Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(O[O:17][C:18]([CH3:21])(C)C)(C)(C)C.[C]=O.[CH2:24]([OH:26])C>>[C:2]1([CH2:1][C:24]([O:17][CH2:18][CH3:21])=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccccc12
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Agent: [C]=O
Product: CCOC(=O)Cc1cccc2ccccc12
Temperature: 120 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
1-Methylnaphthalene (2.13 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 89 mg ethyl 1-naphthaleneacetate was obtained by column chromatography, in a yield of 83%. 1HNMR (400 MHz, CDCl3) δ 1.20 (t, J=7.2 Hz, 3H), 4.06 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.39-7.55 (m, 4H), 7.78-7.80 (m, 1H), 7.84-7.85 (m, 1H), 7.99-8.01 (m, 1H); 13CNMR (100 MHz, CDCl3) δ 14.2, 39.3, 60.9, 123.9, 125.5, 125.8, 126.3, 127.9, 128.0, 128.7, 130.7, 132.2, 133.9, 171.6; HRMS (ESI) calcd. for C14H14NaO2 [M+Na]: 237.0886. found: 237.0889. The ethyl 1-naphthaleneacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 71 mg product 1-naphthaleneacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 92%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: COc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (74 mg, 91%), MS (ISP) m/z=325.4 [(M+H)+], mp 237° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:12](C1C=C(C(O)=O)C(=CC=1)C(O)=O)([O-:14])=[O:13]>[Cl-].[Zn+2].[Cl-]>[N+:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2][CH:11]=1)([O-:14])=[O:13]
Reactant: Cc1ccc2ccccc2n1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=[N+]([O-])c1ccnc2ccccc12

Procedure:
Using a similar reactor as in Synthesis Example 1, chinaldine (14.3 parts), 4-nitrophthalic acid (21.1 parts), zinc chloride (13.6 parts) and ODB (100 parts) were charged, followed by refluxing for 2 hours under stirring. The reaction mixture was filtered, and the filter cake was thoroughly washed with water and then dried to obtain 4-nitroquinoline. In a similar manner as in Synthesis Example 1, the 4-nitroquinoline was reduced for amination, followed by amidation with 2-bromoisobutyric acid bromide to obtain a 2-bromoisobutyric acid substitute. This will be called “Quinoline-1”. In a similar manner as in Synthesis Example 3, the structure of Quinoline-1 was confirmed by NMR and IR. By HPLC, its purity was determined to be 91.0%. By an elemental analysis, the bromine content was found to be 16.5%. A maximum absorption wavelength was measured by the spectrophotometer, and as a result, λmax=445 nm. The structural formula is shown below.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:16]1[C:26]2[CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl[CH2:38]/C=C\CCl>>[CH:27]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]([N:31]3[CH2:32][CH2:33][N:34]([CH2:38]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]4[C:14]5[S:13][C:12]([CH3:15])=[N:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:35][CH2:36]3)[C:22]=2[CH:30]=[CH:29][CH:28]=1.[Cl:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Reactant: ClC/C=C\CCl
Agent: Cc1nc2cccc(OC/C=C\Cl)c2s1
Product: Cc1nc2cccc(OC/C=C\CN3CCN(C4c5ccccc5CCc5ccccc54)CC3)c2s1

Procedure:
The title compound was prepared according to Method GA from cis-7-(3-chloroallyloxy)-2-methyl-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperazine. mp 114° C.; LSIMS m/z 496. The cis-7-(3-chloro-allyloxy)-2-methyl-benzothiazole was prepared by Method IV, with cis-1,4-dichloro-2-butene as the alkylating agent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[C:58]([F:62])[C:59]([F:61])=[CH:60][C:52]=2[F:51])[CH3:55])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cc(F)c(F)cc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 49.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (76 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (130 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2,4,5-trifluoro-α-methylbenzyl alcohol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 46%).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH:14]=O.[BH4-].[Na+].O>CO>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:13])=[C:5]1[CH2:14][NH:2][CH3:1]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.2 %

