Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]=[O:20])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:22]([Mg]Br)([CH3:24])[CH3:23].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]([OH:20])[CH:22]([CH3:24])[CH3:23])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Br
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Reaction time: 1 h

Procedure:
To a solution of 5-formylthiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (138 mg) in tetrahydrofuran (2 mL) was added dropwise a solution (0.25 mL) of 2.0M isopropyl magnesium bromide-tetrahydrofuran on an ice bath. After stirring for 1 hour, an aqueous solution of saturated ammonium chloride was added, and the solution was extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate) and the title compound (57 mg) was obtained as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([CH3:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[N:26][N:27]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:6]2[C:5]([CH3:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH:29]4[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]4)[CH:28]=3)[N:7]=2)[CH2:18][CH2:17]1)(=[O:20])[NH2:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C1(C(N)=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A40 (0.250 g, 0.792 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.422 g, 1.58 mmol), Pd(OAc)2 (0.004 g, 0.016 mmol), Xantphos (0.018 g, 0.032 mmol) and Cs2CO3 (0.774 g, 2.38 mmol) in dioxane (15 mL) was bubbled with N2 for 10 minutes and then stirred in the microwave at 120° C. for 20 minutes. The volatiles were removed in vacuo and the residue was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A43 as a brown solid (0.118 g, 27%). LCMS-D: rt 3.40 min; m/z 546 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3].Cl[C:30]1[C:39]2[C:34](=[CH:35][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:30]4[C:39]5[C:34](=[CH:35][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:37][CH:38]=5)[N:33]=[CH:32][CH:31]=4)=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(3,5-dipropoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(3,5-dipropoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C1CCCN1
Product: N#Cc1c(N2CCCC2=O)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 120 step A from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and pyrrolidin-2-one. Yellow solid. MS (ESI): 348.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[C:15]([O:18][C:19](=O)[CH3:20])(=O)[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:15]([O:18][CH2:19][CH3:20])[CH2:16][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:10][C:9]2=[S:14])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Product: CCOC(Cc1ccccc1)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
As described in Example 1, triethylorthophenylacetate is reacted with 3-(4'-chlorophenyl)-rhodanine in acetic anhydride for 12 hours to yield 3-(4'-chlorophenyl)-5-(1'-ethoxy-2'-phenylethylidene)-rhodanine. To a suspension of the latter (15 g., 0.0385 m.) in 100 ml. of dioxane and 100 ml. of water is added 22 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 3 hours, concentrated in vacuo at 40°-40°C. and the remaining solution is washed with ether, then decolorized. The aqueous layer is acidified with dilute hydrochloric acid and the precipitate is taken up in methylene chloride. The latter solution (after being washed with water and dried) is evaporated in vacuo. The residue is dissolved in 10% sodium hydroxide and water, washed with ether and acidified with dilute hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-hydroxy-2'-phenylethylidene)-rhodanine, m.p. 134°-137°C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH:19]=[CH2:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1.B1C2CCCC1CCC2.[OH-:39].[Na+].OO>>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:19][CH2:20][OH:39])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][O:10]1
