Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C([Li])CCC.[CH3:21][S:22]SC.O>CCOCC.CCCCCC.C1COCC1>[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][O:9][CH2:8][CH2:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[S:22][CH3:21]
Reactant: CSSC
Reactant: COCCOCOCCc1ccsc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCOCCc1ccsc1SC
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred solution of 2-bromo-3-[2(methoxyethoxymethoxy)ethyl]thiophene (51.8 g, 0.175 mol) in anhydrous ether (125 ml) cooled to -70° C. was added n-butyl lithium (109.4 ml of a 1.6M solution in hexane, 0.175 mol) under a nitrogen atmosphere over a 11/2 hour period. A tan suspension resulted which was stirred for an additional 1 hour and then was diluted with dry THF (100 ml) and was passed under nitrogen into a stirred solution of dimethyldisulfide (18.8 g, 0.20 mol) in anhydrous ether (50 ml) at -15° C. The resulting mixture was stirred at -15° C. for 1/2 hour and at reflux for 2 hours. The dark mixture was cooled to 0° C. and water (100 ml) was added carefully. The organic layer was separated and washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature. The crude liquid (44.6 g) was distilled, the product being collected at 110-140° C. at 0.7 mm to give 34.6 g of pure product. Yield 75%. NMR supported the structure.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH2:36])=[O:35])=[O:31])[C@@H:20]([CH3:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:47]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:48]([C:59]([NH:61][CH2:62][C:63]([OH:65])=O)=[O:60])[C@@H:49]([CH3:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[NH:47]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:48]([C:59]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH2:36])=[O:35])=[O:31])[C@@H:20]([CH3:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:65])=[O:60])[C@@H:49]([CH3:58])[O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 77.7 %

Procedure:
By using 30.00 g of Boc-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 19.60 g of Boc-Thr(Bzl)-Gly-OH, and the same procedure as in Reference Example 15 was repeated to obtain 32.36 g (yield: 77.7%) of the above-mentioned objective product.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([N+:18]([O-:20])=[O:19])[CH:6]=1)[CH2:3][CH3:4].[C:21]([OH:30])(=[O:29])[C@H:22]([C@@H:24]([C:26]([OH:28])=[O:27])[OH:25])[OH:23]>CO>[C:21]([OH:30])(=[O:29])[C@H:22]([C@@H:24]([C:26]([OH:28])=[O:27])[OH:25])[OH:23].[NH2:1][C@@H:2]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[C:7]([N+:18]([O-:20])=[O:19])[CH:6]=1)[CH2:3][CH3:4]
Reactant: CCC(N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CO
Product: CC[C@@H](N)c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 4-(1-aminopropyl)-2-nitrobenzoate (5.6 g) in 98% hydrous methanol (112 ml), D-tartaric acid (1.8 g) was added at room temperature, and the mixture was stirred at 60° C. for 1 hour and further stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and dried to obtain the title compound (3.4 g) as a colorless crystal. A small amount of obtained crystal salt was conveted to corresponding free form, and optical purity of obtained dree form was determined by high performance liquid chromatography (HPLC), whereupon it was found to be 62.2% ee. The obtained crystals (3.4 g, 62.2% ee) were suspended in 80% hydrous methanol (68 ml), and the resulting suspension was stirred under heating and refluxed for 1 hour, then further stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and dried to obtain the title compound (2.7 g, 94.4% ee) as a colorless crystal. To improve the optical purity, the obtained crystals (2.7 g, 94.4%ee) were suspended in 80% hydrous methanol (54 ml), and the resulting suspension was stirred under heating and refluxed for 1 hour, then further stirred at room temperature for 5 hours. The precipitated crystals were collected by filtration and dried to obtain the title compound (2.5 g, 99.1% ee) as a colorless crystal.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:27][CH:26]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Br:19])[CH:32]=2)=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2cccc(C)c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Yield: 96 %

