Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=O)[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[NH:2][CH3:1])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN
Reactant: Cc1cc(C)c2c(c1O)C(=O)C1CCCCC21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CNC1c2c(O)c(C)cc(C)c2C2CCCCC21
Temperature: 25 °C

Procedure:
3.4 Milliliters of a methanol solution of 40% methylamine was added to a methanol solution containing 2 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 20 ml of methanol and the mixture was refluxed under heating for 4 hours. Then, thereto were further added 10 ml of methanol and 3.4 ml of a methanol solution of 40% methyl amine, followed by refluxing for 6 hours. After left to stand for cooling, 3.66 g of sodium borohydride was gradually added thereto with stirring at room temperature, followed by stirring for 1 hour at the same temperature. Then, water was added to the reaction mixture and extraction was effected with chloroform. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:1) and then recrystallized from ethanol to obtain 0.70 g of 5,7-dimethyl-8-hydroxy-9-methylamino-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+].Cl>CO.O>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:15]/[N+:12]([O-:14])=[O:13])=[CH:5][C:4]=2[O:9]1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a stirred solution of piperonal (75 g, 500 mmol) in methanol (120 mL) at 10° C. was added nitromethane (27.1 mL, 500 mmol, 1 eq) followed by the dropwise addition of sodium hydroxide (21 g, 525 mmol, 1.05 eq) in sufficient water to achieve a total volume of 50 mL while maintaining the temperature between 10-15° C. The reaction mixture became cloudy, turning to a thick paste. The mixture was stirred for 30 minutes upon completion of the addition, and the mixture was then diluted with ice-water (˜350 mL) maintaining the temperature below 5° C., until solution was achieved. The resultant solution was poured in a narrow stream (such that it just failed to break into drops) into a rapidly stirred solution of 36% hydrochloric acid (100 mL) in water (150 mL). A yellow solid precipitated (nitrostyrene), and this was collected by filtration, washed with water (1.5 L) until the filtrate was neutral. The filter cake was air dried and then recrystallized from hot ethanol (3 L) to yield E-2-(3,4-methylenedioxy)-nitrostyrene as yellow needles (53 g, 55%). 1H NMR (300 MHz, CDCl3) δ 7.94 (1H, d, J=13.5 Hz, 7.47 (1H, d, J=13.5 Hz), 7.09 (1H, dd, J=7.5&2 Hz), 7.01 (1H, d, J=2 Hz), 6.87 (1H, d, J=7.5 Hz), 6.06 (2H, s). MS (DCl/NH3) m/e 194 (M+H)+, 211 (M+H+NH3)+.
Reaction SMILES: [Cl:1]CCCC([C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1)=O.C1(N2CCNCC2)C=CC=CC=1.C(N(CC)CC)C.O>CN(C=O)C>[ClH:1].[ClH:1].[O:11]1[C:10]2[CH:14]=[CH:15][CH:7]=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: O=C(CCCCl)c1ccc2c(c1)OCO2
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: c1ccc2c(c1)OCO2
Temperature: 80 °C
Yield: 296.3 %

Procedure:
To 5-(4-chlorobutyryl)-1,3-benzodioxole (4.0 g) and N-phenylpiperazine (3.0 g) dissolved in DMF (25 ml) was added triethylamine (2.2 g) and the mixture was heated at 80° C. for 40 hours under stirring. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in ethyl acetate and 20% hydrogen chloride in ethanol (6.5 ml) was added. The resulting crystals were collected by filtration and recrystallized from ethanol to give 5-[4-phenyl-1-piperazinyl)butyryl]-1,3-benzodioxole dihydrochloride (5.1 g, 68% yield). The characteristics of this compound are shown in Table 3 as Compound 57.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([NH:21]C(=O)OC(C)(C)C)[O:18][N:17]=1)=[O:15].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]1[O:18][N:17]=[C:16]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:15])[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 3-(2-(5-chloro-1H-indol-3-yl)ethylcarbamoyl)isoxazol-5-ylcarbamate (0.400 g; 0.988 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 h and was then evaporated to dryness to remove the excess of TFA. The residue was dissolved in dichloromethane and the solution was washed with an aqueous solution of sodium carbonate. The organic layer was evaporated and the crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% methanol in dichloromethane) to afford 0.207 g (69%) of 5-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[C:37](=[O:38])[NH:36][N:35]=[CH:34]2)[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:36]2[C:37](=[O:38])[N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[CH:34]=[N:35]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)nc1C