Reactant: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Product: OCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-((3,5-Bis(trifluoromethyl)benzyloxy)methyl)-1-vinylisochroman (125 mg, 0.300 mmol) was dissolved in 9-BBN (0.5 M in tetrahydrofuran, 2.4 mL, 1.2 mmol) and stirred overnight at room temperature. The reaction was cooled to 0° C. and treated with 4 M sodium hydroxide (1 mL) and then 30% hydrogen peroxide (1 mL) dropwise. The reaction was stirred at 0° C. for 1 h and then quenched by addition of saturated ammonium chloride. The mixture was extracted with diethyl ether (2×) which was washed with brine, dried over magnesium sulfate, and purified by column chromatography (25%-->37% EtOAc/Hex) to give 125 mg (96%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.77 (s, 1H), 7.70 (s, 2H), 7.05-7.25 (m, 4H), 4.67 (qAB, JAB=13.1 Hz, 2H), 4.03 (dd, J=7.3, 3.7 Hz, 2H), 3.78 (qAB, JAB=10.4 Hz, 2H), 3.61 (m, 2H), 2.99 (m, 1H), 2.72 (ddd, J=16.2, 3.4, 3.4 Hz, 1H), 2.62 (bs, 1H), 2.36 (m, 1H), 2.12 (ddd, J=15.0, 5.5, 4.6 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 141.1, 136.9, 134.8, 131.8 (q, J=33.6 Hz), 129.2, 127.3, 127.1, 126.6, 125.6, 123.4 (q, J=273 Hz), 121.6, 79.9, 76.4, 72.1, 60.7, 59.3, 39.9, 29.5. Mass spec.: 435.29 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1.[CH2:18](OC(OCC)C=C)[CH3:19].N(CCCC)(CCCC)CCCC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N:13]1[CH:17]=[N:16][N:15]=[N:14]1)[CH3:19]
Reactant: C=CC(OCC)OCC
Reactant: Cc1ccc(-n2cnnn2)c(CCC(=O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)CCc1cc(C)ccc1-n1cnnn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
3-(5-Methyl-2-tetrazol-1-yl-phenyl)-propionic acid: To a mixture of 117A (956 mg, 4.00 mmol), 3,3-diethoxyprop-1-ene (1562 mg, 12.00 mmol), and Bu4NCl (1110 mg, 4.00 mmol) in DMF (22 mL) was added Bu3N (1480 mg, 8.00 mmol). To this mixture under N2 was added Pd(OAc)2 (26.9 mg, 0.12 mmol). The resulting mixture was stirred at 90° C. for 1.5 h, then cooled to rt and quenched with 2N HCl (10 mL). The resulting mixture was stirred for 20 min, then evaporated. The mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by flash chromatography to provide 3-(5-Methyl-2-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (695 mg, 66.8%). LCMS m/z 261.2 (M+H)+. To a solution of this intermediate (690 mg, 2.65 mmol), in THF (10 mL) was added 2N LiOH (10 mL). The resulting mixture was stirred at rt for 3 h, then acidified to pH 3-4 with 2N HCl at 0° C. The mixture was concentrated and extracted with EtOAc (5×20 mL). The combined organic layers were washed with brine, dried over MgSO4, and purified by prep. HPLC to give 117B (567 mg, 92%). LCMS m/z 233.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14]CC)=[O:13])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([OH:14])=[O:13])=[C:5]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 96.7 %

Procedure:
A mixture of ethyl 6-chloro-4-phenyl-3-quinolinecarboxylate (2.5 g), potassium hydroxide (2.24 g) and ethanol (25 ml) was heated for 10 mins. at 80° C. The mixture was diluted with water and acidified with hydrochloric acid to give 6-chloro-4-phenyl-3-quinolinecarboxylic acid as crystals (2.20 g, 96.9%), which was recrystallized from a mixture of methanol and chloroform as pale yellow prisms. m.p. 269°-270° C.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][CH:10]([CH3:42])[C@H:11]([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH2:22]1)[C:12]([O:14]C(C)(C)C)=[O:13].[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>CN(C=O)C>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:3][N:19]([CH2:20][C@H:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)[O:32][C:33]=2[CH3:34])[CH2:22]1)[C@@H:11]([CH:10]([CH3:9])[CH3:42])[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN(C)[C@H](C(=O)O)C(C)C)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg of methyl iodide and 12 mg of potassium carbonate are added to 40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-yl-methoxy)cyclohexylmethyl]amino}butyrate (see Example 42) in 0.5 ml of DMF, and the mixture is stirred at RT overnight. 1 ml of TFA is added to the reaction solution, and the mixture is stirred for a further 1 h. The solution is purified by preparative HPLC, yielding 6.4 mg of (S)-2-{methyl-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}-3-methyl-butyric acid trifluoroacetic acid salt. C25H36N2O4 (542.60); MS (ESI): 543 (MH+).