Procedure:
3′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 3′-Methyl-biphenyl-4-carboxylic acid ethyl ester (3.80 g, 15.81 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.1 g, 17.39 mmol, 1.1 eq.) and 2,2′-azobisisobutyronitrile (0.13 g, 0.79 mmol, 5 mol %). When complete, the reaction was worked up as described leaving 3′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (4.83 g, 96%) as a yellow oil that crystallized on standing.
Reaction SMILES: C(O[C:4](=[O:38])[C:5]([F:37])([F:36])[S:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([S:32]([CH3:35])(=[O:34])=[O:33])([CH3:31])[CH3:30])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:14]=2)[CH:12]=1)C.[CH3:39][Mg+].[Br-].[BH4-].[Na+]>C(Cl)Cl.[NH4+].[Cl-]>[F:36][C:5]([F:37])([S:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([S:32]([CH3:35])(=[O:34])=[O:33])([CH3:30])[CH3:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:14]=2)[CH:12]=1)[CH:4]([OH:38])[CH3:39]
Reactant: C[Mg+]
Reactant: CCOC(=O)C(F)(F)Sc1cncc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(O)C(F)(F)Sc1cncc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of difluoro-(5-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-pyridin-3-ylsulfanyl)-acetic acid ethyl ester from Step 1 (1.0 eq.) in CH2Cl2 (0.2M) at −78° C. was added MeMgBr (3.0 eq.; 3.0M in Et2O). The mixture was warmed to rt, stirred for 12 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in EtOH (0.2M) then NaBH4 (3.0 eq.) was added. The mixture was stirred for 2 h, poured in saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:9) afforded the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 9.04 (d, 1H), 8.97 (dd, 1H), 8.75 (d, 1H), 8.50 (dd, 1H), 8.35–8.34 (m, 2H), 8.26 (d, 1H), 8.13 (s, 1H), 7.85 (dt, 1H), 7.82 (dt, 1H), 7.68 (t, 1H), 7.61 (dd, 1H), 5.15 (d, 1H), 4.20 (m, 1H), 2.76 (s, 3H), 2.03 (s, 6H), 1.37 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([NH2:34])=[O:33])[CH:30]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32](=[O:33])[NH2:34])[CH:30]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: NC(=O)Cn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetamide gives the compound “A25”; HPLC/MS: 0.94 min, [M+H]=338;
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:35]C)=[C:13]([C:15]2[C:20]([O:21]COCCOC)=[C:19]([CH:28]=O)[CH:18]=[C:17]([CH2:30][C:31]([O:33]C)=[O:32])[CH:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[NH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[NH2:48])[C:42]([NH2:44])=[NH:43].C1(=O)C=CC(=O)C=C1.Cl.N1C=CC=CC=1>CO>[C:42]([C:41]1[CH:45]=[CH:46][C:47]2[NH:48][C:28]([C:19]3[CH:18]=[C:17]([CH2:30][C:31]([OH:33])=[O:32])[CH:16]=[C:15]([C:13]4[CH:14]=[C:9]([S:6](=[O:7])(=[O:8])[NH2:5])[CH:10]=[CH:11][C:12]=4[OH:35])[C:20]=3[OH:21])=[N:38][C:39]=2[CH:40]=1)(=[NH:43])[NH2:44]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: COCCOCOc1c(C=O)cc(CC(=O)OC)cc1-c1cc(S(=O)(=O)NC(C)(C)C)ccc1OC
Agent: Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: c1ccncc1
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Temperature: 180 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Methyl [5′-tert-butylsulfamoyl-5-formyl-2′-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (0.496 g, 1.1 mmol), prepared as in Reference 8, was dissolved in methanol (20 mL) and the solution was charged with 3,4-diaminobenzamidine-HCl (1.25 mmol, 0.23 g) and 1,4-benzoquinone (1.25 mmol, 0.135 g). The mixture was refluxed for 2 hours and then concentrated by evaporation. This residue was taken up in trifluoroacetic acid (10 mL) and the mixture was stirred for 1 hour. Evaporation and further pumping down yielded a purple amorphous residue. Pyridine hydrochloride (5.0 g) was added and the reaction mixture was heated at 180° C. for 30 minutes. The mixture was cooled and a resulting solid was dissolved in 20 mL of preparative hplc sample solvent (20% acetonitrile/20 mmol HCl). The product was purified by preparative hplc (C-18, 2,2,25 acetonitrile). The fractions containing the pure product were collected and lyophilized to give [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetic acid (0.31 g, 59%). LCMS: Calcd 481.49; Obsd (MH+)=482.0, (MH−)=480.2. NMR (DMSO-d6) d 3.621 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.15 (br s, 2H), 7.27 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.65 (m, 2H), 7.73 (d of d, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.17 (s, 1H), 9.10, 9.39 (2s, 4H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH:36]([CH3:38])[CH3:37])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12]C(C)C)=[O:11])([CH3:4])[CH3:3].[OH-].[Na+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH:36]([CH3:38])[CH3:37])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: CC(C)OCc1nc(C(C)(C)O)c(C(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 90 %

