Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=O.Cl.Cl.[CH3:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[F:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[CH2:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH3:22])=[O:7]
Reactant: O=C([O-])c1ccc(OCc2ccccn2)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: Cl
Agent: [Li+]
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccccn2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A from 2-Fluoro-4-(pyridin-2-ylmethoxy)-benzoic acid lithium salt and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine dihydrochloride salt. MS (ES+) 398.3
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[CH2:20]([N:22]([CH2:32][CH3:33])[C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][NH2:29])=[CH:25][CH:24]=1)[CH3:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([N:22]([CH2:32][CH3:33])[CH2:20][CH3:21])=[CH:24][CH:25]=2)[N:29]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: CCN(CC)c1ccc(CNN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 18 h with 5.4 g of 4-diethylaminobenzylhydrazine hydrochloride and 6.7 ml of triethylamine in 50 ml of ethanol. The mixture is poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying, 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 125-127° C.
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[OH:13][CH2:14][CH2:15]C#N>>[C:14]([O:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])(=[O:13])[CH3:15]
Reactant: CC(O)C(C#N)c1ccccc1
Reactant: N#CCCO
Product: CC(=O)OC(C)C(C#N)c1ccccc1
Yield: 93 %

Procedure:
This mixture of esters was prepared using the procedure described in Example 5, except 3-hydroxy-2-phenylbutanenitrile was used in place of 2-(2-chloro-5-difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 3-hydroxy-2-phenylbutanenitrile is shown in Example 17. The recovered ester product was a colorless oil (93% yield) as a mixture of diastereoisomers (Esters 9A and 9B), separated by chromatography into two pairs, Rf 0.40 and 0.32 (silica gel, EtOAc:hexane=1:4).
Reaction SMILES: [S:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[NH:2]1.[CH3:8][C:9]([C:11]([CH3:13])=[CH2:12])=[CH2:10].CCCCCC>C(Cl)CCl>[CH3:8][C:9]1[CH2:10][CH:4]2[C:3](=[O:6])[NH:2][S:1](=[O:7])[CH:5]2[CH2:12][C:11]=1[CH3:13]
Reactant: C=C(C)C(=C)C
Reactant: O=C1C=CS(=O)N1
Solvent: ClCCCl
Solvent: CCCCCC
Product: CC1=C(C)CC2C(C1)C(=O)NS2=O
Temperature: 60 °C

