Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[O:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=C(CO)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Yield: 76 %

Procedure:
Prepared in 76.0% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(hydroxymethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=7.8 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.59-7.52 (m, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.09 (q, J=9.0 Hz, 1H), 6.69 (d, J=9.3 Hz, 1H), 6.18 (br. s., 1H), 5.11 (s, 2H), 4.48 (br. s., 1H), 3.98 (t, J=11.2 Hz, 1H), 3.79-3.71 (m, 1H), 3.69 (s, 3H), 3.57-3.45 (m, 2H), 3.07 (d, J=11.3 Hz, 1H), 2.70 (d, J=8.0 Hz, 1H), 2.37 (s, 3H), 1.95 (br. s., 2H), 1.86-1.65 (m, 8H), 1.29 (s, 3H), 1.25 (s, 9H), 1.13 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 706.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>O>[CH3:1][C:2]1([CH3:15])[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: ClCc1ccccn1
Reactant: CC1(C)Oc2cc3nc(S)[nH]c3cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)Oc2cc3nc(SCc4ccccn4)[nH]c3cc2O1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 4.45 g of 2,2-dimethyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 100 ml of alcohol, were added dropwise while stirring 1.63 g of sodium hydroxide in 50 ml of water and, after 30 minutes, there were added 3.4 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of 3N sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from acetonitrile. There were obtained 4.6 g (73.4% of theory) of 2,2-dimethyl-6-[(2-pyridyl-methyl)thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 210°-211° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)[N:22](O)C(=O)C1.C1(N=C=NC2CCCCC2)CCCCC1.N>C(OCC)(=O)C.O1CCCC1.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:17])[NH2:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(N)=O)CC1
Reaction time: 8 h

Procedure:
A solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (15 g, 61.7 mmol) and 1-hydroxysuccinimide (76 g, 61.7 mmol) in ethyl acetate (200 ml) was treated with a solution of dicyclohexylcarbodiimide (12.7 g, 61.7 mmol) in ethyl acetate (50 ml). After stirring overnight the mixture was filtered and evaporated affording a yellow solid. This was redissolved in tetrahydrofuran (300 ml) and treated gaseous ammonia was bubbled through the solution for 15 minutes. Filtration afforded a white solid which was stirred in water (200 ml) for 1 hour. Filtration and drying afforded a white solid (11.3 g, 76%).
Reaction SMILES: C1(P(Cl)Cl)C=CC=CC=1.[C:10]1([P:16]([OH:18])[OH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:12]1[CH:11]=[C:10]([P:16]([OH:18])[OH:17])[CH:15]=[CH:14][CH:13]=1)([O-:21])=[O:20]
Reactant: OP(O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: ClP(Cl)c1ccccc1
Product: O=[N+]([O-])c1cccc(P(O)O)c1

Procedure:
According to my invention phenylphosphorus dichloride is converted to benzenephosphonous acid (B), which is nitrated (I) with nitric acid at a temperature around 0° C. to form m-nitrobenzenephosphonous acid (E) which, to my knowledge, is a compound not previously described in the literature. Compound E is conveniently oxidized by heating (II) the reaction mixture in the presence of additional nitric acid to form m-nitrobenzenephosphonic acid (C), and then compound (D) by subsequent reduction. My contribution, then, includes the nitration of benzenephosphonous acid (B), which is considerably less costly than benzenephosphonic acid (A), to form the novel compound m-nitrobenzenephosphonous acid (E), followed by oxidation to form m-nitrobenzene phosphonic acid (C) which is converted by conventional reduction to form the desired m-aminobenzenephosphonic acid (D).
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[CH3:15][S:16]([NH:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17].C(=O)([O-])O.[Na+].O>CO>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:21][CH2:20][NH:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Reactant: CS(=O)(=O)NCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCNS(C)(=O)=O)c1ccc(NC(C)=O)c(C)c1

