at 195° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.P(=O)(O)(O)O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)n(Cc3ccccc3)c2s1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2c(C3=CCCCC3)c(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 80 °C
Yield: 95 %

Procedure:
A solution (0.2 M) of methyl 6-benzyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (10 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. for 3 h, then was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:30 acetone/toluene) affording the title compound (95%) as a solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
6 g of Boc-Phe-PAM resin (substitution 0.36 mmol/g) was suspended and shaken in TFA/CH2Cl2 (1:1 by volume, 3×50 mL) 10 min. each time at room temperature to remove the Boc-group. The product was isolated by filtration and washed (3×50 mL each) with CH2Cl2 8% DIEA in CH2Cl2 and CH2Cl2 to give the free base of Phe-PAM-resin. This was subjected to sequential solid phase synthesis using the Fmoc-protocol. All couplings were performed using the DCC/HOBt procedure. At step 7 the Fmoc-amino acid, DCC, and HOBt were added with the corresponding reaction times as follows: Fmoc-Asp(OtBu)-OH (2.46 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Trp-OH (2.6 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. Fmoc-Gly-OH (1.8 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min. Fmoc-Met-OH (2.2 g, 6 mmol), DCC (1.24 g, 6 mmol) and HOBt (1.2 g, 9 mmol) were dissolved in 50 mL of 1:1 by volume DMF/CH2Cl2, and allowed to couple for 60 min at room temperature. At this point the peptide-resin was dried under high vacuum to provide 7.98 g of Fmoc-Met-Gly-Trp-Met-Asp(OtBu)-Phe-PAM resin.