Procedure:
Methylamine (0.53 mL, 13.1 mmol) was added to a solution of 1,3-dimethyl-1H indole-2-carbaldehyde (760 mg, 4.3 mmol) in methanol (15 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (159 mg, 4.3 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (690 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([OH:12])[CH2:7][NH:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O.CCOCC>CN(C=O)C>[C:9]([NH:8][CH2:7][CH:6]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)NCC(O)CNC(C)=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCC(CNC(C)=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of N-(3-acetylamino-2-hydroxypropyl)acetamide (synthesized as described in J. Org. Chem., 2000, 65(4), 1200, which is incorporated herein by reference in its entirety) (741 mg, 4.25 mmol) and 1H-imidazole (579 mg, 8.51 mmol) in dry DMF (17 mL), a solution of tert-butylchlorodimethylsilane (962 mg, 6.38 mmol) in dry DMF (8 mL) was added dropwise, and the reaction was stirred at r.t. overnight. The reaction was portioned between H2O/Et2O, the phases were separated and the aqueous layer was washed twice with Et2O and three times with EtOAc. All the organics were combined, dried over Na2SO4, filtered and concentrated, affording N-[3-acetylamino-2-(tert-butyldimethylsilanyloxy) propyl]acetamide (1140 mg, 3.95 mmol, 93% yield) as off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:32]([CH3:34])[CH3:33])[CH:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:43]1([CH2:49][C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1.C(OCC)(=O)C>[Si:25]([O:24][CH:19]([C:20]([F:23])([F:21])[F:22])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:3]1=[O:35])[CH:32]([CH3:33])[CH3:34])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)Cc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h

Procedure:
A 25 mL flask was charged with 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.301 g) dissolved in freshly distilled tetrahydrofuran (6 mL) under nitrogen. Triethylamine (0.09 mL) was added, followed by phenylacetyl chloride (0.08 mL). The cloudy, yellowish solution was stirred overnight; diluted with ethyl acetate (50 mL); washed with 10% hydrochloric acid (three times), saturated aqueous sodium bicarbonate (three times) and brine; dried; and evaporated to give an oil which solidified under vacuum. The soft solid was purified by chromatography, eluting with ethyl acetate:dichloromethane (3:97), to afford N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-(2-oxo-6-phenyl-3-phenylacetylamino-1,2-dihydro-1-pyridyl)acetamide (0.272 g); TLC: Rf =0.54, methanol:dichloromethane (1:99); MS: m/z=630(M+1).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:10])[CH2:6][C:7]([OH:9])=O)[CH:2]=[CH2:3].[CH3:11][C:12]1([CH3:24])[S:16][C@@H:15]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:14]2[C@H:13]1[C:21]([OH:23])=[O:22].[C:25]1(C)[CH:30]=CC=C[CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([CH2:6][C:7]([NH:20][C@@H:17]1[C:18](=[O:19])[N:14]2[CH:13]([C:21]([O:23][CH2:30][CH:25]=[CH2:26])=[O:22])[C:12]([CH3:24])([CH3:11])[S:16][C@H:15]12)=[O:9])=[O:10])[CH:2]=[CH2:3]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: Cc1ccccc1
Reactant: C=CCOC(=O)CC(=O)O
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)CC(=O)N[C@@H]1C(=O)N2C(C(=O)OCC=C)C(C)(C)S[C@H]12
Yield: 46 %

