Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[N:37]=[CH:36][C:35]([S:38]([N:8]2[CH2:17][CH2:16][C:15]3[C@:10]([CH2:28][O:29][CH3:30])([CH2:11][C:12]4[CH:20]=[N:19][N:18]([C:21]5[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=5)[C:13]=4[CH:14]=3)[CH2:9]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 2b using (R)-1-(4-fluorophenyl)-4a-methoxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and 6-chloropyridine-3-sulfonyl chloride. LCMS (Method B): 489 (M+H)+, Retention time 3.9 minutes.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=[C:3]1[C:18]([OH:20])=O.C(Cl)(=O)C(Cl)=O.[C:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1.C(N(CC)CC)C.CC(C)(O)C#N.[OH-].[Na+]>ClCCl.O.CN(C)C=O>[OH:34][C:27]1[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[C:28]=1[C:18]([C:3]1[C:2](=[O:1])[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[N:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)=[O:20]
Reactant: O=C(O)c1nc2cccnc2n(-c2ccccc2)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCC(O)=C1C(=O)c1nc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
6.50 g (24 mmol) of 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylic acid was dissolved in dichloromethane (100 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 3.8 g (30 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (30 mL), and this solution was added dropwise at 0° C. over 5 minutes to a solution prepared by dissolving 2.7 g (24 mmol) of 1,3-cyclohexanedione and 2.5 g (24 mmol) of triethylamine in dichloromethane (30 mL). The reaction solution was returned to room temperature and stirred for 3 hours, and then acetone cyanohydrin (1 mL) and 2.5 g (24 mmol) of triethylamine were added thereto. The mixture was stirred for 12 hours at room temperature. After confirming the completion of the reaction, water (50 mL) was added to the reaction solution, the reaction solution was adjusted to pH 12 using a 10% aqueous solution of sodium hydroxide, and the reaction solution was separated. The aqueous layer was adjusted to pH 1 by adding 6 N hydrochloric acid, and then the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with methanol, to obtain 6.5 g (yield: 73%) of 2-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-4-phenyl-pyrido[2,3-b]pyrazin-3(4H)-one.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:9](=O)[C:8]=2[CH:7]=[CH:6]1)(=[O:4])=[O:3].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)n1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 77.7 %

Procedure:
A mixture of 1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.40 g), aminoguanidine hydrochloride (0.17 g), concentrated hydrochloric acid (0.069 ml), water (0.069 ml) and ethanol (40 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was washed with water, dried and recrystallized from ethanol to give 4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 12) (0.41 g) as colorless crystals.
Reaction SMILES: O[C:2]1C(C)=C2C(=CC=1C)NCC2C.[C:14]([N:19]1[C:27]2[C:22](=[C:23]([CH3:30])[C:24]([OH:29])=[C:25]([CH3:28])[CH:26]=2)[CH:21]([CH3:31])[CH2:20]1)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(Cl)(=O)C(C)C>>[C:14]([N:19]1[C:27]2[C:22](=[C:23]([CH3:30])[C:24]([OH:29])=[C:25]([CH3:28])[CH:26]=2)[CH:21]([CH3:31])[CH2:20]1)(=[O:18])[C:15]([CH3:2])([CH3:17])[CH3:16]
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Agent: CC(C)C(=O)Cl
Product: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)(C)C
Yield: 75 %

Procedure:
Treatment of indoline 10 (160 mg, 0.9 mmoI) according to a procedure similar to one used for preparing 11b, with substitution of pivaloyl chloride for isobutyryl chloride, afforded 11c (176 mg, 75% yield) as a colorless solid, mp 144°-145° C. Spectral data: 13C NMR: δ 11.7, 16.4, 19.5, 27.6, 39.9, 57.4, 117.9, 119.2, 121.9, 133.7, 136.0, 148.8, 176.0; HRMS: calcd. for C16H23NO2 261.1229, fnd. 261.1921. Anal: calcd. for C16H23NO2C, 73.53, H, 8.87, N, 5.36, fnd. C, 73.60, H, 8.91, N, 5.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]([CH2:19][N:20]2[N:24]=[N:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21]2)[N:9]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([CH2:19][N:20]2[N:24]=[N:23][C:22]([C:25]([F:26])([F:27])[F:28])=[N:21]2)[N:9]=1
Reactant: CCOC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
An amount of 1.74 g (4.21 mmol) of ethyl 4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidine-5-carboxylate was dissolved in 12 ml of ethanol and the solution was admixed dropwise at 0° C. with 45% strength aqueous sodium hydroxide solution (5.05 mmol). The reaction was stirred for a further hour and warmed to RT. The ethanol was then removed under reduced pressure and the residue was admixed with ice-water (10 ml). The aqueous phase was extracted with ethyl acetate. The organic phase was discarded. Then the aqueous phase was adjusted to a pH of 3 using hydrochloric acid, and again extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.Cl[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:15]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C1CC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.7 %

