Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-:12].[Na+].O(CC[O:23][C:24]1C=CC=CC=1)C1C=CC=CC=1>>[OH:11][C:2]1[C:3]([C:24]([OH:23])=[O:12])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: [OH-]
Reactant: c1ccc(OCCOc2ccccc2)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 260 °C
Yield: 75.5 %

Procedure:
A stirred autoclave is charged with 1220 parts of β-naphthol, 620 parts of caustic soda solution (50% by weight strength) and 360 parts of 1,2-diphenoxyethane. The mixture is heated while stirring to an internal temperature of 260° C. and kept at this temperature for ten minutes as in Example 4. Residual moisture is removed from the autoclave within five minutes at 100 mm pressure; dehydration is practically complete. Carbon dioxide is then passed into the autoclave at an internal temperature of 260° C. up to a pressure of 7 atmospheres. Carboxylation followed by processing are carried out as in Example 4. The mixture of organic phase and aqueous phase is acidified to about pH 5 at a temperature of 95° C. with vigorous stirring and the β-naphthol liberated is separated with the organic phase. The clear aqueous phase is heated to 85° to 90° C., acidified to pH about 3 with hydrochloric acid and stirred for another thirty minutes. After cooling to 50° C. the yellowish crystals of 2-hydroxy-naphthalene-3-carboxylic acid are suction filtered and dried at 70° C. in vacuo. 550 parts (75.5% of theory based on reacted β-naphthol) of 2-hydroxynaphthalene-3-carboxylic acid is obtained with a melting point of 214° to 216° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].NS(C1C=CC(C(O)=O)=CC=1F)(=O)=O.Cl.Cl.[CH3:31][C:32]1[N:36]([CH:37]2[CH2:43][CH:42]3[N:44]([CH2:45][CH2:46][C:47]4([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)[CH:39]([CH2:40][CH2:41]3)[CH2:38]2)[C:35]2[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=2[N:33]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[F:14][C:11]1[CH:12]=[CH:13][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[C:6]([C:7]([N:50]2[CH2:49][CH2:48][C:47]([CH2:46][CH2:45][N:44]3[CH:39]4[CH2:40][CH2:41][CH:42]3[CH2:43][CH:37]([N:36]3[C:35]5[CH:59]=[CH:60][CH:61]=[CH:62][C:34]=5[N:33]=[C:32]3[CH3:31])[CH2:38]4)([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:52][CH2:51]2)=[O:9])[CH:10]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: NS(=O)(=O)c1ccc(F)cc1C(=O)O
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(C(=O)O)cc1F
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc(F)ccc2S(N)(=O)=O)CC1
Yield: 20 %

Procedure:
The title compound was prepared from a mixture of 2-(aminosulfonyl)-5-fluorobenzoic acid and 4-(aminosulfonyl)-3-fluorobenzoic acid 6b and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-aza bicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydro-chloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 20% methanol in ethyl acetate to afford 4-fluoro-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide 6 as a white solid (9.8 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (t, 1H. J=7.7 Hz), 7.64 (m, 1H), 7.39 (m, 2H), 7.30-7.12 (m, 8H), 5.69 (broad s, 2H), 4.59 (m, 1H), 4.20 (m, 1H), 3.48-3.19 (m, 5H), 2.52 (s, 3H), 2.40-2.32 (m, 3H), 2.18 (m, 1H), 2.04-1.70 (m, 10H), 1.62 (m, 2H). ES-LCMS m/z 630.19 (M+H). Analytical HPLC (Method Y) Rt 4.16 (90.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][NH:9][C:10]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:40])([F:39])[F:38])[CH:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]3[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[C:28]([O:36][C:37]([F:39])([F:38])[F:40])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NCc2ccc(CN)cc2)nc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)c1nc(NCc2ccc(CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)cc2)nc2ccccc12