Procedure:
In a manner similar to that described for Example 1, method A, the title compound (3.53 g, 46%) was prepared from malonic acid monoallyl ester (2.88 g, 20 mmol) and 6-aminopenicillanic acid (4.33 g, 20 mmol) as colorless crystals: m.p. 59°-60° C. (toluene); IR (CHCl3) 1790, 1730, 1685 cm-1; 1 H NMR (CDCl3) δ 1.51 and 1.67 (each 3H, s, C2 -(CH3)2), 3.35-3.47 (2H, m, COCH2CO), 4.48 (1H, s, C3 -H), 4.60-4.70 (4H, m, 2xOCH2CH=CH2), 5.22-5.42 (4H, m, 2xOCH2CH=CH2), 5.56 (1H, d, J=4Hz, C5-H), 5.75 (1H, dd, J=4 and 9Hz, C6 -H), 5.84-6.00 (2H, m, 2xOCH2CH=CH2), 8.03 (1H, d, J=9Hz, NH).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[S:18]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]1>C(O)C.CCCCCCC.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2/[C:15](=[CH:23]/[C:20]1[CH:21]=[CH:22][S:18][CH:19]=1)/[C:16]#[N:17]
Reactant: O=Cc1ccsc1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCCC
Solvent: CCOCC
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccsc3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (204 mg, 3.8 mmol, 1.4 eq.) in anhydrous ethanol (30 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (500 mg, 2.7 mmol, 1.0 eq.) and, after 30 minutes stirring, thiophen-3-carbaldehyde (235 μL, 2.7 mmol, 1.0 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 18 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2) to afford, after trituration with heptane and diethyl ether, the compound (50) as a beige solid (310 mg, 41%). IR νmax (cm−1): 2212 (νCN), 3340 (νN—H); 1H NMR (DMSO, 300 MHz) δ (ppm): 3.82 (3H, s, 5′-methoxy), 6.88 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.38 (1H, d, J7′-6′=8.9 Hz, H7′), 7.42 (1H, d, J4′-6′=2.4 Hz, H4′), 7.69 (1H, d, J4″-5″=5.1 Hz, H4″), 7.70 (1H, m, H3), 7.72 (1H, m, H2′), 7.79 (1H, dd, J5″-4″=5.1 Hz, J5″-2″=1.3 Hz, H5″), 8.10 (1H, m, H2″), 11.54 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 55.5 (5′-methoxy), 101.7 (C4′), 103.8 (C2), 109.9 (C3′), 112.1 (C6′), 113.0 (C7′), 118.1 (C1), 124.0 (C3a′), 126.5 (C4″ and C5″), 127.3 (C2′), 128.0 (C2″), 130.6 (C3), 132.2 (C7a′), 136.6 (C3″), 154.3 (C5′); ESI-MS: m/z 281.1 ([M+H]+), 303.1 ([M+Na]+); HRESI-MS: m/z 303.0568 (calcd for C16H12N2ONaS+, 303.0568).
Reaction SMILES: ClC1[CH:3]=[C:4]([NH:9][CH3:10])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl[C:12]([Cl:22])(OC(=O)OC(Cl)(Cl)Cl)Cl.C1C[O:26][CH2:25]C1>>[Cl:22][C:12]1[CH:7]=[CH:6][C:5]2[NH:8][C:25](=[O:26])[N:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1cc(Cl)ccc1N
Product: Cn1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro-N2-methyl-benzene-1,2-diamine (60) (100 mg, 0.64 mmol, 1 eq), triphosgene (95 mg, 0.32 mmol, 0.5 eq), TEA (0.26 ml) in THF (2 ml) was stirred at rt for 4 hours. The reaction solution was washed with ethyl acetate and concentrated to provide 6-chloro-1-methyl-1,3-dihydro-benzoimidazol-2-one (61).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl.N1C=CC=N1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]([C:18]3[CH:13]=[CH:14][C:15]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:17]=3)[N:20]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCC(=O)c1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: c1cn[nH]c1
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 25.2 %

Procedure:
3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g, 0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (22.4 g, 0.1 mol) were dissolved in 150 mL of absolute ethanol and heated to reflux for 16 hours. The solution was cooled to room temperature, diluted with 100 mL of water and let stand, whereupon crystals of pyrazole formed that were isolated by filtration to provide 8.4 g (25%) of a white solid: mp 185°-187° C.; 1H NMR (CDCl3/300 MHz) 7.89 (d, J=8.7Hz, 2H), 7.76 (d, J=1.8Hz, 1H), 7.43 (d,J=8.7Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.17 (d, J=8.7Hz, 2H), 6.53 (d, J=1.8Hz, 1H), 4.93 (brs 2H). Anal. Calc'd for C15H12N3SO2Cl: C, 53.97; H, 3.62; N, 12.59. Found: C, 54.08; H, 3.57; N, 12.64.
Reaction SMILES: [NH2:1][C:2]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)=[O:5].Cl[C:18](Cl)(Cl)[C:19](N)=[O:20].Cl.[Li+].[OH-:26]>C(O)(=O)C.CO.C1COCC1>[NH:11]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:18]([C:19]([OH:20])=[O:26])[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: NC(=O)C(Cl)(Cl)Cl
Reactant: Nc1cccc(C(=O)Nc2ncc[nH]2)c1N
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirring solution of 200 mg (0.92 mmol) of 2,3-diamino-N-(1H-imidazol-2-yl)-benzamide (synthesized as described in Intermediate-B) in 2.0 mL of acetic acid was added 200 mg (1.15 mmol) of 2,2,2-trichloroacetamide and stirring continued for 30 min at r.t. Then 0.5 mL of 1% HCl in methanol was added and stirred for another 45 min at r.t. Evaporation of the solvent gave the crude ester, which was dissolved in 4:1 THF and methanol (5 mL) and then 1.0 mL of 2N LiOH was added at r.t. The reaction mixture was stirred at r.t. for 30 min, the pH was adjusted to 3.0 and then extracted with ethyl acetate twice (2×25 mL). The combined organic solvents were dried, evaporated to provide 100 mg (40%) of 4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazole-2-carboxylic acid, which was used, for the next step without further purification. LCMS: 272 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[C@@H:28]([OH:29])[C:27](=[O:30])[N:26]([CH2:31][CH2:32][N:33]([CH3:37])[CH2:34][CH2:35][CH3:36])[C:25]3[CH:38]=[CH:39][CH:40]=[CH:41][C:24]=3[S:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:49]([O-:54])(=[O:53])[C:50]([O-:52])=[O:51]>C(Cl)Cl>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[C@@H:28]([O:29][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[N+:11]([O-:13])=[O:12])[C:27](=[O:30])[N:26]([CH2:31][CH2:32][N:33]([CH3:37])[CH2:34][CH2:35][CH3:36])[C:25]3[CH:38]=[CH:39][CH:40]=[CH:41][C:24]=3[S:23]2)=[CH:20][CH:21]=1
Reactant: CCCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2ccccc21
Reactant: O=C([O-])C(=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C)CCN1C(=O)[C@H](OC(=O)c2ccc(Cl)cc2[N+](=O)[O-])[C@H](c2ccc(OC)cc2)Sc2ccccc21
Product: O=C(O)C(=O)O
Yield: 79.5 %