Procedure:
To a solution of 2.2 g (0.02 mole) of 4-isothiazolin-3-one 1-oxide in 50 ml of ethylene dichloride is added 2.0 g (0.024 mole) of 2,3-dimethyl-1,3-butadiene. The mixture is stirred and maintained at 60° C. overnight. Concentration of the mixture yields a thick oil, which affords a white solid on trituration with hexane. The solid is filtered and air dried to yield 3.4 g (90%) or product, m.p. 135°-137° C. which can be recrystallized from ethyl acetate-hexane.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].Cl[Si](C)(C)[CH3:19]>CO>[C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:19])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc(C(=O)O)c2ccccc2n1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)nc2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCl) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCI (161 mg, 1.2 eq. ), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:23]([NH:31][NH2:32])(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:9][CH2:10][C:11]3[N:12]([C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:31][N:32]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)NC(=S)CN=C2c1ccccc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)-n1c(nnc1-c1ccccc1)CN=C2c1ccccc1Cl
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 8-nitro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 9-nitro-1-phenyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:24]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[BH4-].[Na+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH2:24][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(F)(F)F)c2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(F)(F)F)c2CN2CCCC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of N-boc-4-(2-formyl-3-trifluoromethyl-phenyl)piperazine (358 mg, 1 mmol, 1.0 eq.) in MeOH (10 mL) was added pyrrolidine (0.093 mL, 1.1 mmol, 1.1 eq.). The mixture was refluxed overnight. The reaction was cooled to about 0° C., and NaBH4 on alumina (10 wt % on basic alumina, 570 mg, 1.5 mmol, 1.5 eq.) was added. After the addition was compete, the ice bath was removed, and the mixture was stirred at r.t. for about 2 hours. The mixture was filtered through celite, washed with methanol and concentrated. The solution was diluted with EtOAc (50 mL) and washed with saturated NaHCO3 and brine. The aqueous layers were extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (35 g SiO2, 40 mL/min, linear gradient 0-10% MeOH/CH2Cl2 for 25 minutes and 10% MeOH/CH2Cl2 for 7 minutes) gave the title compound (298 mg, 0.72 mmol, 72%). LRMS (ESI+): 414.3 (M+1)
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:30]([CH:40]1[C:49]2[N:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:43][CH2:42][CH2:41]1)[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.[BH4-].[Na+]>CO>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:30]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][CH2:16][C:8]2[NH:7][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[CH:34][CH:33]=1)[CH:40]1[C:49]2[N:48]=[CH:47][CH:46]=[CH:45][C:44]=2[CH2:43][CH2:42][CH2:41]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CNCc2nc3ccccc3[nH]2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(2-trimethylsilylethoxymethyl)-2-formyl-benzimidazole (prepared as described by Bridger et al. U.S. patent application Ser. No. 09/535,314) (0.150 g, 0.54 mmol) in dry MeOH (2.5 mL) was added a dry MeOH (2.5 mL) solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.215 g, 0.54 mmol) under an argon atmosphere. The mixture was stirred at room temperature for 1.5 h then concentrated under reduced pressure and analyzed by 1H NMR. The residue was dissolved in dry MeOH (5 mL) and to the resultant solution was added sodium borohydride (41 mg, 1.08 mmol) and the reaction mixture stirred for 16 h (see General Procedures XX). Purification of the crude product by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 100:1:1 followed by 50:1:1) afforded the desired product (0.165 g, 47%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([CH3:1])=[N:11]2
Reactant: Cc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)ccnc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of the product from Example 1c (320 mg, 2.0 mmol) in 6 mL of POCl3 was heated at 50° C. with stirring for 6 h. Cooled to room temperature and quenched by pouring into ice. Adjusted to pH 10 with NH4OH and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound as a tan solid (322 mg, 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(C(CCCl)c2ccc(F)cc2)cc1
Yield: 76.7 %

Procedure:
A solution of 5.5 parts of 3,3-bis(4-fluorophenyl)-1-propanol and 2.92 parts of thionyl chloride in 39.9 parts of dichloromethane was stirred for 4 hours at 60° C. The reaction mixture was evaporated and then co-evaporated with methylbenzene. The residue was dissolved in ethyl acetate and this solution was washed with Na2CO3 (aq.), water and NaCl (sat.) and was then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; (C2H5)2O/n. hexane 2:98). The eluent of the desired fraction was evaporated, yielding 4.5 parts (76.7%) of 1-[3-chloro-1-(4-fluorophenyl)propyl]-4-fluorobenzene (interm. 22).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)=[CH:14][C:13]=2[OH:27])=[O:10])=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:27][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1O
Yield: 50.5 %

Procedure:
The resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(3,4-dichloro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) prepared as described in Example 197 was reacted with 4-trifluoromethyl-phenyl boronic acid (56.7 mg, 0.3 mmol) as generally described in Example 197 to afford (26.9 mg, 50%) the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C:12]1[C:20]([O:21][CH3:22])=[C:19]([F:23])[C:18]([I:24])=[C:17]([CH3:25])[C:13]=1[C:14]([NH2:16])=O)=[O:10].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:14]([C:13]1[C:17]([CH3:25])=[C:18]([I:24])[C:19]([F:23])=[C:20]([O:21][CH3:22])[C:12]=1[NH:11][C:9](=[O:10])[C:8]([CH3:26])([CH3:7])[CH3:27])#[N:16]
Reactant: COc1c(F)c(I)c(C)c(C(N)=O)c1NC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 939 %