Procedure:
A solution of 13.2 g (113 mmol) of (5S)-dihydro-5-(hydroxymethyl)furan-2(3H)-one in 200 ml of dimethyiformamide was treated sequentially with 9.28 g (136 mmol) of imidazole and 18.84 g (125 mmol) of chloro-t-butyldimethylsilane, the latter in several portions. The resulting solution was stirred at ambient temperature for 6 h, poured into 10% aqueous citric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with two portions of water, one portion of aqueous NaHCO3 and one portion of saturated brine. The organic layer was dried over MgSO4, and concentrated in vacuo to provide 22.04 g (90%) of the desired compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[N:1]([CH2:4][C@@H:5]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate (83 mg, 0.28 mmol) in anhydrous THF (5 mL) at −78° C. was added 1.0 M LHMDS solution in THF (1.1 mL, 1.12 mmol), then stirred at this temperature for 30 min. To this mixture was added MeI (237 mg, 104 μL, 1.67 mmol), then the temperature was allowed to warm to 0° C., and stand for 12 h and −20° C. The reaction mixture was quenched with saturated aq. NH4Cl, extracted with EtOAc (30 mL), the separated organic phase was washed with H2O (2×10 mL), brine, and dried over Na2SO4, and filtered. The filtrate was concentrated, the resulting slurry was purified through flash chromatography on silica gel (eluted with gradient system, 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-yl(methyl)carbamate. MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[C:8]([Cl:21])[CH:7]=1)[CH3:2].Br[C:24]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=1[CH:26]=[O:27]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[C:10]([C:24]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:25]=2[CH:26]=[O:27])[CH:9]=[C:8]([Cl:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][CH:8]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[OH:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:23][CH:24]=1)#[N:2]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (8.52 g, 62.5 mmol) in diethyl ether (100 ml), sodium borohydride (4.73 g, 125 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-oxopropionate (10.17 g, 31.26 mmol) in diethyl ether (50 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) to give the objective substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24](O)=[O:25])(=[O:18])=[O:17])=[O:4].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH2:63])[CH3:59].Cl>CN(C=O)C>[CH2:58]([N:60]([CH2:64][CH3:65])[CH2:61][CH2:62][NH:63][C:24]([C:20]1[S:21][CH:22]=[CH:23][C:19]=1[S:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])=[O:25])[CH3:59]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccsc2C(=O)O)ccc2c1CCCC2
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCN(CC)CCNC(=O)c1sccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 463B (100 mg, 0.253 mmol) in DMF (2.0 mL) was treated with 4-methylmorpholine (111 μL, 1.012 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (192 mg, 0.506 mmol), stirred for one hour at room temperature, treated with N,N-diethylethylenediamine (71 μL, 0.506 mmol), stirred for 3 days at room temperature, treated with 1N HCl, and extracted twice with dichloromethane. The combined extracts were dried (MgSO4), filtered, concentrated, and purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 494 (M+H)+; (ESI(−)) m/e 492 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.06 (br s, 1H), 8.82 (t, 1H), 7.82 (d, 1H), 7.26 (d, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 3.77 (s, 3H), 3.24-3.14 (m, 8H), 2.68 (br s, 2H), 2.55 (br s, 2H), 1.66 (quint, 4H), 1.21 (t, 6H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Cl:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1.77 g N-chlorosuccinimide in 50 ml DMF (dimethylformamide) was added dropwise to a mixture of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide at room temperature. The resulting solution was stirred overnight at room temperature and then poured into 800 ml water. The precipitate was collected, washed with water and dried (P2O5) under vacuum to give 3.1 g solid;
Reaction SMILES: S(O)(=O)(=O)C.[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15](=[O:28])[C:16]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([Br:26])[C:17]=1O)[CH3:7].[C:29](Cl)(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>FC(F)(F)C(O)=O>[CH2:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15](=[O:28])[C:16]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([Br:26])[C:17]=1[C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH3:7]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(O)c(Br)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)c1c(Br)cc(OC)c(OC)c1C(=O)NC[C@@H]1CCCN1CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-bromo-2-hydroxy-5,6-dimethoxybenzamide mesylate (0.48 g, 1 mmol) in 10 ml of trifluoroacetic acid was added palmitoyl chloride (0.55 ml, 2 mmol). The reaction mixture was stirred at ambient temperature over molecular sieves for 20 h. After evaporation of the solvent in vacuo ether was added to the residue and filtered. The filtrate was washed several times with a saturated KHCO3 solution and dried (MgSO4). After evaporation of the solvent in vacuo the resulting oil crystallized on cooling. Yield 0.42 g (67%). M.p. 46°-48° C. Rf value is 0.21 for title compound and 0.32 for starting compound (SiO2, TLC-plates, 20% MeOH in i-Pr2O as eluent).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[C-:13]#[N:14].[Na+].CCOCC>CN(C)C=O.[I-].[Na+]>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: [C-]#N
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 70.9 %