Procedure:
A solution of N2-(4-aminomethyl-benzyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride (50.0 mg, 0.131 mmol), 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (53.3 mg, 0.157 mmol) and diisopropylethylamine (91 μl, 0.524 mmol) in 2-propanol (1.5 mL) was stirred at ambient temperature for 2 hr. The resulting mixture was concentrated, and the residue was purified by column chromatography (silica gel, 10% MeOH in CH2Cl2) to give 4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-2-trifluoromethoxy-benzenesulfonamide as a white crystalline compound (40 mg, 50%).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[CH:21][N:20](C(OCC(C)C)=O)[C:19]=4[CH:30]=3)[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)=[O:3].[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][NH:40]2)[CH:35]=[CH:36][C:37]=1[CH3:38].[CH:45](N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C1COCC1>[F:31][C:32]1[CH:33]=[C:34]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][N:40]2[C:2]([N:4]2[CH2:10][C:9]3[CH:11]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]5[N:22]=[C:21]([CH3:45])[NH:20][C:19]=5[CH:30]=4)[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5]2)=[O:3])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: CC(C)COC(=O)n1cnc2ccc(-c3ccc4c(c3)CN(C(=O)Cl)CCO4)cc21
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C2CCCCN2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCCCC3c3ccc(C)c(F)c3)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.1 %

Procedure:
2-Methylpropyl 6-[4-(chlorocarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazole-1-carboxylate (150 mg, 0.38 mmol) and 2-(3-fluoro-4-methylphenyl)piperidine (reagent preparation 1) (80 mg, 0.41 mmol) were taken into THF (3.5 mL) followed by addition of diisopropylethylamine (0.33 mL, 1.9 mmol) and the resulting solution was heated to reflux for 3 h. The mixture was then cooled to room temperature and partitioned with ethyl acetate and 20% aqueous citric acid. The organic phase was separated, dried over sodium sulfate then filtered and concentrated. The residue obtained was taken up into methanol (5 mL) followed by addition of solid potassium carbonate (518 mg, 3.75 mmol) and the mixture was stirred for 12 h at room temperature. The mixture was then concentrated and the residue taken into a minimum of aqueous acetonitrile and purified by preparative reverse phase HPLC. Lyophillization of the combined pure fraction afforded 4-{[2-(3-fluoro-4-methylphenyl)piperidin-1-yl]carbonyl}-7-(2-methyl-1H-benzimidazol-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (23 mg) as an amorphous solid. 1H NMR (400 MHz, d6-DMSO): 12.18 (br s, 1H), 7.59 (br s, 1H), 7.47 (dd, 2H), 7.40 (d, 1H), 7.27 (dd, 1H), 7.12 (t, 1H), 7.01 (d, 1H), 6.96 (d, 2H), 4.59 (m, 1H), 4.40 (dd, 2H), 4.18 (m, 2H), 3.53 (m, 2H), 3.21 (m, 1H), 3.00 (m, 1H), 2.50 (s, 3H), 2.24 (s, 3H), 1.96 (m, 1H), 1.79 (m, 1H), 1.62-1.38 (m, 4H). MS (EI) for C30H31FN4O2: 499 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[CH2:8]1[C:22](=O)[C:21]2[C:12](=[C:13]([OH:27])[C:14]3[C:19]([C:20]=2[OH:24])=[C:18](O)[CH:17]=[CH:16][C:15]=3O)[C:10](=[O:11])[CH2:9]1>>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:15]1[C:14]2[C:13](=[O:27])[C:12]3[C:21](=[C:22]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH:8]=[CH:9][C:10]=3[OH:11])[C:20](=[O:24])[C:19]=2[C:18]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][OH:1])=[CH:17][CH:16]=1
Reactant: NCCNCCO
Reactant: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Product: O=C1c2c(O)ccc(NCCNCCO)c2C(=O)c2c(NCCNCCO)ccc(NCCNCCO)c21