Yield: 84 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-fluorobenzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 84% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.47-7.30 (m, 2H), 7.11-6.97 (m, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 363.1 (M+
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=1>>[CH3:29][C:24]1[CH:23]=[C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(Br)cc1C
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1C
Yield: 18.5 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (274 mg, 1.00 mmol) synthesized in Reference example 61 and 4-bromo-1,2-dimethylbenzene (278 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 70 mg (yield 18%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OC)cccc2[nH]1
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: CCOC(=O)c1cc2c(OC)cccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 4-methoxy-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-4-methoxy-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 348.3 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.C(OCC)(=O)C>[C:40]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)c2ccccc2)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.5 mg, 0.588 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 mL), then triethylamine (19.7 μL, 0.141 mmol) and benzoyl chloride (8.2 μL, 0.071 mmol) were added thereto. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (26.7 mg) as a colorless solid. (Yield 63%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:25][CH:24]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(#N)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:27][CH:28]=3)[CH2:21][CH2:20]2)[N:3]=1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(Cl)cc(Cl)n3)CC2)cc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (1.0 g) and potassium carbonate (0.84 g) in acetonitrile (20 ml) was added a solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.0 g) obtained in Example 78(2) in acetonitrile (20 ml) under ice-cooling over 5 min. The mixture was stirred at the same temperature for 30 min. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown oil (1.6g). The obtained pale-brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=50:1) to give a crude purification product (0.28 g) of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide and a crude purification product (0.9 g) of N-(4-((4-(2,6-dichloropyriinidin-4-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide. The crude purification product of N-(4-((4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)methyl)phenylmethyl)acetamide was crystallized from ethyl acetate:hexane to give the title compound (0.2 g) as white crystals, m.p.=139-140° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[NH:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CO>[N:1]([CH2:4][C@@H:5]1[CH2:6][C@@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:8][N:9]1[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N+:2]=[N-:3]
Reactant: COC(=O)CBr
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CN1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a solution of the product from Example 201A (290 mg, 1.114 mmol) in triethylamine (388 μl, 2.79 mmol) and methanol (0.3 mL) was added methyl bromoacetate (175 μL, 1.894 mmol), and the resulting mixture was stirred at 65° C. for 18 hours. The cooled mixture was concentrated in vacuo and partitioned between 1 N sodium bicarbonate and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to give the title compound as an oil (203 mg, 54.8%). 1H NMR (500 MHz, pyridine-d5) δ ppm 6.74 (s, 1H), 4.63 (s, 1H), 4.36 (d, J=61.9 Hz, 1H), 4.08 (dt, J=14.2, 6.0 Hz, 1H), 3.81 (dd, J=42.1, 9.2 Hz, 1H), 3.62 (dd, J=11.3, 4.3 Hz, 1H), 3.46-3.27 (m, 1H), 2.23 (dd, J=21.4, 10.3 Hz, 1H), 2.17-2.04 (m, 1H), 1.49 (d, J=8.4 Hz, 11H); MS (ESI) m/z 333 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:17][OH:18])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[C:19](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([NH:1][CH2:2][C@:3]1([CH2:17][OH:18])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: NC[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-C-Aminomethyl-2′-deoxyuridine (13) (0.034 g, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) at ambient temperature. Excess pentafluorophenyl acetate (0.88 g, 0.39 mmol) was then added directly to the reaction mixture as a solid. The