Procedure:
A mixture of 57.6g of 4-acetamino-3-methyl-N-ethylaniline, 52g of βmethanesulfonamidoethyl chloride, 27.7g of sodium hydrogen carbonate, 70g of water and 70ml of methanol were refluxed for 5 hours, and thereafter the methanol was distilled out under reduced pressure. Water was added to the reaction system and an oily product separated out. This oily product was poured into ethyl acetate and cooled to obtain white 4-acetamino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:32].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH+:9]([O-:32])[C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN1CCC(C2=CC(c3ccncc3)=C(c3ccc(F)cc3)[NH+]2[O-])CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a suspension of Compound B (700 mg, 2.0 mmol) in anhydrous dichloromethane (50 ml) under nitrogen at 0° C., was added 3-chloroperoxybenzoic acid (666 mg, 2.2 mmol) slowly. The resulting solution was allowed to stir for 2 hours at 0° C. and for 0.5 hour at room temperature. To the resulting clear solution potassium carbonate (415 mg, 3.0 mmol) was added, and the reaction mixture was stirred for 0.75 hour. The white precipitate was removed by filtration. The crude product was purified by flash silica gel chromatography (MeOH-CH2Cl2, 10:90 v/v containing 1% NH4OH). After drying, 505 mg of 2-(4-fluorophenyl)-5-(N-ethylpiperidin-4-yl)-3-(4-pyridyl)pyrrole N-oxide was obtained. NMR (CD3OD)σ8.26(d, J=6.27 Hz, 2H), 7.35(m, 2H), 7.26(d, J=6.13 Hz, 2H), 7.11(m, 2H), 6.28(s, 1H), 3.35(m, 6H), 2.85(m, 1H), 2.46(m, 2H), 2.00(m, 2H), 1.39(t, J=7.10 Hz, 3H); MS(ESI)=366.3
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=S)C.[S:15](=O)(=O)(O)O.O>>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][SH:15])=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: CC(=S)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(CS)cc1

