Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[N:9][CH:10]=1)[CH2:3][OH:4].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:12]([NH:11][C:8]1[N:9]=[CH:10][C:5]([C@@H:2]([OH:1])[CH2:3][O:4][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)Nc1ccc([C@@H](O)CO)cn1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc([C@@H](O)COS(=O)(=O)c2ccc(C)cc2)cn1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A slurry of (R)-N-(5-(1,2-dihydroxy-ethyl)-pyridin-2-yl)-acetamide (prepared as described in Preparation Three, 71.2 g, 362 mmol) in anhydrous pyridine (362 ml) was cooled to 5° C. and treated with p-toluenesulfonyl chloride (69.18 g, 362 mmol) in one portion. The reaction mixture was stirred at 5° C. for 20 minutes, then the cooling bath was removed and the mixture was stirred at ambient temperature for two hours. The mixture was then concentrated, dissolved in 30 ml of methanol, concentrated and dissolved in toluene (300 ml) and concentrated again. The residue was treated again with methanol and toluene, then the residue was dissolved in ethyl acetate and washed sequentially with half-saturated brine, brine and dried over sodium sulfate. The filtrate was evaporated to afford 102.2 g (80%) of the title product as light buff crystals. Recrystallization from ethanol-cyclohexane afforded the title product as colorless crystals. mp 124-126° C. 1H NMR (dmso-d6): δ=10.5 (br, 1H); 8.21 (d, 1H); 7.94 (d, 1H); 7.68 (d, 2H); 7.51 (d of d, 1H); 7.41 (d, 1H); 5.87 (d, 1H); 4.76 (d of d, 1H); 4.05 (d, 2H); 2.41 (s, 3H); 2.10 (s, 3H). MS (CI): m/z=351 (M+H+). Optical Rotation: −36.181° (c=1.19, acetone). Analysis: Calculated for C16H18N2O5S: C, 54.85%; H, 5.18%; N, 7.99%. Found: C, 54.91%; H, 5.34%; N, 8.06%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@@H:13]([NH:17][S:39]([C:37]2[S:38][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:35][CH:36]=2)(=[O:40])=[O:41])[CH:14]([CH3:15])[CH3:16])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)[C@H](N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@@H](CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(-c2ccccn2)s1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
The product of Example 7, Step (c) (0.050 g) was dissolved in acetone (1 ml). K2CO3 [0.033 g dissolved in H2O (0.5 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.041 g) and the reaction left to stir for 1 hr. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by flash silica column chromatography with 30% EtOAc/68% Hexane/2% TEA as eluent, and then reverse phase HPLC [(50% MeCN/NH4OAcaq (0.1%)] gave the title compound as a solid (0.023 g).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[F:24])=[C:5]([F:25])[C:4]=1[F:26].[I:29]Cl>C(#N)C>[F:25][C:5]1[C:4]([F:26])=[C:3]([I:29])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[F:24]
Reactant: CCCc1ccc(-c2ccc(-c3ccc([Si](C)(C)C)c(F)c3F)c(F)c2)cc1
Reactant: ClI
Solvent: CC#N
Product: CCCc1ccc(-c2ccc(-c3ccc(I)c(F)c3F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
The total amount of the terphenyl 9 is dissolved in 4 ml of absolute acetonitrile and reacted with 1.2 ml (6 mmol) of a 5 M solution of ICl in acetonitrile, and the mixture is stirred at room temperature for 1 hour. The residue is crystallised at −20° C. for 2 hours. The supernatant solution is subsequently sucked off, and the product which remains is washed with 2 M Na2S2O5 (10 ml) and water (10 ml) and dried in an oil-pump vacuum (yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:39]=[C:40]=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCCCCCCCN=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Product: CCCCCCCCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 75 %

Procedure:
6-(2, 6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.348 g of octyl isocyanate according to the general procedure of Example 21. Chromatography, eluting first with ethyl acetate:methyl alcohol:triethylamine (90:10:1) then switching to ethyl acetate:ethanol:triethylamine (9:2:1) gave 1.011 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]-pyrimidin-7-yl}-3-octyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=601; mp 54.5-57.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C(=O)([O-])O.[Na+]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@H](c2ccc(O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-hydroxy-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=347.2 ([M+H]+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][C@H:17]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9][CH:10]=2)=[O:14])[C@H:17]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][N:25]=1
Reactant: C[C@H]1CCCN[C@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1ccnn1-c1ccccc1
Product: C[C@H]1CCCN(C(=O)c2ccnn2-c2ccccc2)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was synthesized following the same general protocol as described in Example 11 using 1-phenyl-1H-pyrazole-5-carboxylic acid and rac-cis-N-((3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 444, [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccncc1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccncc4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and pyridine-4 carbaldehyde. MS (ESI) m/z 470.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14].O>C1COCC1>[CH3:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(c(C)c1C)NC(=O)C2
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(C)c1C)NCC2
Temperature: 60 °C
Yield: 50.4 %