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:65]=[CH:64][C:42]([C:43]([NH:45]/[C:46](/[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])=[CH:47]\[C:48]3[CH:53]=[CH:52][C:51]([O:54][CH:55]4[CH2:57][CH2:56]4)=[CH:50][CH:49]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:65]=[CH:64][C:42]([C:43]([NH:45][CH:46]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][CH:55]4[CH2:56][CH2:57]4)=[CH:52][CH:53]=3)[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: O=C(NCCO)/C(=C/c1ccc(OC2CC2)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(OC2CC2)cc1)C(=O)NCCO)c1ccc(OCCC2CC2)cc1
Yield: 60.4 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(2-cyclopropylethoxy)-N-((Z)-2-[4-(cyclopropyloxy)phenyl]-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (193 mg) to give 117 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:3]Cl.[CH3:13][C@H:14]1[O:19][C@@H:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:2]([CH3:1])[CH2:3][N:16]2[CH2:15][C@H:14]([CH3:13])[O:19][C@H:18]([CH3:20])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(CCl)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(Cc1ccc(Br)cc1)CN1C[C@@H](C)O[C@@H](C)C1

Procedure:
15 parts of 2-methyl-3-(4-bromophenyl)-propyl chloride and 28 parts of cis-2,6-dimethylmorpholine were stirred at 150° C. for 8 hours. The reaction mixture was cooled, poured into 100 parts of water, brought to pH 9-10 with saturated aqueous Na2CO3 solution and extracted with methylene chloride. The organic phase was dried and concentrated and the residue was distilled to give, at a boiling point of 100°-102° C./0.01 mbar, 15.8 parts of 4-[3-(4-bromophenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine of nD22 1.5265.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH:11]2[N+:15]([O-:17])=[O:16])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([CH:11]2[N+:15]([O-:17])=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2C(C(=O)N1Cc1ccccc1)C2[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])C1C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane-2,4-dione (6.00 g) in THF was added a solution of borane in THF (1 M, 100 mL) dropwise. The reaction mixture was refluxed for 1 h, then cooled to rt and quenched with MeOH. The mixture was concentrated in vacuo and the residue was chromatographed by a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to afford the title compound as pale yellow oil (4.30 g, 80.00%), HPLC: 94.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 219.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.51 (m, 2H), 3.14 (d, J=1.8 Hz, 2H), 3.60 (s, 2H), 4.63 (s, 1H), 7.3 (m, 5H) ppm.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OC)(OC)OC.CSC.B.CO>O1CCCC1>[CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Agent: B
Agent: COB(OC)OC
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](OCc1ccccc1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-(benzyloxy)-2-hydroxybutanoic acid (the product of step i) (0.79 g) and trimethyl borate (0.67 mL) in anhydrous tetrahydrofuran (4 mL) at 0° C. was added dropwise borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran). The reaction mixture was stirred at room temperature overnight, then further borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran) was added at 0° C. and the reaction mixture stirred at room temperature for a further 2 d. The mixture was cooled to 0° C. and methanol (10 mL) slowly added. When effervescence had ceased, the volatiles were evaporated, further methanol added and the mixture concentrated again to give the subtitle compound as a yellow oil which was used without further purification. Yield: 0.68 g.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(Cl)Cl.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][CH2:22][NH:23][CH2:24][C:25](=[O:27])[NH2:26])[CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C=O)C.C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:28])[CH2:21][CH2:22][N:23]([CH2:24][C:25](=[O:27])[NH2:26])[C:11](=[O:13])[CH2:10][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:18]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CCNCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(N)=O)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
