Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CCO)CCNCC1.[C:10]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][OH:21])[CH2:15][CH2:14]1)(=[O:12])[CH3:11].C(Cl)(=O)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[S:27]([O:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:10](=[O:12])[CH3:11])[CH2:14][CH2:15]1)(=[O:29])(=[O:28])[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(CCO)CC1
Agent: OCCN1CCNCC1
Solvent: CC(=O)Cl
Product: CC(=O)N1CCN(CCOS(C)(=O)=O)CC1

Procedure:
In the same process, 2-piperazinoethanol is replaced by equivalent 2-(4-acetylpiperazino)ethanol and acetyl chloride is replaced by equivalent methanesulfonyl chloride to produce 2-(4-acetylpiperazino)ethyl mesylate.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:88])[C@@H:76]([NH2:87])[CH2:77][CH2:78][O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]>CN(C=O)C.C(OCC)(=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:88])[C@@H:76]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:77][CH2:78][O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 355 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 3 ml DMF were added 356 μl DIPEA, 328 mg HATU and 400 mg 4-((S)-2-amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester hydrotrifluoroacetate. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 543 mg.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[F:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:1][C@@H:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@@H]1O
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-(4-fluoro-phenoxy)-phenol provided the title compound. MS ESI+: m/z=288 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CO[CH2:7][Cl:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([S:17][CH3:18])[CH:11]=1.O>C(=S)=S>[Cl:8][CH2:7][C:15]1[C:10]([F:9])=[CH:11][C:12]([S:17][CH3:18])=[C:13]([CH3:16])[CH:14]=1
Reactant: CSc1cc(F)ccc1C
Reactant: COCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CSc1cc(F)c(CCl)cc1C
Reaction time: 0.5 h

Procedure:
To a suspension of aluminum chloride (29 g) in carbon disulfide (300 ml) is added chloromethyl methyl ether (17 ml), and the mixture is stirred for 30 minutes. To the mixture is added 4-fluoro-2-methylthiotoluene (17.2 g), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added water, and the mixture is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloromethyl-4-fluoro-2methylthiotoluene (21 g).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>ClCCl>[Cl:16][C:17]1[N:22]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Yield: 65.13 %

Procedure:
Cyclopentylamine (5.17 ml) and N,N-diisopropylethylamine (12.4 ml) were dissolved into 125 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (9.7 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 80 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (7.9 g) in a yield of 65.13%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.38 (s, 1H), 4.59 (m, 1H), 2.13-2.21 (m, 2H), 1.72-1.85 (m, 4H), 1.53-1.71 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)(=[O:4])[CH2:2][CH3:3].[BrH:17].C(O)(=O)C.Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:17][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=[O:4]
Reactant: CCC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reaction time: 2 h

Procedure:
To a solution of 6-propionyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.4 g) and 30% hydrogen bromide-acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (5.12 g) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water. The resultant precipitate was collected by filtration and dissolved in a mixture of ethyl acetate and tetrahydrofuran. The organic solution was washed with a saturated aqueous solution of sodium bicarbonate and brine. The solvent was dried over magnesium sulfate and removed in vacuo to afford a crystalline residue, which was washed with diisopropyl ether to give 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.8 g).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][C:12]=1[CH3:21]>C(Cl)Cl>[Br:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(CO)ccc1Br
Reaction time: 1 h
Yield: 67.9 %

Procedure:
DIBALH (1.0M solution in methylene chloride, 31 mL, 31 mmol) was added dropwise to a solution of methyl 4-bromo-3-methylbenzoate (3.0 g, 14.0 mmol) in methylene chloride (20 mL) at 0° C. After 1 h, the reaction was quenched with 10% aqueous sodium bisulfite (100 mL). The aqueous layer was separated and extracted with methylene chloride (50 mL). The combined organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 17% ethyl acetate/hexane gave 1.90 g (9.50 mmol, 68%) of product: 1H NMR (500 MHz) δ 7.50 (d, J=8.3 Hz, 1H), 7.24 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 2.40 (s, 3H).
Reaction SMILES: [I-].[Na+].[N-:3]=[N+:4]=[N-:5].[Na+].Cl[CH2:8][CH2:9][CH2:10]/[C:11](/[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[N:30][N:31]=1)=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:3]([CH2:8][CH2:9][CH2:10]/[C:11](/[C:27]1[O:28][C:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[N:30][N:31]=1)=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:15]([O:25][CH3:26])[CH:14]=1)=[N+:4]=[N-:5]
Reactant: COc1cc(/C=C(\CCCCl)c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C(\CCCN=[N+]=[N-])c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.5 %