Procedure:
To a solution of 6,7-dimethyl-5-methoxy-1,3-dihydro-2H-indole-2-one (17.5 g, 91.5 mmol) in THF (500 mL) was added dropwise 1M-borane THF complex salt (306 mmol) at 0° C., and the mixture was stirred at 60° C. 3 hours. After ice-cooling, the mixture was added dropwise to water (100 mL). THF was distilled off under reduced pressure, concentrated hydrochloric acid (100 mL) was added, and the mixture was stirred under reflux for 2 hours. After neutralizing with 12N sodium hydroxide under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and purified by small amount silica gel column chromatography (ethyl acetate). The solvent was distilled off under reduced pressure, followed by recrystallization from hexane, to obtain 8.18 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:28])[CH:17](C(OC(C)(C)C)=O)[C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:28])[CH2:17][C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(C(=O)OC(C)(C)C)C(=O)C1CCCN1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 95 %

Procedure:
2-(2-tert-Butoxycarbonyl-3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester (9.74 g, 25.0 mmol) was dissolved toluene (40 mL) and was washed with 1N HCl (2×50 mL). To the resulting solution was added p-toluenesulfonic acid monohydrate (1.00 g, 5.00 mmol) and the solution was heated under nitrogen to 80° C. for 4 hours. The dark mixture was allowed to cool and was washed with water (3×100 mL). The organic layer was concentrated to give 6.87 g (95%) of 2-(3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester as an amber oil. The product was used directly in the subsequent step without further purification. [M+H]+ 290.03.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][S:12][CH:11]=1.CN([CH:22]=[O:23])C>C1COCC1>[Br:9][C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][S:12][C:11]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: CCCCc1cscc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1csc(C=O)c1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a solution of freshly prepared LDA (11.40 mmol) in THF (7 mL) at -78° C. was added slowly 3-bromo-4-butylthiophene of Example 1(a) (2.50 g, 11.40 mmol) in THF (10 mL). After stirring for 15 min, DMF (0.94 mL, 12.10 mmol) in THF (2 mL) was dropwise added. The resulting mixture was stirred for 1 h at -78° C. and then allowed to warm to room temperature. The reaction was quenched with water and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with H2O, brine and dried (MgSO4). After removing the solvent under reduced pressure, column chromatography (silica gel, EtOAc/Hexane, 20:80) of the residue afforded the title compound as an oil (1.87 g, 60%).
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1.Cl[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[Cl:3][C:4]1[N:8]([C:15]([O:17][CH3:18])=[O:16])[C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1
Reactant: Cc1cccc2[nH]c(Cl)nc12
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)n1c(Cl)nc2c(C)cccc21
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
Potassium hydride (0.85 g of 35% in oil, washed with ether to remove oil, 7.4 mmol) was added to a stirred solution of 2-chloro-4-methyl-1H-benzimidazole (1.23 g, 7.4 mmol) in THF (25 mL). Methyl chloroformate (0.7 g, 7.4 mmol) was added and the reaction was stirred 10 minutes. The solvent was removed and the material was partitioned between ethyl acetate and water. Evaporation of the organic layer gave 1.68 g of white solid. Crystallization from hexane gave 1.42 g of white crystals, mp 90°-91° C. Anal. Calc'd for C10H9ClN2O2 : C, 53.47; H, 4.04; C1, 15.78; N, 12.47. Found: C, 53.63; H, 4.11; Cl, 15.81; N, 12.45.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:37]>CO.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:37]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1

Procedure:
The product of Example 34 was dissolved in 0.2 ml of a molar solution of sodium acetate in methanol and 0.4 ml of ethanol was slowly added thereto. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in ethanol and after efflorescence, the mixture was vacuum filtered to obtain 0.047 g of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-aminoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:8]=1[CH3:28])C.FC(F)(F)C(O)=O.[NH:39]([C:41]1[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[N:45][CH:46]=1)[NH2:40].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:47]([C:44]1[N:45]=[CH:46][C:41]([N:39]2[C:6]([C:7]3[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10](=[O:17])[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=4)[C:8]=3[CH3:28])=[CH:5][CH:4]=[N:40]2)=[CH:42][CH:43]=1)#[N:48]
Reactant: CCOC(C#Cc1nc(C(=O)OC)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Reactant: N#Cc1ccc(NN)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccnn2-c2ccc(C#N)nc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 28.2 %

