Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+]>C1COCC1>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:3]([OH:23])=[O:2])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid methyl ester (12.3 g, 34 mmol) in THF (80 mL)/water (20 mL) was added lithium hydroxide (1.63 g, 68 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the residue diluted with water. After extraction with EtOAc, the aqueous phase was acidified to pH 5 by the addition of 2M aqueous hydrochloric acid solution. The aqueous phase was extracted with EtOAc and the extracts dried over magnesium sulfate. Concentration gave the title compound as a pale brown foam (11.54 g, 98%); 1H NMR (400 MHz, DMSO) δ 1.35 (9H, s), 1.74–1.81 (1H, m), 2.03–2.10 (1H, m), 2.81 (2H, m), 3.61 (1H, t), 6.86 (1H, m), 7.28 (1H, dd), 7.54 (1H, dd), 7.59 (1H, d), 12.60 (1H, brs); MS (ES−) m/e=346.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Mg+2].[Cl-].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([F:14])=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1cccc(Cl)c1F
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1F
Temperature: 95 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of 2-(3-chloro-2-fluorophenyl)-2-methylpropanoic acid (1.386 g, 6.40 mmol) and thionyl chloride (60.0 mL, 823 mmol) was stirred at 95° C. for 2 hours. The reaction was concentrated in vacuo, azeotroped using DCM (2×100 mL), and dried in vacuo to give the crude acid chloride. A solution of diethyl malonate (0.967 mL, 6.40 mmol) and MgCl2 (0.263 mL, 6.40 mmol) in ACN (40 mL) at 0° C., was treated dropwise with TEA (1.87 mL, 13.4 mmol), and the mixture was stirred at 25° C. for 3 hours. A solution of the acid chloride in ACN (35 mL) was added, and the mixture was stirred at 50° C. for 18 hours. The solution was concentrated in vacuo, diluted with 10% HCl(aq) (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (75 mL), dried over MgSO4, concentrated, and dried in vacuo. The residue was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give 1.56 g of the title compound. MS m/e=325 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
2-Trifluoromethylaniline (0.483 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.259 g, 0.500 mmol, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH2:10](Br)[CH2:11]Br.[C:14](=[O:17])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:5][CH2:6][S:9][C:11]2[CH:10]=[CH:7][C:8]([O:17][CH3:14])=[CH:3][CH:4]=2)=[CH:5][CH:4]=1
Reactant: BrCCBr
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(S)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(SCCSc2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
30 g of 4-methoxythiophenol, 20.2 g of ethylene bromide, 40 g of potassium carbonate, and 40 ml of dimethylformamide were placed in a 300 ml flask, and stirred for 3 hours as the interior of the flask was maintained at a temperature of from 50° C. to 60° C. The reaction mixture was poured into ice-cold water to deposit crystals. The crystals were recrystallized from methanol/ethyl acetate 1/1 (volume ratio) mixture. Melting point: 108°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.[NH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[NH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[NH:24][CH:23]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(O)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 69 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-hydroxy-1H-indol-3-yl)ethyl)benzamide was prepared according to method A with the 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), 3-(2-aminoethyl)-1H-indol-5-ol hydrochloride (0.081 g; 0.382 mmol), HATU (0.145 g; 0.382 mmol) and N,N-diisopropylethylamine (0.150 mL; 0.869 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.093 g (67%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Br:11])[C:5]([Br:12])=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[Br:16].Cl[CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20].C(N([CH2:30][CH3:31])CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]([O:10][CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[O:9])=[C:6]([Br:11])[C:5]([Br:12])=[C:4]([C:13]([O:15][CH2:18][C:19]([O:21][CH2:22][CH:30]=[CH2:31])=[O:20])=[O:14])[C:3]=1[Br:16]
Reactant: C=CCOC(=O)CCl
Reactant: O=C(O)c1c(Br)c(Br)c(C(=O)O)c(Br)c1Br
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)COC(=O)c1c(Br)c(Br)c(C(=O)OCC(=O)OCC=C)c(Br)c1Br

Procedure:
To a liquid mixture consisting of 24 parts of tetrabromoterephthalic acid and 60 parts of chloroform, were dropped with stirring 20 parts of allyl chloroacetate. Thereafter, 13 parts of triethylamine were added dropwise while cooling the resulting mixture at 15°-20° C. The mixture was heated until chloroform started to reflux. At the same temperature, the mixture was maintained for 8 hours. After allowing the liquid reaction mixture to cool, it was poured in a separation funnel and washed first with dilute hydrochloric acid and then with water. The organic layer was concentrated under reduced pressures and the resulting white solid was recrystallized from ethyl acetate, thereby obtaining 25 parts of bis(allyloxycarbonylmethyl) tetrabromoterephthalate (hereinafter called "Compound E") as white irregular crystals. (m.p. 146°-148° C.).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-].[K+].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:16][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([NH2:10])=[O:9])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: NC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccccc1OCC1CC1