resulting solution was stirred for 18 hours at ambient temperature. The solvent was then removed under vacuum and the residue re-dissolved in water and then washed with toluene. The aqueous layer was then separated and the solvent removed under vacuum. The title compound was obtained as an amorphous solid (0.032 g, 82%). δH(300 MHz, D2O) 7.68(1H, d, H-6), 6.11(1H, dd, H-1′), 5.71(1H, d, H-5), 4.44(1H, dd, H-3′), 4.49(2H, 2d, H-5′), 3.33(2H, 2d, 4′-C—CH2), 2.33(2H, m, H-2′), 1.89(3H, s, CH3CONH); δC(75.45 MHz, D2O) 175.60, 167.08, 152.43, 142.86, 102.93, 88.93, 85.57, 71.91, 63.16, 40.37, 39.15, 22.72; ES +ve m/z 300(M+H)+, 242(M−CH3CONH)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][P:26]([C:31]1[CH:32]=[C:33]([CH2:49][CH2:50][C:51]([OH:53])=O)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][P:39]([O:45][CH:46]([CH3:48])[CH3:47])([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].[C:54]([C:57]1[CH:58]=[C:59]([CH:71]([NH2:73])[CH3:72])[CH:60]=[CH:61][C:62]=1[O:63][CH2:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1)(=[O:56])[NH2:55]>C(Cl)Cl.CN(C=O)C>[CH2:29]([O:28][P:26]([C:31]1[CH:32]=[C:33]([CH2:49][CH2:50][C:51](=[O:53])[NH:73][CH:71]([C:59]2[CH:60]=[CH:61][C:62]([O:63][CH2:64][CH:65]3[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]3)=[C:57]([C:54](=[O:56])[NH2:55])[CH:58]=2)[CH3:72])[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][P:39]([O:45][CH:46]([CH3:47])[CH3:48])([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])(=[O:27])[O:25][CH2:23][CH3:24])[CH3:30]
Reactant: CCOP(=O)(OCC)c1cc(CCC(=O)O)ccc1OCP(=O)(OC(C)C)OC(C)C
Reactant: CC(N)c1ccc(OCC2CCCCC2)c(C(N)=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(CCC(=O)NC(C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)ccc1OCP(=O)(OC(C)C)OC(C)C
Reaction time: 0.08 h
Yield: 81.5 %

Procedure:
HOBt (94 mg, 0.69 mmol) and EDC.HCl (140 mg, 0.73 mmol) were dissolved in 2.5 mL of dry DCM at 0° C. 3-(3-Diethylphosphono-4-diisopropylphosphonomethoxyphenyl)propionic acid (200 mg, 0.42 mmol) in 1.2 mL of dry DMF was added dropwise with stirring. After 5 min, racemic 1-(3-carbamoyl-4-cyclohexylmethoxyphenyl)ethylamine (120 mg, 0.43 mmol) in 0.8 mL of dry DMF was added dropwise. Stirring was continued at 0° C. for 1 hr. The reaction was quenched with 1 mL of saturated NH4Cl, diluted with 17 mL of EtOAc. The organic layer was separated and washed with H2O, 1 N HCl, H2O, 5% NAHCO3, and saturated NH4Cl. The organic layer was dried over Na2SO4 and concentrated to give 253 mg (yield 66%) crude product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[CH3:19][NH:20][CH3:21].[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C.CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([S:14](=[O:16])(=[O:15])[N:20]([CH3:21])[CH3:19])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve commercially available 5-chlorosulfonyl-isophthalic acid dimethyl ester (422 mg, 1.43 mmol) in THF (10 mL) and add dimethylamine (2.0 M in THF, 2.5 mL, 5 mmol). Stir at room temperature 3 h, dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Dissolve the residue in acetone (10 mL) and methanol (5 mL). Add a solution of NaOH (60 mg, 1.43 mmol) in methanol (0.7 mL). Stir at room temperature 16 h and acidify with 1 N HCl to about pH=1. Partition between ethyl acetate and water, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1(C(OC(C)(C)C)=O)CC1.[CH:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.BrCCCCCBr.[Li+].CC([N-]C(C)C)C>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:16]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCCOC(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Agent: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCOC(=O)C1(CCCCCBr)CCCC1

Procedure:
Compound 103f was prepared, likewise the procedure described for 103b, starting from butyl cyclopentanecarboxylate (40.2 g, 0.236 mol), 1,5-dibromopentane (64 mL, 0.45 mol) and LDA (2 M in THF/heptane/ethylbenzene, 200 mL, 0.40 mol) to give, after purification by fractional distillation under reduced pressure, 3f (49.1 g, 93% pure by GC, 61%) as a bright yellow liquid. bp: T=123° C. (p=0.001 Torr). 1H NMR: δ 4.06 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.9 Hz, 2H), 2.15-2.07 (m, 2H), 1.89-1.79 (quintet, J=7.1 Hz, 2H), 1.69-1.56 (m, 8H), 1.49-1.32 (m, 6H), 1.28-1.17 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). 13C NMR: δ 177.7, 64.0, 54.0, 39.0, 36.0 (2×), 33.6, 32.5, 30.7, 28.5, 25.1, 24.8 (2×), 19.1, 13.6. HRMS calcd for C15H27BrO2 (M+): 318.1195, found: 318.1192.