Procedure:
The reaction between 2-(2-hydroxyethylamino)ethylamine and leuco-1,4,5,8-tetrahydroxyanthraquinone is carried out as in Example 1 to give the title compound.
Reaction SMILES: [CH3:1][Li].[SiH3][SiH3].[CH3:5][Si:6]([CH3:18])([O:15][CH2:16][CH3:17])[Si:7]([CH3:14])([O:11][CH2:12][CH3:13])OCC>>[CH3:18][Si:6]([CH3:5])([O:15][CH2:16][CH3:17])[Si:7]([CH3:1])([CH3:14])[O:11][CH2:12][CH3:13]
Reactant: CCO[Si](C)(C)[Si](C)(OCC)OCC
Reactant: [Li]C
Agent: [SiH3][SiH3]
Product: CCO[Si](C)(C)[Si](C)(C)OCC

Procedure:
In the same manner as in Example 1, change of the average molecular weight of the resulting polysilanes was examined by changing the amount of methyl lithium to be used as a reaction starting compound. The results including those of Example 1 and the yields and properties of the products are shown in Table 1. In Example 4, after the disilane compound and methyl lithium were reacted, the reaction mixture was applied to gas chromatography before heating to confirm that 1,1,2-trimethyl-1,2,2-triethoxydisilane and 1,1,2,2-tetramethyl-1,2-diethoxydisilane were produced. From the reaction mixture of Example 4, no solid was obtained by reprecipitation so that low boiling point compounds were removed under conditions of 180° C. and 1 Torr to give a final product.
Reaction SMILES: [CH2:1]1[CH:6]2[CH:7]3[CH:13]4[CH2:14][CH:2]1[CH2:3][CH:4]1[CH:12]4[CH2:11][CH:9]([CH2:10][CH:5]12)[CH2:8]3.[Br-:15].[Al+3].[Br-:17].[Br-]>BrBr>[CH2:14]1[C:2]2([Br:15])[CH2:1][CH:6]3[CH:5]4[CH2:10][C:9]5([Br:17])[CH2:11][CH:12]([CH:4]4[CH2:3]2)[CH:13]1[CH:7]3[CH2:8]5
Reactant: C1C2CC3C4CC5CC(C14)C(C2)C3C5
Reactant: [Br-]
Agent: BrBr
Agent: [Al+3]
Product: BrC12CC3C4CC5(Br)CC3C(C1)C(C5)C4C2
Temperature: 0 °C
Reaction time: 16 h
Yield: 650.1 %

Procedure:
Diamantane (50 g, 0.26 mol) was added over 1 h to bromine (200 mL) at 0° C. Aluminum bromide (5.4 g, 0.02 mol) was added and the mixture was stirred at 0° C. for 3 h and at ambient temperature for 16 h. When glc showed less than 5% monobrominated diamantanes, the bromine was removed under reduced pressure and the residue was triturated with pentane (300 mL). The precipitate was filtered, and was washed with pentane (2×150 mL) and methanol (3×100 mL). The residue was recrystallized from toluene to give 45 g (50%) of 4,9-dibromodiamantane, a white solid: mp 328° C. (lit. mp 324°-326° C.); 1H NMR (CDCl3) δ1.97 (s, 6H) 2.31 (s, 12H); 13C NMR (CDCl3) δ39.64, 48.45, 62.81.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[S:26]1[CH:27]=[CH:28][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25]1
Reactant: C#Cc1ccsc1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#Cc1ccsc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 3-ethynyl-thiophene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (48 mg, 40%); 1H NMR δ (CDCl3): 8.39 (d, J=8.51 Hz, 1H), 7.9 (br s, 1H), 7.36-7.30 (m, 2H), 7.30-7.21 (m, 3H), 7.02 (t, J=7.24 Hz, 1H), 2.21 (s, 3H); LCMS m/z: 241.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15].[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)=CC2
Agent: Cl
Product: CCC(=O)NCCC1=CCc2ccc(OC)cc21