Procedure:
A solution of 393 mg of isopropyl 4-(1-hydroxy-1-methylethyl)-2-isopropoxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 92(b)] in 3 ml of a 1N aqueous solution of sodium hydroxide was stirred at room temperature for 2 hours, and then insoluble matter was filtered off. 3 ml of 1N aqueous hydrochloric acid were added to the filtrate, and the precipitated amorphous powder was collected by filtration, to give 325 mg of the title compound, melting at 153°-161° C. (with softening).
Reaction SMILES: FC(F)(F)C(O)=O.COCCOC[O:14][C:15]1[CH:38]=[CH:37][C:18]2[N:19]=[C:20]([C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([O:29]COCCOC)=[CH:25][CH:24]=3)[S:21][C:17]=2[CH:16]=1>O.CO>[OH:14][C:15]1[CH:38]=[CH:37][C:18]2[N:19]=[C:20]([C:22](=[O:36])[C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[S:21][C:17]=2[CH:16]=1
Reactant: COCCOCOc1ccc(C(=O)c2nc3ccc(OCOCCOC)cc3s2)cc1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(O)cc1)c1nc2ccc(O)cc2s1
Temperature: 70 °C
Reaction time: 48 h
Yield: 94.8 %

Procedure:
0.2 ml of trifluoroacetic acid was added to a solution of 4 g of the Compound 1 obtained in Example 1 in water-methanol. The mixture was stirred for 48 hours at 70° C. After the reaction was completed, methanol was evaporated and the crystals were collected by filtration and dried to give 2.3 g of 6-hydroxy-2-(4-hydroxybenzoyl)benzothiazole (Compound 7). mp: 46° C. 1H-NMR(aceton-d6): 7.01(d,J=8.9 Hz,2H), 7.18(dd,J=8.9,2.4 Hz,1H), 7.52(d,J=2.4 Hz,1H), 8.05(d,J=8.9 Hz,1H), 8.58(d,J=8.9 Hz,2H), 9.15(br,1H), 9.40(br,1H) IR(KBr) cm-1 : 3463, 1602, 1589, 1491, 1249, 1176, 1119, 875 MS m/z: 271(M+), 243, 121 Elementary analysis (C14H9NO3S 0.8 H2O): Calculated (C=58.84,H=3.74,N=4.90); Found (C=58.78,H=3.55,N=4.54)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:19][OH:20])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(Cl)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from sodium hydride, (3-chloro-4-(3,4-difluorophenoxy)phenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(C1C=C(C)C=C(C)C=1O)(C)(C)C.[C:39]([O-:44])(=[O:43])[C:40]([CH3:42])=[CH2:41].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.C(OC)(C)(C)C>[CH2:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:44][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41])=[CH:14][CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCBr)cc2)cc1
Reactant: C=C(C)C(=O)[O-]
Agent: Cc1cc(C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCCOC(=O)C(=C)C)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
118.4 g (0.29 mol) of this ester were dissolved in 50 ml of dimethylformamide at 70° C., 0.3 g of 2-tert-butyl-4,6-dimethylphenol was added as stabilizer, 111.7 g (0.9 mol) of dry potassium methacrylate salt were added, and the mixture was diluted with 70 ml of toluene. The reaction mixture was stirred at 100° C. for 6 h, then cooled and diluted with 800 ml of methyl tert-butyl ether. The precipitate was filtered off with suction, and the washing solution and the filtrate were combined and washed three times with water. They were then concentrated, and the crude product obtained was recrystallized from isopropanol. 4-(4-Methacryloyloxybutoxy)phenyl 4-allyloxybenzoate of m.p. 62-63° C. was obtained in a yield of 83%. Between 41 and 45° C. the ester has a nematic phase which occurs only on supercooling.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:40][C:39]([C:41]([O:43]CC)=[O:42])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)s3)oc2C)c(OC)c1)OCC
Yield: 25.8 %

Procedure:
To a mixture of ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate (1.05 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was heated under reflux for 30 min. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylic acid as colorless crystals (0.26 g, yield 25%) from a fraction eluted with ethyl acetate-methanol (6:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. Melting point: 165-166° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.[Br:18]N1C(=O)CCC1=O.O>O1CCCC1>[Br:18][C:10]1[NH:11][C:5]2[CH:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:3][N:2]([CH3:1])[CH2:8][CH2:7][C:6]=2[CH:9]=1
Reactant: CN1CCc2cc[nH]c2C(c2ccccc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2cc(Br)[nH]c2C(c2ccccc2)C1
Reaction time: 0.67 h