Procedure:
Salicylamide (15.22 g), potassium hydroxide (85%, 7.73 g) and cyclopropylmethyl bromide (16.024 g) were heated together under reflux in absolute ethanol (100 ml) for 91/2 hours. The cooled mixture was filtered to remove inorganic products and the filtrate was evaporated to an oil. The oil was dissolved in 1:1 toluene:ethyl acetate (200 ml) and the solution was washed with 10% potassium hydroxide solution (2×30 ml), water (50 ml) and saturated brine (50 ml), dried (Na2SO4), and concentratred under reduced pressure, leaving 2-(cyclopropylmethoxy)benzamide as an oil which crystallised (17.606 g, 83%), mp 95°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20].C(O)(=O)C.Br>CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7](=[O:10])[NH:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:21]
Reactant: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To 2-(4-bromo-2-fluorophenylamino)-6-methoxy-nicotinic acid methyl ester (1.00 g, 2.82 mmol) in a sealed flask was added glacial acetic acid (10 mL) and HBr (10 mL, 48 wt % in H2O). The reaction mixture was stirred at 90-95° C. for 2 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed with H2O, saturated NaHCO3, saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was triturated twice with dichloromethane/methanol and the resulting solid was collected and dried under vacuum to yield 0.756 g (79%) pure desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#N.Cl.C([O:24]CC)C>CCCCCC>[CH3:7][C:6]1[CH:5]=[C:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:24])[O:3][C:2]=1[CH3:1]
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Reactant: Cc1ccoc1C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C(=O)c2ccccn2)oc1C
Temperature: 0 °C
Yield: 17 %

Procedure:
2,3-Dimethylfuran (5 g) was dissolved in diethyl ether (75 ml) under an argon atmosphere. A 1.6 M hexane solution (35.7 ml) of n-butyllithium was added dropwise thereto at 0° C., and the mixture was stirred under reflux for 2.5 hr. Thereafter, the reaction solution was cooled to −78° C., a solution of 2-cyanopyridine (6.0 g) in diethyl ether (20 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into ice to stop the reaction. The reaction solution was adjusted to pH 5 by the addition of 2 M hydrochloric acid and was then extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(2-pyridyl)-methanone (1.8 g, yield 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([Sn:20]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])Cl)[CH2:17][CH2:18][CH3:19].CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn:20]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH3:19])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of the chloride 2 (18.72 g, 110 mmol) in THF (200 mL) at −78° C. n-BuLi (51 mL, 127 mmol) was added and the reaction mixture was stirred for about 30 minutes. The tributylchlorostannane (25.4 mL, 93 mmol) was added and the mixture was stirred at −78° C. for another 60 minutes, quenched with water [at the same temperature] and allowed to warm up to room temperature. The warmed mixture was extracted with EtOAc, the extract was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluents EtOAc-hexane (15:85), then EtOAc-hexane (25:75) to afford title compound 98 (30.2 g, 77% yield) as a yellow oil. LRMS (M+1) 459.1 (100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH3:20])=[O:14])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:14][C:13]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Cc1ccsc1C(=O)NNC(=O)c1nc(Br)cnc1N
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a suspension of 3-amino-6-bromo-N′-(3-methylthiophene-2-carbonyl)pyrazine-2-carbohydrazide (7.85 g, 22.04 mmol) in anhydrous acetonitrile (117.8 mL) cooled in an ice bath was added DIPEA (8.546 g, 11.52 mL, 66.12 mmol) followed by dibromo(triphenyl)phosphorane (12.09 g, 28.65 mmol) portionwise. The resulting suspension was stirred at room temperature for 30 min and the precipitate isolated by filtration and washed with acetonitrile to give the product as a yellow solid (4.42 g, 52% yield); 1H NMR (400 MHz, DMSO) d 2.64 (s, 3H), 7.21 (d, 1H), 7.91 (3H, m) and 8.44 (s, 1H) ppm; MS (ES+) 340.04
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])(=[O:27])=[O:26]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])(=[O:36])=[O:35])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Yield: 88.5 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 1 from 0.9 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 55 ml of tetrahydrofuran, 1 ml of triethylamine and 1.02 g of 2-methylsulfonylbenzenesulfonyl chloride. 1.5 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a pink solid melting at 228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:45][CH2:46][N:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[C:14]([C:19]3[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=3)[CH:13]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCCN1CCCC1
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1OCCN1CCCC1
Temperature: 25 °C