Procedure:
4-Dimethylaminopyridine (149 mg, 1.22 mmol) was added to a pyridine (100 ml) suspension of 2-(2,2-dimethylpropionylamino)-4-fluoro-5-iodo-3-methoxy-6-methylbenzamide (I-68) (4.97 g, 1.22 mmol), and cooled at 0° C. Trifluoromethanesulfonic acid anhydride (6.17 ml, 36.5 mmol) was dropwise added to it, followed by stirring at room temperature for 1 hour, then ethyl acetate (400 ml) was put thereinto. The organic layer was washed with 1 N hydrochloric acid (300 ml×5), saturated brine (300 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (4.47 g, 94%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([O:16]C)=O)[CH2:3]1.[NH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][NH:18][C:14]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5]1)=[O:16]
Reactant: NCCO
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Solvent: CO
Product: O=C(NCCO)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A mixture of 46.7 g (0.2 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (J. Org. Chem., 26, 1519 (1961)], 36.7 g (0.6 mole) 2-aminoethanol and 500 ml methanol were refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in dichloromethane and extracted with 3×100 ml 1N sodium hydroxide. The aqueous layer was taken to pH 5 with hydrochloric acid, extracted with 3×150 ml dichloromethane, then taken to pH 8 with sodium hydroxide solution and again extracted 3×150 ml dichloromethane. The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic layers were dried over magnesium sulfate, the solvent removed at reduced pressure to yield 47.9 g of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:23][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: Clc1cc2nc(Cl)c3nccn3c2cc1Cl
Product: Clc1cc2nc(NC3CCCCC3)c3nccn3c2cc1Cl

Procedure:
By reacting 4,7,8-trichloroimidazo[1,2-a]quinoxaline example 22 with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylamino-7,8-dichloroimidazo[1,2-a] quinoxalin m.p. (DSC)=162.3° C.(onset); IR (KBr): 3332, 2929, 1587, 1550 cm-1 ; 1H-NMR (CDCl3): δ7.8 (2H,m), 7.7 (1H,s), 7.55 (1H,d, J=2 Hz), 6.2 (1H,d), 4.4 (1H,m), 2.3÷1.2 (10H,m); UV (EtOH): λmax =234, 274, 292, 304, 330, 345 nm. Elementary analysis for C16H16Cl2N4 (m.w. 344.25): calcd. C 55.82, H 4.98, N 16.28%; found C 55.83, H 5.00, N 16.31%.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)/[CH:20]=[CH:21]/N(C)C)=[CH:15][C:14]=1[O:26][CH3:27]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:21][CH:20]=2)=[CH:15][C:14]=1[O:26][CH3:27]
Reactant: N#Cc1ccnc(NN)c1
Reactant: COc1cc(C(=O)/C=C/N(C)C)ccc1Cl
Agent: Cl
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1Cl
Yield: 74 %