Procedure:
1-Chloromethyl-2-methyl-3-nitro-benzene (25 g) was dissolved in 125 ml of N,N-dimethylformamide. To this mixture was added 10.89 g of sodium cyanide (Mallinckrodt, Paris, Ky.) and 0.4 g of sodium iodide (Mallinckrodt) and the heterogeneous mixture was heated to 80° C. for 21 hr. The reaction mixture was cooled to room temperature, poured into ether, washed several times with water, dried, and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane, giving 16.83 g of (2-methyl-3-nitro-phenyl)-acetonitrile as a cream solid. ##STR118##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7](=[CH:10]NC1C=CC=CC=1)[C:8]#[N:9])=[O:6].FC(F)(F)C(O)=O.[CH:28]1([NH:31][C:32](=[O:42])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][NH2:41])[CH:34]=2)[CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[NH2:9][C:8]1[N:40]([C:35]2[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=2[CH3:39])[C:32]([NH:31][CH:28]2[CH2:30][CH2:29]2)=[O:42])[N:41]=[CH:10][C:7]=1[C:5](=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(Cl)c2)c1N

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (72 mg, 0.22 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 10 mL of ethanol was heated to 65° C. for 20 h. After cooling, the mixture was concentrated and the residue purified by flash chromatography on silica gel packed and eluted with 7/3 hexanes/ethyl acetate to remove byproducts followed by 3/2 ethyl acetate/hexanes to elute the title compound (33 mg, 38%) as a brown solid. HPLC (4 minute 10-95 gradient) tR 2.35 min; MS m/z 395.1 [M+H]+; 1H NMR (CD3OD), δ 7.92 (d, J=7.2 Hz, 1 H), 7.77 (m, 4 H), 7.55 (m, 3 H), 2.85 (m, 1 H), 2.23 (s, 3 H), 0.80 (d, J=5.5 Hz, 2 H), 0.63 (d, J=2.0 Hz, 2 H) ppm; 13C NMR (CD3OD), δ 187.1, 168.1, 151.9, 141.0, 140.9, 140.0, 134.9, 133.8, 132.8, 130.9, 130.5, 129.4128.1, 127.0, 126.1, 125.6, 102.6, 22.1, 15.7, 4.6 ppm.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[Cl:17].[CH3:18][N:19](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[C:18]#[N:19]
Reactant: Clc1c(Br)ccc2c1ncn2C1CCCCO1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2c(ncn2C2CCCCO2)c1Cl
Temperature: 110 °C
Yield: 70 %