Procedure:
The two step procedure for the preparation of 4-nitrobenzyl, (see, for example, Horn, W. J., J. Am. Chem. Soc., 43, 2603, 1921), and 2,4-dinitrobenzyl, (see, for example, Zhao Zhengyun, Ph.D. Thesis, London University, 181-182, 1993), mercaptans (17a and 17b, respectively) is indicated in outline in Scheme 3(a). Thus, when 4-nitrobenzyl chloride 15a was treated with an excess both of thioacetic acid and pyridine in THF solution at 50° C., 4-nitrobenzyl thioacetate 16a was obtained in 77% yield. When the latter compound 16a was heated, under reflux, in sulfuric acid--water (1:1 v/v), 4-nitrobenzyl mercaptan 17a was obtained in almost quantitative yield. 2,4-dinitrobenzyl mercaptan, (see, for example, Zhao, loc cit), 17b was similarly prepared from 2,4-dinitrobenzyl chloride, (see, for example, Cohn, P., and Friedlander, P., Ber., 35, 1265, 1902) 15b in 73% overall yield. N-(4-nitrobenzylmercapto)succinimide 18 was prepared [Scheme 3(b) and Experimental below] in 65 % yield by heating a suspension of the lead(II) salt, (see, for example, Pant, B.C., and Noltes, J. G., Inorg. Nucl. Chem. Lett., 7, 63, 1971), of the mercaptan 17a with N-bromosuccinimide (NBS) in benzene. Preliminary attempts to convert 2,4-dinitrobenzyl mercaptan 17b into the corresponding succinimide and phthalimide derivatives (13 and 14, R=2,4-(O2 N)2C6H3) were unsuccessful. However, di-(2,4-dinitrobenzyl) disulfide 19, (see, for example, Zhao, loc cit), which was easily prepared in good yield by the iodine-promoted oxidation [Scheme 3(c) and Experimental below] of the mercaptan 17b, proved (see below) to be an equally effective reagent for the required purpose. Finally, 2-cyanoethyl mercaptan 20, (see, for example, Bauer, L., and Welsh, T. L., J. Org. Chem., 26, 1443, 1961) was converted (see, for example, Behforouz, M., and Kerwood, J. E., J. Org. Chem., 34, 51, 1969), [Scheme 3(d) and Experimental below] via a putative intermediate sulfenyl chloride into N-(2-cyanoethylmercapto)phthalimide 21 which was isolated without chromatography as a crystalline solid in 58% yield. ##STR10## Scheme 4 Reagents and conditions: i, a, PCl3, 1,2,4-1H-triazole, Et3N, THF, -35° C., b, Et3N, H2O, RT; ii, for 24a: 18, Me3SiCl, Et3N, CH2Cl2, RT, for 24b: 19, Me3SiCl,4-methylmorpholine, CH2Cl2, RT, for 24c: 21, Me3SiCl, 4-methylmoxpholine, CH2Cl2, RT; iii, aq. Et NH+ HCO3 --.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]1([CH3:18])[CH3:17])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH3:17][C:8]1([CH3:18])[CH:7]([CH2:6][CH2:4][OH:3])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9]1
Reactant: CCOC(=O)CC1Cc2ccccc2OC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)Oc2ccccc2CC1CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
While cooling with ice, a solution of 50 g (0.2 mol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-chroman in 250 ml of absolute diethyl ether is added dropwise within a period of 1 hour to a suspension of 7.6 g (0.2 mol) of lithium aluminium hydride in 200 ml of absolute diethyl ether. The reaction mixture is then stirred for 3 hours at room temperature and then carefully decomposed with 7.5 ml of water, 7.5 ml of sodium hydroxide solution (15%) and 23 ml of water. The resulting precipitate is filtered off. The filtrate is dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 39.5 g (95% of the theoretical yield) of 2,2-dimethyl-3-(2-hydroxyethyl)-chroman in the form of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)[O:25]C(C)C.C([Li])(C)(C)C.OO>C(OCC)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:25])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: OO
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
A stirred solution of 5.40 g (14.1 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 350 mL diethyl ether was cooled to −100 deg C. and 6.30 mL (5.13 g, 27.7 mmol) triisopropyl borate was added. To this solution, 11.3 mL (16.9 mmol) tert-butyllithium (1.5 M in n-pentane) was added dropwise and the reaction was stirred at this temperature for another 15 min. The reaction was warmed to −75 deg C., stirred for another 15 min., warmed to 0 deg C., stirred again for 15 min. and then 6.85 mL acetic acid (50% in water) and 0.12 g 35% hydrogen peroxide solution were added successively. The cooling bath was removed and the reaction was stirred for 1 h at room temperature. The reaction mixture was extracted with 10% aqueous thiosulfate solution, the organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant to give the compound as a light yellow solid (75.4%).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[O:13][C:11](=O)[C:10]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC1[NH:23][CH2:24][CH2:25][N:26]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:13])[N:23]2[CH2:24][CH2:25][N:26]=[C:14]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: CSC1=NCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1c2ccccc2N(Cc2ccccc2)C2=NCCN12

Procedure:
A mixture of 12.7 g. of N-benzylisatoic anhydride, 5.8 g. of 2-methylmercapto-imidazoline and 2 pellets of sodium hydroxide in 200 ml. of dioxane was refluxed for 2 hours. While still hot, the mixture was then filtered through Celite and the filtrate concentrated to about 50 ml. volume. 50 ml. of diethyl ether was added and the crystalline precipitate removed by filtration. The residue was dissolved in methylene chloride, treated with charcoal, filtered through alumina, and the filtrate evaporated. The residue was crystallized from methylene chloride/diethyl ether to obtain the heading compound, m.p. 203°-205°C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1.CC(=O)OCC>[Cl:1][C:2]1[C:11]([NH:12][S:23]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)(=[O:25])=[O:24])=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cc1nsc2cc(Cl)c(N)cc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc3c(C)nsc3cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-3-methyl-benzo[d]isothiazol-5-ylamine (46 mg) in pyridine (0.26 mL), was added a solution of 3,4-dimethoxybenzenesulfonyl chloride (35 mg) in pyridine (0.26 mL). The resulting reaction mixture was stirred at RT under nitrogen overnight. The reaction mixture was then diluted with EA, washed well with HCl 1M (pH˜2-3), the organic phase was washed with water, brine, dried (MgSO4), filtered and concentrated to yield the title compound as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:10]=[C:9]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: COC(=O)Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(CC(=O)OC)c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (7-nitro-1H-indol-3-yl)acetate from Step B (545 mg, 2.71 mmol) was added cesium carbonate (927 mg, 2.85 mmol) and methyl bromoacetate (0.26 mL, 2.84 mmol) in DMF (10 mL). The reaction mixture was stirred at ambient temperature for 18 h, then quenched with H2O (50 mL). The solid precipitate was collected by filtration to give the title compound. MS: m/z=308 (M+1).
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17]O)[C:9]#[N:10]>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:5]
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc(OCCCO)c(F)c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(OCCCBr)c(F)c1

