Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]I.[CH2:4](OCC)C.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[CH:23][N:22]=[C:21]([N:25]([CH3:37])[C:26]([NH:28][C:29]3[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:36])=[O:27])[CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])[CH3:10]>C1COCC1>[Cl:35][C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:36])[C:29]=1[NH:28][C:26](=[O:27])[N:25]([C:21]1[CH:20]=[C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([C:9]([OH:11])([CH3:4])[CH3:10])=[CH:17][CH:16]=2)[N:24]=[CH:23][N:22]=1)[CH3:37]
Reactant: CCOCC
Reactant: CC(=O)c1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1
Agent: C[Mg]I
Solvent: C1CCOC1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(C(C)(C)O)cc2)ncn1
Reaction time: 5 h

Procedure:
To a freshly prepared solution of methylmagnesium iodide in diethyl ether (8 mL, ˜7 mmol) is added 1-[6-(4-acetyl-phenylamino)-pyrimidin-4-yl]-3-(2,6-dichloro-phenyl)-1-methyl-urea (0.5 g, 1.16 mmol) in several portions. After stirring for 5 h, THF (4 mL) is added. After 16 h the reaction is quenched by the addition of H2O and CH3OH and evaporated in vacuo. The residue is co-evaporated twice with toluene and purified by flash chromatography (CH2Cl2/CH3OH). The combined pure fractions are evaporated to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8].Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][CH:4]1[CH3:8]
Reactant: COC1(c2csc(Sc3ccc(C(C)=O)cc3)c2)CCOC1C
Reactant: NO
Agent: Cl
Product: COC1(c2csc(Sc3ccc(/C(C)=N/O)cc3)c2)CCOC1C
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone oxime in 87% yield, m.p. 105°-107° C.
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.C(Cl)([Cl:47])=S.[C:49](=[O:52])([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1.[CH2:2]1[C:49](=[O:52])[N:44]([Cl:47])[C:42](=[O:43])[CH2:3]1
Reactant: S=C(Cl)Cl
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: O=C1CCC(=O)N1Cl
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2 mmol of NAD+ were dissolved in 10 ml of H2O in a round-bottomed flask with attached bubble-counter, and a little Na2CO3 was added. A solution of 20 mmol of thiophosgene in 10 ml of CHCl3 was added with vigorous stirring at 20° C. The pH was checked every 10 minutes and kept between 5.5 and 8.5 by the addition of small amounts of sodium carbonate. After 3.5 hours there was no longer any change in the pH, and no further gas was evolved. The mixture was evaporated to dryness in vacuo and freeze-dried. The slightly brownish product mixture could be purified of by-products by column chromatography on silica gel using water/acetonitrile as eluent. However, it is advisable to use the product mixture unpurified for the reaction with the polymer (see Example 2), since purification by ultrafiltration of the product immobilized on the polymer is considerably more straightforward and, moreover, the sensitivity of NAD-NCS results in losses due to dimerization and trimerization during purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:25][CH2:24][CH2:23][Cl:22])[C:6]=2[CH:12]=1
Reactant: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2cc([N+](=O)[O-])c(Cl)cc2N1CCCCl
Yield: 40.3 %

Procedure:
Crude 6-Chloro-7-nitro-4H-benzo[1,4]oxazin-3-one (81MF2253a) (2.60 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2253b) (1.23 g, 36%). 1H NMR (CDCl3) δ 7.66 (s, 1H), 7.20 (s, 1H), 4.70 (s, 2H), 4.12 (t, J=7.6 Hz, 2H), 3.67-3.59 (m, 2H), 2.21-2.13 (m, 2H); 13C NMR (CDCl3) δ 163.6, 143.5, 133.3, 133.2, 122.4, 117.2, 115.2, 67.4, 42.1, 39.6, 29.8.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([O:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:7]=1.[NH2:64][C:65]([CH3:70])([CH3:69])[C:66]([NH2:68])=[O:67].C(NCCC(N)=O)C1C=CC=CC=1>>[C:66]([C:65]([NH:64][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[C:14]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:15][NH:16][C:17]=2[CH:18]([CH3:20])[CH3:19])=[C:8]([O:57][CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[CH:7]=1)([CH3:70])[CH3:69])(=[O:67])[NH2:68]
Reactant: CC(C)(N)C(N)=O
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCCCCl)cc1OC1CCOCC1
Agent: NC(=O)CCNCc1ccccc1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccc(OCCCNC(C)(C)C(N)=O)cc1OC1CCOCC1

Procedure:
The title compound was prepared in a similar manner to that described in Example 98 using 4-{[4-(3-chloropropoxy)-2-(tetrahydro-4H-pyran-4-yloxy)phenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole and 2-amino-2-methylpropionamide instead of 4-{[4-(3-chloropropoxy)-2-methylphenyl]methyl}-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole and 3-benzylaminopropionamide, respectively.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1)[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1)[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 120 °C
Yield: 64 %