DhbtOH (9.37 g, 57.4 mmol), N1-thyminyl acetic acid (10.57 g, 57.4 mmol) and CH2Cl2 (100 mL) were added to a solution of N-(carbamoylmethyl)-β-alanine ethylester (10.0 g, 57.4 mmol) in dry DMF (100 mL). The solution was cooled to 0° C. in an ice bath and a solution of DCC (1.90 g, 9.18 mmol) in DMF/CH2Cl2 (100 mL, 1:1 v/v) was added dropwise within 20 minutes. The ice bath was removed and after stirring for 1 hour at room temperature. The reaction mixture was filtered and the precipitate (DCU) was rinsed with CH2Cl2 (50 mL). The organic solution and the CH2Cl2 rinse were combined. A colorless precipitate formed overnight which was filtered and rinsed with CH2Cl2. The precipitate was dried in vacuo to give 12.0 g (61%) (mp 207-208° C.) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:15]=[C:16]([OH:22])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:6][CH:7]([CH3:40])[CH2:8][S:9]([C:12]1[CH:13]=[C:14]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=3)[O:24]2)[CH:15]=[C:16]([O:22][CH2:4][CH2:3][CH2:2][Br:1])[C:17]=1[O:18][CH2:19][CH2:20][CH3:21])(=[O:10])=[O:11]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
1,3-Dibromopropane (0.105 mL, 1.0 mol) was added to a solution of trans-2-[3-(2-hydroxypropylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (102 mg, 0.20 mmol) in DMF (1 mL) containing potassium carbonate (105 mg, 0.76 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 2 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue (143 mg). Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound (89 mg, 70%) as a colorless foam: Rf 0.5; NMR (CDCl3) δ 1.26 (d, CH2CHOHCH3), 3.66 (t, CH2Br).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([NH:11][NH:10][C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[Cl:2])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NNc1ccc(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 1.25 h
Yield: 98 %

Procedure:
A slurry of 101.4 grams (0.4751 mole) of 2,4-dichlorophenylhydrazine hydrochloride in 600 mL of water was stirred, and a solution of 20.9 grams (0.5225 mole) of sodium hydroxide in 100 mL of water was slowly added. During the addition, the reaction mixture thickened. An additional 50 mL of water was added to aid fluidity. Upon completion of addition of the sodium hydroxide solution, an additional 70 mL of water was added. The reaction mixture was stirred for about 75 minutes, then it was extracted with three 300 mL portions of ethyl acetate. The extracts were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate containing free 2,4-dichlorophenylhydrazine (1) was transferred to an appropriate reaction vessel. The stirred solution was cooled to about 10° C., and 58.2 grams (0.5701 mole) acetic anhydride was added dropwise. Upon completion of addition, gas chromatographic (GC) analysis of the reaction mixture indicated the reaction was about 99% complete. The cooling medium was removed, and a solution of 62.5 grams of potassium carbonate in 200 mL of water was added to the reaction mixture. The mixture was stirred for about five minutes and the organic layer was separated. The organic layer was concentrated under reduced pressure, yielding 102.0 grams (98% yield) of 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([N:30]1[C:36](=[O:37])[C:35]([CH3:39])([CH3:38])[C:34](=[O:40])[N:33]([CH3:41])[C:32]2[CH:42]=[C:43]([O:46][CH2:47][CH2:48][CH2:49]I)[CH:44]=[CH:45][C:31]1=2)[CH3:29]>CN(C=O)C>[CH2:28]([N:30]1[C:36](=[O:37])[C:35]([CH3:38])([CH3:39])[C:34](=[O:40])[N:33]([CH3:41])[C:32]2[CH:42]=[C:43]([O:46][CH2:47][CH2:48][CH2:49][N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[CH2:10][N:11]3[CH:16]=[CH:15][C:14]4[O:17][C:18]([CH3:20])=[CH:19][C:13]=4[C:12]3=[O:21])[CH:44]=[CH:45][C:31]1=2)[CH3:29]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4ccccc43)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.28 g) and potassium carbonate (0.9 g) were added to a DMF solution (2 ml) of 1-ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.43 g). The mixture was stirred at 60° C. overnight. After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→4:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.43 g) as a white amorphous solid.