Procedure:
Using (E)-2-(6-methoxyindan-1-ylidene)ethylamine, the procedure of Reference Example 14 was otherwise repeated to provide 2-(5-methoxy-1H-inden-3-yl)ethylamine hydrochloride. Then, starting with this 2-(5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and propionyl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 86%).
Reaction SMILES: Br[CH:2]([C:4]1([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)OCCO1)C.[C:21]([O-:24])(=[O:23])C.[K+]>C(N)=O>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:4]([CH3:2])[C:21]([OH:24])=[O:23])[CH:18]=[CH:17]2
Reactant: COc1ccc2cc(C3(C(C)Br)OCCO3)ccc2c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: NC=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A mixture of 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane (3.37 g; 10 mmol), potassium acetate (1.2 g; 12 mmol) and formamide (50 ml) is heated under stirring at 170° C. for 2.5 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (yield 52%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=O.Cl.[NH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)N>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][C:4]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]([NH2:19])=[O:18])[CH:14]=2)[NH:8][CH:5]=1
Reactant: O=CCCCCl
Reactant: NNc1ccc(CC(N)=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)Cc1ccc2[nH]cc(CCCl)c2c1

Procedure:
A mixture of 4-chlorobutanal (1.8 g) and 2-(4-hydrazinophenyl)acetamide hydrochloride (3 g) in 50% aqueous acetic acid (200 ml) was heated at reflux for 45 min., then cooled and evaporated to give 3-(2-chloroethyl)-1H-indole-5-acetamide as a dark organe-brown foam. τ (DMSO) 6.3(2H); 6,8(2H); (CH2CH2Cl)
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:22][C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[N:56]1([C:62]2[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:20]=[C:21]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:30][CH2:31]1)[CH2:22][C:23]([NH:68][C:65]1[CH:64]=[CH:63][C:62]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[CH:67][CH:66]=1)=[O:25]
Reactant: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(N2CCCCC2)cc1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
HOBt (43 mg, 0.31 mmol) and DIEA (150 mg, 1.1 mmol) were added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.29 mmol) in DMF. The reaction mixture was cooled to 10° C. and EDCI.HCl (111 mg, 0.58 mmol) followed by 4-piperidin-1-yl-phenylamine (61.4 mg, 0.34 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 69 mg (47%) of. LCMS: 503.22 (M+1)+, 94.4%, 1H NMR: (CDCl3): δ 9.3 (d, 1H), 7.8 (d, 1H), 7.7 (m, 2H), 7.5 (m, 3H), 7.0 (d, 2H), 4.5 (s, 1H), 4.1-3.8 (m, 2H), 3.8-3.6 (m, 3H), 3.6-3.4 (m, 3H), 3.3-3.2 (m, 2H), 3.1 (t, 4H), 1.9-1.7 (m, 7H), 1.6 (q, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([Si](C)(C)C)([F:23])[F:22]>CN(C)C=O>[F:20][C:21]([F:23])([F:22])[CH:12]([C:9]1[S:8][C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:11][CH:10]=1)[OH:13]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cnc(N2CCOCC2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cnc(N2CCOCC2)s1)C(F)(F)F
Yield: 65.1 %

Procedure:
According to Reference Example 8-2, by use of 2-morpholinothiazole-5-carbaldehyde (177 mg, 0.893 mmol) dissolved in N,N-dimethylformamide (5.3 mL), potassium carbonate (25 mg, 0.18 mmol) and (trifluoromethyl)trimethylsilane (0.198 mL, 1.34 mmol), the mixture was stirred and reacted at room temperature for 2.3 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(2-morpholinothiazol-5-yl)ethanol (Compound DY) (156 mg, yield: 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2].C(OC(=O)C(CC(C1C=CC([F:42])=CC=1)=O)C(=O)C)C.FC1C=CC(N)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][C:21]([F:42])=[CH:20][CH:19]=2)[C:7]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)c1ccc(F)cc1)C(C)=O
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Agent: Nc1ccc(F)cc1
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1C