Procedure:
To a suspension of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (55 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.8 mg) and tripotassium phosphate (79 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (1 mL) under nitrogen was added Pd(Ph3P)4 (17.31 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, the residue was purified by column chromatography to afford 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D18) (43 mg) as a yellow oil. MS (ES): C23H23F3N2O2S requires 448. found 449.1 (M+H+).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Product: O=c1c(NCCc2ccc(Oc3ccccc3)cc2)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared according to an analogous procedure to that described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 2-(4-phenoxyphenyl)-ethylamine. The reaction mixture was heated to reflux for 2 h instead of stirring 18 h at r.t.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH2:14]1>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:16]2[CH2:17][CH2:18][CH:13]([N:12]([CH3:26])[CH3:11])[CH2:14][CH:15]=2)[N:24]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccccc3Cl)n2)CC1
Product: Cl

Procedure:
Using a method similar to example 24, using 2-chloro-benzoyl chloride (140 mg, 0.80 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 2 (preparation 11, 145 mg, 0.67 mmol) provides the free amine of the title compound as a slightly yellow oil (218 mg, 91%): MS (ES): m/z=356.1 (M+H)+; 1H NMR (CDCl3): δ 8.69 (s, br, 1H), 8.22 (d, 1H), 7.67 (m, 2H), 7.45 (m, 3H), 7.15 (d, 1H), 6.64 (m, 1H), 2.69 (m, 1H), 2.45 (m, 3H), 2.36 (s, 6H), 2.13 (m, 2H), 1.56 (m, 1H). Using a salt formation method similar to that in example 1 gives the hydrochloride salt: Mono-hydrochloride salt: Anal. cal'd for C20H22ClN3O.HCl.1.2H2O: C, 57.91; H, 6.20; N, 10.13. Found: C, 58.18; H, 5.98; N, 9.74.
Reaction SMILES: CC[O-].CC[O-].[Mg+2].[C:8]([O:12][C:13](=[O:18])[CH2:14][C:15]([CH3:17])=[O:16])([CH3:11])([CH3:10])[CH3:9].[Cl:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]([Cl:33])[C:21]=1[C:22](Cl)=[O:23].Cl>C1(C)C=CC=CC=1>[C:8]([O:12][C:13](=[O:18])[CH:14]([C:22](=[O:23])[C:21]1[C:25]([Cl:33])=[CH:26][CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:20]=1[Cl:19])[C:15]([CH3:17])=[O:16])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(C(=O)C(C(C)=O)C(=O)OC(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A suspension of 1.65 g of magnesium ethylate in 30 ml of toluene was kept at 60-70° C. and 2.28 g of acetoacetic tert-butyl ester was added dropwise thereto. After the dropwise addition was completed, the resultant mixture was refluxed for two hours. Then, the reaction solution was cooled to room temperature and 3.85 g of 2,6-dichloro-3-methoxycarbonyl benzoic acid chloride was added dropwise thereto. The reaction mixture was stirred at room temperature for two hours and at 50-100° C. for three hours, then cooled to room temperature, treated with dilute hydrochloric acid, and extracted from ethyl acetate. Then, the organic layer was alkali extracted from an aqueous 5% sodium carbonate solution. The water layer was mixed with chloroform, educed with dilute hydrochloric acid, and extracted again. The organic layer was washed with saturated saline solution and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.80 g of 2-(2,6-dichloro-3-methoxycarbonyl benzoyl) acetoacetic tert-butyl ester. A solution of this ester in 45 ml of toluene and 0.2 g of p-toluene sulfonic acid hydrate added thereto were refluxed together for six hours. The reaction solution was cooled, mixed with 200 ml of ethyl acetate, washed twice with 200 ml of water, further washed with saturated saline solution, and dried over magnesium sulfate. The solution was distilled under a reduced pressure to expel the solvent and obtain 2.10 g of 2,6-dichloro-3-methoxycarbonyl benzoyl acetone. nD22 1.5759.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cn1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.71 g) and 2-nitroamino-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone (1.98 g) in pyridine (12 ml) was refluxed for 22 hr, allowed to cool and the pyridine evaporated at reduced pressure. The residue was washed by decantation with hot water, dissolved in dilute ethanolic hydrochloric acid, and the solvent evaporated yielding 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(6-dimethylaminomethyl-3-pyridylmethyl)-4-pyrimidone. The residue was recrystallised from methanol/dilute ethanolic hydrochloric acid and from methanol/ethanol to give the 3.8 hydrochloride 1.4 hydrate (0.85 g) as a light buff solid m.p. 142°-5° C. Evaporation of the mother liquors and recrystallisation of the residue from methanol/ethanol yields more product (0.62 g) m.p. 138°-142° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[C:10]2=[C:11]3[C:15](=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=[C:9]2[N:8]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7]1)[NH:14][C:13]([C:26]([F:29])([F:28])[F:27])=[C:12]3[C:30]([O:32][CH3:33])=[O:31])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[CH2:19]([O:18][C:16]1[CH:17]=[C:9]2[N:8]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:7][CH:6]([CH2:5][OH:4])[C:10]2=[C:11]2[C:15]=1[NH:14][C:13]([C:26]([F:27])([F:28])[F:29])=[C:12]2[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(COC(C)=O)CN3C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3C(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
In 4 ml of methanol, was suspended 225 mg (0.4 mmol) of methyl 1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate. Thereto 110.6 mg (0.8 mmol) of potassium carbonate was added, and the mixture was stirred for 7 hours. It was neutralized with 10% citric acid, and diluted with water. The precipitated crystalline matter was collected by filtration, washed with water, and dried. Thereby, methyl 5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate was prepared in a colorless crystalline state in a yield of 206.5 mg (99%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([NH:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:26][CH2:27][N:32]2[CH2:33][CH2:34][N:29]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccccc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2b from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(benzyl)-amide and 2-(piperazin-1-yl)-quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]([SH:16])[CH2:14][SH:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:17]([C:19]1[C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH:26]=1)[CH:24]=O)#[N:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[C:17]([C:19]1[C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([C@H:24]2[S:16][C@H:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:14][S:15]2)[CH:26]=1)#[N:18]
Reactant: COc1cc(C(S)CS)cc(OC)c1OC
Reactant: COc1cc(C=O)cc(C#N)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(C#N)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (2.36 g, 9.09 mmole), 5-cyano-3,4-dimethoxybenzaldehyde (49) (1.50 g, 7.85 mmole) and 0.788 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (2.91 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH2:14][OH:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32]([N:10]2[CH2:9][C@H:8]([CH2:14][OH:15])[N:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][C@H:11]2[CH3:13])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: C[C@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](CO)CN1C(=O)COc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of (2R,5S)-1-(4-fluorobenzyl)-2-(hydroxy)methyl-5-methylpiperazine (1.6 g, 6.7 mmol) in CH2Cl2 (30 mL) was added triethylamine (excess) and 4-chlorophenoxyacetyl chloride (1.5 g, 7.4 mmol, dropwise in 10 mL solution of CH2Cl2). The resultant mixture was stirred at ambient temperature. After 20 minutes, analysis by analytical TLC showed complete consumption of starting material had occurred. The mixture was concentrated of volatiles in vacuo and the residue taken up in CH2Cl2. This was washed with saturated aqueous NaHCO3 solution, then water, then brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 2.16 g (79% yield) of (2R,5R)-1-((4-chlorophenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)-5-((hydroxy)methyl)piperazine, as a solid yellow foam: NMR (DMSO-d6) 7.7 (br s, 2), 7.3 (m, 4), 6.9 (d, 2), 5.0-4.2 (m, 5), 4.0-3.2 (m, 7), 1.2 (m, 3) ppm; MS (LSIMS) 406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Br:19]N1C(=O)CCC1=O>ClCCl.[Fe](Cl)(Cl)Cl>[Br:19][C:13]1[S:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)cs1
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1