Reaction SMILES: Cl.[C:2]([C@@H:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][NH:6]1)(=[O:4])N.[OH-:20].[Na+]>Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@@H:8]2[CH2:7][NH:6][C@H:5]([C:2]([OH:20])=[O:4])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.0 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride were dissolved in 40 ml of 2N aqueous hydrochloric acid, and the resulting solution was stirred for 1.5 hours on an oil bath at 95°-100° C. At the end of this time, the solution was cooled to room temperature, and then about 40 ml of a 2N aqueous solution f sodium hydroxide were added to the solution, whilst stirring, to adjust its pH to a value of between 4 and 6. The crystals which separated were collected by filtration, washed with water and dried in the air, to yield 3.25 g of the title compound as crystals, melting at 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:19](=[O:22])([O-])[O-:20].[K+].[K+].[CH3:25]C(C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[O:8][C:25]([C:19]([OH:20])=[O:22])=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-chloro-2-benzoylbenzoic acid (13 g) in acetone (200 ml) was added potassium carbonate (6.9 g), and the mixture was stirred at room temperature for 10 min. to allow precipitation of potassium salt. Then diethyl bromomalonate (13.15 g) and DMF (10 ml) were added, and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was concentrated, and ethyl acetate (100 ml) and water (100 ml) were added to the residue. The mixture was stirred at room temperature for 30 min. After separating the organic layer, the layer was washed with water and brine, dried over sodium sulfate and concentrated. A mixed solution of acetic acid (100 ml) and conc. hydrochloric acid (100 ml) was added to the obtained residue, and the mixture was stirred for 20 hrs at 120° C. After cooling, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The obtained residue was crystallized from isopropyl ether and collected by filtration to give the title compound (9.78 g) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN([CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[N:10]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2sc(N3CCNCC3)cc2c1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Product: c1ccc2sc(N3CCN(Cc4c[nH]c5ncccc45)CC3)cc2c1
Yield: 53.6 %

Procedure:
The title compound was prepared in an analogous manner to Example 6, Step 3 using 1-(benzothiophen-2-yl)piperazine (180 mg, 0.83 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (145 mg, 0.83 mmol). Recrystallisation from ethyl acetatehexane afforded the title compound (155mg, 54%), m.p. 269° C. (dec.); (Found: C, 69.10; H, 5.85; N, 16.08. C20H20N4S requires C, 68.94; H, 5.79; N, 16.08%); δH (DMSO-d6) 2.55 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.18 (4H, t, J 5 Hz, 2×piperazinyl CH2), 3.70 (2H, s, indole-CH2N), 6.26 (1H, s, 3-H-benzothiophene), 7.04 (2H, m, 2×ArH), 7.19 (1H, m, ArH), 7.05 (2H, m, 2× ArH), 7.63 (1H, d, 8 Hz, ArH), 8.06 (1H, d, 8 Hz, ArH), 8.20 (1H, d, 3 Hz, ArH), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 349 (M+1)+.