Procedure:
The title compound was prepared in 74% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(4-chloro-3-methoxyphenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.82 (3H, s), 6.53 (1H, d, J=2.0 Hz), 6.78 (1H, d, J=2.4 Hz), 6.89 (1H, d, J=1.6 Hz), 7.32 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.78 (1H, d, J=1.2 Hz), 8.07 (1H, s), 8.39 (1H, dd, J=5.2, 0.8 Hz). [M+H] Calc'd for C16H11ClN4O, 311. Found, 311.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][O:8][N:29]1[C:30](=[O:39])[C:31]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:32]2[C:33]1=[O:34]
Reactant: COCOCCCO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
A solution of 3-(methoxymethoxy)propanol (5 g, 41.6 mmol), triphenylphosphine (13.1 g, 50 mmol) and N-hydroxyphthalimide (7.25 g, 44 mmol) in dry tetrahydrofuran (150 ml) was cooled to 0°-5° C. and treated with diethyl azodicarboxylate (8.7 g, 50 mmol) in dry tetrahydrofuran (10 ml) over 1/2 hr. The reaction was then stirred at ambient temperature for 18 hr. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (100 ml) and the mixture cooled to 0°-5° C. for 3 hr. The solid was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with hexane:ethyl acetate (70:30) to give the title compound as an oil (4.5 g, 41%). νmax (Film) 2960, 2900, 1800, 1740, 1620, 1480 and 1380 cm-1 ; δH (CDCl3) 2.07 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.38 (3H, s, OCH3), 3.77 (2H, t, J=6.3 Hz, CH2OCH2OCH3), 4.33 (2H, t, J=6.3 Hz, CH2ON), 4.66 (2H, s, OCH2O), 7.83 (4H, m, ArH).
Reaction SMILES: [CH3:1][Al](C)C.[CH2:5]1[O:7][C@@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[C:8]1([C@@H:6]([CH3:1])[CH2:5][OH:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: C[Al](C)C
Solvent: Cc1ccccc1
Product: C[C@@H](CO)c1ccccc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
An oven dried 500.0 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel with a continuous nitrogen blanket is charged with 2.0 M solution of trimethylaluminum (65.6 mL, 131.2 mmol) and toluene (75.0 mL). Reaction solution was then chilled to −60° C. with dry ice/acetone bath. To this solution was then added R-styrene oxide dissolved in 100.0 mL of toluene over a period of 50.0 minutes (reaction is quite exothermic and can be controlled by the rate of addition of substrate). After stirring at this temperature for 60.0 minutes, reaction was brought to room temperature and stirred for 4.0 hours. Reverse quenched reaction at room temperature into a slurry of THF (100.0 mL) and sodium sulfate decahydrate (46.0 g) very cautiously over a period of 90.0 minutes (quenching was quite exothermic with evolution of gas). Filtered the precipitate formed over hyflo, then concentrated filtrate to provide the intermediate title compound, (2R)-2-phenylpropan-1-ol, (11.03 g, 92.6%) as an oil; 1H nmr (CDCl3, 300 MHz) δ 1.28-1.29 (d, 3H, J=6.9Hz), 1.5 (b, 1H), 2.9-3.0 (m, 1H), 3.69-3.70 (d, 2H, J=6.64Hz), 7.24-7.35 (aromatic); 1 nmr (CDCl3, 300 MHz) δ 18.31, 43.15, 69.40, 127.38, 128.20, 129.26144.39.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:9]12[CH2:18][CH2:17][CH2:16][CH2:15][C@:14]1([OH:19])[CH2:13][CH2:12][CH2:11][CH2:10]2)([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1.C(N(CC)CC)C>O1CCCC1>[C:23]([O:19][C@@:14]12[CH2:15][CH2:16][CH2:17][CH2:18][C@:9]1([C:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])([CH3:8])[CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13]2)(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(O)CCCC2
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC(C)(C)[C@]12CCCC[C@@]1(OC(=O)CC(C)=O)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 100 mmol of 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin prepared in the same manner as in Example 4, 110 mmol of diketene, 110 mmol of triethylamine, and 300 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The resulting reaction mixture was subjected to chromatography on a silica gel to yield 8a-acetoacetyloxy-4a-(1-acryloyloxy-1-methylethyl)-cis-decalin represented by the following formula (yield: 89.1%). The conversion rate from 4a-(1-acryloyloxy-1-methylethyl)-8a-hydroxy-cis-decalin was 99%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27](O)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN1C(=O)CCC1>C1COCC1>[Br:18][C:19]1[C:24]([CH:25]=[CH:26][C:27]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:28])=[CH:23][CH:22]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:20]=1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)c(Br)n1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)nc2Br)cc(F)c1NS(C)(=O)=O
Yield: 55.9 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (41.2 mg, 0.148 mmol) was reacted with 3-(2-bromo-6-tert-butyl-pyridin-3-yl)-acrylic acid (1.0 eq, 42 mg), DMTMM (1.0 eq, 41 mg) and NMP (1.2 eq, 20 μl) in THF to give the title compound (42 mg, 55.8%) after purification by column chromatography (Hex/EtOAc=3/2).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1)[C:6]([OH:8])=[O:7].BrC1C=CC([C:22](OC)=[O:23])=C(OC)C=1>>[CH3:22][O:23][C:4]1[CH:3]=[C:11]([C:12]2[CH:16]=[N:15][NH:14][CH:13]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: COc1cc(C(=O)O)ccc1-c1cn[nH]c1
Product: COc1cc(-c2cn[nH]c2)ccc1C(=O)O

Procedure:
Intermediate 2 was synthesized by following a similar route to Intermediate 1 using methyl 4-bromo-2-methoxybenzoate in step 1A. LCMS (ESI) m/z: 219.1 (M+H)+.