Procedure:
A solution of 1,4,5,6,7,8-hexahydro-6-methyl-8-phenylpyrrolo[2,3-d]azepine (0.238 g) in tetrahydrofuran (30 ml) was cooled to -70° C. N-Bromosuccinimide (0.188 g) in tetrahydrofuran (3 ml) was added dropwise over 10 minutes, allowing the temperature to reach -10° C. over 40 minutes. Water was added and the product was extracted into ethyl acetate. The extracts were washed with water, dried and evaporated to give the title product as a solid, m.p. 132°-133° C. (acetonitrile).
Reaction SMILES: [CH3:1][N:2]1[C:9]2[N:5]([N:6]=[CH:7][C:8]=2[C:10]([O:12]C)=[O:11])[CH:4]=[CH:3]1.[OH-].[Na+].Cl>>[C:10]([C:8]1[CH:7]=[N:6][N:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:9]=12)([OH:12])=[O:11]
Reactant: COC(=O)c1cnn2ccn(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccn2ncc(C(=O)O)c12
Yield: 95.9 %

Procedure:
A solution of 1-methyl-7-methoxycarbonyl-1H-imidazo[1,2-b]pyrazole (5.0 g) in 4N-sodium hydroxide aqueous solution (14 ml) was refluxed for 1 hour. The reaction mixture was cooled with ice-bath and adjusted to pH 3.0 with 6N hydrochloric acid. The resultant solid was collected by filtration, washed with cold water and dried over phosphorus pentoxide in vacuo to give 7-carboxy-1-methyl-1H-imidazo[1,2-b]pyrazole (4.42 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([S:7]C(=O)C)[CH2:4][C@H:3]1[C:11]([NH:13][CH3:14])=[O:12].C[O-].[Na+].[ClH:18]>CO>[ClH:18].[CH3:1][N:2]1[CH2:6][C@@H:5]([SH:7])[CH2:4][C@H:3]1[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)[C@@H]1C[C@H](SC(C)=O)CN1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(=O)[C@@H]1C[C@H](S)CN1C
Reaction time: 0.05 h

Procedure:
(2S,4S)-1-Methyl-2-methylaminocarbonyl-4-acetylthiopyrrolidine (215 mg) was dissolved in methanol (2.4 ml), and a solution of sodium methoxide (54 mg) in methanol (1.2 ml) was added thereto at room temperature under nitrogen stream, followed by stirring at the same temperature for 3 minutes. To the reaction mixture, 6N hydrochloric acid (0.38 ml) was added, and the solvent was distilled off. The residue was dissolved in a mixture of dichloromethane and methanol (4:1) and dried over magnesium sulfate. Removal of the solvent gave (2S,4S)-1-methyl-2-methylaminocarbonyl4-mercaptopyrrolidine hydrochloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:19]=[CH:18][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:10]2[F:17])[C:7](=[O:20])[N:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:27][O:28][C:29]1[C:30]([O:49][CH3:50])=[C:31]([CH:46]=[CH:47][CH:48]=1)[C:32](Cl)([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>CN(C)C1C=CN=CC=1.CO>[CH3:27][O:28][C:29]1[C:30]([O:49][CH3:50])=[C:31]([CH:46]=[CH:47][CH:48]=1)[C:32]([O:15][CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:18]=[CH:19][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][C:7]2=[O:20])[C@H:10]([F:17])[C@@H:11]1[OH:12])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: CC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)n1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(NC(C)=O)nc3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Reaction time: 3 h

Procedure:
4 mmol of 4-N-acetyl-2′-fluoro-2′-deoxycytidine are taken up in 25 ml of abs. pyridine in a 100 ml Schlenk flask and, at room temperature, 1.3 g (about 4.4 mmol) of dimethoxytrityl chloride and 20 mg of 4-dimethylaminopyridine are added. After three hours, 1 ml of methanol was added to the mixture, which was then evaporated to dryness in vacuo. The remaining oil is taken up in 50 ml of methylene chloride (deacidified over aluminum oxide) and extracted three times with 50 ml of water. The organic phase is dried over sodium sulfate. After the methylene chloride had been stripped off, the crude product remained as solid foam. The crude product is purified by chromatography on silica gel 60H (column 2×20 cm, mobile phase methylene chloride with 0.1% pyridine, gradient methanol). The product was eluted with 3% methanol in methylene chloride. After the solvent has been stripped off, 1.39 g (59% of theory) of a white foamy solid remain.