Procedure:
A solution of 130 (26 g, 0.082 mol) in dry DMF (550 mL) was degassed for 10 min. To the solution was added sequentially Pd2(dba)3 (1.5 g, 0.00164 mol), dppf (1.8 g, 0.00328 mol) and Zn(CN)2 (9.19 g, 0.0657 mol). After degassing for 15 min the resulting solution was heated to 110° C. for 6 h. After the reaction was complete, the reaction mixture was filtered through a Celite® pad. The pad was washed well with EtOAc. The filtrate was washed with water and saturated brine solution. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 15 g (70%) of 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbonitrile (132) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:16]([OH:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N+](=[CH2:21])=[N-].N(CNC(N)=O)=O.[OH-].[K+].N#N>O1CCCC1.CCOCC>[CH3:21][O:17][C:16](=[O:18])[C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: C=[N+]=[N-]
Agent: N#N
Agent: NC(=O)NCN=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccc([N+](=O)[O-])cc1)NC(C)=O
Temperature: 0 °C

Procedure:
Compound 7 was dissolved in tetrahydrofuran (120 ml) and cooled in an ice bath. Diazomethane was generated by addition of N-nitrosomethylurea to an ice cold, equivolume mixture of ether and 40% aqueous potassium hydroxide. The diazomethane solution was added without purification to the stirred solution of the amino acid derivative. The reaction was complete when N2 was no longer evolved upon addition of diazomethane. Excess diazomethane was consumed by the addition of acetic acid. The solution was extracted successively with saturated saline, 1M sodium bicarbonate, 0.1M HCl, and again with saline and dried (MgSO4). Evaporation left 3.56 g (88.4%) of a solid melting at 110°-112° C. which was pure by TLC (chloroform/methanol acid: 85/10/5). [α]D25 =-13.8 (c=2.1, ethanol)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]1([S:14](Cl)(=[O:16])=[O:15])[NH:12][C:11]([Cl:13])=[CH:10][S:9]1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[S:14]([C:8]1[S:9][CH:10]=[C:11]([Cl:13])[N:12]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Reactant: COCCCN
Solvent: C1CCOC1
Product: COCCCNN(CCCOC)S(=O)(=O)c1nc(Cl)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
40 g of 3-methoxy-n-propylamine were added dropwise at room temperature to a solution of 25.25 g (0 1 mol) of 2,4-dichlorothiazole-sulphonyl chloride from Example 1 in 600 ml of THF, and the mixture was subsequently stirred for 30 minutes at room temperature. After concentrating under a waterpump vacuum, the mixture was stirred with 400 ml of water, the aqueous phase was extracted twice using methylene chloride, and the combined organic phases were dried over magnesium sulphate. After removing the solvent under a waterpump vacuum, 31.3 g of a brown oil were obtained which was chromatographed on silica gel using toluene/ethanol (5:1) as the eluent. 29.3 g (79%) of product were obtained, m.p 55° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C(F)=CC([B:24]2[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]2)=C(O[C@H](CC=C)C)C=1>>[F:9][C:4]1[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:2]([B:24]2[O:31][C:30](=[O:32])[CH2:29][N:28]([CH3:33])[CH2:27][C:26](=[O:34])[O:25]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CC[C@H](C)Oc1c(F)cc(F)cc1Br
Product: C=CC[C@H](C)Oc1c(F)cc(F)cc1B1OC(=O)CN(C)CC(=O)O1
Yield: 40 %

Procedure:
Prepared from (S)-1-bromo-3,5-difluoro-2-(pent-4-en-2-yloxy)benzene in 40% yield following the procedure for (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, J=8.5, 1.8 Hz, 1H), 6.89 (ddd, J=12.5, 7.8, 3.3 Hz, 1H), 5.91-5.73 (m, 1H), 5.17-5.03 (m, 2H), 4.88-4.75 (m, 1H), 4.10-3.95 (m, 1H), 3.92-3.83 (m, 3H), 2.66 (s, 3H), 2.53-2.41 (m, 1H), 2.39-2.28 (m, 1H), 1.24 (d, J=6.3 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −117.18 (d, J=5.2 Hz, 1F), −122.14 (d, J=5.2 Hz, 1F).