Procedure:
Sodium iodide (35 mg) and sodium azide (20 mg) were added to a solution of 2-{4-chloro-1-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}butyl}-5-(4-fluorobenzyl)[1,3,4]oxadiazole (72 mg) in DMF (2 mL), and the reaction solution was stirred at 80° C. for five hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=3:1→ethyl acetate) to obtain 50 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])[C@H:34]([CH2:42][N:43]([S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:25]([O:29][C:30]([N:32]1[CH2:33][C@H:34]([CH2:42][N:43]([CH2:44][CH:45]([CH3:46])[CH3:47])[S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])[C@H:35]([CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH2:12][CH2:11][CH2:10][O:9][CH3:8])[CH:15]=2)[CH2:36]1)=[O:31])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)CN(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C)S(=O)(=O)c1ccccc1
Reactant: COCCCOc1cc(C(=O)Cl)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2CN(CC(C)C)S(=O)(=O)c2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (0.48 mL, 3.43 mmol) followed by 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid chloride (621 mg, 2.4 mmol) (prepared from 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid and SOCl2 in CH2Cl2) is added to a solution of (3S*,4R*)-3-[(benzenesulfonyl-isobutyl-amino)-methyl]-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.07 g, 2.3 mmol) in CH2Cl2 (30 mL) and stirred at RT for 16 h. For workup a sat. solution of NaHCO3 is added and the mixture is extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4), filtered and the solvent is evaporated. Purification of the crude product by flash chromatography on silica gel (eluent gradient: c-hexane/AcOEt 1:1 to 3:7) yields the title compound. TLC, Rf (c-hexane/AcOEt 3:7)=0.40; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.10 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)=[N:9][C:8]=2[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[N:27]3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC1CCC(C(=O)NC(c2ccc3ccc(-c4ccccc4)nc3c2)c2nccnc2Cl)CC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C

Procedure:
A round bottom flask, charged with carbonyldiimidazole (252.2 mg, 1.55 mmol) and 4-methoxy-cyclohexanecarboxylic acid (mixture of cis/trans isomers) (242.9 mg, 1.54 mmol) was evacuated and filled with nitrogen. THF (15 mL) was added and the reaction mixture was stirred at 60° C. for 16 h. (3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)methylamine hydrochloride salt (500 mg, 1.10 mmol) was then added and stirring was continued at 60° C. for another 20 h. After cooled to rt, the reaction mixture was diluted with mL of EtOAc and washed with sat. NaHCO3 (3×30 mL) followed by brine (3×30 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (60% EtOAc in hexane→100% EtOAc). N-[(3-Chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide was obtained as a yellow solid. To a solution of N-[(3-chloropyrazin-2-yl)(2-phenyl-quinolin-7-yl)-methyl]-4-methoxycyclohexanecarboxamide (440 mg, 0.91 mmol) in acetonitrile (20 mL) was added POCl3 (0.17 mL, 1.69 mmol) and DMF (0.3 mL). This mixture was heated to 55° C. under N2 for 2 h, concentrated under reduced pressure, and quenched with 2N NH3 in 2-propanol to pH 9. 2-Propanol was removed under reduced pressure and the residue was dissolved in dichloromethane (50 mL) and water (30 mL). Layers were separated and the organic phase was washed with brine and dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (2%→6% CH3CN in dichloromethane) to afford the individual cis-isomer and trans-isomers:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[OH:33][CH:34]([CH:45]([OH:56])[C:46]([O:48]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:35](=[O:37])[CH:34]([OH:33])[CH:45]([OH:56])[C:46]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:48])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
To a solution of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (intermediate 175.1) (110 mg, 0.22 mmol) in DMF (2.0 mL) was added bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (Intermediate 168.1) (34 mg, 0.10 mmol) and the reaction was stirred for 10 minutes. The solvent was removed under vacuum and the residue was purified by preparative HPLC to give the title compound (23 mg) as a TFA salt. 1H-NMR (400 mHz, CD3OD) δ 7.81 (m, 4H), 7.44 (s, 1H), 7.37 (m, 2H), 6.75 (s, 1H), 4.64 (m, 4H), 4.37 (m, 4H), 3.72 (m, 2H), 3.46 (m, 10H), 3.38 (m, 12H), 3.02 (m, 10H). MS (m/z): 1117.02 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH:50][CH3:51])=[CH:44][CH:43]=1>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][N:50]([CH3:51])[C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (150 mg, 0.42 mmol), CDI (276 mg, 0.84 mmol) and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (80 mg, 0.42 mmol) in DCE (8 mL).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[N:13]=[C:14]1[NH:15][CH2:16][CH2:17][NH:18]1
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c(N=C2NCCN2)c([N+](=O)[O-])c1
Yield: 0.9 %