Procedure:
A solution of 0.88 g of 4-chloro-2-nitrobenzoyl chloride in 3 ml of methylene chloride is added to a mixture of 1.34 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-n-propylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 15 ml of methylene chloride and 0.5 ml of triethylamine. The mixture is treated in the same manner as described in Example 30-(2). The crude product is converted to its oxalate and then recrystallized from ethanol. 1.78 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-chloro-2-nitrobenzoyloxy)-5-[2-(N-methyl-N-n-propylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate are thereby obtained as colorless plates. Yield: 79.5%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+]([O-])=O)[C:4]=1[C:12]#[N:13])#[N:2].[O-:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+].O>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:12]#[N:13])#[N:2]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccccc2)c1C#N
Yield: 60 %

Procedure:
A solution of 1,2-dicyano-3-nitrobenzene (2.77 parts) and sodium phenoxide (2.79 parts) in dimethylformamide (50 parts) was stirred at 120° C. for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether (100 parts). The diethyl ether extract was washed with 5% aqueous potassium hydroxide solution (2×200 parts) and water (2×200 parts) and the diethyl ether was removed under reduced pressure to leave a solid. Recrystallisation of the solid from a 1:1 diethyl ether:petroleum spirit (b.pt.60°-80° C.) gave 1,2-dicyano-3-phenoxybenzene (2.1 parts, 60%) as a pale green solid, m.pt.110°-112° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.BrCC1C=C(C=CC=1)C=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].O>CC(C)=O>[C:21]([S:23][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)(=[O:24])[CH3:22]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: CC([O-])=S
Agent: O=Cc1cccc(CBr)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SCc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-(bromomethyl)-benzaldehyde (Hsung et al. (1995) Organometallics, 14: 4808–4815; Bookser and Bruice (1991) Am. Chem. Soc. 113: 4208–4218; Wagner et al. (1997) Tetrahedron 53: 6755–6790 for the synthesis of 3-(bromomethyl)benzaldehyde) (0.43 g, 2.2 mmol) in acetone (10 mL) was added potassium thioacetate (280 mg, 2.5 mmol) under stirring at rt, then the mixture was refluxed. A precipitate formed after a few minutes. The reaction was monitored by TLC and cooled to rt when no starting material was detectable (3.5 h). Water (25 mL) was added, the mixture was extracted with ethyl acetate (3×30 mL), and the combined organic phases were dried (Na2SO4) and evaporated. Column chromatography over flash silica gel (ethyl ether/hexanes, 1:1) gave 359 mg (85% yield) of a brown oil which darkened upon standing (nonetheless elementary analysis four weeks after exposure to air at rt indicated a high level of purity as listed below). IR (neat): {tilde over (v)} 3052, 2923, 2830, 2737, 1694, 1606, 1576; 1H NMR δ 2.36 (s, 3H), 4.15 (s, 2H), 7.45, 7.81 (AA′BB′, 2×2H), 9.97 (s, 1H); 13C NMR (APT) δ 30.1 (−), 32.9 (+), 129.3 (−), 129.9 (−), 135.2 (+), 144.7 (+), 191.5 (−), 194.3 (+); GC-MS (EI) obsd 194, 152, 119, 91, 43; Anal. Calcd for C10H10O2S: C, 61.83; H, 5.19; S, 16.51; Found: C, 61.97; H, 5.20; S, 16.60.