Procedure:
1.94 g of the compound from Example 2A having a purity of 57% (3.87 mmol) are provided in 35 ml of dichloromethane, 6.04 g (33.9 mmol) of N-bromosuccinimide and a spatula tip of iron trichloride are added and the mixture is heated under reflux for 18 hours. The reaction mixture is concentrated, the residue is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 30:1), and 1.30 g (83% of theory) of the title compound are obtained.
Reaction SMILES: N1C=CC=CC=1.[FH:7].[O:8]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:7][C:10]1([CH2:9][OH:8])[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: F
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Reaction time: 0.42 h

Procedure:
A mixture of 5 ml hydrogen fluoride pyridine and 20 ml methylene chloride was cooled, and 10 ml solution of 4.95 g of benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate in methylene chloride was added dropwise thereinto over 25 min such that the bulk temperature was 0° C. or less. The mixture was stirred for 35 min under ice-cooling. The reaction solution was poured into a mixture of saturated sodium bicarbonate and ice. The organic layer was recovered, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated, and then subjected to silica gel column chromatography to give 2.84 g of the title compound.
Reaction SMILES: [OH-:1].[Na+:2].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([CH2:14][C:15]([OH:24])([P:20]([OH:23])(=[O:22])[OH:21])[P:16]([OH:19])(=[O:18])[OH:17])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[OH2:17].[OH2:1].[C:3]1([C:9]2[NH:10][CH:11]=[C:12]([CH2:14][C:15]([OH:24])([P:20]([OH:22])(=[O:21])[OH:23])[P:16]([O-:19])(=[O:17])[O-:18])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=P(O)(O)C(O)(Cc1c[nH]c(-c2ccccc2)n1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])C(O)(Cc1c[nH]c(-c2ccccc2)n1)P(=O)(O)O

Procedure:
10 ml of 2N aqueous sodium hydroxide solution are added, with stirring, to a suspension of 3,36 g of 2-(2-phenylimidazol-4-yl)-1-hydroxy-ethane-1,1-diphosphonic acid in 10 ml of water. The resulting solution is evaporated to dryness. The residue is triturated with 40 ml of methanol. The crystalline precipitate formed is filtered off and dried yielding disodium 2-(2-phenylimidazol-4-yl)-1-hydroxyethane-1,1-diphosphonate-dihydrate m.p. 281°-283° C. (dec.).