Procedure:
50 gm (0.183 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine nitrate were slowly added over a period of two hours to 70 ml of concentrated sulfuric acid at 5°-10° C., while slightly cooling with ice and thoroughly stirring and the resulting black solution was stirred for one hour more at 5° C. Thereafter, ice was added, the aqueous mixture was made alkaline with 5 N sodium hydroxide, and the precipitate formed thereby was collected, recrystallized from methanol and separated from the mother liquor by suction filtration. The methanol was distilled out of the filtrate, and the residue was eluted on a silicagel column (mobile phase: 20 parts methanol, 10 parts acetone, 50 parts chloroform). The thin-layer chromatographically uniform fractions were combined and evaporated in vacuo, and the solid residue was dried, yielding 0.4 gm (0.86% of theory) of 2-(2-chloro-4-methyl-6-nitro-phenylimino)-imidazolidine, m.p. 198° C., Rf -value 0.7 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts concentrated ammonium hydroxide; carrier: silicagel G, visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)(C#N)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:23](=[O:26])(O)[O-:24].[Na+]>O>[N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:23]([OH:24])=[O:26])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C([O-])O
Reactant: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 100 °C

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (80 mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (3 mL, 100 mmol) and heated to 100° C. for 2 h. The reaction was allowed to cool to room temperature, diluted with water, and the pH was adjusted to pH 7 with sodium bicarbonate. The neutralized solution was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give crude 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxylic acid as a solid (0.025 g. 30%). LCMS calculated for C14H12N3O5 (M+H)+: m/z=302.1. found: 301.9.
Reaction SMILES: I[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1COCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[C:10]3[C:6](=[N:7][S:8][N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: Ic1cccc2nsnc12
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2cccc4nsnc24)CCC3)nc1
Temperature: 45 °C
Reaction time: 48 h
Yield: 11.1 %

Procedure:
Add 4-iodo-[2,1,3]-benzothiadiazole (Maybridge; 350 mg, 1.3 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 300 mg, 1.3 mmol), potassium fluoride (250 mg, 4.3 mmol), and THF (6.0 mL) to a flask under nitrogen. Purge the system with nitrogen for 10 min and add tris(dibenzylideneacetone) dipalladium(0) (120 mg, 0.13 mmol) and tri-tert-butylphosphonium tetrafluoroborate (Strem; 100 mg, 0.039 mmol). Purge the system with nitrogen for 2 min and stir for 48 h at 45° C. Filter the reaction through Celite®, rinse with chloroform/methanol, and concentrate in vacuo. Purify by flash column chromatography followed by reverse-phase preparative HPLC. Collect the pure fractions from the HPLC, concentrate in vacuo, take up the residue in methanol, and treat with MP-carbonate beads. Filter and concentrate in vacuo to provide the title compound (46 mg, 11%) as a pale yellow solid. Melting Range: 140-142° C. MS APCI m/e 320 (M+1). 1H NMR (CDCl3): δ 8.44-8.37 (m, 1H), 7.95-7.89 (m, 1H), 7.60-7.49 (m, 3H), 7.48-7.41 (m, 1H), 7.12-7.02 (m, 1H), 4.37-4.28 (m, 2H), 3.09-2.99 (m, 2H), 2.72-2.60 (m, 2H). HPLC: 98.3%, Rt=15.03 min. TLC (SiO2): Rf0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35]2=[O:40])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(=N\OC1CCN(C)C1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Yield: 83.9 %

Procedure:
2.7 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetate are suspended in 27 ml of methanol, and 4.9 ml of 2N sodium hydroxide solution are added thereto. The mixture is refluxed for 20 minutes under heating. After cooling, the mixtures concentrated under reduced pressure to remove methanol. The residue is adjusted to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated under reduced pressure to remove solvent. Then, the residue thus obtained is crystallized with ether and collected by filtration. 2.15 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.