Procedure:
PBr3 (8.14 g, 0.03 mol) was added drop by drop at 0° C. to a solution of 3-fluoro-4-(3-hydroxypropoxy)-benzonitrile (5.5 g, 0.028 mol, from step (i) above in carbon tetrachloride (50 ml) and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water, and extracted with dichloromethane. Organic layer was washed with water, brine, dried over sodium sulfate and solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using 6% ethyl acetate in petroleum ether as eluent to yield (4.3 g) of the title compound as a liquid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:4]#[C:5][CH3:6].[CH2:22](I)[CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([CH:14]([O:21][CH2:22][CH3:23])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[C:4]#[C:5][CH3:6]
Reactant: CCI
Reactant: CC#CCOc1cc(C(O)c2ccccc2)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(C(OCC)c2ccccc2)ncn1
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
In 1.5 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.2 g of 6-(2-butynyloxy)-4-(α-hydroxybenzyl)pyrimidine was added under ice cooling, followed by stirring for 15 minutes. Then, 0.2 ml of a tetrahydrofuran solution containing 0.18 g of ethyl iodide was slowly added dropwise, followed by further stirring at the same temperature for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 6-(2-butynyloxy)-4-(α-ethoxybenzyl)pyrimidine (the present compound (138)).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6]([Br:20])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Br:20][C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(-c2cccc(F)c2)c(Br)n2c1CNCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a solution of 1.24 g (2.83 mmol) of tert-butyl 8-carbamoyl-6-bromo-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 10 ml of dichloromethane are added slowly 2.8 ml (28 mmol) of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The solid formed is separated out by filtration and rinsed with water, to give 0.92 g of 6-bromo-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a beige-coloured powder after drying under reduced pressure in the presence of potassium hydroxide.
Reaction SMILES: [O:1]=[C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:2]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:1])=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:8]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1ccco1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 52.1 %

Procedure:
Following the method of Menozzi et al. (J. Heterocyclic Chem. 1987, 24, 1669), a mixture of 5.3 g (29.1 mmol) ethyl beta-oxo-2-furanpropionate and 7.7 ml (57.8 mmol) N,N-dimethylformamide dimethyl acetal was stirred for 6.5 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried with sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) afforded 3.6 g (52%) 3-dimethylamino-2-(furan-2-carbonyl)-acrylic acid ethyl ester as a yellow oil. EI-MS m/e (%): 237 (M+, 36), 163 ([M—EtOH—CO]+, 100), 95 (86).
Reaction SMILES: Br[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[NH3:18]>C1(C)C=CC=CC=1>[CH:17]1[C:5]2[CH:4]=[C:3]([CH2:2][NH2:18])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:15][CH:16]=1
Reactant: BrCC1=Cc2ccccc2Oc2ccccc21
Reactant: N
Solvent: Cc1ccccc1
Product: NCC1=Cc2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
1.0 g (3.48 mmol) of 10-bromomethyl-dibenz[b,f]oxepine in 3 ml of toluene is added dropwise at 40° C. to 30 ml of NH3 -saturated methanol and the mixture is stirred at 35°-50° C. for 1 hour and at room temperature overnight. The solvent is partially removed, and the reaction mixture is taken up in tert-butyl methyl ether, washed with 0.1N sodium hydroxide solution and extracted with 1N hydrochloric acid. The aqueous phase is rendered basic with sodium hydroxide pellets and extracted with tert-butyl methyl ether, the organic phase is dried over sodium sulfate and the solvent is removed. 349 mg (1.56 mmol)=45% of N-(dibenz[b,f]oxepin-10-ylmethyl)amine are obtained in the form of a light-yellow oil; TLC (silica gel; ethyl acetate; UV): Rf =0.09.