Procedure:
Prepared in analogy to that of 5-(4-fluoro-phenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid ethyl ester and 4-fluoroaniline. The title compound, ESI MS (m/z): 342 (M+H+).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([CH2:45][NH:46][S:47]([CH2:50][CH:51]([CH3:53])[CH3:52])(=[O:49])=[O:48])=[N:25][C:26]=2[NH:30][CH2:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:39]1([CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][NH:30][C:26]2[N:25]=[C:24]([CH2:45][NH:46][S:47]([CH2:50][CH:51]([CH3:52])[CH3:53])(=[O:48])=[O:49])[N:23]=[C:22]3[C:27]=2[N:28]=[CH:29][N:21]3[C@H:6]2[C@H:5]([OH:4])[C@H:9]([OH:10])[C@@H:8]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH3:20])[N:18]=3)[O:7]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNS(=O)(=O)CC(C)C)nc43)[C@H](O)[C@@H]2O)n1
Yield: 92.5 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-(6-[(2,2-diphenylethyl)amino]-2-{[(isobutylsulphonyl)amino]methyl}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (Preparation 26) (230 mg, 0.31 mmol) and sodium carbonate (130 mg, 1.23 mmol) in methanol (15 ml) and water (1.5 ml) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was partioned between ethyl acetate (50 ml) and water (10 ml). The organic layer was washed with brine (10 ml), dried (anhydrous sodium sulphate) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (97:3 by volume). Product containing fractions were evaporated to afford the title compound as a white powder (190 mg).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Ca+2].O>C1C=CC=CC=1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]([O:30][C:3](=[O:4])[NH2:5])[CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[CH:16][C:15]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=2[O:41][C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(N)=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
64 μl (0.54 mmol) of trichloroacetyl isocyanate, were added to a solution of 272 mg (0.52 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl) acetamide (prepared as described in Example 12) in 6 ml of benzene, and the resulting mixture was stirred for 10 minutes. At the end of this time, a methanolic solution of calcium carbonate was then added, whilst stirring. The reaction mixture was then mixed with water, and the organic phase was separated and dried. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel, using a 15:85 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 135 mg (yield 46%) of the title compound as a foam-like material.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)C.O.[NH2:19][NH2:20].O>CO>[NH2:11][C:9]1[S:10][C:6]([C:4]([NH:19][NH2:20])=[O:3])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1sc(N)nc1-c1ccccc1
Yield: 70 %

Procedure:
2-Amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (5.0 g, 20 mmol) was suspended in methanol. Hydrazine monohydrate (5 mL, 100 mmol) was added and heated to reflux for 2 h. Hydrazine monohydrate (10 mL) was added and heated to reflux for 48 h. Water (100 mL) was added to the reaction mixture and the methanol was removed by evaporation in vacuo. The product precipitates and the solid product is collected by filtration. Yield: 70%.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].O.[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([S:22][CH2:23][C@H:24]([CH3:28])[C:25](Cl)=[O:26])=[O:21])=[CH:18][C:17]=1[S:31](=[O:34])(=[O:33])[NH2:32]>CO>[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([S:22][CH2:23][C@@H:24]([CH3:28])[C:25]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])=[O:26])=[O:21])=[CH:18][C:17]=1[S:31](=[O:34])(=[O:33])[NH2:32]
Reactant: C[C@@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
3 g of L-proline and 2 g of sodium hydrogen carbonate are added to 120 ml of water whereupon 3.5 g of 3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl chloride is addedslowly under ice-cooling and stirring, and the resulting mixture is stirredat room temperature for 3 hours. The reaction mixture is then treated in ananalogous manner of Example 1 to give 1-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-L-proline as white non-crystalline powder, [α]D25 -102.3 (methanol).