Procedure:
To a stirred and ice-cooled solution of 1-(4-chloro-phenyl)-3-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea (0.1 g, 0.2923 mmol), triphenyl phosphine (0.291 g, 1.1078 mmol) and 1-(2-hydroxy ethyl)-pyrrolidine (0.127 g, 1.099 mmol) in THF (25 mL) was added diisopropyl azodicarboxylate (0.224 g, 1.104 mmol) slowly over 10 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred further for 4 hrs at this temperature. THF was evaporated and the syrup was dissolved in DMSO and purified using a Varian preparative HPLC system (60 mL/min flow and λ=240 0.1% TFA/H2O:0.1% TFA/CH3CN). The fractions containing the product were evaporated. The pink colored residue was subjected to 2nd purification using SiO2 flash chromatography (eluant: 1% methanol in DCM to 15% methanol in DCM). The fractions containing the product were evaporated to give a colorless solid that was used directly in the next step.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[S:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[CH2:57][NH2:58]>>[S:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[CH2:57][NH:58][C:41]([C:39]1[S:40][C:36]([N:33]2[CH2:34][CH2:35][N:31]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=3)[C:32]2=[O:45])=[CH:37][C:38]=1[CH3:44])=[O:43]
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2s1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1nc2ccccc2s1
Yield: 81 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[d]thiazol-2-ylmethanamine, the title compound was obtained as a colorless solid in 81% yield: 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J=8.0 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.41-7.34 (m, 1H), 7.31-7.24 (m, 2H), 7.07-6.98 (m, 2H), 6.63 (t, J=5.5 Hz, 1H), 6.13 (s, 1H), 5.01 (d, J=5.5 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.53 (s, 3H); MS (ES+) m/z 481.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C@@H:21]([OH:26])[CH2:22][C@H:23]([OH:25])[CH3:24].COCCOC(N=NC(OCCOC)=O)=O.[N+:43]([C:46]1[CH:54]=[CH:53][C:49]([C:50]([OH:52])=[O:51])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1.O>[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([O:25][C@@H:23]([CH3:24])[CH2:22][C@H:21]([OH:26])[CH3:20])=[O:51])=[CH:53][CH:54]=1)([O-:45])=[O:44].[N+:43]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([OH:52])=[O:51])=[CH:53][CH:54]=1)([O-:45])=[O:44]
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)C[C@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
After triphenylphosphine (565 mg, 2.16 mmol), (2R,4R)-2,4-pentanediol (226 mg, 2.16 mmol), and THF (6 ml) were added to a 50 mL flask, azodicarboxylic acid bis(2-methoxyethyl) ester (505 mg, 2.16 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C. Subsequently, 4-nitrobenzoic acid (300 mg, 1.80 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for one hour. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-nitrobenzoyloxy)pentane-2-ol as a pale yellow solid substance (358 mg, yield: 79%/4-nitrobenzoic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([NH2:16])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CC(N)=O)c2c1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc2cccc(CC#N)c2c1

Procedure:
The (7-methoxynaphth-1-yl)acetamide obtained in step E is suspended in 80 cm3 of anhydrous tetrahydrofuran. Triethylamine is added. The solution is cooled in an ice bath, and then trifluoroacetic anhydride is added dropwise, with magnetic stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[Br:12][CH:13]([CH3:24])[C:14](OCC)(OCC)OCC>>[Br:12][CH:13]([C:24]1[O:6][C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)=[N:7][N:8]=1)[CH3:14]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: CCOC(OCC)(OCC)C(C)Br
Product: CC(Br)c1nnc(-c2cccc(Cl)c2)o1
Yield: 32 %

Procedure:
3-Chloro-benzoic acid hydrazide (170 mg, 1 mmol) and 2-bromo-1,1,1-triethoxypropane (1 ml) were heated in a sealed vial at 120° C. for 10 min. The reaction mixture was place directly onto a flash column (silica gel) and purified using 0-50% dichloromethane in hexanes. The product was re-purified by flash column chromatography using a mixture of ethyl acetate:hexanes:dichloromethane (1:19:20) to afford 2-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (93 mg, 32%, colorless oil). 1H NMR (CDCl3) d (ppm): 8.09 (t, 1H), 7.99 (t, 1H), 7.55 (m, 3H), 5.30 (m, 1H), 2.21 (q, 3H).
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30](OCC)=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1>>[NH:18]1[CH:22]=[C:21]([CH2:23][CH:24]([C:30]2[N:4]3[CH:5]=[C:6]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:7]=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]3=[N:1][N:2]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:20]=[CH:19]1
Reactant: CCOC(=O)C(Cc1c[nH]cn1)C(=O)OCC
Reactant: CCCc1nc(-c2cccnc2)cnc1NN
Product: CCCc1nc(-c2cccnc2)cn2c(C(Cc3c[nH]cn3)C(=O)OCC)nnc12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine with diethyl (imidazol-4-yl-methyl)malonate (J.Chem.Soc. 99, (1911) 1390) there is obtained ethyl rac-α-(imidazol-4-ylmethyl)-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 405 (M)+, which is converted into the above acid by saponification analogously to Example 1.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[CH3:8][N:9]([CH:11](OC)OC)[CH3:10]>>[CH3:10][N:9]([CH3:8])/[CH:11]=[C:5](\[CH3:6])/[C:4](=[O:7])[CH:2]([CH3:3])[CH3:1]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)C(C)C
Product: C/C(=C\N(C)C)C(=O)C(C)C

Procedure:
2-Methyl-3-pentanone (5 g, 49.9 mmol) and DMF-DMA (10 mL, 74.9 mmol) were heated together in a sealed tube for 4 days. The reaction was concentrated in vacuo to afford an orange oil that was used directly in the next reaction (1.64 g, 21%).