Procedure:
Methyl 6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.073 g, 0.17 mmol) and 5-hydrazinopyridine-2-carbonitrile trifluoroacetate (0.050 g, 0.20 mmol) in dioxane (3 ml) were placed in a vial. 2M HCl (0.188 ml) was added and the mixture was stirred at 55° C. for 15 min. After cooling, NaHCO3 (0.048 g) was added and the mixture was extracted with DCM and water. The combined organic phases were washed with water, brine, dried (Na2SO4) and evaporated. The residue was dissolved in acetic acid (10 ml) and the vial was sealed. The solution was stirred at 90° C. for 10 h. After evaporation, the residue was purified by preparative HPLC to give 0.023 g (28%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[NH3:11].O1CCOCC1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:11])(=[O:9])=[O:8])[CH:2]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: N
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of pyridine-3-sulphonyl chloride (1 g, 5.6 mmol, 1 eq, commercially available from Davos) in THF (5 mL) is added ammonia in dioxane (23.9 mL, 2 M, 47.9 mmol, 8.5 eq). The resulting suspension is stirred at room temperature for 1 h. The solvent is removed and the residue is taken up in DCM. The organic phase is washed with a saturated aqueous solution of NH4Cl then brine and the DCM is removed under reduced pressure to afford, after drying under vacuum at 40° C., 637 mg (71%) of the title compound as a yellowish powder. 1H NMR (DMSO-d6) δ 9.20-8.90 (m, 1H), 8.85-8.75 (m, 1H), 8.40-8.05 (m, 1H), 7.80-7.40 (m, 3H).
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: BrCCCCc1ccccc1
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Product: COP(=O)(CC(=O)[C@@H](C)CCCCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-7-phenylheptyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (4-bromobutyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (2.84 g) as a colorless oil; TLC Rf 0.54 (solvent system: 100 v ethyl acetate); MS (ESI+) m/z 313.1 (M+H)+; 1H-NMR (CDCl3) δ 7.22-7.17 (m, 2H), 7.12-7.07 (m, 3H), 3.82-3.68 (m, 6H), 3.07 (s, 1H), 3.01 (s, 1H), 2.71-2.62 (m, 1H), 2.53 (t, J=7.69 Hz, 2H), 1.66-1.47 (m, 4H), 1.28-1.22 (m, 2H), 1.02 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.052/(0.01998 g/1.5 mL)(0.5)=+7.81° (c=1.017, CHCl3).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:23])[CH2:21][CH3:22])[CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3]
Reactant: N#Cc1c(OCC2CCNC2)cccc1[N+](=O)[O-]
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(COc2cccc([N+](=O)[O-])c2C#N)C1

Procedure:
Prepared as in Example 176b from 2-nitro-6-(pyrrolidin-3-ylmethoxy)benzonitrile hydrochloride (Example 196d) and propionyl chloride in 51% as a yellow solid. MS 304 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Cl[CH2:13][C:14](=O)[CH3:15].C(=O)(O)[O-].[Na+].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>CN(C)C=O>[S:23]([OH:26])(=[O:25])(=[O:24])[CH3:22].[NH2:1][C:2]1[C:3]2[N:4]([CH:13]=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)c1cnc(N)c(N)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cc(C(N)=O)cc(N)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.3 %

Procedure:
5,6-diaminonicotinamide (10 g, 66 mmol), chloroacetone (6.1 g, 66 mmol) and sodium bicarbonate (11.2 g, 132 mmol) were added to dimethylformamide (200 ml) and the mixture was stirred for 72 h. at room temperature. Most of the solvent was evaporated under reduced pressure and methanesulfonic acid (6 g, 63 mmol) was added. More solvent was evaporated under reduced pressure and ethanol was added to the residue. Upon warming the mixture to 60° C. the product crysstallized as salt and was filtred off to give 6 g (32%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]([O:15][CH3:16])=[O:14].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CO.N1CCCCC1>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](/[CH:26]=[C:8]2\[O:9][C:5]3[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:18]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COC(=O)c1c(OC)ccc2c1OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)c1c(OC)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of methyl 6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.070 g, 0.32 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.046 g, 0.32 mmol). Then, the mixture was added with 7 drops of piperidine, then the mixture was stirred at room temperature for 2 hours, and the solid formed was collected by filtration to obtain the objective substance. Further, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain the objective substance. Two portions of the objective substance was combined to obtain 0.090 g (80%) of methyl (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[Mg].II.[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=[O:25]>C1COCC1.O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]([OH:25])[CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cccc(CBr)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CC(O)c2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 304.8 %

Procedure:
A mixture of 3-methoxy-benzylbromide (40 mg, 0.2 mmol), magnesium turnings (172 mg, 7.1 mmol) and a small crystal of iodine in dry THF (0.6 mL) was heated at 40° C. until an exothermic reaction to initiated. A solution containing a mixture of 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde (255 mg, 1.0 mmol) and 3-methoxy-benzylbromide (241 mg, 1.2 mmol) in THF (2.5 mL) was then added dropwise to the stirred reaction mixture. After the addition was complete, the mixture was poured into cold water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20:1 CH2Cl2/iPrOH) to provide the desired 1-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-2-(3-methoxy-phenyl)-ethanol (230 mg, 61%) as an off-white solid: ESI MS m/z 377 [C19H18Cl2N2O2+H]+.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Br)ccc1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Br)ccc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.